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Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. [ABSTRACT FROM AUTHOR]

Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1–7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells. [ABSTRACT FROM AUTHOR]

Cancer, the world’s second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1’s regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the inhibitory effect of Polydatin (PD) on endoplasmic reticulum (ER) stress following subarachnoid hemorrhage (SAH) and to elucidate the underlying mechanisms. Methods: A standard intravascular puncture model was established to mimic SAH in mice. Neurological functions were assessed using neurological scoring, Grip test, and Morris water maze. Brain edema and Evans blue extravasation were measured to evaluate blood-brain barrier permeability. Western blot and quantitative real-time polymerase chain reaction (PCR) analyses were performed to examine protein and mRNA expressions related to ER stress. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was used to detect cell apoptosis, and transmission electron microscopy was used to observe the ultrastructure of the endoplasmic reticulum. Results: The results indicated that PD significantly reduced brain edema and Evans blue extravasation after SAH, improving neurological function. Compared to the SAH group, the expression levels of ER stress-related proteins including glucose-regulated protein 78 (GRP78), phosphorylated protein kinase R-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were significantly lower in the PD-treated group. Moreover, PD significantly enhances the protein expression of Sirtuin 1 (SIRT1). Validation with sh-SIRT1 confirmed the critical role of SIRT1 in ER stress, with PD's inhibitory effect on ER stress being dependent on SIRT1 expression. Additionally, PD attenuated ER stress-mediated neuronal apoptosis and SAHinduced ferroptosis through upregulation of SIRT1. Conclusion: PD alleviates ER stress following SAH by upregulating SIRT1 expression, thereby mitigating early brain injury. The protective effects of PD are mediated through SIRT1, which inhibits ER stress and reduces neuronal apoptosis and ferroptosis. [ABSTRACT FROM AUTHOR]

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected. [ABSTRACT FROM AUTHOR]

Background: Inflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively. Methods: We used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins. Results: More than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on. Conclusion: By reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways. [ABSTRACT FROM AUTHOR]

The silent information regulator sirtuin 1 (SIRT1) protein is an NAD+-dependent class-III lysine deacetylase that serves as an important post-transcriptional modifier targeting lysine acetylation sites to mediate deacetylation modifications of histones and non-histone proteins. SIRT1 has been reported to be involved in several physiological or pathological processes such as aging, inflammation, immune responses, oxidative stress and allergic diseases. In this review, we summarized the regulatory roles of SIRT1 during allergic disorder progression. Furthermore, we highlight the therapeutic effects of targeting SIRT1 in allergic diseases. [ABSTRACT FROM AUTHOR]

Histone deacetylates family proteins have been studied for their function in regulating viral replication by deacetylating non-histone proteins. RIG-I (Retinoic acid-inducible gene I) is a critical protein in RNA virus-induced innate antiviral signaling pathways. Our previous research showed that HDAC8 (histone deacetylase 8) involved in innate antiviral immune response, but the underlying mechanism during virus infection is still unclear. In this study, we showed that HDAC8 was involved in the regulation of vesicular stomatitis virus (VSV) replication. Over-expression of HDAC8 inhibited while knockdown promoted VSV replication. Further exploration demonstrated that HDAC8 interacted with and deacetylated RIG-I, which eventually lead to enhance innate antiviral immune response. Collectively, our data clearly demonstrated that HDAC8 inhibited VSV replication by promoting RIG-I mediated interferon production and downstream signaling pathway. [ABSTRACT FROM AUTHOR]

Regular assessment of disease activity in relapsing-remitting multiple sclerosis (RRMS) is required to optimize clinical outcomes. Biomarkers can be a valuable tool for measuring disease activity in multiple sclerosis (MS) if they reflect the pathological processes underlying MS pathogenicity. In this pilot study, we combined multiple biomarkers previously analyzed in RRMS patients into an MS disease activity (MSDA) score to evaluate their ability to predict relapses and treatment response to glatiramer acetate (GA). Response Gene to Complement 32 (RGC-32), FasL, IL-21, SIRT1, phosphorylated SIRT1 (p-SIRT1), and JNK1 p54 levels were used to generate cut-off values for each biomarker. Any value below the cutoff for RGC-32, FasL SIRT1, or p-SIRT1 or above the cutoff for IL-21 or JNK1 p54 was given a +1 value, indicating relapse or lack of response to GA. Any value above the cutoff value for RGC-32, FasL, SIRT1, p-SIRT1 or below that for IL-21 or JNK1 p54 was given a -1 value, indicating clinical stability or response to GA. An MSDA score above +1 indicated a relapse or lack of response to treatment. An MSDA score below -1 indicated clinical stability or response to treatment. Our results showed that the MSDA scores generated using either four or six biomarkers had a higher sensitivity and specificity and significantly correlated with the expanded disability status scale. Although these results suggest that the MSDA test can be useful for monitoring therapeutic response to biologic agents and assessing clinically challenging situations, the present findings need to be confirmed in larger studies. [ABSTRACT FROM AUTHOR]

Autoimmune diseases (AID) have emerged as prominent contributors to disability and mortality worldwide, characterized by intricate pathogenic mechanisms involving genetic, environmental, and autoimmune factors. In response to this challenge, a growing body of research in recent years has delved into genetic modifications, yielding valuable insights into AID prevention and treatment. Sirtuins (SIRTs) constitute a class of NAD-dependent histone deacetylases that orchestrate deacetylation processes, wielding significant regulatory influence over cellular metabolism, oxidative stress, immune response, apoptosis, and aging through epigenetic modifications. Resveratrol, the pioneering activator of the SIRTs family, and its derivatives have captured global scholarly interest. In the context of AID, these compounds hold promise for therapeutic intervention by modulating the SIRTs pathway, impacting immune cell functionality, suppressing the release of inflammatory mediators, and mitigating tissue damage. This review endeavors to explore the potential of resveratrol and its derivatives in AID treatment, elucidating their mechanisms of action and providing a comprehensive analysis of current research advancements and obstacles. Through a thorough examination of existing literature, our objective is to advocate for the utilization of resveratrol and its derivatives in AID treatment while offering crucial insights for the formulation of innovative therapeutic approaches. [ABSTRACT FROM AUTHOR]

Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles--either as promoters or inhibitors--in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer. [ABSTRACT FROM AUTHOR]

Introduction: Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has been shown that some individuals with obesity do not exhibit metabolic syndrome. Adipose tissue neutralizes the detrimental effects of circulating fatty acids, ectopic deposition, and inflammation, among others, through its esterification into neutral lipids that are stored in the adipocyte. However, when the adipocyte is overloaded, i.e., its expansion capacity is exceeded, this protection is lost, resulting in fatty acid toxicity with ectopic fat accumulation in peripheral tissues and inflammation. In this line, this study aimed to investigate whether polymorphisms in genes that control adipose tissue fat storage capacity are potential biomarkers for severe obesity susceptibility and also metabolic complications. Methods: This study enrolled 305 individuals with severe obesity (cases, BMI≥35 kg/m²) and 196 individuals with normal weight (controls, 18.5≤BMI≤24.9 kg/m²). Demographic, anthropometric, biochemical, and blood pressure variables were collected from the participants. Plasma levels of leptin, resistin, MCP1, and PAI1 were measured by Bio-Plex 200 Multiplexing Analyzer System. Genomic DNA was extracted and variants in DBC1 (rs17060940), SIRT1 (rs7895833 and rs1467568), UCP2 (rs660339), PPARG (rs1801282) and ADRB2 (rs1042713 and rs1042714) genes were genotyped by PCR allelic discrimination using TaqMan® assays. Results: Our findings indicated that SIRT1 rs7895833 polymorphism was a risk factor for severe obesity development in the overdominant model. SIRT1 rs1467568 and UCP2 rs660339 were associated with anthropometric traits. SIRT1 rs1467568 G allele was related to lower medians of body adipose index and hip circumference, while the UCP2 rs660339 AA genotype was associate with increased body mass index. Additionally, DBC1 rs17060940 influenced glycated hemoglobin. Regarding metabolic alterations, 27% of individuals with obesity presented balanced metabolic status in our cohort. Furthermore, SIRT1 rs1467568 AG genotype increased 2.5 times the risk of developing metabolic alterations. No statistically significant results were observed with Peroxisome Proliferator-Activated Receptor Gama and ADRB2 polymorphisms. Discussion/Conclusion: This study revealed that SIRT1 rs7895833 and rs1467568 are potential biomarkers for severe obesity susceptibility and the development of unbalanced metabolic status in obesity, respectively. UCP2 rs660339 and DBC1 rs17060940 also showed a significant role in obesity related-traits. [ABSTRACT FROM AUTHOR]

The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.

