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Spermidine is a natural polyamine that stimulates cytoprotective macroautophagy/autophagy. External supplementation of spermidine extends lifespan and health span across species, including in yeast, nematodes, flies and mice. In humans, spermidine levels decline with aging, and a possible connection between reduced endogenous spermidine concentrations and age-related deterioration has been suggested. Recent epidemiological data support this notion, showing that an increased uptake of this polyamine with spermidine-rich food diminishes overall mortality associated with cardiovascular diseases and cancer. Here, we discuss nutritional and other possible routes to counteract the age-mediated decline of spermidine levels.

External supply of the natural polyamine spermidine can extend life span in model organisms including yeast, nematodes, flies and mice. Recent epidemiological evidence suggests that increased uptake of spermidine with food also reduces overall, cardiovascular and cancer-related mortality in humans. Here, we discuss the possible mechanisms of this intriguing spermidine effect. 

Identifying therapies to slow down ageing and delay age-associated diseases is a primary goal of ageing-related research. Resveratrol and rapamycin were first found to promote longevity in yeast, and their effects were then extended to several organisms. Spermidine is a new longevity drug that can increase life span in yeast, nematodes and flies, possibly through an effect on chromatin-mediated regulation of gene expression.

Spermidine is a ubiquitous polycation that is synthesized from putrescine and serves as a precursor of spermine. Putrescine, spermidine and spermine all are polyamines that participate in multiple known and unknown biological processes. Exogenous supply of spermidine prolongs the life span of several model organisms including yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans) and flies (Drosophila melanogaster) and significantly reduces agerelated oxidative protein damage in mice, indicating that this agent may act as a universal anti-aging drug. Spermidine induces autophagy in cultured yeast and mammalian cells, as well as in nematodes and flies. Genetic inactivation of genes essential for autophagy abolishes the life span-prolonging effect of spermidine in yeast, nematodes and flies. These findings complement expanding evidence that autophagy mediates cytoprotection against a variety of noxious agents and can confer longevity when induced at the whole-organism level. We hypothesize that increased autophagic turnover of cytoplasmic organelles or long-lived proteins is involved in most if not all life span-prolonging therapies.

ABSTRACT 

Background: Spermidine administration is linked to increased survival in several animal models. Objective: The aim of this study was to test the potential association between spermidine content in diet and mortality in humans. Design: This prospective community-based cohort study included 829 participants aged 45–84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated foodfrequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred. Results: All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake–adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio–adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio– adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age.

Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity

Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

Over recent decades, increased average life expectancy has brought about a global rise of age-related chronic diseases. Among these, cardiovascular disorders pose an enormous burden on public health and economy and their death toll will continue to rise in absence of effective interventions. In addition, premature cardiovascular disease is fostered by a prevalence of obesity due to chronic consumption of hypercaloric diets and sedentary lifestyle. Therefore, an extended life span comes at the expense of health loss, disability and poor quality of life. The reason for such disparity between life span and health span (i.e., disease-free life period) is likely the failure of pharmacotherapy to sufficiently target the specific mechanisms driving health deterioration in advanced age. Hence, it is of paramount importance to develop more effective anti-aging strategies to improve cardiac and general health, especially among elderly people.

Spermidine, a naturally occurring polyamine, has recently emerged as exhibiting anti-aging properties. Its supplementation increases lifespan and resistance to stress, and decreases the occurrence of age-related pathology and loss of locomotor ability. Its mechanisms of action are just beginning to be understood. Objectives: An up-to-date overview of the so far identified mechanisms of action of spermidine and other polyamines on aging is presented. Methods: Studies of aging and of the molecular effects of polyamines in general and spermidine in particular are used to synthesize our knowledge on what molecular mechanisms spermidine and other polyamines trigger to positively affect aging. Results: Autophagy is the main mechanism of action of spermidine at the molecular level. However, recent research shows that spermidine can act via other mechanisms, namely inflammation reduction, lipid metabolism and regulation of cell growth, proliferation and death. It is suggested that the main pathway used by spermidine to trigger its effects is the MAPK pathway. Conclusions: Given that polyamines can interact with many molecules, it is not surprising that they affect aging via several mechanisms. Many of these mechanisms discovered so far have already been linked with aging and by acting on all of these mechanisms, polyamines may be strong regulators of aging. 

Changes in mitochondrial structure and function are the initial factors of cell aging. Spermidine has an antiaging effect, but its effect on neuronal aging and mitochondrial mechanisms is unclear. In this study, mouse neuroblastoma (N2a) cells were treated with D‑galactose (D‑Gal) to establish cell aging to investigate the antiaging effect and mechanisms of spermidine. Changes in the cell cycle and β-galactosidase activity were analyzed to evaluate the extent of cell aging. Stabilities of mitochondrial mRNA and mitochondrial membrane potential (MMP) were evaluated in the process of cell aging under different treatments. The mitochondrial function was also evaluated using the Seahorse Metabolic Analysis System combined with ATP production. The unfolded protein response (UPR) of the N2a cells was analyzed under different treatments. Results showed that spermidine pretreatment could delay the cell aging and could maintain the mitochondrial stability during D‑Gal treatment. Spermidine increased the proportion of cells in the S phase and maintained the MMP. The oxygen utilization and ATP production in the N2a cells were reduced by D‑Gal treatment but were partially rescued by the spermidine pretreatment. Spermidine ameliorated the N2a cell aging by promoting the autophagy and inhibiting the apoptosis except the UPR. These results showed that spermidine could ameliorate the N2a cell aging by maintaining the mitochondrial mRNA transcription, MMP and oxygen utilization during the D‑Gal treatment.

Dendritic cells (DCs) function is intimately linked to microenvironment and metabolism. Type I interferons (IFNs) condition dendritic cells to respond to weak self-signals, leading to autoimmunity. However, the metabolic adaption in the process is unclear. Here, we identified spermidine as a critical metabolite impacting the metabolic fitness of DC. First, dynamic metabolome screening indicated that spermidine decreased during IFN priming and following TLR7 ligand stimulation, accompanied by metabolic change from oxidative phosphorylation to glycolysis. Second, spermidine supplement restrained the glycolysis and prevented the overactivation of IFN-a primed DC both in vivo and in vitro. Third, mechanism study uncovered that the activity of FOXO3 adapted to the metabolic change, mediating the anti-inflammatory effect of spermidine. More importantly, addition of spermidine in vivo greatly alleviated the development of psoriasis-like symptom in mice. Thus, our studies revealed metabolic changes boosting DC responses and identified spermidine as a potential therapeutic agent for autoimmune diseases.

The polyamines spermidine and spermine are synthesized in almost all organisms and are also contained in food. Polyamine synthesis decreases with aging, but no signifcant decrease in polyamine concentrations were found in organs, tissues, and blood of adult animals and humans. We found that healthy dietary patterns were associated with a preference for polyaminerich foods, and frst reported that increased polyamine intake extended the lifespan of mice and decreased the incidence of colon cancer induced by repeated administration of moderate amounts of a carcinogen. Recent investigations have revealed that changes in DNA methylation status play an important role in lifespan and aging-associated pathologies. The methylation of DNA is regulated by DNA methyltransferases in the presence of S-adenosylmethionine. Decarboxylated S-adenosylmethionine, converted from S-adenosylmethionine by S-adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize spermine and spermidine and acts to inhibit DNMT activity. Long-term increased polyamine intake were shown to elevate blood spermine levels in mice and humans. In vitro studies demonstrated that spermine reversed changes induced by the inhibition of ornithine decarboxylase (e.g., increased decarboxylated S-adenosylmethionine, decreased DNA methyltransferase activity, increased aberrant DNA methylation), whose activity decreases with aging. Further, aged mice fed high-polyamine chow demonstrated suppression of aberrant DNA methylation and a consequent increase in protein levels of lymphocyte function-associated antigen 1, which plays a pivotal role on infammatory process.

Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age-related, diagnostic, and severity-associated PD biomarker. Methods: Comprehensive metabolome analysis of plasma was performed in Cohort A (controls, n = 45; PD, n = 145), followed by analysis of 7 polyamine metabolites in Cohort B (controls, n = 49; PD, n = 186; progressive supranuclear palsy, n = 19; Alzheimer disease, n = 23). Furthermore, 20 patients with PD who were successively examined within Cohort B were studied using diffusion tensor imaging (DTI). Association of each polyamine metabolite with disease severity was assessed according to Hoehn and Yahr stage (H&Y) and Unified Parkinson’s Disease Rating Scale motor section (UPDRS-III). Additionally, the autophagy induction ability of each polyamine metabolite was examined in vitro in various cell lines. Results: In Cohort A, N8-acetylspermidine and N-acetylputrescine levels were significantly and mildly elevated in PD, respectively. In Cohort B, spermine levels and spermine/spermidine ratio were significantly reduced in PD, concomitant with hyperacetylation. Furthermore, N1,N8-diacetylspermidine levels had the highest diagnostic value, and correlated with H&Y, UPDRS-III, and axonal degeneration quantified by DTI. The spermine/spermidine ratio in controls declined with age, but was consistently suppressed in PD.

Abstract: Although autophagy has widely been conceived as a self‐destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies. Similarly, resveratrol can trigger autophagy in cells from different organisms, extend lifespan in nematodes, and ameliorate the fitness of human cells undergoing metabolic stress. These beneficial effects are lost when essential autophagy modulators are genetically or pharmacologically inactivated, indicating that autophagy is required for the cytoprotective and/or anti‐aging effects of spermidine and resveratrol. Genetic and functional studies indicate that spermidine inhibits histone acetylases, while resveratrol activates the histone deacetylase Sirtuin 1 to confer cytoprotection/longevity. Although it remains elusive whether the same histones (or perhaps other nuclear or cytoplasmic proteins) act as the downstream targets of spermidine and resveratrol, these results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity. 

Healthy foods such as beans, mushrooms, vegetables, and seafood and healthy dietary patterns such as the Mediterranean diet and Japanese food have higher concentrations of polyamines (spermine and spermidine). The continuous intake of high-polyamine foods has been shown to increase whole blood polyamine levels in mice and humans. In addition, high-polyamine chow inhibited aging-associated pathological changes in Jc1:ICR male mice and extended their lifespan. Aging is accompanied by decreased DNA methyltransferase activities, increased proinflammatory status, and enhanced abnormal gene methylation status, which is considered to be part of the pathogenesis of aging-associated diseases. In vitro and in vivo experiments have shown that polyamine supplementation reversed such changes induced by aging and polyamine-deficiency. In addition, polyamines have many biological activities that may contribute to the inhibition of lifestyle-related diseases such as diabetes, hyperlipemia, and arteriosclerosis. The possible role of dietary polyamines in human health is discussed.

Organismal lifespan can be extended by genetic manipulation of cellular processes such as histone acetylation, the insulin/IGF‑1 (insulin‑like growth factor 1) pathway or the p53 system. Longevity‑promoting regimens, including caloric restriction and inhibition of TOR with rapamycin, resveratrol or the natural polyamine spermidine, have been associated with autophagy (a cytoprotective self‑digestive process) and in some cases were reported to require autophagy for their effects. We summarize recent developments that outline these links and hypothesize that clearing cellular damage by autophagy is a common denominator of many lifespan‑ extending manipulations.

Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock’s function with age.

Changes in polyamine levels during aging were measured in 3-, 10- and 26-week-old female mice. The level of polyamines in pancreas, brain, and uterus was maintained during these periods. The level of spermidine slightly decreased in intestine, and decreased significantly in thymus, spleen, ovary, liver, stomach, lung, kidney, heart and muscle during these periods. In skin, the level of spermidine was maximal in 10- week-old mice and markedly reduced in 26-week-old mice. The results suggest that maintenance of polyamine levels may play important roles in the function of the pancreas, brain and uterus in 3- to 26-week-old mice. We next looked for polyamine-rich food materials as a dietary source of polyamines. Foods found to be rich in polyamines included wheat germ, rice bran, black rice, Philippine mango, green pepper, Japanese pumpkin, nuts, fermented pickles, pond smelt, turban shell viscera, whelk viscera, salted salmon roe, salted cod roe, beef intestine (boiled) and liver of eel, beef, pork and chicken; and, as previously reported, soybean, fermented soybean (natto), mushrooms, orange and green tea leaf. These results offer useful information when it becomes necessary to ingest polyamines from food.

The polyamines putrescine, spermidine, and spermine are widely distributed polycationic compounds essential for cellular functions. Intracellular polyamine pools are tightly regulated by a complex regulatory mechanism involving de novo biosynthesis, catabolism, and transport across the plasma membrane. In mammals, both the production of polyamines and their uptake from the extracellular space are controlled by a set of proteins named antizymes and antizyme inhibitors. Dysregulation of polyamine levels has been implicated in a variety of human pathologies, especially cancer. Additionally, decreases in the intracellular and circulating polyamine levels during aging have been reported. The differences in the polyamine content existing among tissues are mainly due to the endogenous polyamine metabolism. In addition, a part of the tissue polyamines has its origin in the diet or their production by the intestinal microbiome. Emerging evidence has suggested that exogenous polyamines (either orally administrated or synthetized by the gut microbiota) are able to induce longevity in mice, and that spermidine supplementation exerts cardioprotective effects in animal models. Furthermore, the administration of either spermidine or spermine has been shown to be effective for improving glucose homeostasis and insulin sensitivity and reducing adiposity and hepatic fat accumulation in diet-induced obesity mouse models. 

ABSTRACT: Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE ) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and antiinflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR.

The purpose of this study was to test whether oral intake of foods rich in polyamines (spermine and spermidine) suppresses age-associated pathology in aged mice. Synthetic polyamines were mixed into experimental chows, and 24-week-old Jc1:ICR male mice were fed one of three chows containing differing polyamine concentrations. The spermine and spermidine concentrations in the low, normal, and high polyamine chows were 143 and 224 nmol/g, 160 and 434 nmol/g, and 374 and 1540 nmol/g, respectively. An increase in concentration of polyamine in the blood was found only in mice fed the high polyamine chow at 50 weeks of age. While the body weights of mice in all three groups were similar, the survival rate of mice fed high polyamine chow was significantly higher than those in the other two groups (p = 0.011). Mice fed the high polyamine chow analyzed at 88 weeks of age, corresponding to the end of the study, demonstrated lower incidence of glomerulosclerosis and increased expression of senescence marker protein-30 in both kidney and liver compared to those fed the low polyamine chow. As these pathological changes are associated with senescence, oral polyamine appears to inhibit the progression of age-associated pathologies.

A decline in polyamine levels with age has been implicated in the pathophysiology of aging, and nutritional supplementation of spermidine can reduce age-related pathology and increase lifespan in a number of different organisms. In this issue of Molecular Cell, Zhang and colleagues provide a mechanistic link between polyamines, autophagy, and aging.

Polyamines are polycations that interact with negatively charged molecules such as DNA, RNA and proteins. They play multiple roles in cell growth, survival and proliferation. Changes in polyamine levels have been associated with aging and diseases. Their levels decline continuously with age and polyamine (spermidine or high-polyamine diet) supplementation increases life span in model organisms. Polyamines have also been involved in stress resistance. On the other hand, polyamines are increased in cancer cells and are a target for potential chemotherapeutic agents. In this review, we bring together these various results and draw a picture of the state of our knowledge on the roles of polyamines in aging, stress and diseases.

The polyamines (PAs) spermidine, spermine, putrescine and cadaverine are an essential class of metabolites found throughout all kingdoms of life. In this comprehensive review, we discuss their metabolism, their various intracellular functions and their unusual and conserved regulatory features. These include the regulation of translation via upstream open reading frames, the over-reading of stop codons via ribosomal frameshifting, the existence of an antizyme and an antizyme inhibitor, ubiquitin-independent proteasomal degradation, a complex bi-directional membrane transport system and a unique posttranslational modification—hypusination—that is believed to occur on a single protein only (eIF-5A). Many of these features are broadly conserved indicating that PA metabolism is both concentration critical and evolutionary ancient. When PA metabolism is disrupted, a plethora of cellular processes are affected, including transcription, translation, gene expression regulation, autophagy and stress resistance. As a result, the role of PAs has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer. Despite comprehensive studies addressing PAs, a unifying concept to interpret their molecular role is missing. The precise biochemical function of polyamines is thus one of the remaining mysteries of molecular cell biology.

Polyamines (putrescine, spermidine, and spermine) are a family of molecules that derive from ornithine through a decarboxylation process. They are essential for cell growth and proliferation, stabilization of negative charges of DNA, RNA transcription, translation, and apoptosis. Recently, it has been demonstrated that exogenously administered spermidine promotes longevity in yeasts, flies, worms, and human cultured immune cells. Here, using a cross-sectional observational study, we determined whole-blood polyamines levels from 78 sex-matched unrelated individuals divided into three age groups: Group 1 (31–56 years, n = 26, mean age 44.6– 6.07), group 2 (60–80 years, n = 26, mean age 68.7– 6.07), and group 3 (90–106 years, n = 26, mean age 96.5– 4.59). The total content of polyamines is significantly lower in groups 2 and 3 compared to group 1 ( p = 3.6 · 10 - 12). Interestingly, this reduction is mainly attributable to the lower putrescine content. Group 2 displays the lowest levels of spermidine and spermine. On the other hand, nona/centenarians (group 3) display a significantly higher median relative percentage content of spermine with respect to total polyamines, compared to the other groups (13.2% vs. 14.1% vs. 30.6%, p = 6.0 · 10 - 4 ). 

