Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo.

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.

Ghrelin protects against rotenone-induced cytotoxicity: Involvement of mitophagy and the AMPK/SIRT1/PGC1α pathway.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra and the deposition of Lewy bodies. Mitochondrial dysfunction, oxidative stress, and autophagy dysfunction are involved in the pathogenesis of PD. Ghrelin is a brain-gut peptide that has been reported that protected against 1-methyl-4-phenyl-1,2,3,6- tetrahydropyran (MPTP)/MPP+-induced toxic effects. In the present work, human neuroblastoma SH-SY5Y cells were exposed to rotenone as a PD model to explore the underlying mechanism of ghrelin. We found that ghrelin inhibited rotenone-induced cytotoxicity, mitochondrial dysfunction, and apoptosis by improving cell viability, increasing the ratio of red/green of JC-1, inhibiting the production of reactive oxidative species (ROS), and regulating Bcl-2, Bax, Cytochrome c, caspase-9, and caspase-3 expression. Besides, ghrelin promoted mitophagy accompanied by up-regulating microtubule-associated protein 1 Light Chain 3B-II/I(LC3B-II/I) and Beclin1 but decreasing the expression of p62. Moreover, ghrelin promoted PINK1/Parkin mitochondrial translocation. Additionally, we investigated that ghrelin activated the AMPK/SIRT1/PGC1α pathway and pharmacological inhibition of AMPK and SIRT1 abolished the cytoprotection of ghrelin, decreased the level of mitophagy, and PINK1/Parkin mitochondrial translocation. Taken together, our findings suggested that mitophagy and AMPK/SIRT1/PGC1α pathways were related to the cytoprotection of ghrelin. These findings provided novel insights into the underlying mechanisms of ghrelin, further mechanistic studies on preclinical and clinical levels are required to be conducted with ghrelin to avail and foresee it as a potential agent in the treatment and management of PD.

Sirt1 ameliorates monosodium urate crystal-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway.

OBJECTIVES: Acute gout is an inflammatory response to MSU crystals. In our previous research, Sirt1 was shown to have an effect in preventing acute gouty inflammation. In the current study, we aimed to investigate the underlying mechanism involving Sirt1 in acute gout. METHODS: The cytological changes and Sirt1 expression in the synovium were observed in patients with acute or intermittent gout. The effect of Sirt1 and its mechanism in gout were studied in macrophages, C57BL/6 mice and Sirt1+/- mice. RESULTS: Sirt1 expression was increased in the peripheral blood mononuclear cells (PBMCs) of patients with acute gout but not in the chronic tophus tissue. The arthritis score and numbers of inflammatory cells in injured paw tissue from murine gout models were upregulated in Sirt1+/- mice compared with wild-type mice. A PCR array of the paw tissue from murine gout models indicated that Sirt1 activation might attenuate MSU-induced inflammation by altering the polarization state of macrophages. Furthermore, in patients with acute gout, the phagocytosis of MSU crystals by a macrophage was found in a smear of the joint fluid and large amounts of macrophages were also found in the synovium. The activation of Sirt1 in gouty mice actually decreased the tendency toward M1 polarization. The inhibition of PI3K/Akt partially blocked the anti-inflammatory effect of Sirt1 and the translocation of STAT6, and phosphorylated STAT6 expression was decreased in RAW 264.7 cells treated with MSU crystals. CONCLUSION: Our studies revealed that Sirt1 ameliorates MSU-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway.

Integration of Melatonin Related Redox Homeostasis, Aging, and Circadian Rhythm.