Cancer targeted therapy is essential to minimize damage to normal cells and improve treatment outcomes. The elevated activity of Cystathionine betasynthase (CBS), an enzyme responsible for producing endogenous hydrogen sulfide (H2S), plays a significant role in promoting tumor growth, invasiveness, and metastatic potential. Consequently, the selective inhibition of CBS could represent a promising therapeutic strategy for cancer. Currently, there is much interest in combining paclitaxel with other drugs for cancer treatment. This study aimed to investigate the efficacy of combining benserazide, a CBS inhibitor, with paclitaxel in treating tumors. Firstly, we demonstrated CBS is indeed involved in the progression of multiple cancers. Then it was observed that the total binding free energy between the protein and the small molecule is -98.241 kJ/mol. The release of H2S in the group treated with 100 µM benserazide was reduced by approximately 90% compared to the negative control, and the thermal denaturation curve of the complex protein shifted to the right, suggesting that benserazide binds to and blocks the CBS protein. Next, it was found that compared to paclitaxel monotherapy, the combination of benserazide with paclitaxel demonstrated stronger antitumor activity in KYSE450, A549, and HCT8 cells, accompanied by reduced cell viability, cell migration and invasion, as well as diminished angiogenic and lymphangiogenic capabilities. In vivo studies showed that the combined administration of benserazide and paclitaxel significantly reduced the volume and weight of axillary lymph nodes in comparison to the control group and single administration group. Further mechanistic studies revealed that the combination of benserazide and paclitaxel significantly suppressed the S-sulfhydration of SIRT1 protein, thereby inhibiting the expression of SIRT1 protein and activating SIRT1 downstream Notch1/Hes1 signaling pathway in KYSE450, A549, and HCT8 cells. Meanwhile, we observed that benserazide combined with paclitaxel induced a more significant downregulation of HIF-1a, VEGF-A, VEGF-C, and VEGF-D proteins expression levels in KYSE450, A549, and HCT8 cells compared to paclitaxel alone. These findings indicated that benserazide enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and down-regulating HIF-1α/VEGF signaling pathway. This study suggests that benserazide may have potential as a chemosensitizer in cancer treatment. [ABSTRACT FROM AUTHOR]

Intestinal barrier dysfunction is an important contributor to morbidity caused by sepsis. This study investigates the molecular mechanism by which Ghrelin affects intestinal dysfunction in rat model of sepsis. A rat model of sepsis was established by cecal ligation and puncture (CLP), revealing that Ghrelin was downregulated when sepsis occurs. Increases in the levels of inflammatory factors tumor necrosis factor α (TNF-α), interleukin-1 (IL-1β), IL-6, gastrin, γ-H2AX and 8-OHdG was also detected in this model system, as was an overall increase in oxidative stress. Introduction of exogenous Ghrelin inhibited these increases in inflammatory response and oxidative stress, leading to a reduction of overall sepsis-induced intestinal dysfunction. Ghrelin was then shown to activate SIRT1 expression in vitro, while SIRT1 was found to co-express with KLF4, which in turn was predicted to bind to matrix metalloproteinase 2 (MMP2) promoter. Finally, gainand loss-of-function experiment demonstrated that SIRT1 upregulated the expression of KLF4 to downregulate MMP2. Collectively, Ghrelin inhibits the oxidative stress and intestinal dysfunction to attenuate sepsis by activating SIRT1 and regulating a KLF4/MMP2 regulatory axis. [ABSTRACT FROM AUTHOR]

Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD+) as cosubstrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4'-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies. [ABSTRACT FROM AUTHOR]

Silent information regulator two homolog 1 (SIRT1), an NAD + -dependent histone deacetylase, plays a pivotal regulatory role in a myriad of physiological processes. A growing body of evidence suggests that SIRT1 can exert protective effects in metabolic disorders and neurodegenerative diseases by inhibiting endoplasmic reticulum (ER) stress and the nuclear factor-κB (NF-κB) inflammatory signaling pathway. This review systematically elucidates the molecular mechanisms and biological significance of SIRT1 in regulating ER stress and the NF-κB pathway. On one hand, SIRT1 can deacetylate key molecules in the ER stress pathway, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), PKR-like ER kinase (PERK), inositolrequiring enzyme 1a (IRE1a), and activating transcription factor 6 (ATF6), thereby alleviating ER stress. On the other hand, SIRT1 can directly or indirectly remove the acetylation modification of the NF-κB p65 subunit, inhibiting its transcriptional activity and thus attenuating inflammatory responses. Through these mechanisms, SIRT1 can ameliorate insulin resistance in metabolic diseases, exert cardioprotective effects in ischemia-reperfusion injury, and reduce neuronal damage in neurodegenerative diseases. However, it is important to note that while these findings are promising, the complex nature of the biological systems involved warrants further investigation to fully unravel the intricacies of SIRT1's regulatory mechanisms. Nevertheless, understanding the regulatory mechanisms of SIRT1 on ER stress and the NF-κB pathway is of great significance for expanding our knowledge of the pathogenesis of related diseases and exploring new preventive and therapeutic strategies targeting SIRT1. [ABSTRACT FROM AUTHOR]

Objective: There is a controversy in studies of circulating inflammatory proteins (CIPs) in association with osteoporosis (OP) and fractures, and it is unclear if these two conditions are causally related. This study used MR analyses to investigate the causal associations between 91 CIPs and OP and 9 types of fractures. Methods: Genetic variants data for CIPs, OP, and fractures were obtained from the publicly available genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary analysis, pleiotropy, and heterogeneity tests to analyze the validity and robustness of causality and reverse MR analysis to test for reverse causality. Results: The IVW results with Bonferroni correction indicated that CXCL11 (OR = 1.2049; 95% CI: 1.0308-1.4083; P = 0.0192) can increase the risk of OP; IL-4 (OR = 1.2877; 95% CI: 1.1003-1.5070; P = 0.0016), IL-7 (OR = 1.2572; 95% CI: 1.0401-1.5196; P = 0.0180), IL-15RA (OR = 1.1346; 95% CI: 1.0163-1.2668; P = 0.0246), IL-17C (OR = 1.1353; 95% CI: 1.0272-1.2547; P = 0.0129), CXCL10 (OR = 1.2479; 95% CI: 1.0832-1.4377; P = 0.0022), eotaxin/CCL11 (OR = 1.1552; 95% CI: 1.0525-1.2678; P = 0.0024), and FGF23 (OR = 1.9437; 95% CI: 1.1875- 3.1816; P = 0.0082) can increase the risk of fractures; whereas IL-10RB (OR = 0.9006; 95% CI: 0.8335-0.9730; P = 0.0080), CCL4 (OR = 0.9101; 95% CI: 0.8385-0.9878; P = 0.0242), MCP-3/CCL7 (OR = 0.8579; 95% CI: 0.7506-0.9806; P = 0.0246), IFN-g [shoulder and upper arm (OR = 0.7832; 95% CI: 0.6605-0.9287; P = 0.0049); rib(s), sternum and thoracic spine (OR = 0.7228; 95% CI: 0.5681-0.9197; P = 0.0083)], b-NGF (OR = 0.8384; 95% CI: 0.7473-0.9407; P = 0.0027), and SIRT2 (OR = 0.5167; 95% CI: 0.3296-0.8100; P = 0.0040) can decrease fractures risk. Conclusion: Mendelian randomization (MR) analyses indicated the causal associations between multiple genetically predicted CIPs and the risk of OP and fractures. [ABSTRACT FROM AUTHOR]