Spermidine, a polyamine that induces macroautophagy/autophagy, exhibits anti-aging properties. It is thought that these properties of spermidine are primarily due to its ability to modulate autophagy, but the mechanistic details were hitherto unclear. Studying the effects of spermidine on B lymphocytes, Zhang et al uncover the molecular mechanism that places spermidine at the crossroads of autophagy and immune senescence. Their work highlights the role of spermidine as an anti-aging metabolite that exerts its effects through the translational control of autophagy

The increase in life expectancy has boosted the incidence of age-related pathologies beyond social and economic sustainability. Consequently, there is an urgent need for interventions that revert or at least prevent the pathogenic age-associated deterioration. The permanent or periodic reduction of calorie intake without malnutrition (caloric restriction and fasting) is the only strategy that reliably extends healthspan in mammals including non-human primates. However, the strict and life-long compliance with these regimens is difficult, which has promoted the emergence of caloric restriction mimetics (CRMs). We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans. We anticipate that CRMs will become part of the pharmacological armamentarium against aging and age-related cardiovascular, neurodegenerative, and malignant diseases.

Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used Caenorhabditis elegans models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/ a-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti-aging treatments reduced the impairment. Transgenic expression of hlh-30p::hlh-30, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function. 

Autophagy is the major intracellular degradation system by which cytoplasmic materials are delivered to and degraded in the lysosome. However, the purpose of autophagy is not the simple elimination of materials, but instead, autophagy serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Here we provide a multidisciplinary review of our current understanding of autophagy’s role in metabolic adaptation, intracellular quality control, and renovation during development and differentiation. We also explore how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.All living organisms undergo continuous renovation. In humans, cells and intracellular components are constantly remodeled and recycled. This is, in part, in order to replace old components with fresh, better-quality ones. However, when components are replaced with different types, a net change in character results. Such ‘‘cellular renovation’’ requires synthesis of new components but also degradation of pre-existing materials, which can serve as building blocks. Eukaryotic cells have two major degradation systems, the lysosome and the proteasome. Proteasomal degradation has high selectivity; the proteasome generally recognizes only ubiquitinated substrates, which are primarily short-lived proteins.

Defects in autophagy have been linked to a wide range of medical illnesses, including cancer as well as infectious, neurodegenerative, inflammatory, and metabolic diseases. These observations have led to the hypothesis that autophagy inducers may prevent or treat certain clinical conditions. Lifestyle and nutritional factors, such as exercise and caloric restriction, may exert their known health benefits through the autophagy pathway. Several currently available FDA-approved drugs have been shown to enhance autophagy, and this autophagy-enhancing action may be repurposed for use in novel clinical indications. The development of new drugs that are designed to be more selective inducers of autophagy function in target organs is expected to maximize clinical benefits while minimizing toxicity. This Review summarizes the rationale and current approaches for developing autophagy inducers in medicine, the factors to be considered in defining disease targets for such therapy, and the potential benefits of such treatment for human health.

Autophagy is a major protein turnover pathway by which cellular components are delivered into the lysosomes for degradation and recycling. This intracellular process is able to maintain cellular homeostasis under stress conditions, and its dysregulation could lead to the development of physiological alterations. The autophagic activity has been found to decrease with age, likely contributing to the accumulation of damaged macromolecules and organelles during aging. Interestingly, failure of the autophagic process has been reported to worsen aging-associated diseases, such as neurodegeneration or cancer, among others. Likewise, it has been proposed in different organisms that maintenance of a proper autophagic activity contributes to extending longevity. In this review, we discuss recent papers showing the impact of autophagy on cell activity and age-associated diseases, highlighting the relevance of this process to the hallmarks of aging. Thus, understanding how autophagy plays an important role in aging opens new avenues for the discovery of biochemical and pharmacological targets and the development of novel anti-aging therapeutic approaches.

Autophagy is a self-degradative process responsible for the clearance of damaged or unnecessary cellular components. We have previously found that persistence of dysfunctional organelles due to autophagy failure is a key event in the pathogenesis of COL6/collagen VI-related myopathies, and have demonstrated that reactivation of a proper autophagic flux rescues the muscle defects of Col6a1-null (col6a1¡/¡) mice. Here we show that treatment with spermidine, a naturally occurring nontoxic autophagy inducer, is beneficial for col6a1¡/¡ mice. Systemic administration of spermidine in col6a1¡/¡ mice reactivated autophagy in a dose-dependent manner, leading to a concurrent amelioration of the histological and ultrastructural muscle defects. The beneficial effects of spermidine, together with its being easy to administer and the lack of overt side effects, open the field for the design of novel nutraceutical strategies for the treatment of muscle diseases characterized by autophagy impairment.

Macroautophagy is a major intracellular degradation process recognized as playing a central role in cell survival and longevity. This multistep process is extensively regulated at several levels, including post-translationally through the action of conserved longevity factors such as the nutrient sensor TOR. More recently, transcriptional regulation of autophagy genes has emerged as an important mechanism for ensuring the somatic maintenance and homeostasis necessary for a long life span. Autophagy is increased in many long-lived model organisms and contributes significantly to their longevity. In turn, conserved transcription factors, particularly the helixloop-helix transcription factor TFEB and the forkhead transcription factor FOXO, control the expression of many autophagy-related genes and are important for life-span extension. In this review, we discuss recent progress in understanding the contribution of these transcription factors to macroautophagy regulation in the context of aging. We also review current research on epigenetic changes, such as histone modification by the deacetylase SIRT1, that influence autophagy-related gene expression and additionally affect aging. Understanding the molecular regulation of macroautophagy in relation to aging may offer new avenues for the treatment of age-related diseases

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. 

Cancer treatment has come a long way since the use of mustard gas derivatives in the early 1900s—or has it? When doctors discovered during World War I that mustard gas destroyed bone marrow, they began to experiment with it as a way to kill cancer cells. Although they had little success with the mustard gas, it did pave the way for modern chemotherapy—which involves the most toxic and poisonous substances anyone deliberately puts in his body. These treatments kill much more than cancer cells— they have a devastating effect even on healthy ones. Sometimes it seems as if only a miracle could provide a cure that’s both safe and effective. And a miracle is just what Dr. Mate Hidvegi believed he found when he patented FWGE , a fermented wheat germ extract. Studies have shown that AveFWGE mar reduces cancer recurrence, cuts off the cancer cells’ energy supply, speeds cancer cell death, and helps the immune system identify cancer cells for attack.

Objective: The fermented wheat germ extract (FWGE) nutraceutical (FWGE™), manufactured under “good manufacturing practice” conditions and, fulfilling the self-affirmed “generally recognized as safe” status in the United States, has been approved as a “dietary food for special medical purposes for cancer patients” in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. Methods: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. Results: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p 0.0298. Conclusions: The inclusion of FWGE into the adjuvant protocols of high-risk skin melanoma patients is highly recommended

Background and aim Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name FWGE) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of FWGE in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with FWGE in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving FWGE (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in FWGE has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer. 

The Hungarian Association of Oral and Maxillofacial Surgeons (Magyar Arc-, Állcsont- és Szájsebészeti Társaság) has reviewed the research results related to FWGE and issued its opinion as follows: For patients suffering from head- and neck tumors - primarily malignant tumorous diseases of the oral cavity, the progression of the disease can be slowed significantly, the five-year survival rate increased considerably, the quality of life improved, and the oxidative stress on the patients reduced by the long-term application of the supplementary formula FWGE . The Association considers the supportive treatment with the formula FWGE as an important part of the complex therapeutic protocols applied in stages II, III and IV of malignant tumorous diseases of the oral cavity. 

Objective. To investigate the effect of the fermented wheat germ extract (FWGE ®) in patients with severe rheumatoid arthritis (RA). Methods. Fifteen female RA (Steinbrocker II-III) patients, who had unsuccesfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received FWGE ® as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. Results. At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of FWGE ® were observed. Conclusion. Supplementation of standard therapies with a continuous administration of FWGE ® is beneficial for RA patients

The hypothesis that oxidative stress favours flogistic and immune processes inducing autoimmune rheumatic diseases (ARDs) and their complications is still under discussion. In this review we take into consideration both the aetiopathological role of the diet in such diseases and the possible efficacy of dietary supports as adjuvants for the usual specific therapies. Moreover, we shall examine the hypothetical pathophysiological role of oxidative stress on ARDs and their complications, the methods for its evaluation and the possibility of intervening on oxidative pathways by means of nutritional modulation. It is possible that in the future we will be able to control connective pathology by associating an immuno-modulating therapy (‘re-educating’) with naturalproducts having an anti-oxidant activity to current immunosuppressive treatment (which has potentially toxic effects).
2003 Elsevier B.V. All rights reserved.

Purpose: An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. Methods: Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. Results: During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). 

MSC (FWGE ) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients’ choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox’s proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival. 

“FWGE pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 µg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. FWGE pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered FWGE pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using FWGE pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that FWGE pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.

ACCREDITATION InnoVision Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT InnoVision Communications designates this educational activity for a maximum of 1.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. STATEMENT OF PURPOSE Natural products are being used as supplements by cancer patients, with or without the knowledge of their cancer treatment team. It is important to know which of these products show efficacy against diseases such as cancer, and which are ineffective. It is also essential to define the mechanism(s) of action of natural products, especially as relevant to cancer prevention or treatment. The purpose of this article is to review the use of one such natural product, a fermented wheat germ extract (FWGE ), in the treatment regimen of cancer patients. FWGE has shown efficacy in both animal cancer models and human clinical trials with cancer patients, but more well-controlled trials in humans are necessary to assess the full potential of FWGE in cancer treatment. 

FWGE , the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, FWGE can inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of FWGE treatment have been shown in various human cancers, in cultures of in vitro grown cancer cells, in the prevention of chemical carcinogenesis, and also in some autoimmune conditions. This document reviews the clinical and experimental results obtained with this extract so far. Special references are made for its safety, including its coadministration with anticancer drugs, as well as for its immunomodulatory activity, its molecular targets, and its use in cancer clinical trials.

The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography–mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption, uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation– related and cell differentiation–related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation–related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture. Key Words: Pentose cycle—Ribose synthesis—Fermented wheat germ extract—Nonoxidative glucose metabolism—Cell proliferation—Avemar

The potential of oral treatment with FWGE (FWGE ), a new benzoquinone-containing fermentation product of wheat germ, on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was studied. We assessed the effect of FWGE on the profile of autoantibody production and the response of Th1=Th2 related cytokines as well as the clinical picture of experimental SLE in the SLE-induced mice. When the product was given in the pre-immunization period, down-regulation of autoantibody production (anti-dsDNA, mouse 16=6 Id, and anti-histones) following treatment with FWGE  was noted (eg anti-dsDNA decreased from 0.898 0.097 OD at 405 nm to 0.519 0.103 OD following treatment). This effect was sustained for at least 4 weeks after discontinuation of the therapy. Serological manifestations associated with a delay in Th2 response (IL-4 and IL-10) were recorded (eg IL-4 decreased from 91.7 8.11 to 59.55 7.78 ng=ml in splenocyte condition media). The mice showed normal ESR, WBC and less than 100 mg=dl of protein in the urine in comparison to > 300 mg=dl protein in the SLE non-treated mice. In conclusion, oral intake of FWGE can ameliorate the clinical manifestations of experimental SLE, via affecting the Th1=Th2 network inhibiting Th2 response. Lupus (2001) 10, 622–627.

The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC50 concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G1 peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodideand annexin V-stained cells indicated that the growthinhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased 13C incorporation and pentose cycle substrate flow into RNA ribose. 

The fermented wheat germ extract (code name: MSC, trade name: FWGE), with standardized benzoquinone content has been shown to inhibit tumor propagation and metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of intracellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the ‘sub-G1’ cell population. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence on cytofluorimeter using a monoclonal antibody to the non-polymorphic region of the human MHC class I. MSC stimulated tyrosine phosphorylation of intracellular proteins and the influx of extracellular Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell lines. As a result of the MSC treatment, the amount of the cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells. 

Introduction: Tumor cells, just as other living cells, possess the potential for proliferation, differentiation, cell cycle arrest, and apoptosis. There is a specific metabolic phenotype associated with each of these conditions, characterized by the production of both energy and special substrates necessary for the cells to function in that particular state. Unlike that of normal living cells, the metabolic phenotype of tumor cells supports the proliferative state. Aim: To present the metabolic hypothesis that (1) cell transformation and tumor growth are associated with the activation of metabolic enzymes that increase glucose carbon utilization for nucleic acid synthesis, while enzymes of the lipid and amino acid synthesis pathways are activated in tumor growth inhibition, and (2) phosphorylation and allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate and sustain cell transformation from one condition to another. Conclusion: Evidence is presented that demonstrates opposite changes in metabolic phenotypes induced by TGF-
, a celltransforming agent, and tumor growth-inhibiting phytochemicals such as genistein and Avemar, or novel synthetic antileukemic drugs such as STI571 (Gleevec). Intermediary metabolic enzymes that mediate the growth signaling pathways and promote malignant cell transformation may serve as highefficacy nongenetic novel targets for cancer therapies.

This conference was a successful continuation of previous conferences such as the Hungarian Cell Analysis Conference, Budapest, 1998 and 2000, and the ISAC-Sponsored International Conference for Flow Cytometry and Image Analysis, Epona, 1999. The Cell Analysis Section of the Hungarian Biophysical Society organized all four conferences. The popularity of the conference was hallmarked by the large number of participants (close to 300). The form of the conference proved to be very attractive: In the mornings, experts from specific fields delivered scientific lectures. In addition to Hungarian scientists, such as Margit Bala´zs, Gyula Hadlacky, Be´la Molna´r, La´szlo´ G. Puskas, Ja´nos Szo¨llo¨si, and Gyo¨rgy Vereb, experts from abroad significantly raised the scientific standards of the conference. The international speakers included Peter Adorjan, Francis Mandy, Abe Schwartz, Howard M. Shapiro, and the authors of this introduction. In the afternoons, practical demonstrations were presented, ranging from basic techniques to stateof-the-art instrumentation. Practical training included cell culturing; mechanical cell separation for flow cytometry; methods for detection of cell proliferation; detection of apoptosis; fluorescence microscopy, image acquisition, and processing; confocal laser microscopy; fluorescence in situ hybridization; magnetic cell separation; magnetic mRNA isolation; real-time and traditional polymerase chain reaction; and detection of mutation. 

Fermented foods such as Japanese traditional food ‘‘miso (fermented soy bean paste)’’ have been shown to be rich source of micronutrients with the potential to prevent various human diseases. We have introduced effects of a new dietary supplement of fermented grain foods mixture containing extracts from wheat germ, soybeans, rice bran, tear grass, sesame, wheat, citrus lemon, green tea, green leaf extract and malted rice under the trade name of antioxidant biofactor (AOB). Chemical analysis of AOB shows the presence of various phenolic compounds (catechins, rutin, genistin, daidzin, etc.). AOB has strong antioxidant properties and additional biological effects, which might be of importance in context with the prevention of degenerative diseases. This paper focuses on the effect of supplementing AOB in various animal models and humans.

FWGE ® (Biromedicina Co., Budapest, Hungary), a wheat germ preparation with immunomodulant and antimetastatic activity, was applied simultaneously with cytostatic drugs of different modes of action, in vitro and in vivo, in order to find out whether this simultaneous administration exerts an antagonistic or a synergistic effect on the viability of cell cultures, tumor growth, and survival of animals, inoculated with a transplantable mouse tumor (3LL-HH). In vitro, FWGE did not influence the effect on the viability of MCF-7, HepG2, or Vero cells, exerted by Dacarbazine, 5-fluorouracyl, or Adriblastina. In vivo, FWGE , combined with Endoxan, Navelbine, and doxorubicin, did not prevent the tumor growth inhibitory effect of the cytostatic drugs. The combination of FWGE with the cytostatic drugs did not increase the toxicity of the cytostatic compounds, and did not exert any toxic effect. FWGE may be administered together with cytostatic drugs, without the risk of increasing toxicity or decreasing antiproliferative activity.

This in vitro investigation attempts to see if cultured leukaemic peripheral blood lymphocytes from children with acute lymphoblastic leukaemia (“ALL”) can be corrected by introducing high redox potential quinones into the culture medium. Modern treatments for ALL aim to kill the aberrant cells with minimal effect on normal cells, and perhaps some 70 percent of such patients are restored to health (Stiller, 2004). Inevitably however there are side effects such as hair loss, pain, and subsequently lower IQ levels. In a recent Hungarian clinical trial on colorectal cancer patients (see below) with certain quinone structures such side effects were minimal and metastases were dramatically reduced. Should results of this in vitro study also be found positive, and clinical trials likewise the treatment may ultimately prove adjuvant in reducing the adverse side effects of present interventions.

The effect of fermented wheat germ extract (FWGE, Immunovet-HBM) was studied in chickens challenged with Mycoplasma gallisepticum. Ninety M. gallisepticum- and M. synoviae-free 3-wk-old chickens were exposed to aerosol infection of M. gallisepticum. One group (30 birds) was treated with FWGE, a second group with tiamulin, and a third group was untreated. The fourth group was exposed to PBS aerosol as a negative control. On d 9, all chickens were slaughtered and examined for the presence of gross and histological lesions, the presence of the challenge strain in the organs and specific antibodies in the serum. Body weight gains and feed conversion rates were recorded. In the groups treated with FWGE and with tiamulin, the chickens remained clinically healthy: their BW gains were 441.7 g and 446.8 g, respectively. Feed conversion ratios were 1.72 and 1.71 for FWGE- and tiamulin-treated birds, respectively. Control birds had BW gain of 480.8 g, and feed conversion ratio of 1.78. The numbers of birds with gross lesions (15 and 11, respectively) and lesion scores (25 and 25, respectively) of the FWGE- and tiamulin-treated groups were significantly lower than in the infected untreated group (25 birds, lesion score of 190). No mycoplasma was reisolated from brain, liver, spleen, heart, or kidneys of the FWGE-treated birds, and the number of mycoplasma isolations from the respiratory tract samples was less frequent (10) than from the infected untreated group (64). In addition, 35 samples from other internal organs were also positive. Twenty percent of the birds treated with FWGE showed serological response with a 5.0% reaction score, whereas in the infected untreated group, 83.3% of birds were reactors, with a 62.5% reaction score.