Circadian rhythms (CRs) are intrinsic clocks organizing the behavior and physiology of organisms. These clocks are thought to have coevolved with cellular redox regulation. Metabolism, redox homeostasis, circadian clock, and diet offer insights into aging. Mitochondria play a pivotal role in redox homeostasis, CR, and aging. Melatonin is synthesized in mitochondria, is the key regulator of CRs, and shows substantial antioxidative effects. Melatonin levels tend to decrease significantly with advancing age. Recent reports showed that disruptions of CRs may render aging populations even more susceptible to age-related disorders. Recent and high-quality articles investigating CR, redox homeostasis, aging, and their relationship during aging process were included. Putting special emphasis on the possible effects of melatonin on redox homeostasis and mitochondrial dynamics, recent clinical evidence highlighting the importance of circadian mechanisms was utilized. A deeper understanding of the role of altered mitochondrial redox homeostasis in the pathogenesis of age-related disorders and its relationship with CR could offer novel therapeutic interventions. Chronotherapy, a therapeutic approach considering CR of organisms and best therapeutic times, could potentially reduce side effects and improve therapeutic efficiency. Redox homeostasis, energy metabolism, and CR are all intertwined.

SIRT1/AMPK and Akt/eNOS signaling pathways are involved in endothelial protection of total aralosides of Aralia elata (Miq) Seem against high-fat diet-induced atherosclerosis in ApoE-/- mice.

Total aralosides of Aralia elata (Miq) Seem (TASAESs) possess multiple pharmacological activity, such as anti-inflammation, antioxidation, and antiapoptosis. However, there is no literature reporting the antiatherosclerotic effect and mechanism of TASAES so far. The aim of this study was to investigate the antiatherosclerotic effects in high-fat diet-induced ApoE-/- mice and potential mechanism of TASAES in ox-LDL-injured endothelial cells. In vivo assay, our data demonstrated that TASAES significantly reduced the atherosclerotic plaque size and caspase-3 expression level in aortic valve. In vitro, we found that TASAES could increase endothelial cell viability, attenuated mitochondrial membrane potential depolarization, and endothelial cells apoptosis. In addition, we found that TASAES could activate SIRT1/AMPK and Akt/eNOS signaling pathways. Importantly, EX527, SIRT1 siRNA, and LY294002, Akt siRNA, remarkably abolished the antiapoptotic effects of TASAES. In conclusion, this study demonstrated that SIRT1/AMPK and Akt/eNOS signaling pathways are involved in endothelial protection of TASAES against atherosclerotic mice, suggesting that TASAES is a candidate drug for atherosclerosis treatment.

Maternal eicosapentaenoic acid feeding promotes placental angiogenesis through a Sirtuin-1 independent inflammatory pathway.

Maternal overnutrition or obesity is associated with a wide range of metabolic disorders and may impair placental angiogenesis. Previous studies have shown that n-3 polyunsaturated fatty acids (PUFA) promote fetal growth in both rodents and humans. Whether n-3 PUFA impacts on placental angiogenesis in vivo remains unclear. Sirtuin-1 (SIRT1) is a protein deacetylase that plays an important role in regulating inflammation and endothelial function. Little information is available on a putative role of SIRT1 in placental angiogenesis. The goal of this study was to examine the capability of eicosapentaenoic acid (EPA) to regulate angiogenesis and inflammation in SIRT1-deficient placentas. In the present study, male and female SIRT1+/- mice were mated overnight, then primiparous SIRT1+/- mice were fed a 60% kcal HFD or equienergy EPA diet (4.4% EPA-ethyl ester). We found that the EPA diet significantly improved maternal insulin sensitivity and decreased plasma levels of inflammatory factors IL-6 and TNFα concentration. Moreover, EPA treatment promoted fetus growth and placental angiogenesis, and inhibited the hypoxia inducible factor-1α(HIF1α) pathway. SIRT1 deficiency exhibited an opposite effect, leading to decrease in placental angiogenesis and fetal weight. No significant effect was observed between diet and genotype. Here, we reported for the first time that EPA treatment increased the expression of placental inflammatory genes and promoted translocation of NFκB into the nucleus. On the contrary, SIRT1-deficient placentas showed a decreased inflammation state. Together, these data demonstrate a previously unknown role of EPA to promote placental angiogenesis through a SIRT1 independent inflammatory pathway.

Resveratrol Influences Pancreatic Islets by Opposing Effects on Electrical Activity and Insulin Release.

