Alzheimer's Disease and Parkinson's Disease: A Nutritional Toxicology Perspective of the Impact of Oxidative Stress, Mitochondrial Dysfunction, Nutrigenomics and Environmental Chemicals.

Introduction: Alzheimer's disease is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while Parkinson's disease is primarily a movement disorder illness having movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. While aging is the main risk factor, epidemiological evidence suggests that the exposure to environmental toxicants, mainly pesticides, metals and solvents could increase the risk of developing neurodegenerative conditions.Oxidative stress in neurodegenerative diseases: Mitochondria function impacts cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis. In neurodegenerative diseases, mitochondrial dysfunction is associated with a compromised energy production, impaired calcium buffering, activation of proteases and phospholipases, and increased oxidative stress. Oxidative stress induced microglial cells activation, protein aggregation, neuroinflammation and mitochondrial dysfunction lead to neuronal deaths in these disorders.Role of nutrition: Neurodegenerative disease is not curable, but treatment is available to manage the symptoms and slow down the disease progression. The drugs for treating these diseases only reduce the cognitive impairment and behavioral problems, but do not stop the progression of neurodegeneration. Healthy diet, lifestyle improvement and nutraceuticals targeting of oxidative stress, inflammation, abnormal mitochondrial dynamics and the mitochondrial interaction with abnormal disease-related proteins and assessment of impact of environmental contaminants including occupational exposures to pesticides, can be a promising approach in the treatment of neurodegenerative diseases.Conclusion: These innovations can be benchmarked on firm understanding of nutrigenomics and the personalized management of individuals at risk.

A Randomized Double-Blind, Placebo Controlled, Four-Arm Parallel Study Investigating the Effect of a Broad-Spectrum Wellness Beverage on Mood State in Healthy, Moderately Stressed Adults.

OBJECTIVE: The objective of this study was to investigate the effect of a broad-spectrum wellness beverage (Zeal Wellness [ZW]) on standardized measures of mood states, including overall feelings of vitality, in healthy, moderately stressed adults. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted among 99 eligible participants prescreened for moderate stress. Participants were randomized to one of four groups and received ZW once daily (1-dose-ZW; 14 g), ZW twice daily (2-dose-ZW; 28 g), placebo once daily (1-dose-placebo), or placebo twice daily (2-dose-placebo) for 4 weeks. A stress/vitality questionnaire assessed stress and the Profile of Moods (POMS) Questionnaire assessed vigor via mental/physical energy and global mood state. Safety was assessed by clinical chemistry, liver, kidney function, and anthropometric measures and adverse event reporting. RESULTS: Participants receiving 2-dose-ZW reported a 6.6% decrease in scores on POMS-Total Mood Disturbance (TMD; p < 0.05) and a 6.8% decrease in the anger-hostility mood state (p < 0.022) compared to the combined placebo group at day 29. The 2-dose-ZW provided a 12.8% greater improvement in POMS-TMD scores when compared to participants receiving 1-dose-ZW after 28 days of supplementation (p = 0.014). Within groups, there was a 22.4% and a 9.6% decrease in POMS-TMD scores in participants with 2-dose-ZW and 1-dose-ZW, respectively. In addition, participants receiving 2-dose-ZW showed significant improvements (p = 0.001) in the POMS t-score iceberg profile, which represented a shift to a more healthy profile. CONCLUSION: These data show that daily supplementation with 2-dose-ZW significantly decreased POMS-TMD scores and anger-hostility mood state and shifted the POMS iceberg profile to a healthy profile compared to the combined placebo, reflecting the functional benefit of rice-bran-fruit-vegetable extracts based beverage on health.

Fermented papaya preparation modulates the progression of N-methyl-N-nitrosourea induced hepatocellular carcinoma in Balb/c mice.