The aim of this study is to investigate whether aberrant peripheral blood lymphocytes can be corrected by the addition of a highly diluted quinone to the culture medium. The oxygen uptake of both normal and aberrant lymphocytes is examined before and after the quinone is added. The results will indicate whether the quinone is able to increase the oxygen uptake rate of aberrant lymphocytes, thereby returning them to normal metabolism.

The 2,6-dimethoxy-p-benzoquinone (2,6DMBQ) derived from different plant species is of special interest. The wheat (Triticum vulgaris) is one of the largest known natural sources of these compounds. These compounds occur in glucoside form, and are located in the embryo. In the present work we aimed at developing chromatographic method for precise, sensitive and reliable analysis with high stability of benzoquinones. In the newly worked out method RP-amide C16 column was used with 20% acetonitrile in phosphate buffer as the mobile phase. The method was validated according to calibration curve, precision and recovery tests, limit of detection and quantitation. The results indicated that as low as 0.27 lg/mL can be quantitatively determined by this method with 100.5–101%, and 97% for recovery and precision, respectively. There was significant reduction in the time required for the complete elution of phenol compounds with substantial improvement on the symmetry of their peaks as compared to those noticed with other methods. The standard and sample solutions showed higher stability at refrigeration storage for more than 4 months. As an application of the new method, fermented wheat germ, germinated wheat and extract of wheat seedlings were analysed for their benzoquinone content. The highest level was found in the fermented wheat germ, while minute quantities could be detected in the other samples.

The hypothesis that oxidative stress favours flogistic and immune processes inducing autoimmune rheumatic diseases (ARDs) and their complications is still under discussion. In this review we take into consideration both the aetiopathological role of the diet in such diseases and the possible efficacy of dietary supports as adjuvants for the usual specific therapies. Moreover, we shall examine the hypothetical pathophysiological role of oxidative stress on ARDs and their complications, the methods for its evaluation and the possibility of intervening on oxidative pathways by means of nutritional modulation. It is possible that in the future we will be able to control connective pathology by associating an immuno-modulating therapy (‘re-educating’) with naturalproducts having an anti-oxidant activity to current immunosuppressive treatment (which has potentially toxic effects).
2003 Elsevier B.V. All rights reserved.Role of the diet and dietary supports in autoimmune rheumatic disease In 1880, Sir Jonathan Hutchinson suggested some healthy-life rules in the treatment of systemic lupus erythematosus (SLE). They included selected aliments and dietary support with cod-liver oil w1x. More than 100 years later, the role of the diet and the dietary supports is still under discussion. The complexity of the pathology and the number *Corresponding author. Tel.: q39-10-555-3985; fax: q39- 10-555-6850. E-mail address: samir.sukkar@hsanmartino.liguria.it (S.G. Sukkar). of concurrent factors often frustrate the efforts made in attributing symptomatic remission to a specific therapeutic support.

FWGE , a fermented wheat germ extract, has been applied in the supplementary therapy of human cancers. Because tamoxifen is commonly used in the therapy of ER
breast cancer, in this study the combined effect of tamoxifen and FWGE treatment was investigated on MCF-7 breast cancer cells, in order to detect a possible agonistic or antagonistic action. Cytotoxicity was measured by MTT assay, the percentage of mitoses and apoptotic cells was determined morphologically, apoptosis and S-phase was measured by flow cytometry, and estrogen-receptor activity was determined by semiquantitative measurement of the estrogen-responsive pS2 gene mRNA production. Tamoxifen (1 nM) alone had no effect on the percentage of the apoptotic cell fraction and significantly reduced the percentage of the S-phase, compared to untreated cells. FWGE (625
g/mL) significantly increased apoptosis after 48 hours of treatment. Tamoxifen together with FWGE significantly increased apoptosis already 24 hours after starting treatment but had only a slight (not significant) effect on mitosis and S-phase. Estrogen-receptor activity of MCF-7 cells was enhanced by FWGE , decreased by tamoxifen, and was further decreased by combined tamoxifen and FWGE treatment. As apoptosis increased when FWGE was added to tamoxifen treatment, the use of supplementary therapy with FWGE in the case of ER
breast tumors may enhance the therapeutic effects of tamoxifen.

FWGE (MSC) is a nontoxic fermented wheat germ extract demonstrated to have antitumor effects. FWGE has the potential to significantly improve the survival rate in patients suffering from malignant colon tumors. We studied its effects in the HT-29 human colon carcinoma cell line. FWGE had an inhibiting effect on colonies of HT-29 cells with an IC50 value of 118 lg/ml (7 days of incubation); this value could be decreased to 100 and 75 lg/ml in the presence of vitamin C. In the cell line examined, FWGE induced both necrosis and apoptosis, as demonstrated by Hoechst/propidium iodide staining. The incubation of cells with 3200 lg/ml FWGE for 24 hrs caused necrosis in 28% and the induction of apoptosis in 22% of the cells. FWGE inhibited the cell-cycle progression of HT-29 cells in the G1 phase of the cell cycle. In addition, FWGE inhibited the activity of the key enzyme of de novo DNA synthesis, ribonucleotide reductase. In addition, we determined the effects of FWGE on the activity of cyclooxygenase-1 and -2. Both enzymes were significantly inhibited by FWGE with IC50 values of 100 and 300 lg/ml, respectively. We outline new explanations for its antitumor activity, which might serve as the basis for further studies using FWGE .

Background: The use of complementary and alternative therapies by children with cancer is common. Up to 84% of children have used complementary therapies along with conventional medical treatment for cancer. Methods: We reviewed the PubMed and CINAHL databases for studies published between 1994 and 2004 on the use of complementary and alternative therapies by children with cancer and reports from any publication year through 2004 of clinical trials involving complementary and alternative therapies for children with cancer. Results: Fourteen studies were retrieved reporting the results of survey or interview data collected from parents on children’s use of complementary and alternative therapies during or after childhood cancer. Across studies, the use of such therapies ranged from 31% to 84%. Common reasons for using complementary and alternative therapies were to do everything possible for their child, to help with symptom management, and to boost the immune system. Many parents indicated they also hoped to treat or cure the cancer. In most cases, the child’s treating physician had not been informed of the child’s use of complementary and alternative therapies. Conclusions: Use of complementary therapies by children with cancer is common, although methodological variations limit the ability to compare results across studies. Treating physicians often do not know the child is using complementary therapies in addition to medical treatments. The scientific evidence is limited regarding the effects and mechanisms of action of complementary or alternative therapies, but research is being conducted on these topics

A közlemény áttekintést ad a készítmény colorectalis rák kezelésében betöltött szerepérôl az eddigi experimentális és klinikai eredmények ismeretében. A daganatos betegségek kiegészítô kezelésében speciális – gyógyászati célra szánt – tápszer minôségben törzskönyvezett fermentált búzacsíra-kivonat (kódnév: MSC, kereskedelmi név: Avemar) daganatgátló hatást fejt ki HCR-25 humán coloncarcinoma xenograftban, 5-fluorouracillal szinergizmusban pedig egér C38 colorectalis carcinomában. Azoximetánnal indukálható F-344 patkány coloncarcinomában kemopreventív. A daganatgátló hatás egyik fontos tumorspecifikus mechanizmusa a daganatsejtek apoptosisának fokozása a PARP kaszpázmediált hasításának indukciója útján. A fermentált búzacsíra-kivonat – szupportív terápia keretei közt – daganatgátló hatásúnak bizonyult colorectalis rákban. 30 radikálisan operált lege artis posztoperatív kezelésben részesült beteg közül 12 részesült fermentált búzacsíra-kivonat kiegészítésben, akiknél 9 hónapos megfigyelési idô alatt nem alakult ki távoli áttét, szemben a kontrollcsoport 4 betegével. 34 radikálisan operált posztoperatív kemoterápiában részesült beteg közül 17-nél a kezelést fermentált búzacsíra-kivonattal is kiegészítették; ebben a csoportban a túlélés meghosszabbodását észlelték. Nyílt multicentrikus kohorszalapú vizsgálatban 170 radikálisan operált beteg részesült lege artis kezelésben (kemo-, ill. radioterápia), közülük 66-an emellett fermentált búzacsíra-kivonatot is kaptak. Eredmények (fermentált búzacsíra-kivonat vs. kontroll): új lokális recidíva: 3% vs. 17,3% (p < 0,01), új szervi áttét: 7,65% vs. 23,1% (p < 0,01), exitus: 12,1% vs. 31,7% (p < 0,01). 

Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to FWGE , a fermented wheat germ extract. FWGE synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. FWGE treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of FWGE on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. FWGE treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B–sensitive reporters were also activated by FWGE ; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes, and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer’s disease patients transketolase protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase protein isoforms have been identified. In diabetes mellitus patients reduced transketolase enzyme activities have been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions, thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy. In cancer inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis. All the observed phenomena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate the presence of a second transketolase enzyme (TKTL1) in humans. 

Vertebrate female reproduction is limited by the oocyte stockpiles acquired during embryonic development. These are gradually depleted over the organism’s lifetime through the process of apoptosis. The timer that triggers this cell death is yet to be identified. We used the Xenopus egg/oocyte system to examine the hypothesis that nutrient stores can regulate oocyte viability. We show that pentose-phosphate-pathway generation of NADPH is critical for oocyte survival and that the target of this regulation is caspase-2, previously shown to be required for oocyte death in mice. Pentose-phosphate-pathway-mediated inhibition of cell death was due to the inhibitory phosphorylation of caspase-2 by calcium/calmodulin-dependent protein kinase II (CaMKII). These data suggest that exhaustion of oocyte nutrients, resulting in an inability to generate NADPH, may contribute to ooctye apoptosis. These data also provide unexpected links between oocyte metabolism, CaMKII, and caspase-2.

Background: The fermented wheat germ extract (code name:MSC, trade name: Avemar), is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. The objective of this study was to examine the in vitro cytotoxic activities of Avemar on 5 human gastric carcinoma cell lines and to test whether the mechanism involves induction of apoptosis. Methods: Cytotoxic activities of Avemar on 5 human gastric carcinoma cell lines (SNU-1, SNU-5, SNU-16, SNU-620, MKN-45) were examined using XTT cytotoxicity assay and apoptosis was measured by Sub-G1 fraction on flow histograms and annexin V- and propidium iodide-stained fraction on flow histogram. Results: Avemar dose-dependently suppressed the growth of all 5 examined gastric carcinoma cells by more than 90%, with ascending order of IC50 values: SNU-5 (0.37mg/mL), MKN-45 (0.49mg/mL), SNU-620 (0.52 mg/mL), SNU-1 (0.58 mg/mL) and SNU-16 (0.62mg/mL). Flow cytometry of Sub-G1 cells or annexin V- and propidium iodidestained cells indicated that the growth inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Conclusions: Avemar was found to dose-dependently inhibit the growth of gastric carcinoma cells possibly via an apoptosis-dependent pathway and has a potential to be an additive or synergistic effect with cytotoxic agents.

Targeted drugs tailored against genes and signaling proteins have formed the new era termed Targeted Therapies. Although the field is relatively young, since only about 5 years ago clinical trials started showing promise, there have are already been significant setbacks due to drug resistance caused by point mutations, alterations in gene expression or complete loss of target proteins with disease progression. Although new drugs are continuously designed and tried, it seems inevitable that genetic and signal protein targets pose too broad flexibility and variability, often changing target characteristics and thus escape treatments turning ‘‘magic bullets’’ into rather ‘‘wondering bullets’’. This is especially true in cancer, where old and new targeted therapies continue to fail and the most recent ones do not offer much improvement on clinical outcome parameters. Metabolic targeted therapies are aimed at control points of the metabolic network by targeting particular enzymes of major macromolecule synthesis pathways in cancer. This review summarizes the potential benefits of targeted therapies in the metabolic network as applied with genetic and proteomic approaches. The metabolic target approach is most efficient if and when pathway flux information is available for drug target development using the stable isotope based dynamic metabolic profile (SIDMAP) of tumor cells, in vitro or in vivo.

Comprehensive analysis of the metabolome can contribute to mechanism of action studies for small molecules discovered in phenotypic screens. Examples are presented in this overview of the rapidly developing field of “metabolic profiling.” These examples include the use of NMR in gene function analysis, GC-based studies on the identification of metabolic pathways affected by PPAR-γ agonists, applications of Fourier-transform MS and the use of stable isotope-based metabolic profiling (SIDMAP) to investigate metabolic adaptive changes induced by effective anticancer agents.

The etiology of most chronic angiogenic diseases such as rheumatoid arthritis, atherosclerosis, diabetes complications, and cancer includes the presence of pockets of hypoxic cells growing behind aerobic cells and away from blood vessels. Hypoxic cells are the result of uncontrolled growth and insufficient vascularization and have undergone a shift from aerobic to anaerobic metabolism. Cells respond to hypoxia by stimulating the expression of hypoxia inducible factor (HIF), which is critical for survival under hypoxic conditions and in embryogenesis. HIF is a heterodimer consisting of the O2-regulated subunit, HIF-1R, and the constitutively expressed aryl hydrocarbon receptor nuclear translocator, HIF-1!. Under hypoxic conditions, HIF-1R is stable, accumulates, and migrates to the nucleus where it binds to HIF-1! to form the complex (HIF-1R + HIF-1!). Transcription is initiated by the binding of the complex (HIF-1R + HIF-1!) to hypoxia responsive elements (HREs). The complex [(HIF-1R + HIF-1!) + HREs] stimulates the expression of genes involved in angiogenesis, anaerobic metabolism, vascular permeability, and inflammation. Experimental and clinical evidence show that these hypoxic cells are the most aggressive and difficult angiogenic disease cells to treat and are a major reason for antiangiogenic and conventional treatment failure. Hypoxia occurs in early stages of disease development (before metastasis), activates angiogenesis, and stimulates vascular remodeling. HIF-1R has also been identified under aerobic conditions in certain types of cancer. This review summarizes the role of hypoxia in some chronic degenerative angiogenic diseases and discusses potential functional foods to target the HIF-1R pathways under hypoxic and normoxic conditions. 

Objective. To investigate the effect of the fermented wheat germ extract (FWGE ®) in patients with severe rheumatoid arthritis (RA). Methods. Fifteen female RA (Steinbrocker II-III) patients, who had unsuccesfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received FWGE ® as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. Results. At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of FWGE ® were observed. Conclusion. Supplementation of standard therapies with a continuous administration of FWGE ® is beneficial for RA patients

Az FWGE hazánkban az OÉTI engedélyével immár 7. éve van kereskedelmi forgalomban, 3 évvel ezelôtt pedig az Országos Tisztifôgyógyszerész jóváhagyásával törzskönyvezték onkológiai indikációban. Alkalmazási területét – elsôsorban, de nem kizárólag – a rosszindulatú daganatok szupportív kezelése képezi. Természetes eredetû anyagokból álló orvosi tápszerrôl lévén szó, nem a gyógyszerekre érvényes szabályok szerint kell megítélni az alkalmazás kérdését, annak ellenére, hogy bizonyított hatásai számos tekintetben összevethetôk széles körben alkalmazott daganatellenes gyógyszerek, elsôsorban citosztatikumok hasonló hatásaival. Fontos jellemzôje a toxikus hatások közel teljes hiánya, és az életminôségre gyakorolt pozitív hatása. Több, nagy gyakorlati jelentôségû rosszindulatú megbetegedésben klinikai vizsgálatokkal igazolták szupportív terápia minôségében kifejtett daganatgátló hatását. Kellôen dokumentált kísérletes vizsgálatok és elôzetes klinikai adatok alapján rheumatoid arthritisben és lupus erythematosusban egyaránt hatékonynak találták, ez immunmoduláns hatásával, ezen belül a kóros autoantitestek szintjét csökkentô képességével, és klinikailag is jelentôs COX-gátló hatásával hozható összefüggésbe

FWGE (MSC) is a nontoxic fermented wheat germ extract demonstrated to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in human HL-60 promyelocytic leukemia cells. After 24, 48, and 72 h of incubation, FWGE inhibited the growth of HL-60 cells with IC50 values of 400, 190, and 160 lg/ml, respectively. Incubation with MSC caused dose-dependent induction of apoptosis in up to 85% of tumor cells. In addition, FWGE attenuated the progression from G2–M to G0–G1 phase of the cell cycle and was also found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of de novo DNA synthesis. We conclude that FWGE exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies. 2006 Elsevier Ireland Ltd. All rights reserved.FWGE (MSC), a fermented wheat germ extract standardized to methoxy-substituted benzoquinones, possesses cancer-fighting characteristics. Taken orally, MSC can inhibit metastatic tumor dissemination and proliferation [1]. FWGE is capable of synergistically enhancing the effect of 5-fluorouracil (5-FU) and dacarbazine (DTIC) under experimental conditions when applied in combination with these agents [2]. Moreover, MSC has a marked inhibitory effect on metastasis formation in tumor-bearing animals[3–5], resulting in a decreased survival time of skin grafts and reduced cell proliferation while enhancing apoptosis. Oral co-administration of FWGE inhibits tumor metastasis formation after chemotherapy and surgery in advanced colorectal cancers [6,7]. 

Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactatebased matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

An extract of fermented wheat germ, Avemar, was developed during the 1990s by Hungarian biochemist Mate Hidvegi, Ph.D. Initially, Avemar was available as an over-the-counter dietary supplement, but in 2002 the product was registered as a medical nutriment with an indication for use in cancer treatment by the Hungarian National Institute of Food Safety and Nutrition. “It is not like shark cartilage or cat’s claw or other such products, which may or may not be good, but which are not official cancer treatments. In Hungary, Avemar has become an accepted part of cancer treatment,” Dr. Hidvegi said in an interview. For example, the Hungarian Association of Oral and Maxillofacial Surgeons has issued an official statement indicating that Avemar should be included in the treatment protocol for squamous cell carcinoma of the oral cavity. Avemar is manufactured by Biromedicina Co., Budapest, and is marketed in the United States by American BioSciences Inc., Blauvelt, N.Y. The precise molecular targets by which Avemar produces its immunomodulary effects have not yet been identified, but Dr. Hidvegi and colleagues have proposed several possibilities. 

The Hungarian Association of Oral and Maxillofacial Surgeons (Magyar Arc-, Állcsont- és Szájsebészeti Társaság) has reviewed the research results related to FWGE and issued its opinion as follows: For patients suffering from head- and neck tumors - primarily malignant tumorous diseases of the oral cavity, the progression of the disease can be slowed significantly, the five-year survival rate increased considerably, the quality of life improved, and the oxidative stress on the patients reduced by the long-term application of the supplementary formula FWGE. The Association considers the supportive treatment with the formula FWGE as an important part of the complex therapeutic protocols applied in stages II, III and IV of malignant tumorous diseases of the oral cavity. 

“FWGE pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 µg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. Avemar pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered Avemar pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. 

Arthritis, an inflammation of the joints, is usually a chronic disease that results from dysregulation of pro-inflammatory cytokines (e.g. tumour necrosis factor and interleukin-1b) and pro-inflammatory enzymes that mediate the production of prostaglandins (e.g. cyclooxygenase-2) and leukotrienes (e.g. lipooxygenase), together with the expression of adhesion molecules and matrix metalloproteinases, and hyperproliferation of synovial fibroblasts. All of these factors are regulated by the activation of the transcription factor nuclear factor-kB. Thus, agents that suppress the expression of tumour necrosis factor-a, interleukin-1b, cyclooxygenase-2, lipooxygenase, matrix metalloproteinases or adhesion molecules, or suppress the activation of NF-kB, all have potential for the treatment of arthritis. Numerous agents derived from plants can suppress these cell signaling intermediates, including curcumin (from turmeric), resveratrol (red grapes, cranberries and peanuts), tea polyphenols, genistein (soy), quercetin (onions), silymarin (artichoke), guggulsterone (guggul), boswellic acid (salai guggul) and withanolides (ashwagandha). Indeed, several preclinical and clinical studies suggest that these agents have potential for arthritis treatment. Although gold compounds are no longer employed for the treatment of arthritis, the large number of inexpensive natural products that can modulate inflammatory responses, but lack side effects, constitute ‘goldmines’ for the treatment of arthritis.

ACCREDITATION InnoVision Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT InnoVision Communications designates this educational activity for a maximum of 1.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. STATEMENT OF PURPOSE Natural products are being used as supplements by cancer patients, with or without the knowledge of their cancer treatment team. It is important to know which of these products show efficacy against diseases such as cancer, and which are ineffective. It is also essential to define the mechanism(s) of action of natural products, especially as relevant to cancer prevention or treatment. The purpose of this article is to review the use of one such natural product, a fermented wheat germ extract (Avemar), in the treatment regimen of cancer patients. Avemar has shown efficacy in both animal cancer models and human clinical trials with cancer patients, but more well-controlled trials in humans are necessary to assess the full potential of Avemar in cancer treatment. Avemar has shown efficacy in both animal cancer models and human clinical trials with cancer patients, but more well-controlled trials in humans are necessary to assess the full potential of Avemar in cancer treatment. Avemar exerts its anticancer effect via an array of mechanisms, likely because there are many undefined components in this product that modulate numerous biological systems in cancer patients. 

Background: An in vitro study demonstrated that FWGE increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with FWGE . Then the most effective FWGE dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with FWGE was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by FWGE was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of FWGE with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by FWGE (50% inhibition). The combination of FWGE with Examestane increased the tumor growth inhibition to 60.4% compared to control. 

Background: Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-a and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE. Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies. 

Conclusion: In conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.

 Keywords: Fermented wheat germ extract, in vitro effects, in vivo effects, clinical activity

FWGE, the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, FWGEcan inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of FWGEtreatment have been shown in various human cancers, in cultures of in vitro grown cancer cells, in the prevention of chemical carcinogenesis, and also in some autoimmune conditions. This document reviews the clinical and experimental results obtained with this extract so far. Special references are made for its safety, including its coadministration with anticancer drugs, as well as for its immunomodulatory activity, its molecular targets, and its use in cancer clinical trials.

Fermented wheat germ extract (FWGE; trade name FWGE ) is a natural compound derived from industrial fermentation of wheat germ. Its potential anticancer properties has emerged from recent studies. The aim of this systematic review is to summarize the data available in the scientific literature concerning the in vitro activity of FWGE on malignant cells. A systematic review of English articles in electronic databases has been performed. The primary outcomes of the review regarded types of cancer cell lines subjected to the investigation and the main results concerning cell viability, proliferation, and apoptosis observed within the studies. Sixteen articles were included in the final qualitative analysis. Various types of cancer cells treated with FWGE have been analyzed, showing mainly cytotoxic effects, alteration of the cell cycle, antiproliferative effects, and induction of apoptosis. FWGE can be a promising drug component in cancer treatment; however, further in vitro and in vivo studies are necessary to prove its effectiveness and safety in humans.

MSC (FWGE ) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients’ choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox’s proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.

Background and aim Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name FWGE ) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of FWGE in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with FWGE in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving FWGE (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in FWGE has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer.

Objective: The fermented wheat germ extract (FWGE) nutraceutical (FWGE ™), manufactured under “good manufacturing practice” conditions and, fulfilling the self-affirmed “generally recognized as safe” status in the United States, has been approved as a “dietary food for special medical purposes for cancer patients” in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. Methods: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. Results: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p 0.0298. Conclusions: The inclusion of FWGE into the adjuvant protocols of high-risk skin melanoma patients is highly recommended.

Objective: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists. Methods: In this study, we investigated the activity of FWGE , a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. Results: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate G 0.2) representing 27 biologic pathways (P G 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity. Conclusions: Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. 

The fermented extract of wheat germ, trade name FWGE , is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of FWGE on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC50 concentration of FWGE for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, FWGE inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G1 peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodideand annexin V-stained cells indicated that the growthinhibiting effect of FWGE was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of AvFWGE emar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased 13C incorporation and pentose cycle substrate flow into RNA ribose. 

Purpose: An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (FWGE ) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. 

Methods: Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. 

Results: During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). 

Conclusions: The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.

The Hungarian Association of Oral and Maxillofacial Surgeons (Magyar Arc-, Állcsont- és Szájsebészeti Társaság) has reviewed the research results related to FWGE and issued its opinion as follows: For patients suffering from head- and neck tumors - primarily malignant tumorous diseases of the oral cavity, the progression of the disease can be slowed significantly, the five-year survival rate increased considerably, the quality of life improved, and the oxidative stress on the patients reduced by the long-term application of the supplementary formula FWGE . The Association considers the supportive treatment with the formula FWGE as an important part of the complex therapeutic protocols applied in stages II, III and IV of malignant tumorous diseases of the oral cavity. 

Autophagy is primordial for the maintenance of metabolic and genetic homeostasis in all eukaryotic organisms. Owing to its cell-intrinsic effects, autophagy robustly inhibits malignant transformation, yet can support the progression of established neoplasms as well as their resistance to conventional treatments. The notion that autophagy inhibition sensitizes neoplastic cells to chemotherapy and radiation therapy rivals with the capacity of autophagy to contribute to natural and therapy-driven anticancer immunosurveillance via a multitude of mechanisms. Indeed, autophagy ensures an optimal release of immunostimulatory signals by dying cancer cells and hence boosts their capacity to initiate an immune response. Moreover, autophagy is important for the activity of several components of the immune system involved in tumor recognition and elimination, including antigen-presenting cells and CD8C cytotoxic T lymphocytes. In this review, we discuss how cancer cells disable autophagy to bypass immune control and how strategies aiming to enhance autophagy can be envisaged to improve the efficacy of immunogenic cancer therapies.

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8+ T lymphocyte-dependent anticancer immune responses.

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

 Background: The positive effect of the wheat germ extract FWGE has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. FWGE given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of FWGE is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x105 cell/ml), were treated with FWGE (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with FWGE for 48 hours. To determine the kinase expression pattern Kinase OpenArrayTM plates were used, having over 500 kinase genes with controls in quadruplicates in each plate. Changes in expression was declared if the average value was over 1 (2-fold change in mRNA copy number) and the standard deviation was relatively small (2xSTDEV = AVERAGE). 

This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects

Objective: The fermented wheat germ extract (FWGE) nutraceutical (FWGE ™), manufactured under “good manufacturing practice” conditions and, fulfilling the self-affirmed “generally recognized as safe” status in the United States, has been approved as a “dietary food for special medical purposes for cancer patients” in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. Methods: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. Results: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p 0.0298. Conclusions: The inclusion of FWGE into the adjuvant protocols of high-risk skin melanoma patients is highly recommended

A búzacsírával a Műegyetemen találkozott először. De valahogy úgy, mint mikor Salamon Bélától egy színpadi tréfában megkérdezték, látott-e már nyulat. Hát persze, felelte a legendás színész, az a barna, amit szósszal leöntenek. - Biológus-mérnökként kerültem a Gabona Tröszthöz, s professzorom, Lásztity Radomir hatására elköteleztem magam a gabonakémia mellett. Kikerültem ösztöndíjasként Kanadába, Winnipegbe. Az ajánlóm Holló János volt, a magyar biotechnológia atyja. Az első szabadalmaztatott gyógyhatású készítményemet, az Esterint lucernából kivont anyagokból állítottuk elő. Csak gyanítható, hogy azért fordultam végül a gyógyszerkutatás felé, mert nálunk a családban majd mindenki a gyógyszerészet területén tüsténkedett. Anyai nagyapját említi elsőként a sorban. 

Background and aim Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name FWGE ) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of FWGE in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with FWGE in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving FWGE (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in FWGE has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer.

INTRODUCTION 

Dr. Otto Warburg was awarded the Nobel Prize more than 70 years ago for his discovery that cancer cells use glucose at a rate 10 to 50 times higher than healthy cells through direct glycolysis via non-oxidative pathways.' Called "the Warburg Effect," this characteristic hypermetabolic activity fuels the explosive growth o f cancer, steals glucose from healthy tissue and produces metabolic byproducts that contribute to systemic illness. Warburg theorized that if t he uptake of glucose into cancer cells could be inhibited, their energy supply could be choked off, slowing or stopping cancer growth and fo rcing cancer cells to die.

FWGE , a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids, has been tested as an anti-cancer and immunomodulatory dietary supplement. Proposed mechanisms include anti-oxidant and anti-inflammatory actions. This study has determined whether these actions of FWGE may also be useful in the treatment of cardiovascular diseases. Two experimental rat models of cardiovascular remodeling were used in this project: the deoxycorticosterone acetate (DOCA)-salt-induced model of chronic hypertension (study I) and a high-carbohydrate/high-fat dietinduced model producing chronic symptoms of the metabolic syndrome and its associated cardiovascular complications (study II). Our results in these rat models of hypertension and diet-induced obesity show that treatment with FWGE improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated increased plasma malondialdehyde concentrations. In addition to the changes in the heart, FWGE reversed glucose intolerance, normalized systolic blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet. In conclusion, the fermented wheat germ extract FWGE has a potential role in attenuating chronic hypertension, diabetes or metabolic syndrome-induced cardiovascular symptoms along with metabolic abnormalities such as glucose tolerance and obesity.

Many healthy foods are derived from wheat germ. The molecular composition of these products, however, greatly differs as shown by normal-phase HPLC-mass spectrometry analysis; thus, experimental data obtained by one of them is not necessarily true for the other. FWGE is a nontoxic wheat germ extract registered as a special nutriment for cancer patients in Hungary. It shows potent anticancer activity on cell lines by deeply interfering with glucose metabolism and affecting expressions of several kinases. In in vivo experimental models, FWGE is also effective by enhancing the activity of the immune system such as stimulating NK cell activity (by reducing MHC I molecule expression), enhancing TNF secretion of the macrophages, increasing ICAM 1 molecule expression on the vascular endothelial cells. All of these lead to apoptosis of tumor cells. The wide range of biological activity of FWGE probably cannot be explained by only one active ingredient. Since there are numerous experimental data and the clinical benefit repeatedly confirmed FWGE can be one of the most potent and best researched food supplements available for cancer patients

FWGE (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, FWGE inhibited the growth of sensitive H9 cells with IC50 values of 290 and 200 μg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC50 values of 180 and 145 μg/ml, respectively. Treatment with 300 μg/ml MSC for 48 h caused dosedependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 μg/ml FWGE for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that FWGE exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.

Worldwide medical literature supports the notion that environmental and nutritional factors play a role in the development of cancer. Nutritional recommendations to the public to help prevent cancer are available from the USA’s National Cancer Institute, the American Cancer Society and other organizations. However, when it comes to treating patients who have been diagnosed with cancer, the vast majority of oncologists fail to deal with nutritional and lifestyle factors to help their patients manage their cancers. Evidence continues to mount that some of the same recommendations designed to prevent cancer should also be applied to patients who already have cancer. Implementing such a program of lifestyle modi!cations, improvement in diet, exercise, stress management, optimal exposure to sunlight, improving energy "ow and nutritional supplements should improve cancer patients’ survival statistics and the quality of life of these patients, including signi!cantly reducing the side e#ects of conventional treatments. $is article focuses on dietary changes and nutritional supplements to help clinicians educate cancer patients, so that they may better deal with their illness. Highlighted are principles involving an optimal diet, avoidance of harmful chemicals and use of nutritional supplements. Some of the controversies surrounding nutritional supplements are reviewed. Speci!c topics covered include a broad range supplement program, vitamin C, amygdalin, iodine, and fermented wheat germ extract. Finally, there is a discussion about paradigms in health care and the e#ects of politics and economics on how health care is practiced today.

Worldwide medical literature supports the notion that environmental and nutritional factors play a role in the development of cancer. Nutritional recommendations to the public to help prevent cancer are available from the USA’s National Cancer Institute, the American Cancer Society and other organizations. However, when it comes to treating patients who have been diagnosed with cancer, the vast majority of oncologists fail to deal with nutritional and lifestyle factors to help their patients manage their cancers. Evidence continues to mount that some of the same recommendations designed to prevent cancer should also be applied to patients who already have cancer. Implementing such a program of lifestyle modi!cations, improvement in diet, exercise, stress management, optimal exposure to sunlight, improving energy "ow and nutritional supplements should improve cancer patients’ survival statistics and the quality of life of these patients, including signi!cantly reducing the side e#ects of conventional treatments. $is article focuses on dietary changes and nutritional supplements to help clinicians educate cancer patients, so that they may better deal with their illness. Highlighted are principles involving an optimal diet, avoidance of harmful chemicals and use of nutritional supplements. Some of the controversies surrounding nutritional supplements are reviewed. Speci!c topics covered include a broad range supplement program, vitamin C, amygdalin, iodine, and fermented wheat germ extract. Finally, there is a discussion about paradigms in health care and the e#ects of politics and economics on how health care is practiced today.

n the present study on effect of feeding raw wheat germ, microwave treated wheat germ, gamma irradiated wheat germ and fermented wheat germ on Interferon gamma (IFN-γ ) and Interleukin 10 (IL-10) in serum of rats were investigated. The data indicated that treated and untreated wheat germ had significant increase in (IFNγ ) level in the serum of rats . Fermented wheat germ recorded the highest significant increase in this concept in comparison to control group. Wheat germ supplementation indicated significant changes of (IL-10) level in serum of rats in comparison to control group. Fermented wheat germ recorded the least significant decrease in (IL-10) level in serum of rats in comparison to control group. Treated and untreated wheat germ specially fermented wheat germ raised the immune system of experimental rats .On the other hand, the present study included the vitamins content (vitamins A, E, and C ) of raw ,microwave treated, gamma irradiated, and fermented wheat germ clarifying the role of each vitamin in raising the immune system.

INTRODUCTION

Health is considered as a fundamental human right and a worldwide social goal. It encompasses all humans disregard of age. Geographical conditions, culture, economic status and life style of people have major impact on their health. Thanks to scientific advancements that the life style of the people is tremendously metamorphosing and their physical activities are getting minimal. The food style is not in conformity to the accustomed geographical or cultural conditions. This results in a wide range of health issues visibly seen as obesity, diabetes and related diseases. If this is the scenario midst the affluent population, malnutrition and low immunity - perpetuating secondary diseases are abounding with the poorest of the poor of the population. In such a context, there arises an essentiality for a study addressing the entire gamut of issue through one single medium. With this as the setting to the research problem, the investigator chose to unravel the utility of wheat as the medium, fine tuning to the questions of addressing the health issues of Indian population, of both the affluent and the have-nots. Much not known components of wheat produce such as wheat bran, wheat germ and wheat grass are the subjective components of study as the investigator came across astounding facts of their nutritive values and medicinal potentials in the researcher’s pilot studies conducted. 