SCOPE: Resveratrol is suggested to improve glycemic control by activation of sirtuin 1 (SIRT1) and has already been tested clinically. Our investigation characterizes the targets of resveratrol in pancreatic beta cells and their contribution to short- and long-term effects on insulin secretion. METHODS AND RESULTS: Islets or beta cells are isolated from C57BL/6N mice. Electrophysiology is performed with microelectrode arrays and patch-clamp technique, insulin secretion and content are determined by radioimmunoassay, cAMP is measured by enzyme-linked immunosorbent assay, and cytosolic Ca2+ concentration by fluorescence methods. Resveratrol (25 µmol L-1 ) elevates [Ca2+ ]c and potentiates glucose-stimulated insulin secretion. These effects are associated with increased intracellular cAMP and are sensitive to the SIRT1 blocker Ex-527. Inhibition of EPAC1 by CE3F4 also abolishes the stimulatory effect of resveratrol. The underlying mechanism does not involve membrane depolarization as resveratrol even reduces electrical activity despite blocking KATP channels. Importantly, after prolonged exposure to resveratrol (14 days), the beneficial influence of the polyphenol on insulin release is lost. CONCLUSION: Resveratrol addresses multiple targets in pancreatic islets. Potentiation of insulin secretion is mediated by SIRT1-dependent activation of cAMP/EPAC1. Considering resveratrol as therapeutic supplement for patients with type 2 diabetes mellitus, the inhibitory influence on electrical excitability attenuates positive effects.

Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21.

BACKGROUND AND PURPOSE: Berberine, a compound from rhizome coptidis, is traditionally used to treat gastrointestinal infections, such as bacterial diarrhoea. Recently, berberine was shown to have hypoglycaemic and hypolipidaemic effects. We investigated the mechanisms by which berberine regulates hepatic lipid metabolism and energy expenditure in mice. EXPERIMENTAL APPROACH: Liver-specific SIRT1 knockout mice and their wild-type littermates were fed a high-fat, high-sucrose (HFHS) diet and treated with berberine by i.p. injection for five weeks. Mouse primary hepatocytes and human HepG2 cells were treated with berberine and then subjected to immunoblotting analysis and Oil Red O staining. KEY RESULTS: Berberine attenuated hepatic steatosis and controlled energy balance in mice by inducing autophagy and FGF21. These beneficial effects of berberine on autophagy and hepatic steatosis were abolished by a deficiency of the nutrient sensor SIRT1 in the liver of HFHS diet-fed obese mice and in mouse primary hepatocytes. SIRT1 is essential for berberine to potentiate autophagy and inhibit lipid storage in mouse livers in response to fasting. Mechanistically, the berberine stimulates SIRT1 deacetylation activity and induces autophagy in an autophagy protein 5-dependent manner. Moreover, the administration of berberine was shown to promote hepatic gene expression and circulating levels of FGF21 and ketone bodies in mice in a SIRT1-dependent manner. CONCLUSIONS AND IMPLICATIONS: Berberine acts in the liver to regulate lipid utilization and maintain whole-body energy metabolism by mediating autophagy and FGF21 activation. Hence, it has therapeutic potential for treating metabolic defects under nutritional overload, such as fatty liver diseases, type 2 diabetes and obesity.

Melatonin at pharmacological concentrations suppresses osteoclastogenesis via the attenuation of intracellular ROS.

