Life Extension Magazine®

Issue: Apr 2017

Mediterranean diet, Geroprotectors, Metformin, and Skin pigmentation

Mediterranean diet, Geroprotectors, Metformin, and Skin pigmentation

Mediterranean diet

Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials.

BACKGROUND: The beneficial effects of flavonoid consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence. OBJECTIVE: We aimed to systematically review the effectiveness of different flavonoid subclasses and flavonoid-rich food sources on cardiovascular disease (CVD) and risk factors--ie, lipoproteins, blood pressure, and flow-mediated dilatation (FMD). DESIGN: Methods included a structured search strategy on MEDLINE, EMBASE, and Cochrane databases; formal inclusion or exclusion, data extraction, and validity assessment; and meta-analysis. RESULTS: One hundred thirty-three trials were included. No randomized controlled trial studied effects on CVD morbidity or mortality. Significant heterogeneity confirmed differential effects between flavonoid subclasses and foods. Chocolate increased FMD after acute (3.99%; 95% CI: 2.86, 5.12; 6 studies) and chronic (1.45%; 0.62, 2.28; 2 studies) intake and reduced systolic (-5.88 mm Hg; -9.55, -2.21; 5 studies) and diastolic (-3.30 mm Hg; -5.77, -0.83; 4 studies) blood pressure. Soy protein isolate (but not other soy products or components) significantly reduced diastolic blood pressure (-1.99 mm Hg; -2.86, -1.12; 9 studies) and LDL cholesterol (-0.19 mmol/L; -0.24, -0.14; 39 studies). Acute black tea consumption increased systolic (5.69 mm Hg; 1.52, 9.86; 4 studies) and diastolic (2.56 mm Hg; 1.03, 4.10; 4 studies) blood pressure. Green tea reduced LDL (-0.23 mmol/L; -0.34, -0.12; 4 studies). For many of the other flavonoids, there was insufficient evidence to draw conclusions about efficacy. CONCLUSIONS: To date, the effects of flavonoids from soy and cocoa have been the main focus of attention. Future studies should focus on other commonly consumed subclasses (eg, anthocyanins and flavanones), examine dose-response effects, and be of long enough duration to allow assessment of clinically relevant endpoints.

Am J Clin Nutr. 2008 Jul;88(1):38-50

Polyphenols and cancer cell growth.

Polyphenols constitute an important group of phytochemicals that gained increased research attention since it was found that they could affect cancer cell growth. Initial evidence came from epidemiologic studies suggesting that a diet that includes regular consumption of fruits and vegetables (rich in polyphenols) significantly reduces the risk of many cancers. In the present work we briefly review the effects of polyphenols on cancer cell fate, leading towards growth, differentiation and apoptosis. Their action can be attributed not only to their ability to act as antioxidants but also to their ability to interact with basic cellular mechanisms. Such interactions include interference with membrane and intracellular receptors, modulation of signaling cascades, interaction with the basic enzymes involved in tumor promotion and metastasis, interaction with oncogenes and oncoproteins, and, finally, direct or indirect interactions with nucleic acids and nucleoproteins. These actions involve almost the whole spectrum of basic cellular machinery--from the cell membrane to signaling cytoplasmic molecules and to the major nuclear components--and provide insights into their beneficial health effects. In addition, the actions justify the scientific interest in this class of compounds, and provide clues about their possible pharmaceutical exploitation in the field of oncology.

Rev Physiol Biochem Pharmacol. 2007;159:79-113

Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen study.

BACKGROUND: Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study. METHODS: A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from cross-check dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol. RESULTS: Forty-two cases of first fatal or nonfatal stroke were documented. Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake ( > or = 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI], 0.11 to 0.70). A lower stroke risk was also observed for the highest quartile of beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin C and vitamin E was not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). CONCLUSION: The habitual intake of flavonoids and their major source (tea) may protect against stroke.

Arch Intern Med. 1996 Mar 25;156(6):637-42

Flavonoid intake and risk of chronic diseases.