Lactobacillus plantarum LB1 and Lactobacillus rossiae LB5, isolated from wheat germ and selected based on the kinetics of acidification, were used as starters for the manufacture of sourdough fermented wheat germ. A bread containing sourdough fermented wheat germ as an ingredient (SFWGB) was compared to breads made with (raw wheat germ bread, RWGB) or without (wheat flour bread, WFB) raw wheat germ. The higher concentration of free amino acids mainly differentiated SFWGB from WFB and RWGB. The in vitro protein digestibility of WFB was the highest, even if sourdough fermentation of wheat germ attenuated the difference. Phytase and antioxidant activities of SFWGB were highest. The specific volume and celltotal areas were also the highest for SFWGB. As determined by texture profile analysis, the values of hardness, resilience and fracturability of breads containing wheat germ were lower than those found in WFB. The crust lightness showed a decrease from WFB to SFWGB. As determined by sensory analysis, SFWGB had mainly acid taste and flavour and resulted more salty. Sourdough fermented wheat germ is an ingredient able to enhance nutritional, texture and sensory properties of bread. 

The biochemical effects of ethylacetate extract of wheat (FWGE ) on some serum and liver enzymes were evaluated in T. brucei infected rats. The results show significant increase in specific activities of serum aspartate transaminase (AST) in infected untreated rats when compared with infected treated rats. However, there were no significant difference in serum and liver alanine transaminase (ALT). Liver Alkaline phosphatase (ALP) activities were significantly increased in infected untreated when compared with the infected treated rats. Results also show significant increase in specific activities of serum catalase (CAT) and Superoxide dismutase (SOD) in infected treated rats when compared with infected untreated rats. Whereas, there was no significant difference in specific activities of liver catalase, (CAT) and Superoxide dismutase (SOD) in infected treated rats when compared with infected untreated rats. We hereby conclude that ethylacetate extract of wheat has no toxic effect and can ameliorate the effect caused by T. brucei infection.

We evaluated the antibacterial activities of selected edible Korean plant seeds against the food-borne pathogens Staphylococcus aureus KCTC1927, Escherichia coli KCTC2593, Salmonella typhimurium KCTC2054, and Bacillus cereus KCTC1014. While screening for antibacterial agents, we discovered that wheat germ extract contains 2,6-dimethoxy-1,4-benzoquinone (DMBQ) and is highly inhibitory to S. aureus and B. cereus. This is the first report of the antibacterial activity of wheat germ extract. We also investigated the antibacterial activities of the 1,4- benzoquinone standards 1,4-benzoquinone (BQ), hydroquinone (HQ), methoxybenzoquinone (MBQ), and 2,6-dimethoxy1,4-benzoquinone (DMBQ). DMBQ and BQ were the most highly inhibitory to S. aureus and S. typhimurium, followed by MBQ and HQ. MICs for DMBQ and BQ ranged between 8 and 64 µg/ml against the four foodborne pathogens tested. DMBQ and BQ showed significant antibacterial activity; the most sensitive organism was S. aureus with an MIC of 8 µg/ml. BQ exhibited good activity against S. typhimurium (32 µg/ml) and B. cereus (32 µg/ml). The results suggest that wheat germ extract has potential for the development of natural antimicrobials and food preservatives for controlling foodborne pathogens.

Praise be to ALLAH, the most gracious, the most merciful. He (alone) we worship and he alone we seek for help. The almighty that is never weary of protecting me from childhood to this present stage of life. I wish to express my sincere and unreserved appreciation to my supervisor Prof. Clement O. Bewaji. Thank you for the painstaking and scholarly guidance. I want to particularly acknowledge Dr J.T Ekanem for his support and encouragement throughout these past years. I pray that almighty God will grant him good health and abundant blessing in this world and hereafter. Likewise my appreciation goes to the Ag. Head of Department, Dr. (Mrs.) A. T. Oladiji and other members of staff (teaching and non- teaching) for the assiatance and contribution towards the success of this work. My profound gratitude goes to my parents, brothers and sisters for their love, care, support and encouragement not only in this course of this work. I love you all. At this juncture, l acknowledge everyone that contributed immensely in one way or the other to the successfully completion of this work. Although, I cannot mention everybody’s name, Almighty God knows you and equally appreciates you all. Finally to my beloved one Mr Olanrewaju Ibrahim Shittu, l pray Allah reward you accordingly.

Ethyl acetate extract of wheat (Triticum aestivum) and methanolic extract of garlic (Allium sativum) were obtained by fermenting powdered wheat germ and garlic bulbs. The extracts were assessed for their active constituents. The result of the quantitative phytochemical analysis shows that the plant contain secondary metabolite with high percentage of glycoside (19.513%), alkaloids (4.017%) and saponins (7.992%) for wheat extract and glycoside (21.088%), alkaloids (3.570%) and saponins (0.696%) for garlic extract. The extract exhibit antit-rypanosomal activity by showing decrease in the proliferation of parasite and extension of surviving days of Trypanosoma brucei - infected rats from 8 days of the control (infected-untreated) to 14 days of infected treated with wheat and 17 days for infected treated with garlic extract. This study scientifically demonstrates the potential of fermented wheat germ ethylacetate extract and garlic bulbs methanolic extract in the management of Africa trypanosomiasis. 

A recent prospective epidemiological study suggested that an increase in the nutritional uptake of the natural polyamine spermidine is associated with reduced overall and cancer-specific mortality. Here, we speculate through which mechanisms spermidine might exert such oncopreventive effects.

Spermidine, as a natural component from polyamine members, is originally isolated from semen and also existed in many natural plants, and can be responsible for cell growth and development in eukaryotes. The supplementation of spermidine can extend health and lifespan across species. Although the elevated levels of polyamines and the regulation of rate-limiting enzymes for polyamine metabolism have been identified as the biomarkers in many cancers, recent epidemiological data support that an increased uptake of spermidine as a caloric restriction mimic can reduce overall mortality associated with cancers. The possible mechanisms between spermidine and cancer development may be related to the precise regulation of polyamine metabolism, anticancer immunosurveillance, autophagy, and apoptosis. Increased intake of polyamine seems to suppress tumorigenesis, but appears to accelerate the growth of established tumors. Based on these observations and the absolute requirement for polyamines in tumor growth, spermidine could be a rational target for chemoprevention and clinical therapeutics of cancers.

Prostate cancer is the second leading cancer in men. A large amount of polyamines are synthesised in the human prostate and are involved in prostate cell growth and its physiological functions. The content of intracellular polyamines is closely related to cell growth. An increase in cell growth is accompanied by a rise of intracellular polyamine content, and a depletion of intracellular polyamine pools can cause growth arrest or cell death. Therefore, maintaining polyamine concentrations is critical to the cell. Spermidine/spermine N1 -acetyltransferase (SSAT) is the first and rate-limiting enzyme in the polyamine catabolic pathway. SSAT gene is highly inducible, with many stimuli including polyamine analogues and some anticancer drugs producing dramatic increases in activity. Many studies have focussed on polyamine analogues as inducers of SSAT activity as increases in SSAT are associated with a growth inhibition in many tumour cells. However, the mechanisms of this inhibition are not fully understood with respect to polyamine content. Additionally, in vivo results in SSAT transgenic mice studies are contradictory. For example, prostate carcinogenesis is reduced in TRAMP mice but Apcmin/+ mice show a promoted intestinal tumorigenesis. It is thus necessary to characterise the regulation of polyamine content and metabolism by SSAT in prostate cancer cells. The aim of the present study was to characterise the role of SSAT in both the growth of LNCaP prostate carcinoma cells and the response of these cells to anticancer drugs.

Background: Putrescine, spermidine, and spermine (i.e., polyamines) are small cationic amines synthesized by cells or acquired from the diet or gut bacteria. Polyamines are required for both normal and colorectal cancer (CRC) cell growth. 

Objective: We investigated the association between dietary polyamines and risk of CRC incidence and mortality.

 Design: The study was a prospective analysis in 87,602 postmenopausal women in the Women’s Health Initiative Observational Study. Multivariate Cox regression was used to calculate HRs and 95% CIs. 

Results: Total dietary polyamine intake (mean 6 SD: 289.2 6 127.4 mmol/d) was not positively associated with CRC in fully adjusted models. Instead, intake $179.67 mmol/d was associated with reduced risk of CRC [HR (95% CI): 0.82 (0.68, 1.00), 0.81 (0.66, 0.99), 0.91 (0.74, 1.12), and 0.80 (0.62, 1.02) for quintiles 2–5, respectively, compared with quintile 1]. Reduced risk was not significant across all quintiles. Polyamines were not significantly associated with CRCspecific mortality in fully adjusted models. When stratified by risk factors for CRC, only body mass index (BMI) and fiber intake significantly modified the association between polyamine intake and CRC. In women with BMI (in kg/m2 ) #25 or fiber consumption above the median, polyamine intake was associated with significantly lower risk of CRC.

 Conclusions: No positive association between dietary polyamines and CRC or CRC-specific mortality risk in women was observed. Instead, a protective effect of dietary polyamines was suggested in women with some CRC risk-lowering behaviors in particular. These results are consistent with emerging evidence that exogenous polyamines may be beneficial in colon health and warrant additional study

Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan. 

Response to an online chat question. On Thursday, June 10 we held an online chat about diet and cancer myths. One question was about a dietary supplement (FWGE) for cancer treatment, rather than about food, weight and physical activity. So, we turned to for help with answering this question. Suzanne Dixon, MPH, RD Suzanne developed and taught nutrition science coursework at University of Michigan Medical School. At the university's Comprehensive Cancer Center, Suzanne counseled thousands of cancer patients and represented the school as an appointed member to the National Comprehensive Cancer Network (NCCN) nutrition sub-committee. She has also written numerous articles for both scholarly and popular publications. Suzanne is the recipient of the American Dietetic Association Awards for Distinguished Practice in Oncology (cancer) Nutrition and Innovative Nutrition Education Programs for the Public. Please note the following information is from Ms. Dixon and does not represent views or opinions of AICR. Any decisions you make regarding treatment should be in consultation with your physician or health care provider. 

Case repart:

 The patient is a 46-yearold male of Chinese decent diagnosed with stage IV colon cancer with l0 + metastases to the liver on October 12,2009 (Figure l). His CEA at the time of discovFigure l. MRI of the liver at the time of diagnosis. efy WaS 4,030ng/ml. FOLFOX (s-FU, folinic acid, oxaloplatin) chemotherapy every two weeks was started on October 28, 2OO9. Alternative therapy included fermented wheat germ extract (FWGE ) and high-dose IV Vitamin C (3,0OOmg IV 3 times per week) beginning in the same month and 8glday of fucoidan from Fucus vesiculosis beginning in early December 2009. The patient had minimal side effects from the FOLFOX chemotherapy regimen, reported no GI discomforts, and had no noticeable hair loss during his l2 weeks of FOLFOX. Unfortunately, the patient's tumors did not respond to the chemo regimen, and his CEA reached 7,9oong/ml by fanuary 2010. His oncologist switched his chemo regimen to cetuximab + FOLFIRI (5-FU, folinic acid, irinotecan) while his alternative therapies remained the same.

Wheat germ contains the glycosylated forms of 2-methoxy-p-benzoquinone (2-MBQ) and 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ), both of which have antimicrobial and immunostimulatory effects. Conversion of glycosylated 2-MBQ and 2,6-DMBQ to their more functional unglycosylated forms requires enzymatic action of β-glucosidase. We investigated the applications of lactic acid bacteria and yeast that produce β-glucosidase as starters for production of unglycosylated 2-MBQ and 2,6-DMBQ from wheat germ. Lactobacillus zeae and Pichia pijperi were selected through β-glucosidase enzyme assays for 37 yeast strains and five strains of lactic acid bacteria. Lb. zeae was more efficient than P. pijperi at producing 2-MBQ and 2,6-DMBQ from wheat germ. After 48 hr of fermentation with a mixed culture of Lb. zeae and P. pijperi, the concentration of 2-MBQ was 0.46±0.07 mg/g, indicating an approximately 1.6-fold higher concentration than that obtained by pure culture of Lb. zeae. However, the concentration of 2,6-DMBQ was not significantly enhanced by fermentation with a mixed culture of Lb. zeae and P. pijperi

Nuruk, a traditional Korean fermentation starter, contains 2,6-dimethoxy-ρ-benzoquinoe (2,6- DMBQ), also found in fermented wheat germ extract, and has anti-cancer and immune supporting effects. The presence of 2,6-DMBQ was confirmed by high performance liquid chromatography and mass spectrometry. Among the five traditional nuruks tested, the highest 2,6-DMBQ content of 1.16±0.07 mg/50 g was obtained from nuruk purchased in Hwaseong. The results of this study may explain the health-promoting functions of traditional Korean alcoholic beverages that employ nuruk as a fermentation starter.

Chloropyrifos (CPF) is an organophosphate insecticide is widely used for a variety of agricultural and public health applications. The purpose of this study was to assess the biochemical role of the fermented wheat germ (FWGE ) on the liver and kidney function tests and the oxidative stress induced by chlorpyrifos in rats; moreover the heamatological measurements and histological investigation were studied. Chloropyrifos was added to the different experimental tested diets at two levels of low and high doses (25 and 50 mg/kg diet, respectively). The fermented wheat germ was added at a level of 3g/kg diet. The results demonstrated that there were significant decrease in the total counts of RBC's, WBC's, erythrocyte indices, hemoglobin concentration and hematocrit level in experimental rats fed diets containing low and high levels of CPF. Liver functions is impaired in rats administrated only chlorpyrifos either low or high dose and the results showed a significant increase in enzyme activities such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (γGT), while total proteins, albumin, and globulin showed a significant decrease at high and low doses of CPF treated groups but kidney functions results showed a significant increase in serum creatinine and urea levels. Administration of CPF caused a significant increase in lipid peroxidation level, lipid profile while the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-stransferase (GST) were decreased significantly. So FWGE supplementation caused significant improvement in all results in comparison with those groups administrated CPF.

Fermented wheat germ extract (FWGE) is currently used as nutrition supplement for cancer patients. Limited recent data suggest antiproliferative, antimetastatic and immunological effects which were at least in part exerted by two quinones, 2-methoxy benzoquinone and 2,6-dimethoxybenzquinone as ingredients of FWGE. These activity data prompted us to further evaluate the in vitro antiproliferative activity of FWGE alone or in combination with the commonly used cytotoxic drugs 5-FU, oxaliplatin or irinotecan in a broad spectrum of human tumor cell lines. We used the sulforhodamine B assay to determine dose response relationships and IC50-values were calculated using the Hill equation. Drug interaction of simultaneous and sequential drug exposure was estimated using the model of Drewinko and potential clinical activity was assessed by the model of relative antitumor activity (RAA). Apoptosis was detected by DNA gel electrophoresis. FWGE induced apoptosis and exerted significant antitumor activity in a broad spectrum of 32 human cancer cell lines. The highest activity was found in neuroblastoma cell lines with an average IC50 of 0.042 mg/ml. Furthermore, IC50-range was very narrow ranging from 0.3 mg/ml to 0.54 mg/ml in 8 colon cancer cell lines.

170 broilers have been infected with Salmonella infantis and vaccinated against IBD,(infectious bursal disease) IB, (infectious bronchitis) ND. (Newcastle disease)Feed of 85 broilers has been completed with FWGE (fermented wheat germ extract) Shedding-characteristics of Salmonella infantis and immune reactions after vaccinations were investigated with both broiler groups. Intensity and dynamics of shedding of bacteria by cloacal swabs proved to be equal with both groups and stopped between 18- 19th day after infection, but cecal content remained positive even on 31-33 days after infection. FWGE increased the IBD VN GMT (virusneutralization geometric mean titers) 7 days after vaccination by 26%, but 21 days after immunization there was no difference in the titres. IB ELISA MMT (mathematical mean titers) 28 and 42 days after vaccination have been increased with the FWGE treated group by 820 and 180% compared to the control. ND HI GMT (haemagglutination inhibition geometric mean titers) proved to be 100% higher with the FWGE treated group on the 42nd day of rearing.

Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-a and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE. Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies.

Cancer cells possess unique metabolic signatures compared to normal cells, including shifts in aerobic glycolysis, glutaminolysis, and de novo biosynthesis of macromolecules. Targeting these changes with agents (drugs and dietary components) has been employed as strategies to reduce the complications associated with tumorigenesis. This paper highlights the ability of several food components to suppress tumor-specific metabolic pathways, including increased expression of glucose transporters, oncogenic tyrosine kinase, tumor-specific M2-type pyruvate kinase, and fatty acid synthase, and the detection of such effects using various metabonomic technologies, including liquid chromatography/mass spectrometry (LC/MS) and stable isotope-labeled MS. Stable isotope-mediated tracing technologies offer exciting opportunities for defining specific target(s) for food components. Exposures, especially during the early transition phase from normal to cancer, are critical for the translation of knowledge about food components into effective prevention strategies. Although appropriate dietary exposures needed to alter cellular metabolism remain inconsistent and/or ill-defined, validated metabonomic biomarkers for dietary components hold promise for establishing effective strategies for cancer prevention.