Osteoporosis is linked to age-related decline of melatonin production; however, the direct effects of melatonin on osteoclastogenesis remain unknown. Our study demonstrates that melatonin at pharmacological concentrations, rather than at physiological concentrations, significantly inhibits osteoclastogenesis. Melatonin-mediated anti-osteoclastogenesis involves a reactive oxygen species (ROS)-mediated but not a silent information regulator type 1 (SIRT1)-independent pathway. INTRODUCTION: Osteoporosis is a bone disorder linked to impaired bone formation and excessive bone resorption. Melatonin has been suggested to treat osteoporosis due to its beneficial actions on osteoblast differentiation. However, the direct effects of melatonin on osteoclastogenesis in bone marrow monocytes (BMMs) remain unknown. This study was to investigate whether melatonin at either physiological or pharmacological concentrations could affect osteoclast differentiation. METHODS: Primary BMMs were isolated from the femurs and tibias of C57BL/6 mice and were induced toward multinucleated osteoclasts, in the presence of melatonin at either physiological (0.01 to 10 nM) or pharmacological (1 to 100 µM) concentrations. Tartrate-resistant acid phosphatase (TRAP) staining was used to label multinucleated osteoclasts and the levels of osteoclast-specific genes were evaluated. To further explore the underlying mechanisms, the roles of silent information regulator type 1 (SIRT1) and reactive oxygen species (ROS) were evaluated. RESULTS: We found that melatonin at pharmacological concentrations, rather than at physiological concentrations, significantly inhibited osteoclast formation in a dose-dependent manner. The number of TRAP-positive cells and the gene expression of osteoclast-specific markers were significantly downregulated in melatonin-treated BMMs. The melatonin-mediated repression of osteoclast differentiation involved the inhibition of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. The treatment with SIRT1 inhibitors did not affect osteoclast differentiation but, when supplemented with exogenous hydrogen peroxide, a partial rescue of melatonin-suppressed osteoclastogenesis was observed. CONCLUSION: Melatonin at pharmacological doses directly inhibited osteoclastogenesis of BMMs by a ROS-mediated but not a SIRT1-independent pathway.

Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.

Hypertension-induced renal fibrosis contributes to the progression of chronic kidney disease, and apigenin, an anti-hypertensive flavone that is abundant in celery, acts as an agonist of transient receptor potential vanilloid 4 (TRPV4). However, whether apigenin reduces hypertension-induced renal fibrosis, as well as the underlying mechanism, remains elusive. In the present study, the deoxycorticosterone acetate (DOCA)-salt hypertension model was established in male Sprague-Dawley rats that were treated with apigenin or vehicle for 4 weeks. Apigenin significantly attenuated the DOCA-salt-induced structural and functional damage to the kidney, which was accompanied by reduced expression of transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signaling pathway and extracellular matrix proteins. Immunochemistry, cell-attached patch clamp and fluorescent Ca2+ imaging results indicated that TRPV4 was expressed and activated by apigenin in both the kidney and renal cells. Importantly, knockout of TRPV4 in mice abolished the beneficial effects of apigenin that were observed in the DOCA-salt hypertensive rats. Additionally, apigenin directly inhibited activation of the TGF-ß1/Smad2/3 signaling pathway in different renal tissues through activation of TRPV4 regardless of the type of pro-fibrotic stimulus. Moreover, the TRPV4-mediated intracellular Ca2+ influx activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, which inhibited the TGF-ß1/Smad2/3 signaling pathway. In summary, dietary apigenin has beneficial effects on hypertension-induced renal fibrosis through the TRPV4-mediated activation of AMPK/SIRT1 and inhibition of the TGF-ß1/Smad2/3 signaling pathway. This work suggests that dietary apigenin may represent a promising lifestyle modification for the prevention of hypertension-induced renal damage in populations that consume a high-sodium diet.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

miR-27b overexpression improves mitochondrial function in a Sirt1-dependent manner.

Resveratrol improves mitochondrial function, and recent evidences demonstrate that miRNAs play important roles in certain effects of resveratrol. In the current study, we found that a microRNA, miR-27b, was significantly induced in a dose-dependent way in skeletal muscle and C2C12 myoblast treated with resveratrol. Our results showed that overexpression of miR-27b could mimic the effects of resveratrol on improving mitochondrial function and glucose uptake in skeletal muscle cells. Subsequently, we found that FOXO1 was a potential target of miR-27b, and the effects of resveratrol on mitochondrial function were significantly affected after inhibition of miR-27b. Moreover, the effects of miR-27b on mitochondrial function were lost after inhibition of Sirt1, although miR-27b and FOXO1 expression were not influenced. Taken together, these data suggested that overexpression of miR-27b could benefit mitochondrial function, while the effects of overexpressed miR-27b were Sirt1-dependent.

