Sirtuin Activity Research Articles

Sulforaphane-cisplatin combination inhibits the stemness and metastatic potential of TNBCs via down regulation of sirtuins-mediated EMT signaling axis

BackgroundSulforaphane (SFN) is a naturally occurring organosulfur compound found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage. SFN is known for its multiple therapeutic properties, such as HDAC inhibitory, chemo preventive and anti-cancer effects. Cisplatin (CIS) has limited effect against metastatic triple-negative breast cancer (TNBC). Additionally, CIS impose severe side effects to normal cells, and later TNBC cells develops resistance. Studies suggest that the overexpression of sirtuins (SIRTs) promotes CIS resistance and metastasis by activating epithelial-to-mesenchymal transition (EMT) pathway in TNBC. PurposeIn view of the above information, we investigated the therapeutic efficacy of SFN, in combination with CIS against TNBC metastasis and CIS resistance. MethodsThe anti-cancerous effect of SFN-CIS combination on human TNBC cell lines was demonstrated by utilizing MTT assay and, apoptosis and cell cycle assay followed by FACS analysis. The synergistic effect of SFN-CIS combination on the experimental metastasis was demonstrated by utilizing migration, invasion, chemotaxis, mammosphere and colony formation assay on human TNBC MDA-MB-231 and MDA-MB-468 cells. The role of SIRTs-mediated EMT signaling axis in the metastasis and chemoresistance was investigated by western blotting technique as well as sirtuin activity tests. This was further validated by using Chromatin immunoprecipitation (ChIP) analysis. ResultsWe found that SFN-CIS combination synergistically inhibits cellular growth of MDA-MB-231 and MDA-MB-468 cells. More importantly, SFN was found to protect normal kidney cells from CIS-induced toxicity. Further, SFN-CIS combination was found to synergistically inhibit metastatic-events via significantly altering EMT markers which was further associated with the suppression of SIRTs functions in TNBC cells. ChIP analysis validated that SFN-CIS combination suppresses EMT mechanism through altered chromatin modifications at E-cadherin promoter resulting in its re-expression. ConclusionThe results of the current study suggests that CIS when supplemented with SFN, inhibits metastasis and stemness potential of TNBC cells by down regulating SIRTs-mediated EMT cascade. Overall this study affirms that, this novel combination could be a promising strategy against SIRT-mediated TNBC metastasis and CIS-resistance.

Melatonin Alleviates Cardiac Dysfunction Via Increasing Sirt1-Mediated Beclin-1 Deacetylation and Autophagy During Sepsis.

Cardiac dysfunction is a major cause leading to multiple organ failure in sepsis. Beclin-1-dependent autophagy has been evidenced to exert protective effects on hearts in sepsis. However, the mechanisms on how Beclin-1 and autophagy are regulated remains enigmatic. To explore the detailed mechanisms controlling Beclin-1-dependent autophagy in septic heart and whether melatonin could protect against sepsis via regulating cardiac autophagy, adult Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Rats were intraperitoneally administrated with 30 mg/kg melatonin within 5-min post-CLP surgery. Our data showed that sepsis induced Becline-1 acetylation and inhibited autophagy in hearts, resulting in impaired cardiac function. However, melatonin treatment facilitated Beclin-1 deacetylation and increased autophagy in septic hearts, thus improved cardiac function. Moreover, melatonin increased the expression and activity of Sirtuin 1 (Sirt1), and inhibition of Sirt1 abolished the protective effects of melatonin on Beclin-1 deacetylation and cardiac function. In conclusion, increased Beclin-1 acetylation was involved in impaired autophagy in septic hearts, while melatonin contributed to Beclin-1 deacetylation via Sirt1, leading to improved autophagy and cardiac function in sepsis. Our study sheds light on the important role of Beclin-1 acetylation in regulating autophagy in sepsis and suggests that melatonin is a potential candidate drug for the treatment of sepsis.

Resveratrol reverses the programmed high-susceptibility to non-alcoholic fatty liver disease by targeting the hepatic SIRT1-SREBP1c pathway in prenatal ethanol-exposed rat offspring.