AIM AND MAIN METHOD: The medicinal properties of fermented papaya preparation (FPP) derived from Carica papaya fruit was investigated in order to determine its ability to modulate the progression of N-methyl-N-nitrosourea induced hepatocellular carcinoma in Balb/c mice. KEY FINDINGS: As well as reducing the physical symptoms associated with N-methyl-N-nitrosourea (MNU)-induced hepatocellular carcinoma, supplementation of Balb/c mice with 500mg FPP/kg BW for 92days normalized the blood cell count, led to an increased activity of several key antioxidant enzymes (SOD: +20%, CAT: +81%, GPx: +66.1%, GR: +54.4%; P<0.001 vs. MNU control), increased the ferrous reducing antioxidant potential (+36.7%, P<0.001 vs. MNU control) and reduced the extent of lipid peroxidation in the liver by 44.3% (P<0.001 vs. MNU control). SIGNIFICANCE: Results demonstrated the ability of FPP to preserve the integrity of liver against oxidative damage and protect hepatocytes against irreversible DNA structural modifications induced by MNU, highlighting its potential role as an immune-defense modulator during hepatocarcinoma.

Diabetes as a risk factor to cancer: functional role of fermented papaya preparation as phytonutraceutical adjunct in the treatment of diabetes and cancer.

Oncologists and diabetologists quote scientific data from epidemiological and in vitro studies to show that high levels of insulin and glucose, in combination with oxidative stress and chronic inflammation, can heighten the risk of developing cancer amongst patients with diabetes. Although the cancers that have been consistently associated with type 2 diabetes include pancreatic, colorectal, breast and liver cancer, the preponderance of the disease risk factors such as obesity, inflammation, hyperglycemia, hyperinsulinaemia (as a result of insulin resistance and oxidative ß-cell damage) and the indirect influence of anti-diabetic medications are increasingly being defined. Fermented papaya preparation (FPP) has defined antioxidant and immune-modulating potentials. The ability of FPP influence signaling cascades associated with cell growth and survival presents a rational for chemopreventive adjunct that can be used in combination with traditional redox based therapies that target oxidative stress in the cancer micro environment. It is further suggested that the demonstrated efficacy FPP to control blood glucose, excessive inflammation and modulate free radical-induced oxidative damage which are triggers of liver, bladder, breast and prostate cancers in type 2 diabetics, may favorably mitigate the side effects of ensuing diabetes and cancer therapy. What remains paramount is early cancer detection and early determination of propensity risks for diabetes. The education of patients, proper dietary management and compliance with therapeutic regime directed at cancer and diabetes encapsulate challenges of global magnitude.

Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone.

The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

Effectiveness of green tea in a randomized human cohort: relevance to diabetes and its complications.

Epidemiological studies have argued that green tea could mitigate diabetes and its complications. This study investigated the phytophenolic profile of Mauritian green tea and its antioxidant propensity. The effect of green tea on the risk factors: waist-hip ratio, glucose level, arterial pressure, antioxidant status, and alanine aminotransferase (ALT) in prediabetics was assessed. The experimental group consumed 3 cups of green tea daily for 14 weeks followed by a 2-week washout period. The control group followed a water regimen. Green tea contained high level of phenolics related to its antioxidant power. Green tea suppressed waist-hip ratio of women from a significant increase and suppressed mean arterial pressure of men and women from a significant decrease after week 14. It reduced ALT level in women by 13.0% (P < 0.1) while increasing the antioxidant potential of men and women sera by 2.7% (P < 0.1) and 5.1% (P < 0.1). The study timescale may have been too short to enable demonstration of effects on fasting plasma glucose and HbA1c outcomes. Green tea regimen could form part of a healthy lifestyle that might ameliorate features of metabolic syndrome and subsequent risks for diabetes and its complications. This trial is registered with ClinicalTrials.gov NCT01248143.

Effect of Aegle marmelos leaf extract on N-methyl N-nitrosourea-induced hepatocarcinogensis in Balb/c mice.