The high prevalence of obesity in Mexico starting from the early stages of life is concerning and represents a major public health problem. Genetic association studies have reported that single nucleotide variants (SNVs) in SIRT1, an NAD+- dependent deacetylase that plays an important role in the regulation of metabolic cellular functions, are associated with multiple metabolic disorders and the risk of obesity. In the present study, we analyzed the effect that the SNVs rs1467568 and rs7895833 of the SIRT1 gene may have on cardiometabolic risk factors in a young adult population from Mexico. A cross-sectional study was carried out with young adults between the ages of 18 and 25 who had a body mass index (BMI) greater than 18.5 kg/m2. This study included 1122 young adults who were classified into the normal weight (n = 731), overweight group (n = 277), and obesity group (n = 114) according to BMI of whom 405 and 404 volunteers were genotyped for rs1467568 and rs7895833 respectively using TaqMan probes through allelic discrimination assays. We found that the male sex carrying the G allele of rs7895833 had slightly lower BMI levels (p = 0.009). Furthermore, subjects carrying rs1467568 (G allele) showed a 34% lower probability of presenting with hyperbetalipoproteinemia where female carrying rs1467568 had lower levels of total cholesterol (p = 0.030), triglycerides (p = 0.026) and LDL cholesterol (p = 0.013). In conclusion, these findings suggest that the presence of both SNVs could have a non-risk effect against dyslipidemia in the Mexican population. [ABSTRACT FROM AUTHOR]

Introduction: Sirtuin 1 (SIRT1) is known to be involved in sensing cellular energy levels and regulating energy metabolism. This study aimed to evaluate fasting serum SIRT1 levels in healthy children, and to analyse the influence of age, sex, puberty, body weight, height, and diet on its concentration. Methods: 47 healthy children aged 4-14 with weight and height within normal range and no chronic disease were included into the study. Fasting serum SIRT1 concentrations were estimated by Enzyme Linked Immunosorbent Assay (ELISA). Results: Results showed that serum SIRT1 concentrations in healthy children did not differ with respect to sex, age, height, weight and puberty. Whereas, it appeared that a higher frequency of fruits, vegetables and dairy products consumption was associated with an increase in serum SIRT1 levels. Discussion: Studying SIRT1 in the context of children’s health may have implications for a broader understanding of growth processes, pubertal development, metabolic disorders and nutrition. [ABSTRACT FROM AUTHOR]

Mitochondria plays a role in cell differentiation and apoptosis processes. Maintaining mitochondrial function is critical, and this involves various aspects of mitochondrial quality control such as protein homeostasis, biogenesis, dynamics, and mitophagy. Osteoporosis, a metabolic bone disorder, primarily arises from two factors: the dysregulation between lipogenic and osteogenic differentiation of aging bone marrow mesenchymal stem cells, and the imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Mitochondrial quality control has the potential to mitigate or even reverse the effects. Among the Sirtuin family, consisting of seven Sirtuins (SIRT1-7), SIRT1-SIRT6 play a crucial role in maintaining mitochondrial quality control. Additionally, SIRT1, SIRT3, SIRT6, and SIRT7 are directly involved in normal bone development and homeostasis by modulating bone cells. However, the precise mechanism by which these Sirtuins exert their effects remains unclear. This article reviews the impact of various aspects of mitochondrial quality control on osteoporosis, focusing on how SIRT1, SIRT3, and SIRT6 can improve osteoporosis by regulating mitochondrial protein homeostasis, biogenesis, and mitophagy. Furthermore, we provide an overview of the current state of clinical and preclinical drugs that can activate Sirtuins to improve osteoporosis. Specific Sirtuin-activating compounds are effective, but further studies are needed. The findings of this study may offer valuable insights for future research on osteoporosis and the development of clinical prevention and therapeutic target strategies. [ABSTRACT FROM AUTHOR]

Silent information regulator 2 (Sir2) is a conserved NAD+-dependent histone deacetylase crucial for regulating cellular stress response and the aging process in Saccharomyces cerevisiae. In this study, we investigated the molecular mechanism underlying how the absence of Sir2 can lead to altered stress susceptibilities in S. cerevisiae under different environmental and physiological conditions. In a glucose-complex medium, the sir2Δ strain showed increased sensitivity to H2O2 compared to the wild-type strain during the post-diauxic phase. In contrast, it displayed increased resistance during the exponential growth phase. Transcriptome analysis of yeast cells in the post-diauxic phase indicated that the sir2Δ mutant expressed several oxidative defense genes at lower levels than the wild-type, potentially accounting for its increased susceptibility to H2O2. Interestingly, however, the sir2Δras2Δ double mutant exhibited greater resistance to H2O2 than the ras2Δ single mutant counterpart. We found that the expression regulation of the cytoplasmic catalase encoded by CTT1 was critical for the increased resistance to H2O2 in the sir2Δras2Δ strain. The expression of the CTT1 gene was influenced by the combined effect of RAS2 deletion and the transcription factor Azf1, whose level was modulated by Sir2. These findings provide insights into the importance of understanding the intricate interactions among various factors contributing to cellular stress response. [ABSTRACT FROM AUTHOR]

The human sirtuin 2 gene (SIRT2) encodes a full-length Sirt2 protein (i.e., the Sirt2 isoform 1), which primarily functions as a cytoplasmic α-tubulin deacetylase, and which promotes the growth of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) replication itself, or HBV X (HBx) protein-mediated transcriptional transactivation, enhances Sirt2.1 expression; therefore, Sirt2.1 itself is capable of positively increasing HBV transcription and replication. Sirt2.1 is linked to liver fibrosis and epithelial-to-mesenchymal transition and, consequently, augments the risk of HCC. The Sirt2.1 protein enhances the HBV replication cycle by activating the AKT/glycogen synthase kinase 3 beta (GSK3β)/β-catenin pathway. It also activates the transcription of the viral enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The Sirt2 isoform 2 (Sirt2.2) is mainly localized in the cytoplasm, and the N-terminus is shorter by 37 amino acids than that of Sirt2.1. Despite the truncation of the N-terminal region, Sirt2.2 is still capable of enhancing HBV replication and activating the AKT/GSK3β/β-catenin signaling pathway. The Sirt2 isoform 5 (Sirt2.5) is primarily localized to the nucleus, it lacks a nuclear export signal (NES), and the catalytic domain (CD) is truncated. Upon HBV replication, expression of the Sirt2 isoforms is also enhanced, which further upregulates the HBV replication, and, therefore, supports the vicious cycle of viral replication and progression of the disease. Sirt2 diversely affects HBV replication such that its isoform 1 intensely augments HBV replication and isoform 2 (despite of the truncated N-terminal region) moderately enhances HBV replication. Isoform 5, on the other hand, tends to protect the cell (for smooth long-term continued viral replication) from HBV-induced extreme damage or death via a discrete set of regulatory mechanisms impeding viral mRNAs, the hepatitis B core/capsid protein (HBc), core particles, replicative intermediate (RI) DNAs, and covalently closed circular DNA (cccDNA) levels, and, consequently, limiting HBV replication. In contrast to Sirt2.1 and Sirt 2.2, the Sirt2.5-mediated HBV replication is independent of the AKT/GSK3β/β-catenin signaling cascade. Sirt2.5 is recruited more at cccDNA than the recruitment of Sirt2.1 onto the cccDNA. This recruitment causes the deposition of more histone lysine methyltransferases (HKMTs), including SETDB1, SUV39H1, EZH2, and PR-Set7, along with the respective corresponding transcriptional repressive markers such as H3K9me3, H3K27me3, and H4K20me1 onto the HBV cccDNA. In HBV-replicating cells, Sirt2.5 can also make complexes with PR-Set7 and SETDB1. In addition, Sirt2.5 has the ability to turn off transcription from cccDNA through epigenetic modification via either direct or indirect interaction with HKMTs. [ABSTRACT FROM AUTHOR]

Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD+) as co-substrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4′-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies.

Thrombosis is a major cause of morbidity and mortality worldwide, with a complex and multifactorial pathogenesis. Recent studies have shown that SIRT1, a member of the sirtuin family of NAD + -dependent deacetylases, plays a crucial role in regulating thrombosis, modulating key pathways including endothelial activation, platelet aggregation, and coagulation. Furthermore, SIRT1 displays anti-inflammatory activity both in vitro, in vivo and in clinical studies, particularly via the reduction of oxidative stress. On these bases, several studies have investigated the therapeutic potential of targeting SIRT1 for the prevention of thrombosis. This review provides a comprehensive and critical overview of the main preclinical and clinical studies and of the current understanding of the role of SIRT1 in thrombosis.

The human sirtuin 2 gene (SIRT2) encodes a full-length Sirt2 protein (i.e., the Sirt2 isoform 1), which primarily functions as a cytoplasmic α-tubulin deacetylase, and which promotes the growth of hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) replication itself, or HBV X (HBx) protein-mediated transcriptional transactivation, enhances Sirt2.1 expression; therefore, Sirt2.1 itself is capable of positively increasing HBV transcription and replication. Sirt2.1 is linked to liver fibrosis and epithelial-to-mesenchymal transition and, consequently, augments the risk of HCC. The Sirt2.1 protein enhances the HBV replication cycle by activating the AKT/glycogen synthase kinase 3 beta (GSK3β)/β-catenin pathway. It also activates the transcription of the viral enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The Sirt2 isoform 2 (Sirt2.2) is mainly localized in the cytoplasm, and the N-terminus is shorter by 37 amino acids than that of Sirt2.1. Despite the truncation of the N-terminal region, Sirt2.2 is still capable of enhancing HBV replication and activating the AKT/GSK3β/β-catenin signaling pathway. The Sirt2 isoform 5 (Sirt2.5) is primarily localized to the nucleus, it lacks a nuclear export signal (NES), and the catalytic domain (CD) is truncated. Upon HBV replication, expression of the Sirt2 isoforms is also enhanced, which further upregulates the HBV replication, and, therefore, supports the vicious cycle of viral replication and progression of the disease. Sirt2 diversely affects HBV replication such that its isoform 1 intensely augments HBV replication and isoform 2 (despite of the truncated N-terminal region) moderately enhances HBV replication. Isoform 5, on the other hand, tends to protect the cell (for smooth long-term continued viral replication) from HBV-induced extreme damage or death via a discrete set of regulatory mechanisms impeding viral mRNAs, the hepatitis B core/capsid protein (HBc), core particles, replicative intermediate (RI) DNAs, and covalently closed circular DNA (cccDNA) levels, and, consequently, limiting HBV replication. In contrast to Sirt2.1 and Sirt 2.2, the Sirt2.5-mediated HBV replication is independent of the AKT/GSK3β/β-catenin signaling cascade. Sirt2.5 is recruited more at cccDNA than the recruitment of Sirt2.1 onto the cccDNA. This recruitment causes the deposition of more histone lysine methyltransferases (HKMTs), including SETDB1, SUV39H1, EZH2, and PR-Set7, along with the respective corresponding transcriptional repressive markers such as H3K9me3, H3K27me3, and H4K20me1 onto the HBV cccDNA. In HBV-replicating cells, Sirt2.5 can also make complexes with PR-Set7 and SETDB1. In addition, Sirt2.5 has the ability to turn off transcription from cccDNA through epigenetic modification via either direct or indirect interaction with HKMTs.

Introduction: Diabetic cardiomyopathy (DCM) is one of the most prevalent complications of diabetes with complex pathogenesis. YuNü-Jian (YNJ) is a traditional Chinese medicinal formula widely used for diabetes with hypoglycemic and cardioprotective effects. This study aims to investigate the actions and mechanisms of YNJ against DCM which has never been reported. Methods: Network pharmacology approach was used to predict the potential pathways and targets of YNJ on DCM. Molecular docking between hub targets and active components of YNJ was performed and visualized by AutoDock Vina and PyMOL. Then type 2 diabetic model was employed and intervened with YNJ for 10 weeks to further validate these critical targets. Results: First, a total of 32 main ingredients of YNJ were identified and 700 potential targets were screened to construct herb-compound-target network. Then 94 differentially expressed genes of DCM were identified from GEO database. After that, PPI network of DCM and YNJ were generated from which hub genes (SIRT1, Nrf2, NQO1, MYC and APP) were assessed by topology analysis. Next, functional and pathway analysis indicated that the candidate targets were enriched in response to oxidative stress and Nrf2 signaling pathway. Furthermore, molecular docking revealed strong affinity between core targets and active components of YNJ. Finally, in rats with type 2 diabetes, YNJ obviously attenuated cardiac collagen accumulation and degree of fibrosis. Meanwhile, YNJ significantly upregulated protein expression of SIRT1, Nrf2 and NQO1 in diabetic myocardium. Discussion: Collectively, our findings suggested that YNJ could effectively ameliorate cardiomyopathy induced by diabetes possibly through SIRT1/Nrf2/NQO1 signaling. [ABSTRACT FROM AUTHOR]

Histone deacetylation is an important mechanism involved in human breast cancer tumorigenesis and recent veterinary oncology studies also demonstrate a similar relationship in some canine neoplasms. The use of HDAC inhibitors in vitro and in vivo has demonstrated antitumor action on several strains of human and animal cancers. The present study aims to correlate the expression of H3K9Ac, H4K12Ac, HDAC1, HDAC2 and HDAC6 in simple mammary carcinomas in dogs with clinicopathological parameters and overall survival time. To this end, 61 samples of simple breast carcinomas were analyzed by the immunohistochemistry technique with subsequent validation of the antibodies by the Western Blot technique. The expressions obtained via a semi-quantitative way were categorized by assigning scores and classified into high or low expressions according to the given score, except for HDAC6, when the marking percentage was considered and subdivided into high and low expressions using the median value. For statistical analysis, the chi-square test or Fisher exact test were used as univariate analysis and correspondence analysis as a multivariate test, in addition to the Kaplan-Meier survival analysis. In the studied samples, the highest frequencies were determined for the high expression proteins H4K12Ac (88.5%), HDAC2 (65.6%) and HDAC6 (56.7%) and the low expression proteins H3K9Ac (73.8%) and HDAC1 (54.1%). An association between the low expression of HDAC1 and the presence of lymph node metastasis (p = 0.035) was indicated by univariate analysis while the high expression of HDAC1 was associated with favorable prognostic factors, such as the absence of lymph node metastasis and low mitotic index by multivariate analysis. Also, by multivariate analysis, the low expression of HDAC6 was correlated with the low expression of Ki67, smaller tumors, and better prognosis factors as well. Protein expression was not correlated with patients' overall survival time (p > 0.05). The high expressions of HDAC2 and HDAC6 in mammary carcinomas in female dogs may be useful information for research involving therapeutic targets with iHDACs since their inhibition favors hyperacetylation and transcription of tumor suppressor genes. [ABSTRACT FROM AUTHOR]