An increased susceptibility to non-alcoholic fatty liver disease (NAFLD) in female rat offspring that experienced prenatal ethanol exposure (PEE) has been previously demonstrated. The present study further investigated the potential mechanism. Based on the results from both fetal and adult studies of offspring rats that experienced PEE (4 g/kg/day), the fetal weight, serum glucose and triglyceride levels decreased significantly and hepatocellular ultra-structure was altered. Fetal livers exhibited inhibited expression and activity of sirtuin 1 (SIRT1), enhanced expression of lipogenic genes: sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FASN), acetyl-coenzyme A carboxylase α (ACCα), stearyl-coenzyme A desaturase 1 (SCD1). In adult offspring fed with high-fat diet, the PEE offspring revealed obviously catch-up growth, increased food intake, elevated serum metabolic phenotypes, suppressed hepatic SIRT1-SREBP1c pathway, and formation of NAFLD. Resveratrol (the chemical activator of SIRT1) could remarkably reverse the serum metabolic phenotypes and alleviate the hepatocyte steatosis in relation to the PEE offspring through activating the hepatic SIRT1-SREBP1c pathway. Therefore, increased susceptibility to diet-induced NAFLD in PEE offspring appears to be mediated by intrauterine programming of hepatic lipogenesis via the SIRT1-SREBP1c pathway. This altered programming effect could partially be reversed by resveratrol intervention after birth in PEE offspring rats.

Research Article Short Alkyl Chain-Length Resorcinol Olivetol Protects Against Obesity with Mitochondrial Activation by Pgc-1α Deacetylation

Summary: The deacetylation of PGC-1α by the activation of sirtuins (SIRTs) with resveratrol (Res) promotes mitochondrial function and metabolic homeostasis. However, Res may not have the ability to specifically promote the deacetylation of PGC-1α by activating SIRT1. We investigated whether the specific deacetylation of PGC-1α is enhanced by increasing the rate of the enzyme-catalyzed reaction of SIRT1 and affects mitochondrial function and metabolic homeostasis. We previously demonstrated that alkylresorcinols (ARs) raised the Vmax of recombinant SIRT1 for NAD+ and extended the Drosophila melanogaster lifespan. Herein, we observed that treatment with the short alkyl chain-length resorcinol olivetol protected mice against diet-induced obesity with SIRT1 activation for PGC-1α. These olivetol effects were superior to Res for all parameters. Olivetol effects were associated with an induction of genes for lipid metabolism and were largely explained by PGC-1α deacetylation. Olivetol specifically activated PGC-1α deacetylation, increased mitochondrial numbers, and accelerated fat burning.

Live-Cell Imaging of Sirtuin Activity Using a One-Step Fluorescence Probe.

Sirtuins (SIRTs) are a family of NAD+-dependent histone deacetylases (HDACs). In mammals, dysfunction of SIRTs is associated with age-related metabolic diseases, cancers, and even aging. Therefore, the detection of SIRT activity in living cells or tissues would be helpful for diagnosis of a wide range of SIRT-associated diseases. Here, we present methodology to measure SIRT activity in living cells by using our newly developed SIRT fluorescence probe, KST-F-DA.

Nicotinamide Supplementation Attenuates Renal Interstitial Fibrosis via Boosting the Activity of Sirtuins