CONTEXT AND OBJECTIVE: Tobacco smoke and nitrostable foods containing N-methyl N-nitrosourea (MNU) are among the primary causes of liver cancer. To substantiate the beneficial claims ascribed to Aegle marmelos (L.) Corrêa (Rutaceae), the hepatoprotective potential of its leaf extract was studied using an MNU-induced hepatocarcinogenesis model in Balb/c mice. MATERIALS AND METHODS: After dose selection, 40 mice were randomly assigned to 4 groups: I (control), II (intraperitoneally (i.p.) primed with 50 mg/kg MNU), III (100 mg/kg A. marmelos hydroalcoholic extract (HEAM) i.p.) and IV (MNU + HEAM, i.p.). Inflammatory (IL-1ß, IL-6), anti-inflammatory (IL-4) cytokine expression, apoptosis (Bcl-2) and tumor-related (p53, c-jun) genes were assessed at mRNA level. HEAM effects on hematological parameters were examined. RESULTS AND DISCUSSION: HEAM treatment decreased IL-1ß, IL-6, Bcl-2 and c-jun respectively expressions by 90, 25, 53 and 30%, respectively. p53 and IL-4 expression was up-regulated by 1.5- and 2-fold. MNU decreased hemoglobin concentration (25%), lymphocyte count (42%) and increased leukocyte (100%), platelet (4-fold), neutrophil (43%), monocyte (10-fold) and eosinophil (10-fold) counts in Group II mice while HEAM modulated the same parameters by -7%, -21%, +24%, +3-fold, +12%, +3-fold and +4-fold, respectively, in MNU-induced mice compared to control. HEAM protective effect was confirmed by Raman spectroscopy where the MNU-induced peak at 1252 cm(-1) was normalized. DNA fragmentation data suggest apoptosis as one of the protective mechanisms of HEAM. CONCLUSION: The hepatoprotective, anti-carcinogenic and immunomodulatory effects of A. marmelos extract indicate potential beneficial effects in cancer therapy.

Functional benefits of ergothioneine and fruit- and vegetable-derived nutraceuticals: overview of the supplemental issue contents.

For good reason, there is increasing interest in assessing the clinical efficacy of dietary supplements, naturally occurring compounds, and nutraceuticals intended for improving health and reducing disease. This is also a pressing interest in mitigating the effects of age-dependent chronic diseases. This opportunity argues for the need to develop a clear understanding of the basic molecular mechanisms responsible for the actions of dietary biofactors that can contribute to the slowing or preventing of diseases and the possibility of enhancing these improvements by coupling them with healthy lifestyle changes.

Effects of a short term supplementation of a fermented papaya preparation on biomarkers of diabetes mellitus in a randomized Mauritian population.

OBJECTIVE: Clinical evidence and cellular models have shown an inverse relationship between the intakes of plant and fruit based diets and oxidative stress, suggesting the suitability of natural antioxidants in the management of diabetes mellitus and its complications. METHOD: A randomized controlled clinical trial was conducted at the Cardiac Centre, SSRN Hospital, Pamplemousses, (Mauritius) to determine the effect of a short term supplementation of a fermented papaya preparation (FPP®) on biomarkers of diabetes and antioxidant status in a multi-ethnical neo-diabetic population from November 2010 to March 2011. RESULT: Supplementation of 6g FPP®/day for a period of 14 weeks could improve the general health status of several organs targeted by oxidative stress during diabetes. When comparing experimental to control groups with independent samples t-test, C-reactive protein levels significantly decreased (P=0.018), LDL/HDL ratio was considerably changed (P=0.042), and uric acid levels were significantly improved (P=0.001). ANOVA results also validated the same findings with significant differences in C-reactive protein, LDL/HDL ratio, uric acid and in serum ferritin levels. CONCLUSION: FPP® may present a novel, economically feasible nutraceutical supplement for the management of diabetes and for those at risk for cardiovascular disease, neurological disease and other conditions worsened by overt inflammation and oxidative stress.

The effect of black tea on risk factors of cardiovascular disease in a normal population.

OBJECTIVES: A prospective randomized controlled clinical trial determined the effect of Mauritian black tea consumption on fasting blood plasma levels of glucose, lipid profiles and antioxidant status in a normal population. METHODS: The study group (71%) consumed 3 x 200 ml of black tea infusate/day for 12 weeks without additives followed by a 3 week wash-out. The control group (29%) consumed equivalent volume of hot water for same intervention period. RESULTS: The tea used had high levels of gallic acid derivatives (50 ± 0.4 mg/L), flavan-3-ols (42 ± 2 mg/L), flavonols (32 ± 1 mg/L) and theaflavins (90 ± 1 mg/L). Daily 9 g supplementation of black tea infusate induced, in a normal population, a highly significant decrease of fasting serum glucose (18.4%; p<0.001) and triglyceride levels (35.8%; p<0.01), a significant decrease in LDL/HDL plasma cholesterol ratio (16.6%; p<0.05) and a non significant increase in HDL plasma cholesterol levels (20.3%), while a highly significant rise in plasma antioxidant propensity (FRAP: 418%; p<0.001) was noted . CONCLUSION: Black tea consumed within a normal diet contributes to a decrease of independent cardiovascular risk factors and improves the overall antioxidant status in humans.