Model experiment was conducted with growing pigs fed diets containing zero or two levels (1 or 2 g/kg) of fermented wheat germ extract (FWGE). In the first part of the experiment (19 days between 49 and 68 days of age) weight gain and feed conversion were tested. The 2nd part of the experiment (21 days between 68 and 89 days of age) served to measure the effect of FWGE on some compartments of the immune system. In the first part of the experiment supplementation of the starters’ diet with FWGE yielded 7.8 and 14.2% additional daily weight gain in the 1st and 2nd experimental groups, respectively (P<0.05). Humoral immune response to purified horse globulin (PHG) antigen was unaffected by the treatment. The blastogenic response of lymphocytes to non specific mitogens (PHA, Con-A, PWM), phagocytic activity and phagocytic index as well as the intradermal PHA test was consistently and significantly enhanced by the treatments.

Wheat has been used as food and folk medicine. We have earlier reported that the administration of ethyl acetate extract of ferrmented wheat at 300 mg/kg body weight have anti-trypanosomal activity. To better understand the active constituent for anti-trypanosomal properties, the crude extract was partially purified using column chromatography to give fractions A, B and C, which were further characterized by gas chromatographic – mass spectral (GC/MS) analysis. The fractions identified 12, 14 and 23 compounds respectively. The major volatile compounds were classified into oxygenated hydrocarbon (manool, hexadecyl acetate and butyl dodecanoate) and n-hydrocarbon (1- eicosene).

Objective: The fermented wheat germ extract, which is the active ingredient of nutraceuticals widely used by cancer patients in Europe, Korea and the United States, possesses cytotoxic and anti-metastatic effects in various human malignancies. In estrogen responsive MCF-7 breast cancer cells, it has been shown to potentiate the induction of apoptosis by tamoxifen. However, its effects in triple-negative and Her2-overexpressing breast cancer cells and interactions with chemotherapy have not been investigated until now. Methods: Cytotoxicity of FWGE lyophilisate alone and in combination with docetaxel was assessed by MTT and clonogenic assays in MCF-7 estrogen responsive, HCC-38 triple-negative and SKBR-3 Her2/neu overexpressing cells. Cell cycle phase distribution was determined by FACS. Apoptosisassociated activaton of caspase-3/7 was measured by Caspase-Glo Assay. Inhibition of tumor cell invasion was quantified using the ORIS Cell Invasion kit. Results: FWGE lyophilisate exhibited highest cytotoxic activity against triple negative HCC-38 cells in MTT and clonogenic assays with IC50 values of 180 and 15 lg/ml, respectively, indicating likely clinical activity.

Over the years, I have read about dozens of alternative treatments that have been promoted for controlling or reversing cancer, including, but by no means limited to, laetrile, macrobiotics, Hoxsey, Gerson, and Krebiozen.While conventional treatments (surgery, chemotherapy, and radiation) are often brutal—and serious questions remain about their long-term effectiveness—a certain skepticism is warranted when it comes to claims of alternative therapies for cancer. In the late 1960s, I was convinced that laetrile had real merit—until a study funded by the drug’s advocates found that vitamin A was more effective. I do believe that some alternative therapies for cancer have been of exceptional value, such as a 1950s-era immune-enhancing therapy known as Krebiozen (and a later variation known as Carcalon), although it faded into history with the death of its chief researcher and clinician, Andrew Ivy, MD, in 1978. Likewise, considerable research now supports the use of high-dose intravenous vitamin C as an adjunct treatment for cancer.1,2 Many alternative therapies have grown out of personal or anecdotal reports—that is, by sharing the knowledge of an unexpected benefit.

We all know someone who has been touched by cancer. This disease is personal, no matter who you are. And unfortunately, it’s only getting worse… President Nixon declared a “War on Cancer” when he signed the National Cancer Act in 1971. Since then, many health authorities have pointed to statistics that supposedly illustrate our progress. Most often, they cite an increasing survival rate. But they’re missing the full picture. Modern technology and aggressive screening programs detect cancer at a much earlier stage. Plus, researchers include nonthreatening cancers in the survival statistics. So if your cousin Harry is still alive five years after he had that mole removed from his hand… he’s counted as a “survivor.” Regardless of how the numbers are presented, cancer continues to increase. Since the 1970s, the incidence rate, the mortality rate, and the number of diagnoses have all gone up. A hundred years ago, one out of every 33 people was diagnosed with cancer in their lifetime. 

Background & objectives: Nutritional compounds which display anti-inflammatory and antioxidant effects have specific applications in preventing oxidative stress and endothelial dysfunction. In this study we evaluated the effect of Lisosan G (powder of Triticum sativum grains) on human microvascular endothelial cells (HMEC-1) exposed to oxidized low density lipoprotein (ox-LDL). Methods: The protective effects of Lisosan G were evaluated on human microvascular endothelial cells exposed to ox-LDL. Intercellular adhesion molecular-1 (ICAM-1), endothelin-1 (ET-1), and interleukin-6 (IL-6) concentrations and the expression of the respective genes were evaluated in response to incubation with ox-LDL, after co-incubation with ox-LDL and Lisosan G or exposed to Lisosan G alone. The analysis of LOX-1 gene was performed with RT-PCR semi quantitative method. The degree of oxidation induced in relation to control, was established by measurement of malondialdehyde (MDA) production. Results: The incubation with ox-LDL induced a significant increase in ICAM-1, IL-6 and ET-1 levels compared to the basal condition (P<0.01, P<0.05, and P<0.01, respectively), while in presence of Lisosan G, ICAM-1 levels showed a significant reduction both compared to the cultures treated with ox-LDL and control (P<0.01). 

Objective: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists. Methods: In this study, we investigated the activity of FWGE , a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. Results: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate G 0.2) representing 27 biologic pathways (P G 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity. Conclusions:

To provide guidelines on antimicrobial prophylaxis for adult neutropenic oncology outpatients and on selection and treatment as outpatients of those with fever and neutropenia. Methods A literature search identified relevant studies published in English. Primary outcomes included: development of fever and/or infections in afebrile neutropenic outpatients and recovery without complications and overall mortality in febrile neutropenic outpatients. Secondary outcomes included: in afebrile neutropenic outpatients, infection-related mortality; in outpatients with fever and neutropenia, defervescence without regimen change, time to defervescence, infectious complications, and recurrent fever; and in both groups, hospital admissions, duration, and adverse effects of antimicrobials. An Expert Panel developed guidelines based on extracted data and informal consensus. Results Forty-seven articles from 43 studies met selection criteria. Recommendations Antibacterial and antifungal prophylaxis are only recommended for patients expected to have
100 neutrophils/
L for 7 days, unless other factors increase risks for complications or mortality to similar levels. Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott’s rules). 

Az FWGE , amely a rákos megbetegedésekben szenvedő betegek részére az FDA által jóváhagyott kiegészítő készítmény, serkenti a sejtszintű immunitást, javítja a hematológiai paramétereket, apoptózist indukál malignus sejtekben, valamint mérsékli az autoimmun reakciókat. Ezen hatások arra utalnak, hogy az FWGE gátló hatást fejthet ki a humán/állati immunszuppresszív vírusokra. Célok: A vizsgálat célja az FWGE által az etiológiai ágensre (macska immundeficiencia vírus, FIV) és annak tranzaktivációs kofaktorára (macska adenovírus, FeADV) kifejtett gátló hatásának in vitro tanulmányozása macska AIDS-modellben. Módszerek: Macska limfoid (MBM) és vese (CrFK) sejtkultúrákat amerikai (FIV-Pet) és európai (FIVPisa/M2) FIV izolátumokkal fertőztünk meg és tenyésztettünk a FIV-et folyamatosan termelő FL-4 limfoid sejtekkel egyetemben. Emellett humán méhnyakrák sejtvonalat (HeLa) és CrFK sejteket fertőztünk meg FeAdV-vel. A fertőzött és a nem fertőzött sejteket FWGE hígítási sorral kezeltük, majd a szer toxikus hatását (fotometriás assay segítségével), valamint a virális citopátiás hatást és a vírusterhelést (p24 antigén ELISA) monitoroztuk.

Fermented wheat germ extract (FWGE) is a multi-substance composition and currently used as nutrition supplement for cancer patients. Nanotechnology holds promise for medication and nutrition because materials at the nanometer dimension exhibit novel properties different from those of both isolated atom and bulk material. Selenium nano particle (Nano-Se) is a novel Se species with novel biological activities and low toxicity. The aim of our study is to evaluate antitumor activity of fermented wheat germ extract and fermented wheat germ extract in combination with selenium nanoparticles (FWGE-nano-Se mixture). The two prepared materials were applied on an experimental carcinogenesis model in order to evaluate their in vitro and in vivo antitumor potential; against animal carcinogenesis "Ehrlich carcinoma". Cytotoicity assay of different concentrations of FWGE and FWGE-nano-Se mixture on EAC cells was evaluated by trypan blue exclusion method. In vivo studies were done by induction of solid tumors produced by intramuscular inoculation of EAC in the right thigh of the lower limb of each mouse and treating Erlich tumor bearing mice orally with FWGE and FWGE-nano-Se mixture for 6 weeks. Tumor volume was determined all over the experimental period. Blood, liver and tumor tissue samples were collected after 2 and 6 weeks from the beginning of treatment.

Chemotherapie in der Onkologie Krebs stellt nach kardiovaskulären Erkrankungen die häufigste Todesursache in den Industrienationen dar. Die Weltgesundheitsorganisation WHO rechnet mit einem massiven Anstieg der Krebsinzidenz in den nächsten Jahrzehnten. Betrug die Zahl neuer Krebsfälle im Jahr 2007 weltweit noch ca. 11 Millionen, so werden für das Jahr 2030 mehr als 15 Millionen Neuerkrankungen prognostiziert (http://www.who.int/features/qa/15/en/index.html). Fortschritte in der onkologischen Forschung haben dazu geführt, dass heute effektive und nebenwirkungsärmere Medikamente für die Krebstherapie zur Verfügung stehen (Deininger et al. 2005; Kawai und Akaza 2010). Das Konzept, Krebserkrankungen chemotherapeutisch zu behandeln, fand ihren Anfang in der ersten Hälfte des 20. Jahrhunderts. Der deutsche Chemiker und Nobelpreisträger Paul Ehrlich führte erstmals chemische Modifizierungen an bekannten Arsenverbindungen durch, um ihre Nebenwirkung („Giftigkeit“) zu mindern, aber ihre Wirksamkeit zu erhalten. Dieses systematische Vorgehen führte 1909 zur Entdeckung von Salvarsan, einem arsenhaltigen Medikament zur Therapie der Syphilis. Ehrlichs Anstrengungen, mit der Strategie der gezielten chemischen Synthese auch Medikamente zur Krebsbehandlung zu entwickeln, blieben dagegen erfolglos.

Many plants exhibit antioxidant properties which may be useful in the prevention of oxidative stress reactions, such as those mediated by the formation of free radical species in different pathological situations. In recent years a number of studies have shown that whole grain products in particular have strong antioxidant activity. Primary cultures of rat hepatocytes were used to investigate whether and how a fermented powder of wheat (Lisosan G) is able to modulate antioxidant and detoxifying enzymes, and whether or not it can activate Nrf2 transcription factor or inhibit NF-kB activation. All of the antioxidant and detoxifying enzymes studied were significantly up-regulated by 0.7 mg/ml Lisosan G treatment. In particular, NAD(P)H:quinone oxidoreductase and heme oxygenase-1 were induced, although to different degrees, at the transcriptional, protein and/or activity levels by the treatment. As for the Nrf2 transcription factor, a partial translocation of its protein from the cytosol to the nucleus after 1 h of Lisosan G treatment was revealed by immunoblotting. Lisosan G was also observed to decrease H2O2-induced toxicity Taken together, these results show that this powder of wheat is an effective inducer of ARE/Nrf2-regulated antioxidant and detoxifying genes and has the potential to inhibit the translocation of NF-kB into the nucleus.

Millions of Americans will be eating out at restaurants or at loved one’s homes this holiday season. But be careful, you may be gobbling down more than just turkey dinner! More on that dinner-time disaster later, but first let’s talk tummy troubles. Sam, a pleasant forty-five year old attorney sought my help for a decade old struggle with irritable bowel syndrome (IBS). His problem was bloating, gas, and an uneasy sensation in his abdomen. These symptoms were a source of stress for him in an already stressful environment—the courtroom. I explained to Sam that IBS is a very common condition. It affects approximately 30 percent of the US adult population. 

There is growing evidence that tumor-associated immune imbalance is an important prognostic factor in several types of malignancy. Results from basic research as well as several case reports on sarcoma patients suggest that immune function may be improved by plant immunomodulators. Such treatments hold promise to partially restore the impaired balance along the regulatory access of the innate immune system that may be critical for clinical outcomes. There is also some evidence that combined therapy with plant preparations such as mistletoe extract injections with fixed Viscum album lectin content (0.5 to 1.0 ng/kg twice a week), rice bran preparation with a fixed dose of arabinoxylan (12 to 45 mg/kg twice a week) and wheat germ extract with a fixed dose of 2.6-dimethoxy-p-benzoquinone (50 to 80 mg/kg four times a week) on top of conventional oncotherapy may result in complete remission of hepatic metastases. These results suggest that the combination of these plant immunomodulators with conventional oncologic treatments can render possible complete remissions which are rarely attainable by oncologic therapies only. Studies using SF-36 questionnaires reported improved quality of life in advanced stages of various malignancies with plant-derived lectin immunomodulator. Combined therapy with plant immunomodulators, which are able to bind pattern recognition receptors on effector cells of innate immune system, may improve outcomes compared to conventional oncotherapy. However, further studies are required to provide additional evidence. 

Abstract Defatted wheat germ peptides (DWGPs) were prepared by fermentation with Bacillus Subtilis B1 and the antioxidant activities of DWGPs were investigated. The fermentation condition was optimized by response surface method (RSM) with three factors and three levels according to Box-Behnken theory. A maximal yield of DWGPs was achieved 8.69 mg/mL under optimal conditions: inoculum size 8%, fermentation temperature 31 °C and time 48 h. The main portion in the hydrolysates after fermentation was not free amino acid but peptide. The main molecular weight distribution of DWGPs was lower than 1000 Da. A positive correlation (R2 =0.9911) was found between concentration of DWGPs and total antioxidant capacity (T-AOC). DWGPs presented a significant does-dependent on scavenging activities of DPPH, hydroxyl and superoxide anion radicals. The EC50 values for the scavenging rates of DPPH, hydroxyl and superoxide anion radicals were 3.16 mg/mL, 6.04 mg/mL and 7.46 mg/mL, respectively. The results suggested that DWGPs produced by fermentation could be used as a promising antioxidant ingredient.

Abstract: Background: Metastatic hepatocellular carcinoma often has a multifocal tumor pattern with markedly depressed hepatic function. Hepatic resection in many cases results in no long-term benefit. After a chemotherapy hepatic tumors rarely disappear completely and the duration of responses is short. In the last decades growing evidence suggested that a disturbed balance in the innate system can also play a role in the poor prognosis of hepatic tumors. Objectives: The aim of this article is to present and discuss several favorable clinical responses of patients with hepatic metastases who parallel to conventional oncologic therapy, were treated with immunologically effective and standardized plant extracts. Course of Therapy and Results: In accordance with the bell-shaped dose-response relationship of mistletoe lectins (MLs), the patients were treated with a fermented mistletoe extract (ME) preparation, standardized for the active sugarbinding lectin contents. Thus, an optimal dose between 0.5 and 1.0ng/kg MLs was given twice a week subcutaneously. In addition to ML therapy, a heteropolysaccharide rice bran preparation standardized for arabinoxylan (12-45mg/kg MGN-3/BiobranR twice a week) and wheat germ extract (WGE) standardized for 2, 6-dimethoxy-p-benzoquinone (50- 80mg/kg FWGE four times a week) was also given. In these case reports the clinical progress of seven patients showed a complete or nearly complete remission of hepatic metastases. 

Abstract Background: In the last decade, several studies described the promising cytotoxic activity of fermented wheat germ towards cancer cell lines and during in vivo clinical trials. Recent data suggested that the antiproliferative, antimetastatic and immunological effects of this preparation are mainly attributed to quinones. This study aimed at exploiting the potential of sourdough lactic acid bacteria fermentation to release 2-methoxy benzoquinone, and 2,6-dimethoxybenzoquinone, which are naturally present in wheat germ as glycosylated and non-physiologically active form. Results: Preliminarily, forty strains of lactic acid bacteria, previously isolated from wheat germ, were in vitro screened based on β-glucosidase activity. Lactobacillus plantarum LB1 and Lactobacillus rossiae LB5 were selected based on the highest enzyme activity and on technology features. These strains were used in combination to ferment wheat germ. Raw wheat germ, without bacterial inoculum, was subjected to the same incubation and used as the control. 

Professor Hidvegi, how did you come up with the idea of working on the wheat germ and the original fermentation process? Drug research has always been fundamental in my family. My Transylvanian­Armenian grandfather, Professor Lajos David was the organizer of the Department of Pharmacy of the University of Szeged in the 1920’s. He was elected as the Dean of the Faculty of Medicine, the first and only pharmacist who has reached this highest position at the University since. My grandfather was a devout Roman catholic, who publicly opposed Nazi persecution of Jews during the Holocaust. One of his colleagues and, perhaps his best friend, was Albert Szent­Gyorgyi, the Nobel laureate who discovered vitamin C. After II. World War Szent­Gyorgyi moved to the United States where he made significant contributions to muscle biochemistry. In his later years he turned to cancer research with the goal to find a cure for cancer.

Colorectal cancer is the leading cause of cancer-related mortality in the western world. It is also the third most common cancer diagnosed in both men and women in the United States with a recent estimate for new cases of colorectal cancer in the year 2012 being around 103,170. Various risk factors for colorectal cancer include life-style, diet, age, personal and family history, and racial and ethnic background. While a few cancers are certainly preventable but this does not hold true for colon cancer as it is often detected in its advanced stage and generally not diagnosed until symptoms become apparent. Despite the fact that several options are available for treating this cancer through surgery, chemotherapy, radiation therapy, immunotherapy, and nutritionalsupplement therapy, but the success rates are not very encouraging when used alone where secondary complications appear in almost all these therapies. To maximize the therapeutic-effects in patients, combinatorial approaches are essential. In this review we have discussed the therapies previously and currently available to patients diagnosed with colorectal-cancer, focus on some recent developments in basic research that has shaded lights on new therapeutic-concepts utilizing macrophages/dendritic cells, natural killer cells, gene delivery, siRNA-, and microRNAtechnology, and specific-targeting of tyrosine kinases that are either mutated or over-expressed in the cancerous cell to treat these cancer. Potential strategies are discussed where these concepts could be applied to the existing therapies under a comprehensive approach to enhance the therapeutic effects. 

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.

Abstract Designer foods are normal foods fortified with health promoting ingredients. These foods are similar in appearance to normal foods and are consumed regularly as a part of diet. In this article we have reviewed the global regulatory status and benefits of available designer foods such as designer egg, designer milk, designer grains, probiotics, designer foods enriched with micro and macronutrients and designer proteins. Designer foods are produced by the process of fortification or nutrification. With the advances in the biotechnology, biofortification of foods using technologies such as recombinant DNA technology and fermentation procedures are gaining advantage in the industry. The ultimate acceptability and extensive use of designer foods depend on proper regulation in the market by the regulatory authorities of the country and by creating consumer awareness about their health benefits through various nationwide programs.

The aim of this experiment was to determine whether wheat germ extract has an increasing cytotoxic activity or any cytotoxic activity on the malignant glioblastoma cancer cells. Thus, this paper includes the comparison of cell viability after the exposition to different concentrations of Wheat Germ Extract (WGE) in medium. My research question was: “How does the cytotoxic activity measured by the percentage of remaining living cells found in Methylthiazol Tetrazolium Assay test (MTT) of glioblastoma multiforme cells differ according to their exposition to different concentrations of wheat germ extract?” My hypothesis was: “As the concentration of applied WGE increases, the cytotoxic activity in glioblastoma cells will also increase. It is expected that the rapidly proliferating cells will be slowed down and largely killed as the WGE concentration increases.” To answer the research question, WGE was produced and given to glioblastoma cells in 6 different concentrations starting from 10% to 35%, increasing 5 by 5 in growth medium. Distilled water was given to the control group at the same concentrations in medium as distilled water was used during the production of WGE and it was important to check whether WGE or distilled water had the cytotoxic effect on cells. The cells were left in a CO2 incubator for 48 hours. After 48 hours, the medium, distilled water, WGE were extracted from the cells and were replaced with MTT. An MTT test was applied and viability was calculated with the results. It was clear that the cytotoxic activity increased as the WGE concentration increased and more than half of the cells went through apoptosis at 35% WGE exposure. Such a conclusion gives hope towards the future of curing of cancer and raises new questions about the usage of WGE.

Abstract: A wide range of health benefits have been attributed to wheatgrass, the young grass of the common wheat plant Triticum aestivum. Its components include chlorophyll, flavonoids, and vitamins C and E. Forms of wheatgrass include fresh juice, frozen juice, tablets, and powders, with compositions varying according to their production processes, as well as to the growing conditions of the wheatgrass. Laboratory in vitro studies, mostly using the fermented wheat germ extract, have demonstrated anticancer potential and have identified apoptosis as a possible mechanism. In animal experiments, wheatgrass demonstrated benefits in cancer prevention and as an adjunct to cancer treatment, as well as benefits to immunological activity and oxidative stress. Clinical trials show that wheatgrass may induce synergistic benefits to chemotherapy and may attenuate chemotherapy-related side effects, as well as benefit rheumatoid arthritis, ulcerative colitis, hematological diseases, diabetes, obesity, and oxidative stress. However, all the trials were small and a number of methodological problems arose. No adverse events of wheatgrass have been reported, although some forms pose problems of tolerability. The popularity of wheatgrass continues to grow. Nevertheless, the advantages seen in the clinical trials need to be proved in larger studies before clinical recommendations for the public can be given.

2,6-Dimethoxy-1,4-benzoquinone (2,6-DMBQ) is the major bioactive compound found in fermented wheat germ extract. Although fermented wheat germ extract has been reported to show antiproliferative and anti-metabolic effects in various cancers, the anticancer potential and molecular mechanisms exerted by 2,6-DMBQ have not been investigated in non-small cell lung cancer (NSCLC) cells. Here, we report that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibiting activation of AKT and p38 MAPK. 2,6-DMBQ significantly suppressed anchorage-dependent and independent cell growth. Additionally, 2,6-DMBQ induced G2 phase cell cycle arrest through inhibiting the expression and phosphorylation of cyclin B1 and CDC2, respectively. Furthermore, 2,6-DMBQ strongly suppressed NSCLC cell migration through induction of E-cadherin expression. To determine the molecular mechanism(s) exerted by 2,6-DMBQ upon NSCLC cell lines, various signaling kinases were screened; the results indicate that 2,6-DMBQ strongly inhibits the phosphorylation of AKT and p38 MAPK. Additionally, the growth kinetics of cells treated with an AKT or p38 MAPK inhibitor in combination with 2,6-DMBQ indicate that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibition of AKT and p38 MAPK. Taken together, our results suggest that 2,6-DMBQ is a potential anticancer reagent against NSCLC cells and could be useful for treating lung cancer patients. © 2021 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society

Abstract

Background:  Fermented wheat germ extract has been reported to exert various pharmacological activities,

including anti-oxidant, anti-cell growth and cell apoptosis in various cancer cells. Although 2,6-dimethoxy-1,4-

benzoquinone (2,6-DMBQ) is a benzoquinone compound and found in fermented wheat germ extract, its

anticancer effects and molecular mechanism(s) against gastric cancer have not been investigated.

Methods: Anticancer effects of 2,6-DMBQ were determined by MTT, soft agar, cell cycle and Annexin V analysis.

Potential candidate proteins were screened via in vitro kinase assay and Western blotting. mTOR knockdown cell

lines were established by lentiviral infection with shmTOR. The effect of 2,6-DMBQ on tumor growth was assessed

using gastric cancer patient-derived xenograft models.

Results: 2,6-DMBQ significantly reduced cell growth and induced G1 phase cell cycle arrest and apoptosis in gastric

cancer cells. 2,6-DMBQ reduced the activity of mTOR in vitro. The inhibition of cell growth by 2,6-DMBQ is

dependent upon the expression of the mTOR protein. Remarkably, 2,6-DMBQ strongly reduced patient-derived

xenograft gastric tumor growth in an in vivo mouse model.

Conclusions: 2,6-DMBQ is an mTOR inhibitor that can be useful for treating gastric cancer. It has therapeutic

implications for gastric cancer patients.

Keywords:  2,6-DMBQ, mTOR, p70S6K, Gastric cancer, Patient-derived xenograft

Objective: The fermented wheat germ extract (FWGE) nutraceutical (FWGE™), manufactured under “good manufacturing practice” conditions and, fulfilling the self-affirmed “generally recognized as safe” status in the United States, has been approved as a “dietary food for special medical purposes for cancer patients” in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients. Methods: In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE. Results: At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p 0.0298. Conclusions: The inclusion of FWGE into the adjuvant protocols of high-risk skin melanoma patients is highly recommended.

Background and aim Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name FWGE) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of FWGE in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with FWGE in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving FWGE (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in FWGE has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer. 

The Hungarian Association of Oral and Maxillofacial Surgeons (Magyar Arc-, Állcsont- és Szájsebészeti Társaság) has reviewed the research results related to FWGE and issued its opinion as follows: For patients suffering from head- and neck tumors - primarily malignant tumorous diseases of the oral cavity, the progression of the disease can be slowed significantly, the five-year survival rate increased considerably, the quality of life improved, and the oxidative stress on the patients reduced by the long-term application of the supplementary formula FWGE . The Association considers the supportive treatment with the formula FWGE as an important part of the complex therapeutic protocols applied in stages II, III and IV of malignant tumorous diseases of the oral cavity. 

Objective. To investigate the effect of the fermented wheat germ extract (FWGE ®) in patients with severe rheumatoid arthritis (RA). Methods. Fifteen female RA (Steinbrocker II-III) patients, who had unsuccesfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received FWGE ® as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used. Results. At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of FWGE ® were observed. Conclusion. Supplementation of standard therapies with a continuous administration of FWGE ® is beneficial for RA patients.

The hypothesis that oxidative stress favours flogistic and immune processes inducing autoimmune rheumatic diseases (ARDs) and their complications is still under discussion. In this review we take into consideration both the aetiopathological role of the diet in such diseases and the possible efficacy of dietary supports as adjuvants for the usual specific therapies. Moreover, we shall examine the hypothetical pathophysiological role of oxidative stress on ARDs and their complications, the methods for its evaluation and the possibility of intervening on oxidative pathways by means of nutritional modulation. It is possible that in the future we will be able to control connective pathology by associating an immuno-modulating therapy (‘re-educating’) with naturalproducts having an anti-oxidant activity to current immunosuppressive treatment (which has potentially toxic effects).
2003 Elsevier B.V. All rights reserved.

Purpose: An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (FWGE ) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. Methods: Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. Results: During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). Conclusions: The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.

MSC (FWGE) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients’ choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox’s proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival. 

FWGE pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 µg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. FWGE pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered FWGE pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using FWGE pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that FWGE pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.

ACCREDITATION InnoVision Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT InnoVision Communications designates this educational activity for a maximum of 1.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. STATEMENT OF PURPOSE Natural products are being used as supplements by cancer patients, with or without the knowledge of their cancer treatment team. It is important to know which of these products show efficacy against diseases such as cancer, and which are ineffective. It is also essential to define the mechanism(s) of action of natural products, especially as relevant to cancer prevention or treatment. The purpose of this article is to review the use of one such natural product, a fermented wheat germ extract (FWGE ), in the treatment regimen of cancer patients. FWGE has shown efficacy in both animal cancer models and human clinical trials with cancer patients, but more well-controlled trials in humans are necessary to assess the full potential of FWGE in cancer treatment. FWGE exerts its anticancer effect via an array of mechanisms, likely because there are many undefined components in this product that modulate numerous biological systems in cancer patients. 

In this study, the protective effect of a fermented wheat germ extract (FWGE) against LPS-induced inflammation and oxidative stress in IPEC-J2 porcine intestinal epithelial cells was studied. Enterocytes were treated with LPS derived from Salmonella enterica ser. Typhimurium and Escherichia coli O55:B5, O111:B4, and O127:B8 strains. Intracellular ROS level and extracellular H2O2 level were followed up by two fluorescent assays (DCFH-DA and Amplex Red). The effect of FWGE on the intestinal barrier integrity was determined by transepithelial electric resistance measurements and using a FD4 fluorescent tracer dye. IL-6 concentration of supernatants was also measured by the ELISA method. Our data revealed that FWGE had a significant lowering effect on the inflammatory response especially related to oxidative stress. Treatment with FWGE (1-2%) significantly decreased the level of intracellular ROS compared to LPS-treated cells. Furthermore, LPS-triggered partial disruption of epithelial integrity was reduced after FWGE application.

Abstract--The acute and subacute toxicity of five biogenic amines--tyramine, spermidine, spermine, putrescine and cadaverine--were examined in Wistar rats. Tyramine and cadaverine had a low acute oral toxicity of more than 2000 mg/kg body weight. Putrescine had an acute oral toxicity of 2000 mg/kg body weight and spermidine and spermine each of 600 mg/kg body weight. All amines investigated caused a dose-related decrease in blood pressure after intravenous administration, except for tyramine, where an increase was h~und. In 6-wk studies the biogenic amines were administered in the diet to groups of 10 male and 10 female rats. Tyramine and cadaverine were given at levels of 0, 200, 2000 or 10,000 ppm, spermine and putrescine at levels of 0, 200, 2000 or 5000 ppm and spermidine at levels of 0, 20, 200 or 500/1000 ppm in the first study and at levels of 0 or 10,000 ppm in a second study. Spermine was the most toxic. The high dose level showed a great number of changes, such as emaciation, aggressiveness, convulsions and paralysis of the hind legs. Growth, food intake and water intake were considerably decreased. Slight anaemia (males) and changes in plasma clinical chemistry occurred. The relative weights of the thyroid, adrenals, spleen and heart were increased and that of the liver decreased. Impaired kidney function, together with renal histopathological changes and changes in plasma electrolytes and urea, occurred with ,;permine. Histopathological examinations also revealed decreased glycogen content in the liver, reduction of spermatogenesis, severe depletion of splenic white pulp, acute involution of the thymus and moderate myocardial degeneration in the heart. 

Supplementation of spermidine, an autophagy‐inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28‐days repeated‐dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3‐month randomized, placebo‐ controlled, double‐blind Phase II trial was conducted with supplementation of the spermidine‐rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo‐treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self‐reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine‐rich plant extract is safe and well‐tolerated in mice and older adults. These findings allow for longer‐term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

FWGE pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 µg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. FWGE pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered FWGE pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using FWGE pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that FWGE pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.

abstract

 2,6-Dimethoxy-1,4-benzoquinone (2,6-DMBQ) is the major bioactive compound found in fermented

wheat germ extract. Although fermented wheat germ extract has been reported to show antiproliferative and anti-metabolic effects in various cancers, the anticancer potential and molecular

mechanisms exerted by 2,6-DMBQ have not been investigated in non-small cell lung cancer (NSCLC)

cells. Here, we report that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibiting

activation of AKT and p38 MAPK. 2,6-DMBQ significantly suppressed anchorage-dependent and independent cell growth. Additionally, 2,6-DMBQ induced G2 phase cell cycle arrest through inhibiting the

expression and phosphorylation of cyclin B1 and CDC2, respectively. Furthermore, 2,6-DMBQ strongly

suppressed NSCLC cell migration through induction of E-cadherin expression. To determine the molecular mechanism(s) exerted by 2,6-DMBQ upon NSCLC cell lines, various signaling kinases were

screened; the results indicate that 2,6-DMBQ strongly inhibits the phosphorylation of AKT and p38

MAPK. Additionally, the growth kinetics of cells treated with an AKT or p38 MAPK inhibitor in combination with 2,6-DMBQ indicate that 2,6-DMBQ suppresses NSCLC cell growth and migration through

inhibition of AKT and p38 MAPK. Taken together, our results suggest that 2,6-DMBQ is a potential

anticancer reagent against NSCLC cells and could be useful for treating lung cancer patients.

ÖSSZEFOGLALÁS

Az AIDS kórfejlődésének vizsgálatára alkalmas modellállat a macska. Az ember

és a macska immundeficienciáját okozó vírusok (HIV és FIV) hasonlóak, egyéb

vírusaik, mint a macska-adenovírus, elősegítik a betegség progresszióját, együttes kezelésük nehéz. A szerzők vizsgálataiban a fermentált búzacsíra-alapú Avemar granulátum daganatellenes készítmény gátolta az akut és krónikus fertőzési modellekben a FIV szaporodását, apoptosis révén pusztította a FIV-termelő

sejteket. Az Avemar a macska-adenovírus replikációját normál sejtekben igen,

daganatos sejtekben minimálisan gátolta. A daganatos sejtekben és a vírusszaporodásban egyaránt szerepet játszó ribonukleotid reduktáz gátlása lehet a

közös pont a gátlási folyamatokban.

Abstract

Background:  Fermented wheat germ extract has been reported to exert various pharmacological activities,

including anti-oxidant, anti-cell growth and cell apoptosis in various cancer cells. Although 2,6-dimethoxy-1,4-

benzoquinone (2,6-DMBQ) is a benzoquinone compound and found in fermented wheat germ extract, its

anticancer effects and molecular mechanism(s) against gastric cancer have not been investigated.

Methods: Anticancer effects of 2,6-DMBQ were determined by MTT, soft agar, cell cycle and Annexin V analysis.

Potential candidate proteins were screened via in vitro kinase assay and Western blotting. mTOR knockdown cell

lines were established by lentiviral infection with shmTOR. The effect of 2,6-DMBQ on tumor growth was assessed

using gastric cancer patient-derived xenograft models.

Results: 2,6-DMBQ significantly reduced cell growth and induced G1 phase cell cycle arrest and apoptosis in gastric

cancer cells. 2,6-DMBQ reduced the activity of mTOR in vitro. The inhibition of cell growth by 2,6-DMBQ is

dependent upon the expression of the mTOR protein. Remarkably, 2,6-DMBQ strongly reduced patient-derived

xenograft gastric tumor growth in an in vivo mouse model.

Conclusions: 2,6-DMBQ is an mTOR inhibitor that can be useful for treating gastric cancer. It has therapeutic

implications for gastric cancer patients.