Background: Progressive tubulointerstitial fibrosis (TIF) is the final common pathway leading to ESRD. There is an urgent need to develop effective approaches slowing the progression of TIF. Previous studies showed that systemic supplementation of nicotinamide (NAM) increases renal NAD⁺ and reverses ischemic-reperfusion induced acute renal injury. However, the role and mechanism of NAM in TIF has been unclear. Methods: In vivo, we injected NAM (0.25 mg/g) 3 days before unilateral ureter obstruction (UUO) till day 7 post-operation. In vitro, mouse primary proximal tubular epithelial cells (PTCs), rat renal NRK-49F cells, and human renal proximal tubular epithelial cell (HK-2) were pretreated with the indicated concentration of NAM 1 h before incubation with transform growth factor-β1 (TGF-β1) or aristolochic acid (AA) for 24 or 48 h. To evaluate the role of sirtuins (SIRTs), PTCs were pretreated with EX527 or resveratrol 30 min before incubation with NAM and TGF-β1. Results: In the present study, we demonstrated that NAM supplementation prevented UUO-induced TIF, and AA-induced renal injury. NAM also decreased the expression of pro-fibrotic proteins and pro-inflammatory cytokines (IL-6 and TNF-α) and attenuated interstitial inflammation. In vitro experiment showed that, NAM inhibited AA-induced G2/M arrest of HK-2 cells by downregulating the expression of cyclin G1, a target gene of p53. In addition, NAM inhibited TGF-β1-induced fibroblast proliferation and activation shown as downregulated expression of collagen I, fibronectin, PCNA, cyclin D1, IL-6, and TNF-α. NAM decreased the acetylation of Smad3 and p53. EX527, an inhibitor of SIRT1, reversed the effect of NAM on TGF-β1-induced matrix protein production. However, resveratrol, a SIRT1 activator, did not further boost the protective effect of NAM on reducing matrix protein production. Conclusions: Taken together, these data indicate that NAM supplementation could inhibit TIF at least partially by boosting the activity of sirtuins.

Lapachol-Induced Upregulation of Sirt1/Sirt3 is linked with Improved Skin Wound Healing in Alloxan-induced Diabetic Mice.

Timely repair of damaged skin is very important to maintain the integrity and homeostasis of skin, but the wound healing process is compromised in diabetic patients due to several extrinsic and intrinsic factors thus lead to leg amputation and death eventually. Sirtuins, a family of seven conserved proteins are known to be associated with pathophysiological processes of the skin. The most important among them are sirt1and sirt3 involved in cell regeneration and cell survival. Naphthoquinone derivatives have a wide range of therapeutic properties, but the potential diabetic wound healing activity of lapachol has not been identified yet. The present study thus aimed to investigate the wound healing effects of lapachol in a diabetic mouse model. Diabetic wounded mice were divided into 3 groups; vehicle, lapachol 0.05%, and lapachol 0.1%. Skin samples collected from diabetic wounded mice on different time points after treatment for 10 consecutive days were subjected to downstream analysis by western blot, ELISA and histology. Lapachol treatment was found to enhance the expression of sirt1/sirt3 and other proteins involved in cell migration and blood vessel formation. The tissue development rate was increased by lapachol treatment with better collagen deposition. Interestingly, lapachol treatment also gave rise to a high concentration of growth factors resulting in speedy and timely recovery of injured skin. In summary, our findings suggest that lapachol promotes efficient wound healing in a diabetic mouse model by increasing the expression of sirt1 and sirt3 and other proteins related to wound repair and skin regeneration including α-PAK, RAC1/CDC42, VEGF and growth factors viz PDGF and VEGF. This research work finds a novel potential activator of sirtuins in the form of lapachol and depicts the role of activated sirtuins in diabetic wound healing.

Research progress of sirtuins in renal and cardiovascular diseases.

Sirtuins are a family of nicotinamide adenine dinucleotide+-dependent enzymes catalyzing target protein deacetylation to modulate cellular metabolism, response to oxidative stress and inflammation, senescence, autophagy and apoptosis. In this review, we provide an overview of recent studies regarding the alterations and roles of sirtuins in a variety of renal and cardiovascular diseases. We are also going to highlight activators and inhibitors of sirtuins in the prevention of these diseases. This will help us to understand how this field may change in the future. Recent studies have elucidated how physical or diseased conditions alter the expressions and enzyme activity of sirtuins and expounded sexual differences in sirtuins functions. In addition, interventions by targeting sirtuins have been applied in preclinical and clinical studies to prevent or slow the development of related diseases. The advantages of female sex in renal and cardiovascular diseases are partially due to the expression and function of sirtuins. Estrogen activates sirtuins and in turn sirtuins promote estrogen receptor signaling. In addition, the hypoglycemic agents, sodium-glucose cotransporter 2 inhibitors protect against diabetic nephropathy at least in part via activating SIRT-1. Although several compounds targeted sirtuins are promising drug candidates in a variety of renal and cardiovascular diseases, well designed large clinical trials are still required to identify their efficacy and safety.