Applications and bioefficacy of the functional food supplement fermented papaya preparation.

Fermented papaya preparation (FPP) (a product of yeast fermentation of Carica papaya Linn) is a food supplement. Studies in chronic and degenerative disease conditions (such as thalassemia, cirrhosis, diabetes and aging) and performance sports show that FPP favorably modulates immunological, hematological, inflammatory, vascular and oxidative stress damage parameters. Neuroprotective potential evaluated in an Alzheimer's disease cell model showed that the toxicity of the ß-amyloid can be significantly modulated by FPP. Oxidative stress trigger apoptotic pathways such as the c-jun N-terminal kinase (JNK) and p38-mitogen activated protein kinase (MAPK) are preferentially activated by pro-inflammatory cytokines and oxidative stress resulting in cell differentiation and apoptosis. FPP modulated the H2O2-induced ERK, Akt and p38 activation with the reduction of p38 phosphorylation induced by H2O2. FPP reduces the extent of the H2O2-induced DNA damage, an outcome corroborated by similar effects obtained in the benzo[a]pyrene treated cells. No genotoxic effect was observed in experiments with FPP exposed to HepG2 cells nor was FPP toxic to the PC12 cells. Oxidative stress-induced cell damage and inflammation are implicated in a variety of cancers, diabetes, arthritis, cardiovascular dysfunctions, neurodegenerative disorders (such as stroke, Alzheimer's disease, and Parkinson's disease), exercise physiology (including performance sports) and aging. These conditions could potentially benefit from functional nutraceutical/food supplements (as illustrated here with fermented papaya preparation) exhibiting anti-inflammatory, antioxidant, immunostimulatory (at the level of the mucus membrane) and induction of antioxidant enzymes.

Bioactive phenolics and antioxidant propensity of flavedo extracts of Mauritian citrus fruits: potential prophylactic ingredients for functional foods application.

The flavedo extracts of twenty-one varieties of citrus fruits (oranges, satsumah, clementine, mandarins, tangor, bergamot, lemon, tangelos, kumquat, calamondin and pamplemousses) grown in Mauritius were examined for their total phenolic, flavonoid and vitamin C contents and antioxidant activities. Total phenolics correlated strongly with the trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant capacity (FRAP) and hypochlorous acid (HOCl) scavenging activity assays (r > 0.85). Based on their antioxidant activities in these three assays nine citrus fruits namely, one orange, clementine, tangor and pamplemousse variety, two tangelo varieties and three mandarin varieties, were further characterized for their flavanone, flavonol and flavone levels by HPLC and their antioxidant activities were assessed by the copper-phenanthroline and iron chelation assays. The flavanone, hesperidin, was present at the highest concentrations in all flavedo extracts except for pamplemousses where it was not detected. Contents in hesperidin ranged from 83 ± 0.06 to 234 ± 1.73 mg/g FW. Poncirin, didymin, diosmin, isorhoifolin and narirutin were also present in all extracts whereas naringin was present only in one mandarin variety. The nine flavedo extracts exhibited good DNA protecting ability in the cuphen assay with IC50 values ranging from 6.3 ± 0.46 to 23.0 ± 0.48 mg FW/mL. Essentially the flavedos were able to chelate metal ions however, tangor was most effective with an IC50 value of 9.1 ± 0.08 mg FW/mL. The flavedo extracts of citrus fruits represent a significant source of phenolic antioxidants with potential prophylactic properties for the development of functional foods.

Black tea reduces uric acid and C-reactive protein levels in humans susceptible to cardiovascular diseases.