BACKGROUND: Flavonoids are effective antioxidants and may protect against several chronic diseases. OBJECTIVE: The association between flavonoid intake and risk of several chronic diseases was studied. DESIGN: The total dietary intakes of 10 054 men and women during the year preceding the baseline examination were determined with a dietary history method. Flavonoid intakes were estimated, mainly on the basis of the flavonoid concentrations in Finnish foods. The incident cases of the diseases considered were identified from different national public health registers. RESULTS: Persons with higher quercetin intakes had lower mortality from ischemic heart disease. The relative risk (RR) between the highest and lowest quartiles was 0.79 (95% CI: 0.63, 0.99: P for trend = 0.02). The incidence of cerebrovascular disease was lower at higher kaempferol (0.70; 0.56, 0.86; P = 0.003), naringenin (0.79; 0.64, 0.98; P = 0.06), and hesperetin (0.80; 0.64, 0.99; P = 0.008) intakes. Men with higher quercetin intakes had a lower lung cancer incidence (0.42; 0.25, 0.72; P = 0.001), and men with higher myricetin intakes had a lower prostate cancer risk (0.43; 0.22, 0.86; P = 0.002). Asthma incidence was lower at higher quercetin (0.76; 0.56, 1.01; P = 0.005), naringenin (0.69; 0.50, 0.94; P = 0.06), and hesperetin (0.64; 0.46, 0.88; P = 0.03) intakes. A trend toward a reduction in risk of type 2 diabetes was associated with higher quercetin (0.81; 0.64, 1.02; P = 0.07) and myricetin (0.79; 0.62, 1.00; P = 0.07) intakes. CONCLUSION: The risk of some chronic diseases may be lower at higher dietary flavonoid intakes.

Am J Clin Nutr. 2002 Sep;76(3):560-8

Flavonoid intake and cognitive decline over a 10-year period.

In the PAQUID (Personnes Agées Quid) study, the authors prospectively examined flavonoid intake in relation to cognitive function and decline among subjects aged 65 years or older. A total of 1,640 subjects free from dementia at baseline in 1990 and with reliable dietary assessment were reexamined four times over a 10-year period. Cognitive functioning was assessed through three psychometric tests (Mini-Mental State Examination, Benton's Visual Retention Test, "Isaacs" Set Test) at each visit. Information on flavonoid intake was collected at baseline. A linear mixed model was used to analyze the evolution of cognitive performance according to quartiles of flavonoid intake. After adjustment for age, sex, and educational level, flavonoid intake was associated with better cognitive performance at baseline (p = 0.019) and with a better evolution of the performance over time (p = 0.046). Subjects included in the two highest quartiles of flavonoid intake had better cognitive evolution than did subjects in the lowest quartile. After 10 years' follow-up, subjects with the lowest flavonoid intake had lost on average 2.1 points on the Mini-Mental State Examination, whereas subjects with the highest quartile had lost 1.2 points. This gradient persisted after adjustment for several other potential confounders. This study raises the possibility that dietary flavonoid intake is associated with better cognitive evolution.

Am J Epidemiol. 2007 Jun 15;165(12):1364-71

Flavonoids: a review of probable mechanisms of action and potential applications.

The aim of this review, a summary of the putative biological actions of flavonoids, was to obtain a further understanding of the reported beneficial health effects of these substances. Flavonoids occur naturally in fruit, vegetables, and beverages such as tea and wine. Research in the field of flavonoids has increased since the discovery of the French paradox,ie, the low cardiovascular mortality rate observed in Mediterranean populations in association with red wine consumption and a high saturated fat intake. Several other potential beneficial properties of flavonoids have since been ascertained. We review the different groups of known flavonoids, the probable mechanisms by which they act, and the potential clinical applications of these fascinating natural substances.

Am J Clin Nutr. 2001 Oct;74(4):418-25

Flavonoids and intestinal cancers.

Cancers of the gastrointestinal tract are amongst the most common causes of death from cancer, but there is substantial variation in incidence across populations. This is consistent with a major causative role for diet. There is convincing evidence that fruits and vegetables protect against cancers of the upper alimentary tract and the large bowel, and this has focused attention on biologically active phytochemicals, and on flavonoids in particular. Many flavonoids exert anticarcinogenic effects in vitro and in animals, and many of these effects occur via signalling pathways known to be important in the pathogenesis of colorectal, gastric and oesophageal cancers. However dietary flavonoid intakes are generally low and their metabolism in humans is extremely complex. The advent of new post-genomic technologies will do much to address these problems by making it possible to monitor patterns of gene expression in humans to provide essential molecular biomarkers of early disease. By combining such data with knowledge of the dietary exposure and bioavailability of the most effective compounds it will be possible to predict the most effective dietary sources and to properly evaluate the potential role of flavonoids in clinical nutrition.

Br J Nutr. 2008 May;99 E Suppl 1:ES53-9

Flavonoids in food and their health benefits.

There has been increasing interest in the research of flavonoids from dietary sources, due to growing evidence of the versatile health benefits of flavonoids through epidemiological studies. As occurrence of flavonoids is directly associated with human daily dietary intake of antioxidants, it is important to evaluate flavonoid sources in food. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. However, there is still difficulty in accurately measuring the daily intake of flavonoids because of the complexity of existence of flavonoids from various food sources, the diversity of dietary culture, and the occurrence of a large amount of flavonoids itself in nature. Nevertheless, research on the health aspects of flavonoids for humans is expanding rapidly. Many flavonoids are shown to have antioxidative activity, free-radical scavenging capacity, coronary heart disease prevention, and anticancer activity, while some flavonoids exhibit potential for anti-human immunodeficiency virus functions. As such research progresses. further achievements will undoubtedly lead to a new era of flavonoids in either foods or pharmaceutical supplements. Accordingly, an appropriate model for a precise assessment of intake of flavonoids needs to be developed. Most recent research has focused on the health aspects of flavonoids from food sources for humans. This paper reviews the current advances in flavonoids in food, with emphasis on health aspects on the basis of the published literature, which may provide some guidance for researchers in further investigations and for industries in developing practical health agents.

Plant Foods Hum Nutr. 2004 Summer;59(3):113-22

Oxidized LDL and NO synthesis—Biomarkers of endothelial dysfunction and ageing.

Oxidized LDL (oxLDL) and nitric oxide (NO) exert contradictory actions within the vascular endothelium microenvironment influencing key events in atherogenesis. OxLDL and NO are so far regarded as representative parameters of oxidative stress and endothelial dysfunction, new targets in prevention, diagnosis and therapy of cardiovascular diseases, and also as candidate biomarkers in evaluating the human biological age. The aim of this review is to explore recent literature on molecular mechanisms and pathophysiological relationships between LDL oxidation, NO synthesis and vascular endothelium function/dysfunction in ageing, focusing on the following aspects: (1) the impact of metabolic status on both LDL oxidation and NO synthesis in relation with oxidative stress, (2) the use of oxidized LDL and NO activity as biomarkers in human studies reporting on cardiovascular outcomes, and (3) evidences supporting the importance of oxidized LDL and NO activity as relevant biomarkers in vascular ageing and age-related diseases.

Mech Ageing Dev. 2015 Nov;151:101-13

Sirtuins and resveratrol-derived compounds: a model for understanding the beneficial effects of the Mediterranean diet.

The beneficial effects of the Mediterranean diet (MD) had been first observed about 50 years ago. Consumption of fresh vegetables and fruits, cereals, red wine, nuts, legumes, etc. has been regarded as the primary factor for protection from many human pathologies by the Mediterranean diet. Subsequently, this was attributed to the presence of polyphenols and their derivatives that, by exerting an anti-inflammatory and anti-oxidative effect, can be involved in the prevention of many diseases. Clinical trials, observational studies and meta-analysis have demonstrated an antiageing effect of MD accompanied by a reduced risk of age-related pathologies, such as cardiovascular, metabolic and neurodegenerative diseases, as well as cancer. The scientific explanation of such beneficial effects was limited to the reduction of the oxidative stress by compounds present in the MD. However, recently, this view is changing thanks to new studies aimed to uncover the molecular mechanism(s) activated by components of this diet. In particular, a new class of proteins called sirtuins have gained the attention of the scientific community because of their antiageing effects, their ability to protect from cardiovascular, metabolic, neurodegenerative diseases, cancer and to extend lifespan in lower organisms as well as in mammals. Interestingly, resveratrol a polyphenol present in grapes, nuts and berries has been shown to activate sirtuins and such activation is able to explain most of the beneficial effects of the MD. In this review, we will highlight the importance of MD with particular attention to the possible molecular pathways that have been shown to be influenced by it. We will describe the state of the art leading to demonstrate the important role of sirtuins as principal intracellular mediators of the beneficial effects of the MD. Finally, we will also introduce how Mediterranean diet may influence microbioma composition and stem cells function.

Endocr Metab Immune Disord Drug Targets. 2014;14(4):300-8


A review of the possible mechanisms of action of tocotrienol - a potential antiosteoporotic agent.

Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in finding novel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, is poised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixture demonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments further demonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator of nuclear factor kappa B signaling against osteoclastogenesis. Additionally, tocotrienol was also shown to be a strong 3- hydroxy-3-methyl-glutaryl-CoA reductase down-regulator with a mechanism different from that of statins. Inhibition of the mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonly used isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavenge free radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidant defense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effects of tocotrienol on Wnt/b-catenin signaling essential in osteoblastogenesis have not been determined. More mechanistic studies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required to confirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent and much research effort should be invested to develop it as an agent to curb osteoporosis.

Curr Drug Targets. 2013 Dec;14(13):1533-41

The biological effects of tocotrienol on bone: a review on evidence from rodent models.