Keywords:  2,6-DMBQ, mTOR, p70S6K, Gastric cancer, Patient-derived xenograft

Bioactive compounds such as benzoquinone derivates presented in fermented wheat germ extract (FWGE) have several positive

effects on overall health status of humans and animals alike. Since available data regarding the antioxidant activity of FWGE are

limited, the aim of our study was to investigate its effects on the cellular redox homeostasis applying primary hepatocyte cell

cultures of rat origin. Cultures were challenged to lipopolysaccharide (LPS) treatment for 2 or 8 hours to trigger inflammatory

response. Further, culture media were concomitantly supplemented with or without FWGE (Immunovet®, 0.1% and 1%). In

order to monitor the metabolic activity of the cell cultures, CCK-8 test was applied, while reactive oxygen species (ROS)

production was measured using Amplex Red method. Malondialdehyde concentration of culture media as a specific marker of

lipid peroxidation and the activity of glutathione peroxidase in cell lysates were also determined to monitor the redox status of

the cultures. Based on our findings, it can be concluded that FWGE did not show cytotoxic effects in any applied concentration

in cell cultures. Furthermore, FWGE efficiently decreased cellular ROS production and lipid peroxidation rate in case of LPSinduced inflammatory response. However, without LPS treatment, higher concentration of FWGE increased the rate of both

ROS and malondialdehyde synthesis. This observation may refer to the prooxidant activity of high dose FWGE, which is an

important beneficial effect regarding tumor cells. 

Summary

Preliminary studies which may be of signicance for research against

coronaviruses, including SARS-CoV-2, which has caused an epidemic

in China, are presented. An analysis was made of publicly available

data that contain information about important metabolites neutralizing

coronaviruses. Preliminary studies show that especially Ficus, barley,

thistle and sundew should be additionally tested with the aim of producing

medicines for coronavirus.

Key words: coronavirus, meta-analysis, avonoids, rhoifolin, pectolinarin,

herbacetin, ANOVA, Tukey's HSD test, barley, Ficus, thistle, sundew,

wheat, soybean, Brachypodium distachyon

The effect of fermented wheat germ extract (FWGE) (Immunovet®) was evaluated with cotreatments with deoxynivalenol (DON)

and T-2 toxin (T-2). These mycotoxins are produced by Fusarium mold species. The effects of FWGE on IPEC-J2 with DON and T2 have not been studied until now. The IPEC-J2 porcine, nontumorigenic cell line was selected to investigate the outcome of the

individually and simultaneously added compounds, as it has in vivo-like properties. The cells were treated for 24 h with the

selected solutions; then, the IPEC-J2 cells were allowed to regenerate in a culture medium for an additional 24 h. In our results,

DON and T-2 significantly increased the adverse impacts on cell viability and integrity of the cell monolayer. To elucidate the

extent of oxidative stress, extracellular H2O2 concentrations and intracellular reactive oxygen species (ROS) were measured.

FWGE appeared to be beneficial to IPEC-J2 cells given the separately and significantly decreased ROS levels. 1% and 2% FWGE

could significantly reduce mycotoxin-induced oxidative stress. In conclusion, the results demonstrate that FWGE exerted

protective effects to counteract the oxidative stress-provoking properties of applied fusariotoxins in the nontumorigenic IPEC-J2

cell line.

Abstract

Introduction:  Glioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential

for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been

done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel

KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This

pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with “classic”

4:1 KD.

Method:  GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate]

ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated

adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and

blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention,

treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were

survival time from treatment initiation and time to MRI progression

Abstract

The global cancer burden has increased, and about 9.6 million cancer-related deaths were recorded in 2018. Genetic makeup,

unhealthy lifestyle, urbanization, obesity, and dietary preferences are key risk factors associated with cancer incidence and

development. Next to lung cancer, colorectal cancer is the most perilous cancer type in terms of mortality rate. Diet plays a

major role in colorectal cancer risk. The consumption of vegetables, unprocessed cereals, fish product, and fermented foods are

associated with lower cancer risk, while raw and processed red meats and refined foods are associated with increased cancer

risk. The anti-cancer properties of fermented foods and their possible mechanisms are summarized in this review. Some studies

indicated that the consumption of fermented foods reduced the risk of cancer and improved the health status of cancer patients.

However, some other research findings suggested that the intake of fermented foods was not associated with reduced cancer

risk. Several signaling pathways (p38 MAPK, ERK1/2, energy deprivation, and death-receptor mediated pathways) are involved

in the anti-proliferative and growth suppressive properties of fermented foods. Overall, the literature survey suggested that the

consumption of fermented foods might reduce cancer risk and improve health status in association with other factors, such as

genetics and healthy lifestyle.

Keywords:  fermented foods; anticancer; apoptosis; inflammation; diet.

Practical Application: The manuscript summarizes the anti-cancer properties and possible mechanism of fermented foods,

which highlights the benefits of fermented foods.

Abstract  

This systematic review and meta-analysis aim to

evaluate the association of wheat germ interventions and

metabolic markers. An electronic search was performed by

mid-May 2019 in the PubMed, Google Scholar, and Web

of Science databases. Quality was evaluated using the risk

of bias assessment tools. Thirty-three randomized controlled trials (RCTs) were identified, among which ten were

suitable and systematically reviewed based on biomarkers

(cholesterol, triglycerides, glucose, and oxidative stress).

Three biomarkers in five eligible studies were investigated

by meta-analysis. Total cholesterol showed non-significant

results (p = 0.98), with standard mean difference (SMD) of

- 0.01 (95% confidence interval; - 0.17, 0.16). The SMD

was - 0.06 (95% CI - 0.41, 0.29, n = 4) for triglycerides

and - 0.09 (95% CI - 0.62, 0.45, n = 2) for glucose. No

biomarkers showed heterogeneity (0%). This review

revealed non-significant association between wheat germ

interventions and metabolic markers. Sensitive analysis

with high-quality RCTs may be worth trying.

Keywords 

Wheat germ  Metabolic markers

Cholesterol  Triglycerides  Glucose

ABSTRACT

2,6-Dimethoxy-1,4-benzoquinone is a natural phytochemical

present in fermented wheat germ. It has been reported to exhibit anti-inflammatory, antitumor, and antibacterial activities. However, the anti-adipogenic effects of 2,6-dimethoxy1,4-benzoquinone and the mechanisms responsible have not

previously been elucidated. Such findings may have ramifications for the treatment of obesity. 2,6-Dimethoxy-1,4-benzoquinone (5 and 7.5 µM) significantly reduced the expression of

various adipogenic transcription factors, including peroxisome

proliferator-activated receptor-γ and CCAAT/enhancer binding protein α as well as adipocyte protein 2 and fatty acid synthase. 2,6-Dimethoxy-1,4-benzoquinone upregulated AMPdependent protein kinase phosphorylation and inhibited the

mature form of sterol regulatory element-binding protein 1c.

Notably, 2,6-dimethoxy-1,4-benzoquinone attenuated mammalian target of rapamycin complex 1 activity in 3T3-L1 and

mouse embryonic fibroblast cells. These findings highlight a

potential role for 2,6-dimethoxy-1,4-benzoquinone in the

suppression of adipogenesis. Further studies to determine the

anti-obesity effects of 2,6-dimethoxy-1,4-benzoquinone in

animal models appear warranted.

ABSTRACT

Goldnanoparticles (AuNPs) have well applied in imaging and carriers of drugs and/or biomolecules for diseases

and cancers therapeutics, due to their tunable physicochemical properties, easy functionalized with biomolecules and biocompatibility. AuNPs conjugated with biopolymer such as collagen has been demonstrated that

increased the cell proliferation, migration and cell differentiation. Avemar (Ave) is a nutraceutical from natural

components and dietary supplement for healthcare of tumor related anorexia/cachexia. Moreover, Ave has revealed the excellent bio-efficacy of anti-proliferation, cell cycle disturbing and apoptosis induction in numerous

types of tumor cells in in vivo and in vitro. However, the effects of Ave on cellular uptake mechanisms still

unclear. In this study, we fabricate the Ave-deposited AuNP-collagen nanocarrier (AuNP-Col-Ave) and investigate their endocytic mechanisms in transformed SCC oral cancer cells and non-transformed BAEC and HSF

cell lines. By using DLS assay, Ave-deposited AuNP-Col have shown a particle size of 303 ± 35.2 nm. Both

UV–vis absorption assay and FTIR spectrum analysis were also demonstrated that the Ave conjugated onto

AuNP-Col. Further, both MTT assay and Calcein AM assay were revealed that AuNP-Col-Ave induced a significant cytotoxicity in cancerous SCC cells and showed nontoxicity and biocompatibility for non-transformed

BAEC and HFS cells. In addition, AuNP-Col-Ave has showed an excellent uptake capacity in all these cell lines as

compared to AuNP-Col group. 

Cereals are one of the major food sources in human diet and a large quantity of by-products is generated throughout their processing chain. These by-products mostly consist of the germ and outer layers (bran), deriving from dry and wet milling of grains, brewers' spent grain originating from brewing industry, or others originating during bread-making and starch production. Cereal industry by-products are rich in nutrients, but still they end up as feed, fuel, substrates for biorefinery, or waste. The above uses, however, only provide a partial recycle. Although cereal processing industry side streams can potentially provide essential compounds for the diet, their use in food production is limited by their challenging technological properties. For this reason, the development of innovative biotechnologies is essential to upgrade these by-products, potentially leading to the design of novel and commercially competitive functional foods. Fermentation has been proven as a very feasible option to enhance the technological, sensory, and especially nutritional and functional features of the cereal industry by-products. Through the increase of minerals, phenolics and vitamins bioavailability, proteins digestibility, and the degradation of antinutritional compounds as phytic acid, fermentation can lead to improved nutritional quality of the matrix. In some cases, more compelling benefits have been discovered, such as the synthesis of bioactive compounds acting as antimicrobial, antitumoral, antioxidant agents. When used for baked-goods manufacturing, fermented cereal by-products have enhanced their nutritional profile.

Abstract:  Wheat germ is rich in quinones that exist as glycosides. In this study, we used Celluclast

1.5L to release the hydroxyquinones, which turn into benzoquinone, and prepared the water extract

from enzyme-treated wheat germ (EWG). We investigated whether enzyme treatment altered

the anti-inflammatory activity compared to the water extract of untreated wheat germ (UWG).

UWG inhibited the production of inducible nitric oxide synthase (iNOS) and interleukin (IL)-12 and

induced the production of IL-10 and heme oxygenase (HO)-1 in lipopolysaccharide (LPS)-stimulated

macrophages. Enzyme treatment resulted in greater inhibition of iNOS and IL-10 and induction of

HO-1 compared to UWG, possibly involving the modulation of nuclear factor (NF)-κB, activator protein

1 (AP-1) and nuclear factor erythroid 2-related factor (Nrf2). Mice fed UWG or EWG had decreased

serum tumor necrosis factor (TNF)-α and increased serum IL-10 levels after intraperitoneal injection

of LPS, with UWG being more effective for IL-10 and EWG more effective for TNF-α. Hepatic HO-1

gene was only expressed in mice fed EWG. We provide evidence that enzyme treatment is a useful

biotechnology tool for extracting active compounds from wheat germ.

Keywords: wheat germ; enzyme; benzoquinone; inflammation; macrophages

Abstract

The diagnosis of cancer in a child leaves parents and families devastated and vulnerable. In an effort to do

everything possible, families often choose an integrative medicine approach to their child’s care. Surveys have

found that 31%–84% of children with cancer use complementary and alternative medicine and most often as

supportive care agents. Several systematic reviews have demonstrated a clinical benefit for some select therapies;

however, the safety and efficacy of the combination of biological therapies with conventional treatment remain

largely unknown and garner concern due to the potential for interactions with conventional therapy. Given the

sustained use and potential benefit of integrative medicine, additional research is warranted in pediatric oncology.

Utilizing the available literature, clinical providers should aim to conduct open and nonjudgmental discussions

with families about the use of integrative medicine so as to guide the safe integration of the two modalities.

Keywords:  integrative medicine, nutrition, complementary/alternative medicine, pediatrics, cancer

Abstract.  Avemar, a derivative of fermented wheat germ

extract, is a non-toxic and natural compound that is used as

a dietary supplement by cancer patients undergoing chemotherapy and radiotherapy. Avemar has numerous biological

activities, and several recent studies have reported that it

may also have metastatic and anti-angiogenic effects. In the

present study, the mechanism of the anti-angiogenic effect of

Avemar on human cancer cells was investigated. The human

cell lines NCI-N87 (gastric tubular adenocarcinoma), PC3

(prostate carcinoma), HeLa (endocervical adenocarcinoma)

and A549 (lung adenocarcinoma) were treated with various

doses (400, 800, 1,600 and 3,200 µg/ml) of Avemar, and the

changes in mRNA and protein levels of two important markers

of angiogenesis, vascular endothelial growth factor (VEGF)

and cyclooxygenase-2 (Cox-2), were assessed by reverse transcription-quantitative polymerase chain reaction and ELISA.

VEGF and Cox‑2 protein and mRNA levels were significantly

lower in Avemar-treated cells than in untreated cells. The

data suggest that Avemar may exert an anti-angiogenic effect

on cancer cells. Thus, it is suggested to medical doctors as a

potential agent for the anti-angiogenic treatment of cancer.

Abstract  – Recent scientific researches proved a strong link between the diet adapted and the prevalence

of some diseases (cardiovascular diseases, diabetes, obesity…). The use of functional products may

contribute in solving this problem. Wheat is a cereal quite present in Mediterranean diet as it has an

energetic and nutritional interest (proteins, carbohydrate, fibers, vitamins…). Consumers in occidental

countries become more and more interested by mini-processed, without chemicals, natural, safe food

products. Sprouts are in agreement with this trend. Sprouting is a physiological event where a complex

nutrients transfer occurs. The aim of this review was to describe sprouting process and its impact on

nutritional properties of wheat seeds. During germination, storage molecules (proteins, starch) are

degraded under enzymatic action. Added to, some bioactive compounds such as polyphenols,

vitamins… are newly synthesized. Altogether, contribute in improving wheat nutritional quality.

Sprouting affects also functional and sensory properties of wheat. All modifications occurring during

sprouting make sprouted wheat seeds a functional ingredient, naturally enhanced by bioactive

molecules. Its use in food industry would provide an added value. 

Keywords: Wheat, Sprouting, Functional ingredient, Bioactive compounds, Wheat Technology

Abstract

Non-Hodgkin lymphoma (NHL) affects over 400,000 people in the United States; its incidence increases with age. Treatment options are numerous and expanding, yet efficacy is

often limited by toxicity, particularly in the elderly. Nearly 70% patients eventually die of the

disease. Many patients explore less toxic alternative therapeutics proposed to boost antitumor immunity, despite a paucity of rigorous scientific data. Here we evaluate the lymphomacidal and immunomodulatory activities of a protein fraction isolated from fermented

wheat germ. Fermented wheat germ extract was produced by fermenting wheat germ with

Saccharomyces cerevisiae. A protein fraction was tested for lymphomacidal activity in vitro

using NHL cell lines and in vivo using mouse xenografts. Mechanisms of action were

explored in vitro by evaluating apoptosis and cell cycle and in vivo by immunophenotyping

and measurement of NK cell activity. Potent lymphomacidal activity was observed in a panel

of NHL cell lines and mice bearing NHL xenografts. This activity was not dependent on

wheat germ agglutinin or benzoquinones. Fermented wheat germ proteins induced apoptosis in NHL cells, and augmented immune effector mechanisms, as measured by NK cell killing activity, degranulation and production of IFNγ. Fermented wheat germ extract can be

easily produced and is efficacious in a human lymphoma xenograft model. The protein fraction is quantifiable and more potent, shows direct pro-apoptotic properties, and enhances

immune-mediated tumor eradication. The results presented herein support the novel concept that proteins in fermented wheat germ have direct pro-apoptotic activity on lymphoma

cells and augment host immune effector mechanisms.

Abstract:  Fermented wheat germ extract (FWGE; trade name AVEMAR) is a natural compound

derived from industrial fermentation of wheat germ. Its potential anticancer properties has emerged

from recent studies. The aim of this systematic review is to summarize the data available in the

scientific literature concerning the in vitro activity of FWGE on malignant cells. A systematic review

of English articles in electronic databases has been performed. The primary outcomes of the review

regarded types of cancer cell lines subjected to the investigation and the main results concerning cell

viability, proliferation, and apoptosis observed within the studies. Sixteen articles were included in

the final qualitative analysis. Various types of cancer cells treated with FWGE have been analyzed,

showing mainly cytotoxic effects, alteration of the cell cycle, antiproliferative effects, and induction of

apoptosis. FWGE can be a promising drug component in cancer treatment; however, further in vitro

and in vivo studies are necessary to prove its effectiveness and safety in humans.

Keywords: FWGE; AVEMAR; fermented wheat germ extract; nutraceuticals; cancer treatment

Abstract

Wheat grains and its fractions contain significant level of antioxidant activity and many

phytochemicals, such as phenolic acids (ferulic and vanillic acids), carotenoids, and

tocopherol are beneficial in curing many disorders. The beneficial phytochemicals

are mostly present in aleurone fraction of wheat bran. The phytochemicals and antioxidants present in wheat have several health benefits, such as their ability to act as

antioxidants, immunoenhancers, and inhibitors of certain lesions, which have been

demonstrated for phenolic. Many wheat antioxidants are similar to the antioxidants

present in wheat, but their characteristics are also unique in nature. The regular consumption of these antioxidant compounds in whole grains is associated with a reduced

risk of many heart diseases and several forms of cancers and improves the regulation of

blood glucose. Wheat antioxidants play a vital role in bakery industry mostly in bread

industry. People are getting aware to use the bakery products that are prepared from

the white flour due to proper nutrition, healthy lifestyle, improved nutritional composition, and functional properties. In nutshell, wheat antioxidants including phytochemicals synergistically improve the health status of consumers by consuming the products

having complete nutrition.

Keywords:  wheat antioxidants, phytochemicals, bakery products, health perspectives