The effect of black tea on the level of uric acid (UA) and C-reactive proteins (CRP) in humans susceptible to ischemic heart diseases was assessed in a prospective randomized controlled study. The study group consumed 9 g of black tea (equivalent to three cups of tea) daily for 12 weeks without additives followed by a 3-week wash-out (with control group consuming equivalent volume of hot water). Black tea consumption induced a highly significant decrease in the high uric acid baseline groups > 6 mg/dL by 8.5%; p < 0.05. For men and women in the base line group > 7 mg/dL, the decrease was 9.4% and 7.1%, respectively. In the low baseline serum uric acid levels there was a non-significant increase of 3.7% and 15% in men and women, respectively. C-reactive protein in the high risk group > 3mg/L was significantly decreased by 53.4% and 41.1% in men and women, respectively. For the non-supplemented group in this range the changes were 3.7% decrease for men and 2.9% increase for women. Tea supplementation-associated decrease in plasma uric acid and C-reactive protein levels may benefit humans at high risk of cardiovascular events and may augment drug therapy.

Targeting specific cell signaling transduction pathways by dietary and medicinal phytochemicals in cancer chemoprevention.

Natural phytochemicals derived from dietary sources or medicinal plants have gained significant recognition in the potential management of several human clinical conditions. Much research has also been geared towards the evaluation of plant extracts as effective prophylactic agents since they can act on specific and/or multiple molecular and cellular targets. Plants have been an abundant source of highly effective phytochemicals which offer great potential in the fight against cancer by inhibiting the process of carcinogenesis through the upregulation of cytoprotective genes that encode for carcinogen detoxifying enzymes and antioxidant enzymes. The mechanistic insight into chemoprevention further includes induction of cell cycle arrest and apoptosis or inhibition of signal transduction pathways mainly the mitogen-activated protein kinases (MAPK), protein kinases C (PKC), phosphoinositide 3-kinase (PI3K), glycogen synthase kinase (GSK) which lead to abnormal cyclooxygenase-2 (COX-2), activator protein-1 (AP-1), nuclear factor-kappaB (NF-κB) and c-myc expression. Effectiveness of chemopreventive agents reflects their ability to counteract certain upstream signals that leads to genotoxic damage, redox imbalances and other forms of cellular stress. Targeting malfunctioning molecules along the disrupted signal transduction pathway in cancer represent a rational strategy in chemoprevention. NF-κB and AP-1 provide mechanistic links between inflammation and cancer, and moreover regulate tumor angiogenesis and invasiveness, indicating that signaling pathways that mediate their activation provide attractive targets for new chemotherapeutic approaches. Thus cell signaling cascades and their interacting factors have become important targets of chemoprevention and phenolic phytochemicals and plant extracts seem to be promising in this endeavor.

Effect of an antioxidant functional food beverage on exercise-induced oxidative stress: a long-term and large-scale clinical intervention study.

The efficacy of long-term intake of a novel functional food supplement Funciona™ containing vitamins and juiced fruits was evaluated in order to assess the net effect of physical activity and antioxidant potentials in healthy older adult population. The long-term (2 years) and large-scale (400 older adult subjects) interventional study was based on both moderate-intensity exercise practice and concurrent supplementation. Sustained exercise-induced oxidative stress as reflected in significantly increased blood thiobarbituric acid-reactive substances (TBARS) (+15%), protein carbonyl groups (PC) (+18%) and oxidized glutathione (GSSG) (+112%) concentrations, and leukocyte 8-OHdG contents (23%). Exercise decreased the reduced/oxidized glutathione (GSH/GSSG) molar ratio (-43%) and plasma vitamin C levels (-22%). Supplementation with Funciona™ was significant in preventing oxidative damage to lipid, protein and DNA, and normalizing blood GSSG, GSH/GSSG and vitamin C levels. Thus daily intake of the antioxidant functional beverage counteracts the exercise-induced oxidative stress in free-living older subjects, and might be necessary to restore impaired antioxidant balance due long-term regular exercise.

The effect of active hexose correlated compound in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine- and methotrexate-induced liver injury in rodents.

BACKGROUND: Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). METHODS: Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). RESULTS: Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. CONCLUSION: Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining.