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Background: The prevalence of dementia around the world is increasing, and these patients are more likely to have cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorders over their lifetime. Previous studies have proven that melatonin could improve memory loss, but its specific mechanism is still confused. Methods: In this study, we used in vivo and in vitro models to examine the neuroprotective effect of melatonin on scopolamine (SCOP)‐induced cognitive dysfunction. The behavioral tests were performed. 18F‐FDG PET imaging was used to assess the metabolism of the brain. Protein expressions were determined through kit detection, Western blot, and immunofluorescence. Nissl staining was conducted to reflect neurodegeneration. MTT assay and RNAi transfection were applied to perform the in vitro experiments. Results: We found that melatonin could ameliorate SCOP‐induced cognitive dysfunction and relieve anxious‐like behaviors or HT22 cell damage. 18F‐FDG PET‐CT results showed that melatonin could improve cerebral glucose uptake in SCOP‐treated mice. Melatonin restored the cholinergic function, increased the expressions of neurotrophic factors, and ameliorated oxidative stress in the brain of SCOP‐treated mice. In addition, melatonin upregulated the expression of silent information regulator 1 (SIRT1), which further relieved endoplasmic reticulum (ER) stress by decreasing the expression of phosphorylate inositol‐requiring enzyme (p‐IRE1α) and its downstream, X‐box binding protein 1 (XBP1). Conclusions: These results indicated that melatonin could ameliorate SCOP‐induced cognitive dysfunction through the SIRT1/IRE1α/XBP1 pathway. SIRT1 might be the critical target of melatonin in the treatment of dementia. [ABSTRACT FROM AUTHOR]

In this study, we examined the changes in the mitochondrial structure and function in cumulus granulosa cells of patients with diminished ovarian reserve (DOR) to explore the causes and mechanisms of decreased mitochondrial quality. The mitochondrial ultrastructure was observed by transmission electron microscope, and the function was determined by detecting the ATP content, reactive oxygen species (ROS) levels, the number of mitochondria, and the mitochondrial membrane potential. The expression of ATP synthases in relation to mitochondrial function was analyzed. Additionally, protein immunoblotting was used to compare the expression levels of mitochondrial kinetic protein, the related channel protein in the two groups. Patients with DOR had abnormal granulosa cell morphology, increased mitochondrial abnormalities, decreased mitochondrial function, and disturbed mitochondrial dynamics. Additionally, the silent information regulator 1 (SIRT1)/phospho-AMP-activated protein kinase (P-AMPK)-peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) pathway expression was decreased, which was speculated to be associated with the decreased mitochondrial mass in the DOR group. The mitochondrial mass was decreased in granulosa cells of patients in the DOR group. The mitochondrial dysfunction observed in granulosa cells of patients in the DOR group may be associated with dysregulation of the SIRT1/P-AMPK-PGC-1α-mitochondrial transcription factor A (TFAM) pathway. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin‐induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14–28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor‐β1‐induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho‐Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1‐mediated antifibrotic effectiveness. This suggests that targeting SIRT1‐mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone‐based therapy for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Cardiac remodeling is a commonly observed pathophysiological phenomenon associated with the progression of heart failure in various cardiovascular disorders. Carnosol, a phenolic compound extracted from rosemary, possesses noteworthy pharmacological properties including anti‐inflammatory, antioxidant, and anti‐apoptotic activities. Considering the pivotal involvement of inflammation, oxidative stress, and apoptosis in cardiac remodeling, the present study aims to assess the effects of carnosol on cardiac remodeling and elucidate the underlying mechanisms. In an in vivo model, cardiac remodeling was induced by performing transverse aortic constriction (TAC) surgery on mice, while an in vitro model was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II. Our results revealed that carnosol treatment effectively ameliorated TAC‐induced myocardial hypertrophy and fibrosis, thereby attenuating cardiac dysfunction in mice. Moreover, carnosol improved cardiac electrical remodeling and restored connexin 43 expression, thereby reducing the vulnerability to ventricular fibrillation (VF). Furthermore, carnosol significantly reduced Ang II‐induced cardiomyocyte hypertrophy in NRCMs and alleviated the upregulation of hypertrophy and fibrosis markers. Both in vivo and in vitro models of cardiac remodeling exhibited the anti‐inflammatory, anti‐oxidative, and anti‐apoptotic effects of carnosol. Mechanistically, these effects were mediated through the Sirt1/PI3K/AKT pathway, as the protective effects of carnosol were abrogated upon inhibition of Sirt1 or activation of the PI3K/AKT pathway. In summary, our study suggests that carnosol prevents cardiac structural and electrical remodeling by regulating the anti‐inflammatory, anti‐oxidative, and anti‐apoptotic effects mediated by Sirt1/PI3K/AKT signaling pathways, thereby alleviating heart failure and VF. [ABSTRACT FROM AUTHOR]

