The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies. Also key to better understanding is why and how the anti-diabetic drug metformin (the world’s most prescribed pharmaceutical product) preferentially kills oxidant-deficient mesenchymal p53(- -)cells. A much faster timetable should be adopted towards developing more new drugs effective against p53(- -) cancers.
This study was conducted with the objective of testing the hypothesis that tomato fruits from organic farming accumulate more nutritional compounds, such as phenolics and vitamin C as a consequence of the stressing conditions associated with farming system. Growth was reduced in fruits from organic farming while titratable acidity, the soluble solids content and the concentrations in vitamin C were respectively +29%, +57% and +55% higher at the stage of commercial maturity. At that time, the total phenolic content was +139% higher than in the fruits from conventional farming which seems consistent with the more than two times higher activity of phenylalanine ammonia lyase (PAL) we observed throughout fruit development in fruits from organic farming. Cell membrane lipid peroxidation (LPO) degree was 60% higher in organic tomatoes. SOD activity was also dramatically higher in the fruits from organic farming. Taken together, our observations suggest that tomato fruits from organic farming experienced stressing conditions that resulted in oxidative stress and the accumulation of higher concentrations of soluble solids as sugars and other compounds contributing to fruit nutritional quality such as vitamin C and phenolic compounds.
The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.
Thirdhand smoke (THS) is the accumulation of secondhand smoke on environmental surfaces. THS is found on the clothing and hair of smokers as well as on surfaces in homes and cars of smokers. Exposure occurs by ingestion, inhalation and dermal absorption. Children living in homes of smokers are at highest risk because they crawl on the floor, touch parents' clothing/hair and household objects. Using mice exposed to THS under conditions that mimic exposure of humans, we show that THS increases cellular oxidative stress by increasing superoxide dismutase (SOD) activity and hydrogen peroxide (H2O2) levels while reducing the activity of antioxidant enzymes catalase and glutathione peroxidase (GPx) that break down H2O2 into H2O and O2. This results in lipid peroxidation, protein nitrosylation and DNA damage. Consequences of these cell and molecular changes are hyperglycemia and insulinemia. Indeed, we found reduced levels of insulin receptor, PI3K, AKT, all important molecules in insulin signaling and glucose uptake by cells. To determine whether these effects on THS-induced insulin resistance are due to increase in oxidative stress, we treated mice exposed to THS with the antioxidants N-acetyl cysteine (NAC) and alpha-tocopherol (alpha-toc) and showed that the oxidative stress, the molecular damage, and the insulin resistance, were significantly reversed. Conversely, feeding the mice with chow that mimics “western diet”, which is known to increase oxidative stress, while exposing the mice to THS, further increased the oxidative stress and aggravated hyperglycemia and insulinemia. In conclusion, THS exposure results in insulin resistance in the form of non-obese type II diabetes (NODII) through oxidative stress. If confirmed in humans, these studies could have a major impact on how people view exposure to environmental tobacco toxins, in particular to children, elderly and workers in environments where tobacco smoke has taken place.
Increased oxidative stress contributes to development and progression of several human chronic inflammatory diseases. Cherries are a rich source of polyphenols and vitamin C which have anti-oxidant and anti-inflammatory properties. Our aim is to summarize results from human studies regarding health benefits of both sweet and tart cherries, including products made from them (juice, powder, concentrate, capsules); all referred to as cherries here. We found 29 (tart 20, sweet 7, unspecified 2) published human studies which examined health benefits of consuming cherries. Most of these studies were less than 2 weeks of duration (range 5 h to 3 months) and served the equivalent of 45 to 270 cherries/day (anthocyanins 55-720 mg/day) in single or split doses. Two-thirds of these studies were randomized and placebo controlled. Consumption of cherries decreased markers for oxidative stress in 8/10 studies; inflammation in 11/16; exercise-induced muscle soreness and loss of strength in 8/9; blood pressure in 5/7; arthritis in 5/5, and improved sleep in 4/4. Cherries also decreased hemoglobin A1C (HbA1C), Very-low-density lipoprotein (VLDL) and triglycerides/high-density lipoprotein (TG/HDL) in diabetic women, and VLDL and TG/HDL in obese participants. These results suggest that consumption of sweet or tart cherries can promote health by preventing or decreasing oxidative stress and inflammation.
Glyphosate tolerant genetically modified (GM) maize NK603 was assessed as ‘substantially equivalent’ to its isogenic counterpart by a nutrient composition analysis in order to be granted market approval. We have applied contemporary in depth molecular profiling methods of NK603 maize kernels (sprayed or unsprayed with Roundup) and the isogenic corn to reassess its substantial equivalence status. Proteome profiles of the maize kernels revealed alterations in the levels of enzymes of glycolysis and TCA cycle pathways, which were reflective of an imbalance in energy metabolism. Changes in proteins and metabolites of glutathione metabolism were indicative of increased oxidative stress. The most pronounced metabolome differences between NK603 and its isogenic counterpart consisted of an increase in polyamines including N-acetyl-cadaverine (2.9-fold), N-acetylputrescine (1.8-fold), putrescine (2.7-fold) and cadaverine (28-fold), which depending on context can be either protective or a cause of toxicity. Our molecular profiling results show that NK603 and its isogenic control are not substantially equivalent.
Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compounds play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.
Influence of methylsulfonylmethane on markers of exercise recovery and performance in healthy men: a pilot study.
- Journal of the International Society of Sports Nutrition
- Published over 7 years ago
BACKGROUND: Methylsulfonylmethane (MSM) has been reported to provide anti-inflammatory and antioxidant effects in both animal and man. Strenuous resistance exercise has the potential to induce both inflammation and oxidative stress. Using a pilot (proof of concept) study design, we determined the influence of MSM on markers of exercise recovery and performance in healthy men. METHODS: Eight, healthy men (27.1 +/- 6.9 yrs old) who were considered to be moderately exercise-trained (exercising <150 minutes per week) were randomly assigned to ingest MSM at either 1.5 grams per day or 3.0 grams per day for 30 days (28 days before and 2 days following exercise). Before and after the 28 day intervention period, subjects performed 18 sets of knee extension exercise in an attempt to induce muscle damage (and to be used partly as a measure of exercise performance). Sets 1--15 were performed at a predetermined weight for 10 repetitions each, while sets 16--18 were performed to muscular failure. Muscle soreness (using a 5-point Likert scale), fatigue (using the fatigue-inertia subset of the Profile of Mood States), blood antioxidant status (glutathione and Trolox Equivalent Antioxidant Capacity [TEAC]), and blood homocysteine were measured before and after exercise, pre and post intervention. Exercise performance (total work performed during sets 16--18 of knee extension testing) was also measured pre and post intervention. RESULTS: Muscle soreness increased following exercise and a trend was noted for a reduction in muscle soreness with 3.0 grams versus 1.5 grams of MSM (p = 0.080), with a 1.0 point difference between dosages. Fatigue was slightly reduced with MSM (p = 0.073 with 3.0 grams; p = 0.087 for both dosages combined). TEAC increased significantly following exercise with 3.0 grams of MSM (p = 0.035), while homocysteine decreased following exercise for both dosages combined (p = 0.007). No significant effects were noted for glutathione or total work performed during knee extension testing (p > 0.05). CONCLUSION: MSM, especially when provided at 3.0 grams per day, may favorably influence selected markers of exercise recovery. More work is needed to extend these findings, in particular using a larger sample of subjects and the inclusion of additional markers of exercise recovery and performance.
Vitamin E is a fat-soluble vitamin with antioxidant properties. Tocopherols are the predominant form of vitamin E found in the diet and in supplements and have garnered interest for their potential cancer therapeutic and preventive effects, such as the dephosphorylation of Akt, a serine/threonine kinase with a pivotal role in cell growth, survival, and metabolism. Dephosphorylation of Akt at Ser(473) substantially reduces its catalytic activity and inhibits downstream signaling. We found that the mechanism by which α-tocopherol and γ-tocopherol facilitate this site-specific dephosphorylation of Akt was mediated through the pleckstrin homology (PH) domain-dependent recruitment of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1) to the plasma membrane. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential recruitment of these proteins to membranes containing tocopherols. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. By describing a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser(473), we provide insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.
- Indian journal of dermatology, venereology and leprology
- Published almost 4 years ago
Glutathione is a low molecular weight thiol-tripeptide that plays a prominent role in maintaining intracellular redox balance. In addition to its remarkable antioxidant properties, the discovery of its antimelanogenic properties has led to its promotion as a skin-lightening agent. It is widely used for this indication in some ethnic populations. However, there is a dichotomy between evidence to support its efficacy and safety. The hype around its depigmentary properties may be a marketing gimmick of pharma-cosmeceutical companies. This review focuses on the various aspects of glutathione: its metabolism, mechanism of action and the scientific evidence to evaluate its efficacy as a systemic skin-lightening agent. Glutathione is present intracellularly in its reduced form and plays an important role in various physiological functions. Its skin-lightening effects result from direct as well as indirect inhibition of the tyrosinase enzyme and switching from eumelanin to phaeomelanin production. It is available in oral, parenteral and topical forms. Although the use of intravenous glutathione injections is popular, there is no evidence to prove its efficacy. In fact, the adverse effects caused by intravenous glutathione have led the Food and Drug Administration of Philippines to issue a public warning condemning its use for off-label indications such as skin lightening. Currently, there are three randomized controlled trials that support the skin-lightening effect and good safety profile of topical and oral glutathione. However, key questions such as the duration of treatment, longevity of skin-lightening effect and maintenance protocols remain unanswered. More randomized, double-blind, placebo-controlled trials with larger sample size, long-term follow-up and well-defined efficacy outcomes are warranted to establish the relevance of this molecule in disorders of hyperpigmentation and skin lightening.