Ketosis may promote brain macroautophagy by activating Sirt1 and hypoxia-inducible factor-1.

Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.

Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization.

Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.

Novel role of resveratrol: suppression of high-mobility group protein box 1 nucleocytoplasmic translocation by the upregulation of sirtuin 1 in sepsis-induced liver injury.

BACKGROUND: High-mobility group protein box 1 (HMGB1) is essential in the response to injury during sepsis. We hypothesized that resveratrol (RESV) administration would inhibit nuclear-cytoplasmic HMGB1 translocation in hepatocytes, which is associated with sirtuin 1 (SIRT1) upregulation. We investigated the regulatory role of SIRT1 in HMGB1 nucleocytoplasmic translocation and its effect on sepsis-induced liver injury. METHODS: Rats were randomly assigned to pretreatment with RESV (60 mg/kg per day), nicotinamide (60 mg/kg per day), or vehicle (olive oil), which was administered by gavage for 3 days directly before cecal ligation and puncture was performed to induce sepsis. Parallel control groups were established. Rats were killed 24 h after surgery, and cytokine production, histology, apoptosis, SIRT1, serum HMGB1, nuclear and cytoplasmic HMGB1/ac-HMGB1, and the interaction between SIRT1 and HMGB1 were evaluated. In vitro evaluations were performed in human liver L02 cells subjected to lipopolysaccharide-induced injury, and siRNA-mediated SIRT1 knockdown experiments were performed. RESULTS: Sepsis-induced serum aminotransferase activities and proinflammatory chemokine levels were reduced by RESV pretreatment, which also improved liver histological parameters in association with SIRT1 upregulation. Resveratrol inhibited HMGB1 cytoplasmic translocation. Nicotinamide, an SIRT1 inhibitor, reduced the SIRT1-mediated suppression of HMGB1 translocation and aggravated cecal ligation and puncture-induced liver damage. Sirtuin 1 knockdown in vitro confirmed that RESV increased the SIRT1-mediated repression of HMGB1 translocation. In vivo, SIRT1 and HMGB1 physically interacted in the nucleus, and SIRT1 regulated HMGB1 acetylation in response to septic liver injury. CONCLUSIONS: Resveratrol protects against sepsis-induced liver injury through the SIRT1-mediated HMGB1 nucleocytoplasmic translocation pathway, a new potential therapeutic target in sepsis-induced liver injury.

Dietary restriction in cerebral bioenergetics and redox state.

The brain has a central role in the regulation of energy stability of the organism. It is the organ with the highest energetic demands, the most susceptible to energy deficits, and is responsible for coordinating behavioral and physiological responses related to food foraging and intake. Dietary interventions have been shown to be a very effective means to extend lifespan and delay the appearance of age-related pathological conditions, notably those associated with brain functional decline. The present review focuses on the effects of these interventions on brain metabolism and cerebral redox state, and summarizes the current literature dealing with dietary interventions on brain pathology.

Sirtuin 1-mediated inhibition of p66shc expression alleviates liver ischemia/reperfusion injury.

OBJECTIVES: Ischemia/reperfusion is a leading cause of liver damage after surgical intervention, trauma, and transplantation. It has been reported that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 attenuates myocardial, cerebral, and renal ischemia/reperfusion damage. This study aimed to investigate the involvement of sirtuin 1-mediated p66shc inhibition in liver ischemia/reperfusion and explore the effect of carnosic acid and ischemic preconditioning on liver ischemia/reperfusion-induced damage. DESIGN: Laboratory investigation. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats and HepG2 cells. INTERVENTIONS: The rats were subjected to 45 minutes of ischemia to 70% of the liver, followed by 3-hour reperfusion. The HepG2 cells were subjected to hypoxia/reoxygenation-induced injury. MEASUREMENTS AND MAIN RESULTS: In the rats with liver ischemia/reperfusion injury, carnosic acid pretreatment and ischemic preconditioning dramatically reduced the serum aminotransferase activity and proinflammatory chemokine levels and improved the liver histological evaluations. Carnosic acid and ischemic preconditioning also increased manganese superoxide dismutase and Bcl-xL, but down-regulated cleaved caspase-3. Interestingly, the protective effect of carnosic acid and ischemic preconditioning was positively associated with sirtuin 1 activation. By contrast, p66shc, a kinase that promotes oxidative injury and apoptosis, was inhibited by carnosic acid and ischemic preconditioning. Sirtuin 1 small interfering RNA knockdown experiments confirmed that carnosic acid increased sirtuin 1-mediated repression of p66shc in HepG2 cells and that the protective effect of carnosic acid against hypoxia/reoxygenation injury was inhibited by the sirtuin 1 inhibitor nicotinamide. These results suggest that carnosic acid protects hepatocytes from hypoxia/reoxygenation damage through sirtuin 1-mediated p66shc suppression. To support this notion, we further demonstrated that the sirtuin 1 activator resveratrol achieved a protective effect similar to that of carnosic acid against hypoxia/reoxygenation injury, whereas sirtuin 1 small interfering RNA and nicotinamide had the opposite effect. CONCLUSIONS: Carnosic acid and ischemic preconditioning protect against ischemia/reperfusion-induced liver injury. Mechanistically, the protective effect involves the sirtuin 1-mediated inhibition of p66shc, suggesting that this pathway is a novel potential therapeutic target for protecting the liver from ischemia/reperfusion injury.

The epigenetic language of circadian clocks.

Epigenetic control, which includes DNA methylation and histone modifications, leads to chromatin remodeling and regulated gene expression. Remodeling of chromatin constitutes a critical interface of transducing signals, such as light or nutrient availability, and how these are interpreted by the cell to generate permissive or silenced states for transcription. CLOCK-BMAL1-mediated activation of clock-controlled genes (CCGs) is coupled to circadian changes in histone modification at their promoters. Several chromatin modifiers, such as the deacetylases SIRT1 and HDAC3 or methyltransferase MLL1, have been shown to be recruited to the promoters of the CCGs in a circadian manner. Interestingly, the central element of the core clock machinery, the transcription factor CLOCK, also possesses histone acetyltransferase activity. Rhythmic expression of the CCGs is abolished in the absence of these chromatin modifiers. Here we will discuss the evidence demonstrating that chromatin remodeling is at the crossroads of circadian rhythms and regulation of metabolism and cellular proliferation.

Resveratrol vs. calorie restriction: data from rodents to humans.

Calorie restriction extends lifespan and confers metabolic benefits similar to the effect of lifestyle interventions. Poor compliance to long-term dietary restriction, however, hinders the success of this approach. Evidence is now persuasive for a role of resveratrol supplementation (a polyphenol in red grapes) as potential alternative to calorie restriction. This review summarizes the latest literature on the effects and the molecular mechanisms by which calorie restriction and resveratrol confer health benefits. Resveratrol activates SIRT1 and the associated improvement in energy utilization and insulin sensitivity closely resembles the benefits of calorie restriction. Current data largely support resveratrol as a potential calorie restriction mimetic to improve metabolic and probably functional health. Future studies which characterize the bioavailability and efficacy of resveratrol supplementation are critical to provide evidence for its long-term health benefits.

Sirtuin deacylases: a molecular link between metabolism and immunity.

Lysine deacetylation by the NAD(+)-dependent family of sirtuins has been recognized as an important post-translational modification regulating a wide range of cellular processes. These lysine deacetylases have attracted much interest based on their ability to promote survival in response to stress. Sirtuins require NAD(+) for their enzymatic activity, suggesting that these enzymes may represent molecular links between cell metabolism and several human disorders, including diabetes and cancer. Inflammation represents a pathological situation with clear connections to metabolism and aging in humans, raising the possibility that sirtuins may also play an important role during a normal and/or a pathological immune response. A growing body of data has confirmed the immunomodulatory properties of sirtuins, although often with contrasting and opposing conclusions. These observations will be summarized herein and the possible strategies that may lead to the development of novel therapeutic approaches to treat inflammation briefly discussed.