High calorie diet background alters the expression of sirtuins in the testes of mice under caloric restriction

Caloric restriction (CR) is considered one of the most efficient interventions that extend lifespan and healthspan by delaying the onset of many age-related diseases in a variety of organisms. CR appears to activate sirtuins, which in turn modulate a wide range of cellular activities related to pathophysiological conditions such as stress and inflammation, DNA repair, apoptosis, and the processes of aging.In this work we aimed to determine whether CR can counteract the detrimental effects of a high-calorie diet (HCD) on the mRNA and protein levels of sirtuins in testes of a murine experimental model.We report in here that short-term CR increased the mRNA and protein expression of all sirtuins in the animals previously feed standard food. However, short-term CR failed to activate sirtuins in the animals previously fed an HCD for a period of 4 months. Moreover, histologic analysis of adipocyte/lipid infiltration by oil red O assay, in the mice testis, showed that the highest lipid content was found in the animals with an HCD background, exposed to CR.Mechanistic actions, as well as substrates that modify sirtuins transcriptional and translational expression in the mice male reproductive system, are still not well understood. We believe that deeper insights into how the potential selective modulation of SIRT family members and sirtuins activators affect the different organs, individually and as a whole system will eventually led to the development of preventative and therapeutic strategies to promote health and longevity.

The Effect of Repeated Whole-Body Cryotherapy on Sirt1 and Sirt3 Concentrations and Oxidative Status in Older and Young Men Performing Different Levels of Physical Activity.

Background: The activity of antioxidant enzymes and sirtuins (Sirt) decreases along with age, which is counteracted by aerobic training. Sirtuins increase antioxidant defence. Whole-body cryotherapy (WBC) increases total antioxidant capacity (TAC) in young men. The aim of our study was to assess the impact of 24 WBC treatments on the blood concentration of selected sirtuins and the level of antioxidant defence as well as oxidative stress index of training and non-training men depending on age. Methods: The study involved 40 males. In each group, there were 10 non-training older and young men (60 NTR and 20 NTR), and 10 older and young long-distance runners (60 TR, 20 TR). During an 8-week period, participants underwent 24 WBC treatments (3 min −130 °C), which were performed three times a week (Monday, Wednesday, Friday). The concentrations of Sirt1, Sirt3, TAC, total oxidative status and the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in the blood were determined before 1 WBC and after 1 WBC, 12 WBC and 24 WBC. Results: After 1 WBC, the activity of GPx and the concentration of Sirt1 and TAC in 60 TR and TAC in 60 NTR increased. After 12 WBC, the level of Sirt1 in 20 NTR and SOD in 20 TR increased. After 24 WBC, the level of Sirt1 increased in 60 TR and in 20 NTR, Sirt3 in 60 TR and SOD in 20 TR. Conclusions: Cryogenic temperatures increase blood levels of Sirt1 and Sirt3 and systemic antioxidant defence in men, but the effect is dependent on age, level of performed physical activity and the number of applied treatments.

Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT

Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.

Development of Second Generation Activity-Based Chemical Probes for Sirtuins.

NAD+ (nicotinamide adenine dinucleotide)-dependent protein deacylases, namely, the sirtuins, are important cell adaptor proteins that alter cell physiology in response to low calorie conditions. They are thought to mediate the beneficial effects of calorie restriction to extend longevity and improve health profiles. Novel chemical probes are highly desired for a better understanding of sirtuin’s roles in various biological processes. We developed a group of remarkably simple activity-based chemical probes for the investigation of active sirtuin content in complex native proteomes. These probes harbor a thioacyllysine warhead, a diazirine photoaffinity tag, as well as a terminal alkyne bioorthogonal functional group. Compared to their benzophenone-containing counterparts, these new probes demonstrated improved labeling efficiency and sensitivity, shortened irradiation time, and reduced background signal. They were applied to the labeling of individual recombinant proteins, protein mixtures, and whole cell lysate. These cell permeable small molecule probes also enabled the cellular imaging of sirtuin activity change. Taken together, our study provides new chemical biology tools and future drug discovery strategies for perturbing the activity of different sirtuin isoforms.

Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis

SummaryThe processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD+) that is due to dysregulation of NAD+ homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD+-synthesizing enzymes is unaltered. Boosting NAD+ via genetic or pharmacological CD38 targeting or NAD+ precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. In mechanistic experiments, CD38 was found to reduce NAD+ levels and sirtuin activity to augment cellular fibrotic responses, while inhibiting CD38 had the opposite effect. Thus, we identify CD38 upregulation and resulting disrupted NAD+ homeostasis as a fundamental mechanism driving fibrosis in SSc, suggesting that CD38 might represent a novel therapeutic target.

A Theacrine-Based Supplement Increases Cellular NAD+ Levels and Affects Biomarkers Related to Sirtuin Activity in C2C12 Muscle Cells In Vitro

There is evidence in rodents to suggest that theacrine-based supplements modulate tissue sirtuin activity as well as other biological processes associated with aging. Herein, we examined if a theacrine-based supplement (termed NAD3) altered sirtuin activity in vitro while also affecting markers of mitochondrial biogenesis. The murine C2C12 myoblast cell line was used for experimentation. Following 7 days of differentiation, myotubes were treated with 0.45 mg/mL of NAD3 (containing ~2 mM theacrine) for 3 and 24 h (n = 6 treatment wells per time point). Relative to control (CTL)-treated cells, NAD3 treatments increased (p < 0.05) Sirt1 mRNA levels at 3 h, as well as global sirtuin activity at 3 and 24 h. Follow-up experiments comparing 24 h NAD3 or CTL treatments indicated that NAD3 increased nicotinamide phosphoribosyltransferase (NAMPT) and SIRT1 protein levels (p < 0.05). Cellular nicotinamide adenine dinucleotide (NAD+) levels were also elevated nearly two-fold after 24 h of NAD3 versus CTL treatments (p < 0.001). Markers of mitochondrial biogenesis were minimally affected. Although these data are limited to select biomarkers in vitro, these preliminary findings suggest that a theacrine-based supplement can modulate select biomarkers related to NAD+ biogenesis and sirtuin activity. However, these changes did not drive increases in mitochondrial biogenesis. While promising, these data are limited to a rodent cell line and human muscle biopsy studies are needed to validate and elucidate the significance of these findings.

Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

MicroRNA-214 contributes to Ang II-induced cardiac hypertrophy by targeting SIRT3 to provoke mitochondrial malfunction.

Reduction of expression and activity of sirtuin 3 (SIRT3) contributes to the pathogenesis of cardiomyopathy via inducing mitochondrial injury and energy metabolism disorder. However, development of effective ways and agents to modulate SIRT3 remains a big challenge. In this study we explored the upstream suppressor of SIRT3 in angiotensin II (Ang II)-induced cardiac hypertrophy in mice. We first found that SIRT3 deficiency exacerbated Ang II-induced cardiac hypertrophy, and resulted in the development of spontaneous heart failure. Since miRNAs play crucial roles in the pathogenesis of cardiac hypertrophy, we performed miRNA sequencing on myocardium tissues from Ang II-infused Sirt3-/- and wild type mice, and identified microRNA-214 (miR-214) wassignificantly up-regulated in Ang II-infused mice. Similar results were also obtained in Ang II-treated neonatal mouse cardiomyocytes (NMCMs). Using dual-luciferase reporter assay we demonstrated that SIRT3 was a direct target of miR-214. Overexpression of miR-214 in vitro and in vivo decreased the expression of SIRT3, which resulted in extensive mitochondrial damages, thereby facilitating the onset of hypertrophy. In contrast, knockdown of miR-214 counteracted Ang II-induced detrimental effects via restoring SIRT3, and ameliorated mitochondrial morphology and respiratory activity. Collectively, these results demonstrate that miR-214 participates in Ang II-induced cardiac hypertrophy by directly suppressing SIRT3, and subsequently leading to mitochondrial malfunction, suggesting the potential of miR-214 as a promising intervention target for antihypertrophic therapy.