Silent information regulator 2 (Sir2) is a conserved NAD+-dependent histone deacetylase crucial for regulating cellular stress response and the aging process in Saccharomyces cerevisiae. In this study, we investigated the molecular mechanism underlying how the absence of Sir2 can lead to altered stress susceptibilities in S. cerevisiae under different environmental and physiological conditions. In a glucose-complex medium, the sir2Δ strain showed increased sensitivity to H2O2 compared to the wild-type strain during the post-diauxic phase. In contrast, it displayed increased resistance during the exponential growth phase. Transcriptome analysis of yeast cells in the post-diauxic phase indicated that the sir2Δ mutant expressed several oxidative defense genes at lower levels than the wild-type, potentially accounting for its increased susceptibility to H2O2. Interestingly, however, the sir2Δras2Δ double mutant exhibited greater resistance to H2O2 than the ras2Δ single mutant counterpart. We found that the expression regulation of the cytoplasmic catalase encoded by CTT1 was critical for the increased resistance to H2O2 in the sir2Δras2Δ strain. The expression of the CTT1 gene was influenced by the combined effect of RAS2 deletion and the transcription factor Azf1, whose level was modulated by Sir2. These findings provide insights into the importance of understanding the intricate interactions among various factors contributing to cellular stress response. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a complication of diabetes mellitus (DM) and the main cause of excess mortality in patients with type 2 DM. The pathogenesis and progression of DN are closely associated with disorders of glucose and lipid metabolism. As a member of the sirtuin family, SIRT6 has deacetylation, defattyacylation, and adenosine diphosphate-ribosylation enzyme activities as well as anti-aging and anticancer activities. SIRT6 plays an important role in glucose and lipid metabolism and signaling, especially in DN. SIRT6 improves glucose and lipid metabolism by controlling glycolysis and gluconeogenesis, affecting insulin secretion and transmission and regulating lipid decomposition, transport, and synthesis. Targeting SIRT6 may provide a new therapeutic strategy for DN by improving glucose and lipid metabolism. This review elaborates on the important role of SIRT6 in glucose and lipid metabolism, discusses the potential of SIRT6 as a therapeutic target to improve glucose and lipid metabolism and alleviate DN occurrence and progression of DN, and describes the prospects for future research. [ABSTRACT FROM AUTHOR]

IntroductionEpigenetic enzymes can interact with a wide range of genes that actively participate in the progression or repression of a diseased condition, as they are involved in maintaining cellular homeostasis. Sirtuins are a family of Class III epigenetic modifying enzymes that regulate cellular processes by removing acetyl groups from proteins. They rely on NAD+ as a coenzyme in contrast to classical histone deacetylases (HDACs) (Class I, II, and IV) that depend on Zn+ for their activation, linking their function to cellular energy levels. There are seven mammalian sirtuin isoforms (Sirt1-7), each located in different subcellular compartments. Sirtuins have emerged as a promising target, given that inhibitors of natural and synthetic sources are highly warranted. Imidazole derivatives are often investigated as sirtuin regulators due to their ability to interact with the binding site and modulate their activity. Imidazole bestows many possible substitutions on its ring and neighboring atoms to design and synthesize derivatives with specific target selectivity and improved pharmacokinetic properties, optimizing drug development.Materials and methodsLigand preparation, protein preparation, molecular docking, molecular dynamics, density function theory (DFT) analysis, and absorption, distribution, metabolism, and excretion (ADME) analysis were performed to understand the interacting potential and effective stability of the ligand with the protein. RT-PCR and Western blot analyses were performed to understand the impact of ligands on the gene and protein expression of Class III HDAC enzymes.Results and discussionWe evaluated the sirtuin inhibition activity of our in-house compound comprised of imidazole derivatives by docking the molecules with the protein data bank. ADME properties of all the compounds used in the study were evaluated, and it was found that all fall within the favorable range of being a potential drug. The molecule with the highest docking score was analyzed using DFT, and the specific compound was used to treat the non-small cell lung cancer (NSCLC) cell lines A549 and NCI-H460. The gene and protein expression data support the in-silico finding that the compound Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate has an inhibitory effect on nuclear sirtuins. In conclusion, targeting sirtuins is an emerging strategy to combat carcinogenesis. In this study, we establish that Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl) acetate possesses a strong inhibitory effect on nuclear sirtuins in NSCLC cell lines.

Ischemic stroke is one of the main causes of mortality and disability worldwide. However, the majority of patients are currently unable to benefit from intravenous thrombolysis or intravascular mechanical thrombectomy due to the limited treatment windows and serious complications. Silent mating type information regulation 2 homolog 1 (Sirt1), a nicotine adenine dinucleotide-dependent enzyme, has emerged as a potential therapeutic target for ischemic stroke due to its ability to maintain brain homeostasis and possess neuroprotective properties in a variety of pathological conditions for the central nervous system. Animal and clinical studies have shown that activation of Sirt1 can lessen neurological deficits and reduce the infarcted volume, offering promise for the treatment of ischemic stroke. In this review, we summarized the direct evidence and related mechanisms of Sirt1 providing neuroprotection against cerebral ischemic stroke. Firstly, we introduced the protein structure, catalytic mechanism and specific location of Sirt1 in the central nervous system. Secondly, we list the activators and inhibitors of Sirt1, which are primarily divided into three categories: natural, synthetic and physiological. Finally, we reviewed the neuroprotective effects of Sirt1 in ischemic stroke and discussed the specific mechanisms, including reducing neurological deficits by inhibiting various programmed cell death such as pyroptosis, necroptosis, ferroptosis, and cuproptosis in the acute phase, as well as enhancing neurological repair by promoting angiogenesis and neurogenesis in the later stage. Our review aims to contribute to a deeper understanding of the critical role of Sirt1 in cerebral ischemic stroke and to offer novel therapeutic strategies for this condition. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation has been reported as a potential contributing factor to brain diseases, and is characterized by activated microglia with release of multiple inflammatory mediators. 2,3,5,6-Tetramethylpyrazine (TMP) is an active alkaloid in Ligusticum chuanxiong Hort. and has various biological activities, including anti-inflammatory and neuroprotection properties. However, the anti-neuroinflammatory activity of TMP has been less studied and its potential molecular mechanisms in this field remain unclear. This study aimed to investigate the effects of TMP and its underlying mechanisms in neuroinflammation. Methods: In vitro, lipopolysaccharide (LPS)-stimulated BV2 microglia were used to assess the effects of TMP on inflammatory cytokines as well as the components of the SIRT1/NF-κB signaling pathway, which were measured by using ELISA, western blotting, qRT-qPCR and immunofluorescence. Moreover, LPS-induced acute neuroinflammation model in mice was performed to detect whether TMP could exert anti-neuroinflammatory effects in vivo, and the EX527, a SIRT1 inhibitor, were given intraperitoneally every two days prior to TMP treatment. Serums and spinal trigeminal nucleus (Sp5) tissues were collected for ELISA assay, and the Sp5 tissues were used for HE staining, Nissl staining, immunofluorescence, qRT-PCR and western blotting. Results: In vitro, TMP treatment significantly reduced the secretion of pro-inflammatory cytokines, including TNF-α and IL-6, promoted SIRT1 protein expression and inactivated NF-κB signaling pathway in LPS-induced neuroinflammation. Interestingly, pretreatment with EX527 blocked the therapeutic effects of TMP on neuroinflammation in vitro. Furthermore, TMP reduced the levels of pro-inflammatory cytokines and chemokines, and prevented microglia from polarizing towards a pro-inflammatory state through activating SIRT1 and inhibiting NF-κB activation in LPS-induced neuroinflammation in mice. And EX527 reversed the beneficial effects of TMP against LPS exposure in mice. Conclusion: In summary, this study unravels that TMP could mitigate LPS-induced neuroinflammation via SIRT1/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated immunoinflammatory response plays a critical role in exacerbating early brain injury (EBI) after subarachnoid hemorrhage (SAH). Salvianolic acid B (SalB) has previously been shown to suppress neuroinflammatory responses in many disorders. Meanwhile, a previous study has demonstrated that SalB mitigated oxidative damage and neuronal degeneration in a prechiasmatic injection model of SAH. However, the therapeutic potential of SalB on immuno-inflammatory responses after SAH remains unclear. In the present study, we explored the therapeutic effects of SalB on neuroinflammatory responses in an endovascular perforation SAH model. We observed that SalB ameliorated SAH-induced functional deficits. Additionally, SalB significantly mitigated microglial activation, pro-inflammatory cytokines release, and neuronal injury. Mechanistically, SalB inhibited NLRP3 inflammasome activation and increased sirtuin 1 (SIRT1) expression after SAH. Administration of EX527, an inhibitor of SIRT1, abrogated the anti-inflammatory effects of SalB against SAH and further induced NLRP3 inflammasome activation. In contrast, MCC950, a potent and selective NLRP3 inflammasome inhibitor, reversed the detrimental effects of SIRT1 inhibition by EX527 on EBI. These results indicated that SalB effectively repressed neuroinflammatory responses and neuronal damage after SAH. The action of SalB appeared to be mediated by blocking NLRP3 inflammasome and promoting SIRT1 signaling. [ABSTRACT FROM AUTHOR]

Introduction: Novel therapeutics are emerging to mitigate damage from perinatal brain injury (PBI). Few newborns with PBI suffer from a singular etiology. Most experience cumulative insults from prenatal inflammation, genetic and epigenetic vulnerability, toxins (opioids, other drug exposures, environmental exposure), hypoxia-ischemia, and postnatal stressors such as sepsis and seizures. Accordingly, tailoring of emerging therapeutic regimens with endogenous repair or neuro-immunomodulatory agents for individuals requires a more precise understanding of ligand, receptor-, and non-receptor-mediated regulation of essential developmental hormones. Given the recent clinical focus on neurorepair for PBI, we hypothesized that there would be injury induced changes in erythropoietin (EPO), erythropoietin receptor (EPOR), melatonin receptor (MLTR), NAD-dependent deacetylase sirtuin-1 (SIRT1) signaling, and hypoxia inducible factors (HIF1α, HIF2α). Specifically, we predicted that EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α alterations after chorioamnionitis (CHORIO) would reflect relative changes observed in human preterm infants. Similarly, we expected unique developmental regulation after injury that would reveal potential clues to mechanisms and timing of inflammatory and oxidative injury after CHORIO that could inform future therapeutic development to treat PBI. Methods: To induce CHORIO, a laparotomy was performed on embryonic day 18 (E18) in rats with transient uterine artery occlusion plus intra-amniotic injection of lipopolysaccharide (LPS). Placentae and fetal brains were collected at 24 h. Brains were also collected on postnatal day 2 (P2), P7, and P21. EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α levels were quantified using a clinical electrochemiluminescent biomarker platform, qPCR, and/or RNAscope. MLT levels were quantified with liquid chromatography mass spectrometry Results: Examination of EPO, EPOR, and MLTR1 at 24 h showed that while placental levels of EPO and MLTR1 mRNA were decreased acutely after CHORIO, cerebral levels of EPO, EPOR and MLTR1 mRNA were increased compared to control. Notably, CHORIO brains at P2 were SIRT1 mRNA deficient with increased HIF1α and HIF2α despite normalized levels of EPO, EPOR and MLTR1, and in the presence of elevated serum EPO levels. Uniquely, brain levels of EPO, EPOR and MLTR1 shifted at P7 and P21, with prominent CHORIO-induced changes in mRNA expression. Reductions at P21 were concomitant with increased serum EPO levels in CHORIO rats compared to controls and variable MLT levels. Discussion: These data reveal that commensurate with robust inflammation through the maternal placental-fetal axis, CHORIO impacts EPO, MLT, SIRT1, and HIF signal transduction defined by dynamic changes in EPO, EPOR, MLTR1, SIRT1, HIF1α and HIF2α mRNA, and EPO protein. Notably, ligand-receptor mismatch, tissue compartment differential regulation, and non-receptormediated signaling highlight the importance, complexity and nuance of neural and immune cell development and provide essential clues to mechanisms of injury in PBI. As the placenta, immune cells, and neural cells share many common, developmentally regulated signal transduction pathways, further studies are needed to clarify the perinatal dynamics of EPO and MLT signaling and to capitalize on therapies that target endogenous neurorepair mechanisms. [ABSTRACT FROM AUTHOR]

Maternal exercise during pregnancy has emerged as a potentially promising approach to protect offspring from cardiovascular disease, including hypertension. Although endothelial dysfunction is involved in the pathophysiology of hypertension, limited studies have characterized how maternal exercise influences endothelial function of hypertensive offspring. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were assigned either to a sedentary lifestyle or to swimming training daily, and fetal histone deacetylase-mediated epigenetic modification and offspring vascular function of mesenteric arteries were analyzed. Maternal exercise ameliorated the impairment of acetylcholine-induced vasodilation without affecting sodium nitroprusside-induced vasodilation in mesenteric arteries from the hypertensive offspring. In accordance, maternal exercise reduced NADPH oxidase-4 (Nox4) protein to prevent the loss of nitric oxide generation and increased reactive oxygen species production in mesenteric arteries of hypertensive offspring. We further found that maternal exercise during pregnancy upregulated vascular SIRT1 (sirtuin 1) expression, leading to a low level of H3K9ac (histone H3 lysine 9 acetylation), resulting in the transcriptional downregulation of Nox4 in mesenteric arteries of hypertensive fetuses. These findings show that maternal exercise alleviates oxidative stress and the impairment of endothelium-dependent vasodilatation via SIRT1-regulated deacetylation of Nox4, which might contribute to improved vascular function in hypertensive offspring. [ABSTRACT FROM AUTHOR]

In recent years, epigenetic modifications have been widely researched. As humans age, environmental and genetic factors may drive inflammation and immune responses by influencing the epigenome, which can lead to abnormal autoimmune responses in the body. Currently, an increasing number of studies have emphasized the important role of epigenetic modification in the progression of autoimmune diseases. Sirtuins (SIRTs) are class III nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and SIRTmediated deacetylation is an important epigenetic alteration. The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus. SIRTs are key regulators of various physiological processes such as cellular differentiation, apoptosis, metabolism, ageing, immune response, oxidative stress, and mitochondrial function. We discuss the association between SIRTs and common autoimmune diseases to facilitate the development of more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to investigate the effect of running exercise on improving bone health in aging mice and explore the role of the SIRT1 in regulating autophagy and osteogenic differentiation of Bone marrow Mesenchymal Stem Cells (BMSCs). Methods: Twelve-month-old male C57BL/6J mice were used in this study as the aging model and were assigned to treadmill running exercise for eight weeks. Non-exercise male C57BL/6J mice of the same old were used as aging control and five-month-old mice were used as young controls. BMSCs were isolated from mice and subjected to mechanical stretching stimulation in vitro. Results: The results showed that aging mice had lower bone mass, bone mineral density (BMD), and autophagy than young mice, while running exercise improved BMD and bone mass as well as upregulated autophagy in bone cells. Mechanical loading increased osteogenic differentiation and autophagy in BMSCs, and knockdown of SIRT1 in BMSCs demonstrated that SIRT1-regulated autophagy involved the mechanical loading activation of osteogenic differentiation. Conclusion: Taken together, this study revealed that exercise improved bone health during aging by activating bone formation, which can be attributed to osteogenic differentiation of BMSCs through the activation of SIRT1-mediated autophagy. The mechanisms underlying this effect may involve mechanical loading. [ABSTRACT FROM AUTHOR]

SIRT1 is a member of the sirtuin family functioning in the process of removal of acetyl groups from different proteins. This protein has several biological functions and is involved in the pathogenesis of metabolic diseases, malignancy, aging, neurodegenerative disorders and inflammation. Several long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) have been found to interact with SIRT1. These interactions have been assessed in the contexts of sepsis, cardiomyopathy, heart failure, non-alcoholic fatty liver disease, chronic hepatitis, cardiac fibrosis, myocardial ischemia/reperfusion injury, diabetes, ischemic stroke, immune-related disorders and cancers. Notably, SIRT1-interacting non-coding RNAs have been found to interact with each other. Several circRNA/miRNA and lncRNA/miRNA pairs that interact with SIRT1 have been identified. These axes are potential targets for design of novel therapies for different disorders. In the current review, we summarize the interactions between three classes of non-coding RNAs and SIRT1. [ABSTRACT FROM AUTHOR]

Introduction: Severe COVID-19 results initially in pulmonary infection and inflammation. Symptoms can persist beyond the period of acute infection, and patients with Post-Acute Sequelae of COVID (PASC) often exhibit a variety of symptoms weeks or months following acute phase resolution including continued pulmonary dysfunction, fatigue, and neurocognitive abnormalities. We hypothesized that dysregulated NAD metabolism contributes to these abnormalities. Methods: RNAsequencing of lungs from transgenic mice expressing human ACE2 (K18-hACE2) challenged with SARS-CoV-2 revealed upregulation of NAD biosynthetic enzymes, including NAPRT1, NMNAT1, NAMPT, and IDO1 6 days post-infection. Results: Our data also demonstrate increased gene expression of NAD consuming enzymes: PARP 9,10,14 and CD38. At the same time, SIRT1, a protein deacetylase (requiring NAD as a cofactor and involved in control of inflammation) is downregulated. We confirmed our findings by mining sequencing data from lungs of patients that died from SARS-CoV-2 infection. Our validated findings demonstrating increased NAD turnover in SARS-CoV-2 infection suggested that modulating NAD pathways may alter disease progression and may offer therapeutic benefits. Specifically, we hypothesized that treating K18-hACE2 mice with nicotinamide riboside (NR), a potent NAD precursor, may mitigate lethality and improve recovery from SARS-CoV-2 infection. We also tested the therapeutic potential of an anti- monomeric NAMPTantibody using the same infection model. Treatment with high dose anti-NAMPTantibody resulted in significantly decreased body weight compared to control, which was mitigated by combining HD anti-NAMPTantibody with NR. We observed a significant increase in lipid metabolites, including eicosadienoic acid, oleic acid, and palmitoyl carnitine in the low dose antibody + NR group. We also observed significantly increased nicotinamide related metabolites in NR treated animals. Discussion: Our data suggest that infection perturbs NAD pathways, identify novel mechanisms that may explain some pathophysiology of CoVID-19 and suggest novel strategies for both treatment and prevention. [ABSTRACT FROM AUTHOR]

A distinctive feature of cancer is the upregulation of sirtuin proteins. Sirtuins are class III NAD+-dependent deacetylases involved in cellular processes such as proliferation and protection against oxidative stress. SIRTs 1 and 2 are also overexpressed in several types of cancers including non-small cell lung cancer (NSCLC). Sirtinol, a sirtuin (SIRT) 1 and 2 specific inhibitor, is a recent anti-cancer agent that is cytotoxic against several types of cancers including NSCLC. Thus, sirtuins 1 and 2 represent valuable targets for cancer therapy. Recent studies show that sirtinol functions as a tridentate iron chelator by binding Fe3+ with 3:1 stoichiometry. However, the biological consequences of this function remain unexplored. Consistent with preliminary literature, we show that sirtinol can deplete intracellular labile iron pools in both A549 and H1299 non-small cell lung cancer cells acutely. Interestingly, a temporal adaptive response occurs in A549 cells as sirtinol enhances transferrin receptor stability and represses ferritin heavy chain translation through impaired aconitase activity and apparent IRP1 activation. This effect was not observed in H1299 cells. Holo-transferrin supplementation significantly enhanced colony formation in A549 cells while increasing sirtinol toxicity. This effect was not observed in H1299 cells. The results highlight the fundamental genetic differences that may exist between H1299 and A549 cells and offer a novel mechanism of how sirtinol kills NSCLC cells. [ABSTRACT FROM AUTHOR]

Purpose: Silent mating type information regulator 2 homolog 1 (SIRT1) and autophagy have a two-way action (promoting cell death or survival) on the progression and treatment of gastric cancer (GC) under different conditions or environments. This study aimed to investigate the effects and underlying mechanism of SIRT1 on autophagy and the malignant biological behavior of GC cells under conditions of glucose deprivation (GD). Materials and methods: Human immortalized gastric mucosal cell GES-1 and GC cell lines SGC-7901, BGC-823, MKN-45 and MKN-28 were utilized. A sugarfree or low-sugar (glucose concentration, 2.5 mmol/L) DMEM medium was used to simulate GD. Additionally, CCK8, colony formation, scratches, transwell, siRNA interference, mRFP-GFP-LC3 adenovirus infection, flow cytometry and western blot assays were performed to investigate the role of SIRT1 in autophagy and malignant biological behaviors (proliferation, migration, invasion, apoptosis and cell cycle) of GC under GD and the underlying mechanism. Results: SGC-7901 cells had the longest tolerance time to GD culture conditions, which had the highest expression of SIRT1 protein and the level of basal autophagy. With the extension of GD time, the autophagy activity in SGC-7901 cells also increased. Under GD conditions, we found a close relationship between SIRT1, FoxO1 and Rab7 in SGC-7901 cells. SIRT1 regulated the activity of FoxO1 and upregulated the expression of Rab7 through deacetylation, which ultimately affected autophagy in GC cells. In addition, changing the expression of FoxO1 provided feedback on the expression of SIRT1 in the cell. Reducing SIRT1, FoxO1 or Rab7 expression significantly inhibited the autophagy levels of GC cells under GD conditions, decreased the tolerance of GC cells to GD, enhanced the inhibition of GD in GC cell proliferation, migration and invasion and increased apoptosis induced by GD. Conclusion: The SIRT1-FoxO1-Rab7 pathway is crucial for the autophagy and malignant biological behaviors of GC cells under GD conditions, which could be a new target for the treatment of GC. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis (NASH) is becoming more widespread, and some similarities exist between its etiology and ferroptosis. However, there are limited investigations on which ferroptosis-related genes (FRGs) are regulated in NASH and how to regulate them. We screened and validated the pivotal genes linked to ferroptosis in NASH to comprehend the function of ferroptosis in the development of NASH. Methods: Two mRNA expression data were obtained from the Gene Expression Omnibus (GEO) as the training set and validation set respectively. FRGs were downloaded from FerrDb. The candidate genes were obtained from the intersection between differentially expressed genes (DEGs) and FRGs, and further analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The hub genes were identified by the protein-protein interaction (PPI) network and Cytoscape. Then, FRGs closely related to the severity of NASH were identified and further confirmed using the validation set and mouse models. Ultimately, based on these genes, a diagnostic model was established to differentiate NASH from normal tissues using another data set from GEO. Results: A total of 327 FRGs in NASH were acquired and subjected to GSEA. And 42 candidate genes were attained by overlapping the 585 FRGs with 2823 DEGs, and enrichment analysis revealed that these genes were primarily engaged in the fatty acid metabolic, inflammatory response, and oxidative stress. A total of 10 hub genes (PTGS2, IL1B, IL6, NQO1, ZFP36, SIRT1, ATF3, CDKN1A, EGR1, NOX4) were then screened by PPI network. The association between the expression of 10 hub genes and the progress of NASH was subsequently evaluated by a training set and verified by a validation set and mouse models. CDKN1A was up-regulated along with the development of NASH while SIRT1 was negatively correlated with the course of the disease. And the diagnostic model based on CDKN1A and SIRT1 successfully distinguished NASH from normal samples. Conclusion: In summary, our findings provide a new approach for the diagnosis, prognosis, and treatment of NASH based on FRGs, while advancing our understanding of ferroptosis in NASH. [ABSTRACT FROM AUTHOR]

Background: Owing to the lack of valid biomarkers, the diagnosis of autism spectrum disorder (ASD) diagnosis relies solely on the behavioral phenotypes of children. Several researchers have suggested an association between ASD and inflammation; however, the complex relationship between the two is unelucidated to date. Therefore, the current study aims to comprehensively identify novel circulating ASD inflammatory biomarkers. Methods: Olink proteomics was applied to compare the plasma inflammationrelated protein changes in a group of the healthy children (HC, n = 33) and another with ASD (n = 31). The areas under the receiver operating characteristic curves (AUCs) of the differentially expressed proteins (DEPs) were calculated. The functional analysis of the DEPs was performed using Gene Ontology and Kyoto Encyclopedia Genes and Genomes. Pearson correlation tests were used employed to analyze the correlation between the DEPs and clinical features. Results: A total of 13 DEPs were significantly up-regulated in the ASD group compared with the HC group. The four proteins, namely, STAMBP, ST1A1, SIRT2, and MMP-10 demonstrated good diagnostic accuracy with the corresponding AUCs (95% confidence interval, CI) of 0.7218 (0.5946-0.8489), 0.7107 (0.5827-0.8387), 0.7016 (0.5713-0.8319), and 0.7006 (0.568-0.8332). Each panel of STAMBP and any other differential protein demonstrated a better classification performance [AUC values from 0.7147 (0.5858-0.8436, STAMBP/AXIN1) to 0.7681 (0.6496-0.8867, STAMBP/MMP-10)]. These DEP profiles were enriched in immune and inflammatory response pathways, including TNF and NOD-like receptor signaling pathways. The interaction between STAMBP and SIRT2 (R = 0.97, p = 8.52×10-39) was found to be the most significant. In addition, several DEPs related to clinical features in patients with ASD, particularly AXIN1 (R = 0.36, p = 0.006), SIRT2 (R = 0.34, p = 0.010) and STAMBP (R = 0.34, p = 0.010), were positively correlated with age and parity, indicating that older age and higher parity may be the inflammation-related clinical factors in ASD. Conclusion: Inflammation plays a crucial role in ASD, and the up-regulated inflammatory proteins may serve as potential early diagnostic biomarkers for ASD. [ABSTRACT FROM AUTHOR]

Introduction: Chronic non-healing wound is a considerable clinical challenge and research into the discovery of novel pro-healing agents is underway as existing therapeutic approaches cannot sufficiently meet current needs. Method: We studied the effects of corylin in cell line fibroblasts and macrophages by Western blots, PCR, Flow cytometry assay, Immunofluorescence. Results: We showed that corylin, a main flavonoid extracted from Psoralea corylifolia L, reduced inflammatory responses, promoted collagen deposition, and accelerated the healing of full-thickness skin wounds in mice. Exploration of the underlying mechanisms showed that corylin activated the PI3K/AKT signaling, leading to fibroblasts' migration, proliferation, and scratch healing. Corylin also activated sirtuin 1 (SIRT1) signaling, enhanced the deacetylation and cytoplasmic translocation of NF-κB p65, and therefore reduced lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Furthermore, inhibition of PI3K/AKT and sirtuin 1 pathway with LY294002 and EX527 prevent the therapeutic potency of corylin against chronic wounds. Conclusion: In summary, our results suggested that corylin may be a candidate for the development of novel pro-healing agents. [ABSTRACT FROM AUTHOR]

Ferroptosis represents a novel non-apoptotic form of regulated cell death that is driven by iron-dependent lipid peroxidation and plays vital roles in various diseases including cardiovascular diseases, neurodegenerative disorders and cancers. Plenty of iron metabolism-related proteins, regulators of lipid peroxidation, and oxidative stress-related molecules are engaged in ferroptosis and can regulate this complex biological process. Sirtuins have broad functional significance and are targets of many drugs in the clinic. Recently, a growing number of studies have revealed that sirtuins can participate in the occurrence of ferroptosis by affecting many aspects such as redox balance, iron metabolism, and lipid metabolism. This article reviewed the studies on the roles of sirtuins in ferroptosis and the related molecular mechanisms, highlighting valuable targets for the prevention and treatment of ferroptosis-associated diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation and neuroimmunology-associated disorders, including ischemic stroke and neurodegenerative disease, commonly cause severe neurologic function deficits, including bradypragia, hemiplegia, aphasia, and cognitive impairment, and the pathological mechanism is not completely clear. SIRT2, an NAD+-dependent deacetylase predominantly localized in the cytoplasm, was proven to play an important and paradoxical role in regulating ischemic stroke and neurodegenerative disease. This review summarizes the comprehensive mechanism of the crucial pathological functions of SIRT2 in apoptosis, necroptosis, autophagy, neuroinflammation, and immune response. Elaborating on the mechanism by which SIRT2 participates in neuroinflammation and neuroimmunology-associated disorders is beneficial to discover novel effective drugs for diseases, varying from vascular disorders to neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Previous research has linked polymorphisms in the SIRT1 gene to depressive symptoms, particularly in Chinese individuals. However, it is not clear how personality traits may contribute to this association. Methods: To explore the potential mediating effect of personality traits, we utilized a mediation model to examine the relationship between the SIRT1 rs12415800 polymorphism and depressive symptoms in 787 Chinese college students. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, while personality traits were measured using the Big Five Inventory (BFI). Results: Our analysis indicated a significant association between the SIRT1 rs12415800 polymorphism and depressive symptoms, with this relationship partially mediated by the personality traits of neuroticism and conscientiousness. Specifically, individuals who were heterozygous for the rs12415800 polymorphism and had higher levels of conscientiousness were less likely to experience depressive symptoms. Conversely, those who were homozygous for the rs12415800 polymorphism and had higher levels of neuroticism were more likely to experience depressive symptoms. Conclusion: Our results suggest that personality traits, particularly neuroticism and conscientiousness, may play a critical role in the association between the SIRT1 rs12415800 polymorphism and depressive symptoms among Chinese college students. These findings highlight the importance of considering both genetic factors and personality traits when exploring the etiology of depressive symptoms in this population. [ABSTRACT FROM AUTHOR]

Phytopathogenic fungi must adapt to the different environmental conditions found during infection and avoid the immune response of the plant. For these adaptations, fungi must tightly control gene expression, allowing sequential changes in transcriptional programs. In addition to transcription factors, chromatin modification is used by eukaryotic cells as a different layer of transcriptional control. Specifically, the acetylation of histones is one of the chromatin modifications with a strong impact on gene expression. Hyperacetylated regions usually correlate with high transcription and hypoacetylated areas with low transcription. Thus, histone deacetylases (HDACs) commonly act as repressors of transcription. One member of the family of HDACs is represented by sirtuins, which are deacetylases dependent on NAD+, and, thus, their activity is considered to be related to the physiological stage of the cells. This property makes sirtuins good regulators during environmental changes. However, only a few examples exist, and with differences in the extent of the implication of the role of sirtuins during fungal phytopathogenesis. In this work, we have performed a systematic study of sirtuins in the maize pathogen Ustilago maydis, finding Sir2 to be involved in the dimorphic switch from yeast cell to filament and pathogenic development. Specifically, the deletion of sir2 promotes filamentation, whereas its overexpression highly reduces tumor formation in the plant. Moreover, transcriptomic analysis revealed that Sir2 represses genes that are expressed during biotrophism development. Interestingly, our results suggest that this repressive effect is not through histone deacetylation, indicating a different target of Sir2 in this fungus. [ABSTRACT FROM AUTHOR]

Upregulation of pyruvate kinase M2 (PKM2) is critical for the orchestration of metabolism and inflammation in critical illness, while autophagic degradation is a recently revealed mechanism that counter-regulates PKM2. Accumulating evidence suggests that sirtuin 1 (SIRT1) function as a crucial regulator in autophagy. The present study investigated whether SIRT1 activator would downregulate PKM2 in lethal endotoxemia via promotion of its autophagic degradation. The results indicated that lethal dose of lipopolysaccharide (LPS) exposure decreased the level of SIRT1. Treatment with SRT2104, a SIRT1 activator, reversed LPS-induced downregulation of LC3B-II and upregulation of p62, which was associated with reduced level of PKM2. Activation of autophagy by rapamycin also resulted in reduction of PKM2. The decline of PKM2 in SRT2104-treated mice was accompanied with compromised inflammatory response, alleviated lung injury, suppressed elevation of blood urea nitrogen (BUN) and brain natriuretic peptide (BNP), and improved survival of the experimental animals. In addition, coadministration of 3-methyladenine, an autophagy inhibitor, or Bafilomycin A1, a lysosome inhibitor, abolished the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response and multiple organ injury. Therefore, promotion of autophagic degradation of PKM2 might be a novel mechanism underlying the anti-inflammatory benefits of SIRT1 activator. [ABSTRACT FROM AUTHOR]