Studies have demonstrated a close correlation between MicroRNA and the occurrence of aortic dissection (AD). However, the molecular mechanisms underlying this relationship have not been fully elucidated and further exploration is still required. In this study, we found that miR‐485‐3p was significantly upregulated in human aortic dissection tissues. Meanwhile, we constructed in vitro AD models in HAVSMCs, HAECs and HAFs and found that the expression of miR‐485‐3p was increased only in HAVSMCs. Overexpression or knockdown of miR‐485‐3p in HAVSMCs could regulate the expression of inflammatory cytokines IL1β, IL6, TNF‐α, and NLRP3, as well as the expression of apoptosis‐related proteins BAX/BCL2 and Cleaved caspase3/Caspase3. In the in vivo AD model, we have observed that miR‐485‐3p regulates vascular inflammation and apoptosis, thereby participating in the modulation of AD development in mice. Based on target gene prediction, we have validated that SIRT1 is a downstream target gene of miR‐485‐3p. Furthermore, by administering SIRT1 agonists and inhibitors to mice, we observed that the activation of SIRT1 alleviates vascular inflammation and apoptosis, subsequently reducing the incidence of AD. Additionally, functional reversal experiments revealed that overexpression of SIRT1 in HAVSMCs could reverse the cell inflammation and apoptosis mediated by miR‐485‐3p. Therefore, our research suggests that miR‐485‐3p can aggravate inflammation and apoptosis in vascular smooth muscle cells by suppressing the expression of SIRT1, thereby promoting the progression of aortic dissection. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury (CI–AKI) in mice with type 1 diabetic mellitus(DM) using diffusion tensor imaging(DTI).Methods: Mice with DM were divided into two groups. In the diabetic + contrast medium(DCA) group, the changes of the mice kidneys were monitored at 1, 24, 48, and 72 h after the injection of iodixanol(4gI/kg). The mice in the diabetic + contrast medium + quercetin(DCA + QE) group were orally given different concentrations of quercetin for seven days before injection of iodixanol. In vitro experiments, renal tubular epithelial (HK-2) cells exposed to high glucose conditions were treated with various quercetin concentrations before treatment with iodixanol(250 mgI/mL).Results: DTI-derived mean diffusivity(MD) and fractional anisotropy(FA) values can be used to evaluate CI-AKI effectively. Quercetin significantly increased the expression of Sirt 1 and reduced oxidative stress by increasing Nrf 2/HO-1/SOD1. The antiapoptotic effect of quercetin on CI-AKI was revealed by decreasing proteins level and by reducing the number of apoptosis-positive cells. In addition, flow cytometry indicated quercetin-mediated inhibition of M1 macrophage polarization in the CI-AKI.Conclusions: DTI will be an effective noninvasive tool in diagnosing CI-AKI. Quercetin attenuates CI-AKI on the basis of DM through anti-oxidative stress, apoptosis, and inflammation.

We aimed to evaluate the influence of sirtuin1 (sirt1) on the ESCC chemotherapeutic sensitivity to cisplatin. We used ESCC cell ablation sirt1 for establishing a xenograft mouse tumor model. The tumor volume was then detected. sirt1 was over-expressed significantly in ESCC patients and cells. Moreover, sirt1 knockdown raised ESCC sensitivity to cisplatin. Besides, glycolysis was associated with ESCC cell chemotherapy resistance to cisplatin. Furthermore, sirt1 increased ESCC cells’ cisplatin chemosensitivity through HK2. Sirt1 enhanced in vivo ESCC chemosensitivity to cisplatin. Overall, these findings suggested that sirt1 knockdown regulated the glycolysis pathway and raised the ESCC chemotherapeutic sensitivity.

Recent studies underscore the anti-inflammatory role of SIRT1; however, its levels during inflammatory states remain ambiguous. We synthesized relevant studies up to 20 March 2024 to evaluate the relationship between SIRT1 and inflammation, using data from three major databases. Employing a random-effects model, we analyzed both cross-sectional and longitudinal studies, calculating weighted mean differences (WMDs) for pooled effect sizes. Subgroup and sensitivity analyses, along with a risk of bias assessment, were also conducted. We reviewed 13 publications, encompassing 21 datasets and 2,028 participants. The meta-analysis indicated higher SIRT1 levels in inflammatory groups compared to control groups pre-adjustment (WMD, 3.18 ng/ml; 95% CI 2.30, 4.06 ng/ml; P

Acer tegmentosum Maxim (AT) is a medicinal plant used to treat hepatic, neurological diseases, and cancer. However, the beneficial effects of AT on endothelial dysfunction have not been reported yet. In this study, we evaluated the effects of AT and the main compounds against TNF-α-mediated inflammatory responses and their possible mechanism of action. The anti-inflammatory effect and its molecular mechanism were analyzed by adhesion assay, immunoblotting, promoter-luciferase assay, ELISA, RT-PCR, immunocytochemistry, immunoprecipitation, siRNA gene knockdown, docking, and molecular dynamics simulation. AT and its compounds salidroside and tyrosol reduced TNF-α-induced adhesion between monocytes and endothelial cells. Fermentation of AT with Bacillus subtilis converted salidroside to tyrosol, which is salidroside’s aglycone. The fermented AT product (ATF) potently inhibited TNF-α-mediated monocyte adhesion with higher potency than AT. AT or ATF abrogated TNF-α-induced expression of adhesion molecules (VCAM-1 and ICAM-1) and production of MCP-1 with the inhibition of phosphorylated MAP kinases. TNF-α-mediated NF-κB transactivation and RelA/p65 acetylation were suppressed by AT and ATF through the interaction of NF-κB with sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase. Sirt1 gene knockdown diminished the protective effects of AT and ATF against TNF-α-mediated signaling and inflammatory response. Interestingly, SIRT1 protein expression was significantly increased by ATF and tyrosol rather than by AT and salidroside, respectively. Molecular docking showed that the tyrosol moiety is critical for the interaction with Glu230 of SIRT1 (PDB ID: 4ZZH and 4ZZJ) for the deacetylase activity. Molecular dynamics revealed that tyrosol can induce the movement of the N-terminal domain toward the catalytic domain of SIRT1. This study demonstrates the potential of AT and ATF to prevent endothelial inflammation and vascular dysfunction of the retina by the MAPK/NF-κB/SIRT1 signaling pathways and targeting of the tyrosol moiety to Glu230 in SIRT1.

Background: Psychological stress-related infertility is often attributed to a decline in both the quality and quantity of oocytes. Kai Yu Zhong Yu (KYZY) recipe, a classic herbal formula in Traditional Chinese Medicine (TCM), has been employed for centuries to address stress-related infertility. Our previous studies have demonstrated its effectiveness in counteracting the reduction in oocyte competence induced by psychological stress. Purpose: To investigate the mechanism by which KYZY mitigates the adverse effects of stress. Methods: Female ICR mice were randomly assigned to one of five groups: control, CUMS, KYZY-H, KYZY-M, and KYZY-L. Except for the control group, the other groups underwent a six-week Chronic Unpredictable Mild Stress (CUMS) procedure. Following CUMS, the three KYZY groups were received high (38.2 g kg-1), medium (19.1 g kg-1), and low (9.6 g kg-1) doses of the KYZY recipe intragastrically for four weeks. Additionally, RNA interference was used to reduce Sirt1 expression in the ovary to assess the involvement of the SIRT1 pathway. ELISA, HE staining, follicle counting, TUNEL staining, and Western blot were conducted to explore the mechanism of KYZY in treatment of stress-related infertility. Results: KYZY treatment significantly reduced concentrations of IL-6, IL-1β and TNF-α, reversed the loss of small follicles, and alleviated follicular apoptosis and autophagy. KYZY also elevated SIRT1/FOXO1/3 activity, reduced BAX expression, increased BCL-2 expression, and restored Beclin-1-dependent autophagy. Sirt1 silencing downregulated the activity of the SIRT1/FOXO1/3 pathway and triggered Caspase-3-mediated cleavage of Beclin-1 in mouse ovary. Conversely, Sirt1 silencing nullified the effect of KYZY recipe on inflammation and the regulation of apoptosis and autophagy. Conclusion: KYZY enhances SIRT1/FOXO1/3 pathway activity, shifting the balance from apoptosis towards autophagy to safeguard oocyte capacity against the effects of psychological stress.

Cadmium (Cd), a potentially toxic elements, has the potential to cause harm to the kidneys. Studies has demonstrated that autophagosome-lysosome fusion blockade and consequent autophagy inhibition is related to Cd-induced kidney injury. Studies indicate that acetylation of forkhead box protein O1 (FOXO1) as a transcriptional factor of lysosomal and autophagy genes, but its roles in Cd-exposed kidney tissues remains unclear till now. Therefore, the present study was conducted to elucidate this issue. Data found that Cd enhances the acetylation level of FOXO1 and inhibits the expression level of silent information regulator 1 (Sirt1, deacetylase of FOXO1). Pharmacological activation of Sirt1 (SRT2104 treatment) decreases Cd-increased acetylation level of FOXO1, enhances Cd-inhibited transcription level of Ras-related protein 7 (Rab7), restores Cd-blocked fusion of autophagosome and lysosome, and alleviates Cd-induced autophagy inhibition. Moreover, data corroborated that inhibiting the acetylation level of FOXO1 is conductive to mitigating Cd-induced kidney injury. Collectively, these results demonstrate that acetylation of FOXO1 mediates the autophagosome-lysosome fusion blockade and autophagy inhibition during Cd-induced kidney injury, while regulating the acetylation level of FOXO1 may be a potential mechanism of treating nephrotoxicity after Cd exposure.

Background: Brain injury often results in high mortality rates and significant sequelae following severe heatstroke (HS). Neuroinflammation aggravates HS-induced brain injury, yet the involvement of microglia in heat-induced neuroinflammation deserves further investigation. Methods: Our study investigated activation status, phenotype markers, production of pro-inflammatory cytokine and reactive oxygen species (ROS) of microglia both in vitro and in vivo under HS. Utilizing high-throughput sequencing, we identified SIRT1 as a potential modulator of microglia phenotype, and observed that SIRT1 alleviated severe heatstroke-induced brain injury following intraperitoneal administration of the SIRT1 agonist SRT-1720 and the inhibitor selisistat. Additionally, the effects of SRT-1720 and selisistat on mitochondrial dynamics and microglial phenotype transition were examined in BV2 cells in vitro. Results: Heatstroke promotes microglia activation, as evidenced by the increased production of pro-inflammatory cytokine and reactive oxygen species. High-throughput sequencing revealed elevated expression of SIRT1 in BV2 cells under HS. Upon inhibition of SIRT1 expression, there was a corresponding increase in pro-inflammatory cytokine, iNOS, and ROS expression in BV2 cells. In vivo experiments with the SIRT1 agonist SRT-1720 showed a mitigation of neuron injury under HS, as assessed by Nissl and HE staining. Activation of SIRT1 was associated with a reduction in mitochondrial injury and a decrease in the phosphorylation of mitochondrial fission protein Drp1ser616. Furthermore, the heat-induced activation of microglia was reversed by the Drp1 inhibitor, Mdivi. Conclusions: Our findings provided evidence that SIRT1 played a crucial role in inhibiting heat stress-induced microglial activation. By suppressing the phosphorylation of mitochondrial fission protein Drp1, SIRT1 contributed to the reduction of neuroinflammation and severity of heatstroke-induced brain injury.

AimThis study aimed to gain deeper insights into the hepatotoxicity mechanisms of valproic acid (VPA), as well as to identify potential risk markers for VPA-induced hepatotoxicity.MethodsTwenty-two children with epilepsy treated with VPA monotherapy were divided into a normal liver function (NLF) group, a mild abnormal liver function (ANLF1) group, and a serious abnormal liver function (ANLF2) group based on their liver function indicator levels. The full quantitative targeted metabolomics technique was used to systematically investigate how the differential endogenous metabolic components change with the development of liver injury.ResultsA total of 195 metabolic components were quantitatively analyzed. Nineteen identified metabolites, including five organic acids, four short-chain fatty acids, four amino acids, three fatty acids, and three benzenoids, differed significantly among the three groups, showing a strong association with VPA-induced hepatotoxicity. Only three bile acid metabolites, taurodeoxycholic acid, taurochenodeoxycholic acid, and deoxycholic acid, were significantly different between the ANLF1 and ANLF2 groups, increasing at first and then decreasing with the aggravation of liver injury. The mechanistic evaluation showed that SRT1720 activation could alleviate the severity of liver function abnormalities induced by VPA. Immunocoprecipitation indicated that VPA significantly increased the acetylation level of FXR, and the application of agonist SRT1720 can antagonize the acetylation of FXR by VPA.ConclusionNineteen identified metabolites showed a strong association with hepatotoxicity and three bile acid metabolites changed with the development of liver injury. The SIRT1–FXR pathway was firstly proposed to participate in VPA-induced hepatotoxicity.

Background Hirschsprung’s disease (HSCR) is a congenital disorder characterized by aganglionosis in the intermuscular and submucosal nerve plexuses of the gut, leading to impaired gastrointestinal function. Although the precise cause and pathophysiology of HSCR remain elusive, increasing evidence points to a significant role of autophagy in its development, warranting further investigation into its underlying mechanisms. Methods This study utilized publicly available microarray expression profiling datasets, GSE96854 and GSE98502, from the Gene Expression Omnibus (GEO). The R software (version 4.2.0) was employed to identify autophagy-related genes potentially showing differential expression in HSCR. Subsequent analyses included correlation analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analysis using the STRING database (version 11.0) and Cytoscape software (version 3.8.2). Ultimately, HSCR samples were used to verify the mRNA levels of important genes by quantitative real-time polymerase chain reaction (qRT-PCR) in a laboratory setting. Results We have discovered 20 genes that are involved in autophagy and show variable expression. Among these genes, 15 are up-regulated and five are down-regulated. The enrichment analysis using the GO and KEGG pathways revealed a notable enrichment in pathways related to the control of autophagy. Nine hub genes were found via the investigation of the PPI network constructed from STRING database and module analysis using Cytoscape. Moreover, the concordance between SIRT1 expression in the HSCR model and the bioinformatics analysis of mRNA chip findings was validated using qRT-PCR. Conclusion Utilizing bioinformatics analysis, we identified 20 potential genes associated with Hirschsprung’s disease that play a role in autophagy. Notably, the upregulation of SIRT1 may profoundly influence the progression of HSCR by regulating autophagy-related pathways, offering a novel perspective on the disease’s pathogenesis.

Intermittent fasting (IF) has demonstrated extensive health benefits through the regulation of fatty acid metabolism and modulation of the neuroimmune microenvironment, primarily via the activation of key signaling pathways such as AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). IF not only facilitates fatty acid oxidation and improves metabolic health, but also enhances mitochondrial function, mitigates oxidative stress, promotes autophagy, and inhibits apoptosis and ferroptosis. These mechanisms contribute to its substantial preventive and therapeutic potential in various conditions, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, autoimmune diseases, and neurotraumatic conditions. While supportive evidence has been obtained from animal models and preliminary clinical studies, further large-scale, long-term randomized controlled trials are imperative to establish its safety and evaluate its clinical efficacy comprehensively.

Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin's effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53–SIRT1signaling pathway in adult rats' PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function.

Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100 mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6 N male mice. Furthermore, Cd significantly increased β-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50 mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.

Heart failure (HF) is a syndrome of symptoms and signs caused by cardiac insufficiency and have become a serious global health problem. The aim of this study is to clarify the role and mechanism failure of MIR17HG. We established the in vitro HF model by using H2O2-treated AC-16 and HCM cells, and the reactive oxygen species (ROS) level and natriuretic peptide precursor B (NPPB) expression were also detected. The RNA expression of MIR17HG, miR-153-3p, SIRT1, and NPPB were detected by quantitative reverse transcription PCR while the SIRT1 and NPPB expression were detected by western blot. The binding relationship among MIR17HG, miR-153-3p, and SIRT1 were assessed by dual-luciferase reporter assay and RNA binding protein immunoprecipitation assay. Then, MIR17HG and SIRT1 were overexpressed by lentivirus transfection, and the influence of MIR17HG and SIRT1 on H2O2-induced apoptosis mediated by p53 were evaluated. The results show that MIR17HG and SIRT1 were significantly downregulated, while miR-153-3p was significantly upregulated in HF model. Overexpression of MIR17HG reduced miR-153-3p and alleviated HF, while knockdown of SIRT1 weakened the effects of MIR17HG, suggesting that SIRT1 was the direct target of MIR17HG/miR-153-3p axis. MIR17HG is significantly downregulated in HF model. Our research shows that MIR17HG protects cardiomyocytes from ROS-induced damage via the MIR17HG/miR-153-3p/SIRT1 axis, suggesting that MIR17HG and SIRT1 are potential therapeutic targets in HF.

Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.

Abstract Objectives Specific miRNAs are evident to be overexpressed with age, lifestyle, and environmental changes. Previous studies reported miR‐124 overexpression in different scenarios in aged skin, age‐related cognitive impairment, ischemic heart disease, muscle atrophy, and fractures. Thus miR‐124 was considered to be a reliable miRNA target to establish a hypothesis on aging epigenome. Parallelly the hypothesis focuses on the expression of SIRT1 and VDR genes as a target for this specific miRNA expression as these genes were believed to be related to aging. This study aims to derive facts and evidence from past studies on aging. The objective was to establish a hypothetical linkage between miR‐124 with age‐related genes like SIRT1 and VDR. Methods An in silico search was performed in the TargetScan and miRbase databases to analyze the aging‐associated miRNAs and their gene targets, the Python seaborn library was used, and the results were represented in terms of a bar plot. Results Based on an in silico analysis and studies available in the literature, we identified that miR‐124‐3p.1 and miR‐124‐3p.2 targets 3′ UTR of VDR and SIRT1 genes, and hence thereby indicates that the miR‐124 can regulate the expression of these genes. Further, few in vitro research studies have observed that miR‐124 overexpression leads to the downregulation of VDR and SIRT1 gene expression. These results indicate that the suppression of these target genes accelerates early aging and age‐related disorders. Conclusions Overall, this study hypothesizes that the overexpression of miR‐124 diminishes the expression of VDR and SIRT1 genes, and thereby advances the process of aging, resulting in the development of age‐associated complications.