Physcion 8-O-β-glucopyranoside ameliorates liver fibrosis through inflammation inhibition by regulating SIRT3-mediated NF-κB P65 nuclear expression

Physcion 8-O-β-glucopyranoside (PSG), an anthraquinone extracted from Rumex japonicus Houtt, has various pharmacological effects, however, the effect of PSG on liver fibrosis and its related mechanism remain to be determined. We here showed that PSG ameliorated liver injury and liver fibrosis, decreased collagen deposition and inhibited inflammation in carbon tetrachloride (CCl4)-induced rats. Consistent with the in vivo results, PSG suppressed the transforming growth factor-β1 (TGF-β1)-induced cell viability, liver fibrosis and secretion of inflammatory factors in hepatic stellate cells (HSCs). Interestingly, PSG increased the enzyme activity and promoter activity of sirtuin 3 (SIRT3) in fibrotic liver and activated HSCs. In addition, PSG notably increased the mRNA and protein expression of SIRT3 both in vivo and in vitro. Depletion of SIRT3 either by using 3-TYP (SIRT3 selective inhibitor) or SIRT3 siRNA attenuated the anti-inflammatory effect of PSG in activated HSCs. Further study found that TGF-β1 increased the nuclear expression of NF-κB p65, but showed no obvious effect on the total NF-κB p65 expression. Compared to the control adenovirus (Ad.mk), overexpression of SIRT3 by infecting adenovirus encoding SIRT3 (Ad.SIRT3) notably decreased the nuclear expression of NF-κB p65 in activated HSCs. Our results demonstrated that PSG attenuated inflammation by regulating SIRT3-mediated NF-κB P65 nuclear expression in liver fibrosis, providing novel molecular insights into the anti-fibrotic effect of PSG.

Sirtuins and their role as physiological modulators of metabolism

The sirtuins are a family of highly evolutionary conserved NAD+-dependent deacetylases (SIRT1, 2, 3, 5). Certain human sirtuins (SIRT4, 6) have, in addition, an ADP-ribosyltransferase activity. SIRT1 and SIRT2 are located in the nucleus and cytoplasm; SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. The mammalian sirtuins have emerged as key metabolic sensors that directly link environmental nutrient signals to metabolic homeostasis. SIRT1 is involved in the regulation of gluconeogenesis and fatty acid oxidation, as well as inhibiting lipogenesis and inflammation in the liver. In addition, they contribute to the mobilization of fat in white adipose tissue, sense nutrient availability in the hypothalamus; regulate insulin secretion in the pancreas; as well as modulating the expression of genes responsible for the activity of the circadian clock in metabolic tissues. Sirtuins are implicated in a variety of cellular functions ranging from gene silencing, through the control of the cell cycle, to energy homeostasis. Caloric restriction, supported by polyphenols, including resveratrol, which is the SIRT1 activator, plays a special role in maintaining energy homeostasis. On a whole body level, the wide range of cellular activities of the sirtuins suggests that they could constitute a therapeutic target to combat obesity and related metabolic diseases. In addition, this work presents the current state of knowledge in the field of sirtuin activity in relation to nutritional status and lifespan.

A Molecular Perspective on Sirtuin Activity.

The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD+ as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.

Sirtuins in female meiosis and in reproductive longevity.

Transmission of genetic material through high-quality gametes to progeny requires accurate homologous chromosome recombination and segregation during meiosis. A failure to accomplish these processes can have major consequences in reproductive health, including infertility, and development disorders in offspring. Sirtuins, a family of NAD+ -dependent protein deacetylases and ADP-ribosyltransferases, play key roles in genome maintenance, metabolism, and aging. In recent years, Sirtuins have emerged as regulators of several reproductive processes and interventions aiming to target Sirtuin activity are of great interest in the reproductive biology field. Sirtuins are pivotal to protect germ cells against oxidative stress, a major determinant influencing ovarian aging and the quality of gametes. Sirtuins also safeguard the integrity of the genome through epigenetic programs required for regulating gene repression, DNA repair, and chromosome segregation, among others. Although these functions are relatively well characterized in many somatic tissues, how they contribute to reproductive functions is not well understood. This review summarizes our current knowledge on the role of Sirtuins in female reproductive systems and discusses the underlying molecular pathways. In addition, we highlight the importance of Sirtuins as antiaging factors in the ovary and summarize current preclinical efforts to identify treatments to extend female reproductive longevity.