Osteoporosis causes significant health care and economic burden to society, leading to a relentless search for effective preventive agents. Tocotrienol, a member of the vitamin E family, has demonstrated promising potential as an osteoporosis-preventing agent. This review summarizes evidence on the effects of tocotrienol on bone in animal models. Techniques used to examine the effects of tocotrienol on bone in animals included bone histomorphometry, X-ray microtomography, dual-energy X-ray absorptiometry, bone turnover markers, bone calcium content, and biomechanical strength. Tocotrienol was shown to improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture in osteopenic rats. It also decreased osteoclast number and bone erosion in the rats. Tocotrienol supplementation resulted in an improvement in bone mineral density, although biomechanical strength was not significantly altered in the rats. The beneficial effects of tocotrienol on bone can be attributed to its role as an antioxidant, anti-inflammatory agent, suppressor of the mevalonate pathway, and modulator of genes favorable to bone formation.

Drug Des Devel Ther. 2015 Apr 8;9:2049-61

Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan.

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Nature. 2016 Feb 11;530(7589):184-9

Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: a culture study.

Cellular senescence is reportedly involved in cholangiopathy in primary biliary cirrhosis and oxidative stress is proposed as a pathogenetic factor in biliary epithelial cells (BECs). This study investigated the involvement of proinflammatory cytokines (IFN-beta, IFN-gamma and TNF-alpha) and ataxia telangiectasia-mutated (ATM)/p53/ p21(WAF1/Cip1) pathway with respect to oxidative stress in cellular senescence of BECs. H(2)O(2) treatment (oxidative stress) induced phosphorylation (activation) of ATM and p53 and also p21(WAF1/Cip1) expression in BECs. Treatment with inflammatory cytokines generated reactive oxygen species (ROS) in cultured BECs followed by activation of the ATM/p53/p21(WAF1/Cip1) pathway and the induction of cellular senescence. Pre-treatment with ATM inhibitor (2-aminopurine) and antioxidant (N-acetylcysteine) significantly blocked the cellular senescence of BECs induced by oxidative stress or inflammatory cytokines. In conclusion, proinflammatory cytokines induce ROS generation and activate the ATM/p53/p21(WAF1/Cip1) pathway, followed by biliary epithelial senescence. This senescent process may be involved in the development of destructive cholangiopathy in humans.

Free Radic Res. 2008 Jul;42(7):625-32

Regulation of Muscle Stem Cell Functions: A Focus on the p38 MAPK Signaling Pathway.

Formation of skeletal muscle fibers (myogenesis) during development and after tissue injury in the adult constitutes an excellent paradigm to investigate the mechanisms whereby environmental cues control gene expression programs in muscle stem cells (satellite cells) by acting on transcriptional and epigenetic effectors. Here we will review the molecular mechanisms implicated in the transition of satellite cells throughout the distinct myogenic stages (i.e., activation from quiescence, proliferation, differentiation, and self-renewal). We will also discuss recent findings on the causes underlying satellite cell functional decline with aging. In particular, our review will focus on the epigenetic changes underlying fate decisions and on how the p38 MAPK signaling pathway integrates the environmental signals at the chromatin to build up satellite cell adaptive responses during the process of muscle regeneration, and how these responses are altered in aging. A better comprehension of the signaling pathways connecting external and intrinsic factors will illuminate the path for improving muscle regeneration in the aged.

Front Cell Dev Biol. 2016 Aug 30;4:91

Myricetin induces human osteoblast differentiation through bone morphogenetic protein-2/p38 mitogen-activated protein kinase pathway.

Myricetin (3,3',4',5,5',7-hexahydroxyflavone), a flavonoid compound, is present in vegetables and fruits. By means of alkaline phosphatase (ALP) activity, osteocalcin, and type I collagen enzyme-linked immunosorbent assay (ELISA), we have shown that myricetin exhibits a significant induction of differentiation in MG-63 and hFOB human osteoblasts. Alkaline phosphatase and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicate that myricetin stimulates osteoblast differentiation at various stages, from maturation to terminally differentiated osteoblasts. Induction of differentiation by myricetin is associated with increased bone morphogenetic protein-2 (BMP-2) production. The BMP-2 antagonist noggin blocked myricetin-mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 production is required in myricetin-mediated osteoblast maturation and differentiation. Induction of differentiation by myricetin is associated with increased activation of SMAD1/5/8 and p38 mitogen-activated protein kinases. Cotreatment of p38 inhibitor SB203580 inhibited myricetin-mediated ALP upregulation and osteocalcin production. In conclusion, myricetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and p38 MAPK, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass.

Biochem Pharmacol. 2007 Feb 15;73(4):504-14

Systems Pharmacology Dissection of the Protective Effect of Myricetin Against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart.

In this paper, we investigated the multi-target effect of myricetin as a therapeutic for cardiovascular disease, using an acute ischemia/reperfusion-induced myocardial injury model to gain insight into its mechanism of action. The compound-target interaction profiles of myricetin were determined using a combination of text mining, chemometric and chemogenomic methods. The effect of myricetin on cardiac function was investigated by carrying out experiments in rats subjected to ischemia/reperfusion (I/R) using Langendorff retrograde perfusion technology. Compared to the I/R group, pretreatment with 5 µM myricetin was observed to improve the maximum up/down rate of left ventricular pressure (dp/dt max) and coronary flow, raise left ventricular developed pressure, and decrease creatine kinase and lactate dehydrogenase levels in coronary flow. In addition, myricetin treatment was shown to have beneficial effects through its ability to reduce both infarct size and levels of cardiomyocyte apoptosis. Myricetin was also observed to have antioxidant properties, as evidenced by its ability to reduce MDA levels, while increasing both SOD levels and the GSH/GSSG ratio. Finally, an upregulation of 6-phosphogluconate dehydrogenase and fatty acid synthase expression and a downregulation of cyclooxygenase-2, cytochrome P450 and p38 mitogen-activated protein kinase expression suggest that myricetin acts through mechanisms which alter relevant signaling pathways. In summary, our results demonstrate that myricetin has protective cardiovascular effects against I/R-induced myocardial injury.

Cardiovasc Toxicol. 2016 Aug 2

Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia/reperfusion-induced injury.

Flavonoids exhibit a variety of beneficial effects in cardiovascular diseases. Although their therapeutic properties have been attributed mainly to their antioxidant action, they have additional protective mechanisms such as inhibition of signal transducer and activator of transcription 1 (STAT1) activation. Here, we have investigated the cardioprotective mechanisms of strong antioxidant flavonoids such as quercetin, myricetin and delphinidin. Although all of them protect the heart from ischemia/reperfusion-injury, myricetin and delphinidin exert a more pronounced protective action than quercetin by their capacity to inhibit STAT1 activation. Biochemical and computer modeling analysis indicated the direct interaction between STAT1 and flavonoids with anti-STAT1 activity.

FEBS Lett. 2009 Feb 4;583(3):531-41

Improvement of insulin sensitivity in obese Zucker rats by myricetin extracted from Abelmoschus moschatus.

In an attempt to develop new substances for treating insulin resistance, obese Zucker rats were employed to screen the effect of myricetin, an active principle of Abelmoschus moschatus (Malvaceae), on insulin resistance. Myricetin purified from the aerial portion of the plant was administered intravenously ( I. V.) into animals. A dose-dependent decrease in the plasma glucose concentration of obese Zucker rats was observed 30 min following an I. V. injection. Moreover, repeated I. V. injection of myricetin (1 mg/kg) into obese Zucker rats 3 times daily for 1 week reduced the value of the glucose-insulin index, an index of insulin resistance calculated from the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Additionally, repeated myricetin treatments overturned the inability of insulin to increase the expression of glucose transporter subtype 4 (GLUT 4) and to increase the protein levels and phosphorylation of insulin receptor substrate-1 (IRS-1) in soleus muscle of these obese rats. The inability of insulin to increase expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and to promote Akt serine phosphorylation in soleus muscle of these rats were also overturned by repeated myricetin treatments. These findings indicate that myricetin improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. Myricetin might be used as a model substance for the development of antidiabetic compounds.

Planta Med. 2007 Aug;73(10):1054-60

Myricetin: A Dietary Molecule with Diverse Biological Activities.

Myricetin is a common plant-derived flavonoid and is well recognised for its nutraceuticals value. It is one of the key ingredients of various foods and beverages. The compound exhibits a wide range of activities that include strong anti-oxidant, anticancer, antidiabetic and anti-inflammatory activities. It displays several activities that are related to the central nervous system and numerous studies have suggested that the compound may be beneficial to protect against diseases such as Parkinson's and Alzheimer's. The use of myricetin as a preserving agent to extend the shelf life of foods containing oils and fats is attributed to the compound's ability to protect lipids against oxidation. A detailed search of existing literature revealed that there is currently no comprehensive review available on this important molecule. Hence, the present work includes the history, synthesis, pharmaceutical applications and toxicity studies of myricetin. This report also highlights structure-activity relationships and mechanisms of action for various biological activities.

Nutrients. 2016 Feb 16;8(2):90


Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.

RATIONALE: The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. OBJECTIVE: Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. METHODS AND RESULTS: In primary hepatocytes from healthy animals, metformin and the IKKb (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-a-dependent IkB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1b, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKa/b activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages, metformin specifically blunted secretion of proinflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive diabetes mellitus population cohort, we observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02-0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22-2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). CONCLUSION: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. This may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups.

Circ Res. 2016 Aug 19;119(5):652-65

Metformin improves healthspan and lifespan in mice.

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.

Nat Commun. 2013;4:2192

Can people with type 2 diabetes live longer than those without?
A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.

AIMS: Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes. METHODS: We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables. RESULTS: We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy.CONCLUSIONS: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

Diabetes Obes Metab. 2014 Nov;16(11):1165-73

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.

The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):E2501-9

Diabetes mellitus, metformin and head and neck cancer.

INTRODUCTION: Diabetes mellitus (DM (Diabetes Mellitus)) is directly associated with some cancers. However, studies on the association between diabetes mellitus and head and neck cancer (HNC (Head and Neck Cancer)) have rendered controversial results. The objective of this study was to evaluate the association between DM and HNC, as well as the impact of metformin use on the risk of HNC. MATERIAL AND METHODS: This case-control study was conducted within the framework of the Brazilian Head and Neck Genome Project in 2011-2014. The study included 1021 HNC cases with histologically confirmed squamous cell carcinoma of the head and neck admitted to five large hospitals in São Paulo state. A total of 1063 controls were selected in the same hospitals. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression. RESULTS: Diabetic participants had a decreased risk of HNC (OR=0.68; 95% CI: 0.49-0.95) than non-diabetic participants, and this risk was further decreased among diabetic metformin users (OR=0.54; 95% CI: 0.29-0.99). Diabetic metformin users that were current smokers (OR=0.13; 95% CI: 0.04-0.44) or had an alcohol consumption of >40g/day (OR=0.31; 95% CI: 0.11-0.88) had lower risk of HNC than equivalent non-diabetic participants. CONCLUSION: The risk of HNC was decreased among diabetic participants; metformin use may at least partially explain this inverse association.

Oral Oncol. 2016 Oct;61:47-54

The Effect of Metformin Use on Left Ventricular Ejection Fraction and Mortality Post-Myocardial Infarction.

BACKGROUND: Animal studies showed that the use of metformin after myocardial infarction (MI) resulted in a protective effect on cardiac myocytes. In this study, we examined the effect of metformin in patients with diabetes mellitus (DM) on left ventricular ejection fraction (LVEF) and post-MI mortality. METHODS: We reviewed charts of patients with MI admitted to the UAMS medical center. Baseline characteristics and 12-month follow up data were collected. Patients were classified into three groups: Control group- no DM (n = 464), Metformin group- DM + MI (n = 88) and No-Metformin group- DM + MI (n = 168). First, we compared Metformin and No-Metformin groups to the Control group. Second, we performed propensity-score matching in patients with DM, and compared Metformin to No-Metformin groups. RESULTS: All-cause 30-day and 12-month mortality was significantly higher in the No-Metformin group compared to controls (13.5 vs 9.3% p = 0.03 at 30 days, 23.7 vs 15.9 % p = 0.03 at 12 months). However, all-cause 30-day and 12-month mortality were similar in the Controls and Metformin group (9.3 vs 6.8 % p = 0.93 at 30 days, 15.9 vs 11.4 % p = 0.97 at 12 months). Mean LVEF on presentation (45 % in the three groups) and at follow up (47.84, 46.38 and 43.62 % in Control, Metformin, and No-Metformin groups, respectively) were not statistically different. There were no significant differences in regard to re-hospitalization, re-intervention, new stroke, CHF development, new MI, or identifiable arrhythmias. Metformin was an independent predictor of lower 30-day and 12-month all-cause mortality in patients with DM (HR 0.25, p = 0.02 and HR 0.32, p = 0.01, respectively). In the matched analysis, 30-day all-cause mortality was significantly higher in the No-Metformin compared to the Metformin group (21.1 vs 8.8 %, p = 0.05). However the difference in 12-month all-cause mortality did not reach statistical significance (24.6 vs 15.8 %, p = 0.15). CONCLUSION: This proof-of-concept study shows that use of metformin in patients with DM is associated with lower 30-day all-cause mortality and tendency for a lower 12-month all-cause mortality following MI without discernible improvement in LVEF.

Cardiovasc Drugs Ther. 2015 Jun;29(3):265-75

AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.

Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-b1 (TGF-b1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-b1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-b1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-b1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-b1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.

Diabetes. 2016 Aug;65(8):2295-310

Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial.

BACKGROUND: Our aim was to assess the effects of metformin on menstrual frequency, fasting plasma glucose (FPG), insulin resistance assessed as HOMA-index, weight, waist/hip ratio, blood pressure (BP), serum lipids, and testosterone levels in women with polycystic ovary syndrome (PCOS) METHODS: In a randomized, controlled, double-blinded setup, 56 women aged 18-45 with PCOS were treated with either metformin 850 mg or placebo twice daily for 6 months. After a wash-out period of 3 months participants received the alternate treatment for 6 months. The changes in the measured parameters were analysed by intention-to-treat and per protocol. RESULTS: There were no changes in menstrual frequency. In the intention-to-treat analysis, weight and systolic BP were reduced on metformin treatment (p=0.009 and 0.047, respectively), while high-density lipoprotein (HDL) increased (p=0.001). On placebo, weight and FPG increased (p<0.05). Post-hoc subgrouping according to BMI revealed reductions in testosterone (p=0.013), FPG (p=0.018), insulin (p=0.045) and HOMA-index (p=0.022) in obese women. Per protocol analysis showed the following differences between the changes on placebo and metformin (mean (5 - 95 % percentiles): weight (-4.2 (-7.0, -1.9) kg, p<0.001), FPG (-0.23 (-0.44, -0.01) mmol/l, p=0.041), insulin (-4.17 (-8.10, -0.23) mIU/l, p=0.039) and HOMA index (-1.50 (-2.53, -0.47) mIU/l*mmol/l, p=0.006). Weight, FPG and HOMA index were lower after metformin than after placebo. CONCLUSIONS: Metformin treatment lowered weight and systolic blood pressure and increased HDL in women with PCOS. In post-hoc analysis it increased insulin sensitivity and lowered testosterone in obese women. Non-obese women did not benefit from metformin.

Hum Reprod. 2007 Nov;22(11):2967-73

Skin pigmentation

Mechanisms regulating skin pigmentation: the rise and fall of complexion coloration.

Skin pigmentary abnormalities are seen as aesthetically unfavorable and have led to the development of cosmetic and therapeutic treatment modalities of varying efficacy. Hence, several putative depigmenting agents aimed at modulating skin pigmentation are currently being researched or sold in commercially available products. In this review we will discuss the regulation of processes that control skin complexion coloration. This includes direct inhibition of tyrosinase and related melanogenic enzymes, regulation of melanocyte homeostasis, alteration of constitutive and facultative pigmentation and down-regulation of melanosome transfer to the keratinocytes. These various processes, in the complex mechanism of skin pigmentation, can be regulated individually or concomitantly to alter complexion coloration and thus ameliorate skin complexion diseases.

Int J Mol Sci. 2009 Sep 15;10(9):4066-87

Quasi-drugs developed in Japan for the prevention or treatment of hyperpigmentary disorders.

Excess production of melanin or its abnormal distribution, or both, can cause irregular hyperpigmentation of the skin, leading to melasma and age spots. To date, various quasi-drugs that prevent or improve hyperpigmentary disorders have been developed and officially approved by the Ministry of Health, Labor and Welfare of Japan. Many of these inhibit the activity of tyrosinase, an enzyme required for melanin synthesis, for example, by competitive or non-competitive inhibition of its catalytic activity, by inhibiting its maturation, or by accelerating its degradation. In this review, we categorize the quasi-drugs developed in Japan to prevent or treat hyperpigmentary disorders, or both, and discuss perspectives for future development.

Int J Mol Sci. 2010 Jun 18;11(6):2566-75

The protective role of melanin against UV damage in human skin.

Human skin is repeatedly exposed to UVR that influences the function and survival of many cell types and is regarded as the main causative factor in the induction of skin cancer. It has been traditionally believed that skin pigmentation is the most important photoprotective factor, as melanin, besides functioning as a broadband UV absorbent, has antioxidant and radical scavenging properties. Besides, many epidemiological studies have shown a lower incidence for skin cancer in individuals with darker skin compared to those with fair skin. Skin pigmentation is of great cultural and cosmetic importance, yet the role of melanin in photoprotection is still controversial. This article outlines the major acute and chronic effects of UVR on human skin, the properties of melanin, the regulation of pigmentation and its effect on skin cancer prevention.

Photochem Photobiol. 2008 May-J

Shining light on skin pigmentation: the darker and the brighter side of effects of UV radiation.

The term barrier function as applied to human skin often connotes the physical properties of this organ that provides protection from its surrounding environment. This term does not generally include skin pigmentation. However, skin pigmentation, which is the result of melanin produced in melanocytes residing in the basal layer of the skin and exported to the keratinocytes in the upper layers, serves equally important protective function. Indeed, changes in skin pigmentation are often the most readily recognized indicators of exposure of skin to damaging agents, especially to natural and artificial radiation in the environment. Several recent studies have shed new light on (1) the mechanisms involved in selective effects of subcomponents of UV radiation on human skin pigmentation and (2) the interactive influences between keratinocytes and melanocytes, acting as "epidermal melanin unit," that manifest as changes in skin pigmentation in response to exposure to various forms of radiation. This article provides a concise review of our current understanding of the effects of the nonionizing solar radiation, at cellular and molecular levels, on human skin pigmentation.

Photochem Photobiol. 2012 Sep-Oct;88(5): 1075-82

Hyperpigmentation and melasma.

Facial and neck pigmentations are significant cosmetic problems. They are common in middle-aged women, related to endogenous (hormones) and exogenous factors (cosmetics, perfumes, sun exposure), and often represent paramount causes of emotional distress. Although melasma is the most common cause of facial pigmentation, there are many other forms including drug-induced and postinflammatory hyperpigmentation. We review pathogenesis, clinical and histopathological data, effect on quality of life, and treatment options in facial hyperpigmentation disorders.

J Cosmet Dermatol. 2007 Sep;6(3):195-202

Cellular mechanisms regulating human melanogenesis.

The major differentiated function of melanocytes is the synthesis of melanin, a pigmented heteropolymer that is synthesized in specialized cellular organelles termed melanosomes. Mature melanosomes are transferred to neighboring keratinocytes and are arranged in a supranuclear cap, protecting the DNA against incident ultraviolet light (UV) irradiation. The synthesis and distribution of melanin in the epidermis involves several steps: transcription of melanogenic proteins, melanosome biogenesis, sorting of melanogenic proteins into the melanosomes, transport of melanosomes to the tips of melanocyte dendrites and finally transfer into keratinocytes. These events are tightly regulated by a variety of paracrine and autocrine factors in response to endogenous and exogenous stimuli, principally UV irradiation.

Cell Mol Life Sci. 2009 May;66(9):1493-506

The melanocortin-1 receptor is a key regulator of human cutaneous pigmentation.

The cloning and characterization of the human melanocortin-1 receptor (MC1R) and the demonstration that normal human melanocytes respond to the melanocortins, alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotrophic hormone (ACTH), with increased proliferation and eumelanogenesis had put an end to a long-standing controversy about the role of melanocortins in regulating human cutaneous pigmentation. We have shown that alpha-MSH and ACTH bind the human MC1R with equal affinity, and are equipotent in their mitogenic and melanogenic effects on human melanocytes. We also showed that the activation of the MC1R is important for the melanogenic response of human melanocytes to ultraviolet radiation (UVR). The MC1R is also the principal mediator of the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its own ligands alpha-MSH and ACTH, as well as by UVR and endothelin-1. Recent studies that we conducted on the expression of MC1R variants by human melanocytes and the implications of these variants on the function of the MC1R revealed the following. Human melanocytes homozygous for Arg160Trp mutation in the MC1R demonstrated a significantly reduced response to alpha-MSH. Also, this culture responded poorly to ASP and exhibited an exaggerated cytotoxic response to UVR. Another culture, which was homozygous for Val92Met mutation in the MC1R, demonstrated a normal response to alpha-MSH. Heterozygous mutations that are frequently expressed in various melanocyte cultures did not disrupt MC1R function. These results begin to elucidate the significance of MC1R variants in the function of the receptor. Our data emphasize the significance of a normally functioning MC1R in the response of melanocytes to melanocortins, ASP, and UVR.

Pigment Cell Res. 2000;13 Suppl 8:156-62

Melasma update.

Melasma is an acquired pigmentary disorder characterized by symmetrical hyperpigmented macules on the face. Its pathogenesis is complex and involves the interplay of various factors such as genetic predisposition, ultraviolet radiation, hormonal factors, and drugs. An insight into the pathogenesis is important to devise treatment modalities that accurately target the disease process and prevent relapses. Hydroquinone remains the gold standard of treatment though many newer drugs, especially plant extracts, have been developed in the last few years. In this article, we review the pathogenetic factors involved in melasma. We also describe the newer treatment options available and their efficacy. We carried out a PubMed search using the following terms "melasma, pathogenesis, etiology, diagnosis, treatment" and have included data of the last few years.

Indian Dermatol Online J. 2014 Oct;5(4):426-35