Abstract Background Hyperlipidemia is a vital etiology of acute pancreatitis (AP), 12 to 20% of which have a history of hyperlipidemia. Multiple organ failure is the major cause of the high mortality rate of AP. Liver injury has been discovered in 80% of AP patients. The relationship and role of IRF9 and SIRT1 have not been presented in AP and hyperlipidemia AP (HLAP) with liver injury. This investigation was designed to explore the function and relationship of IRF9 and SIRT1. Methods HLAP model in vivo was performed by feeding high-fat forage and induced by peritoneal injection with 20% L-arginine. The severity of pancreas and liver tissues was assessed. Cell apoptosis in the liver was determined by the TUNEL experiment. IRF9, SIRT1, p53, and acetylated p53 (Ac-p53) expression levels in liver tissues were detected by qRT-PCR and Western blot. The association of IRF9 expression with SIRT1 levels was evaluated. The relevance of triglyceride level to tissue damage was analyzed. Results Our observation exhibited more distinct liver damage, a large number of hepatic cell apoptosis, marked raised IRF9, Ac-p53, and sharply dropped SIRT1 in the AP and HLAP groups. Compared with other groups, HLAP showed the most significant changes in liver injury, hepatic cell apoptosis, protein, and mRNA levels. The declined expression of SIRT1 was correlated with the elevated expression of IRF9. The damage of the pancreas and liver exacerbated with the increase in triglyceride levels. Conclusion Elevated IRF9 in pancreatitis with liver injury raised cell apoptosis and tissue damage by decreasing SIRT1 expression.

Chronic renal failure (CRF) is a severe syndrome affecting the urinary system for which there are no effective therapeutics. In this study, we investigate the effects and mechanisms of aminophylline in preventing CRF development. A rat model of chronic renal failure is established by 5/6 nephrectomy. The levels of serum creatinine (SCR), urinary protein (UPR), and blood urea nitrogen (BUN) are detected by ELISA. Histological evaluations of renal tissues are performed by H&E, Masson staining, and PAS staining. Functional protein expression is detected by western blot analysis or immunofluorescence microscopy. Glomerular cell apoptosis is determined using the TUNEL method. Results show that Aminophylline significantly reduces the levels of SCR, UPR, and BUN in the CRF model rats. Histological analyses show that aminophylline effectively alleviates renal tissue injuries in CRF rats. The protein expression levels of nephrin, podocin, SIRT1, p-AMPK, and p-ULK1 are greatly increased, while p-mTOR protein expression is markedly decreased by aminophylline treatment. Additionally, the protein level of LC3B in CRF rats is significantly increased by aminophylline. Moreover, aminophylline alleviates apoptosis in the glomerular tissues of CRF rats. Furthermore, resveratrol promotes SIRT1, p-AMPK, and p-ULK1 protein expressions and reduces p-mTOR and LC3B protein expressions in CRF rats. Selisistat (a SIRT1 inhibitor) mitigates the changes in SIRT1, p-AMPK, p-ULK1, p-mTOR, and LC3B expressions induced by aminophylline. Finally, RAPA alleviates renal injury and apoptosis in CRF rats, and 3-MA eliminates the aminophylline-induced inhibition of renal injury and apoptosis in CRF rats. Aminophylline suppresses chronic renal failure progression by modulating the SIRT1/AMPK/mTOR-mediated autophagy process.

Background and purpose: Atrophy of the skeletal system caused by spinal cord injury (SCI) can cause secondary systemic metabolic dysfunction, such as glucose intolerance, type 2 diabetes, and insulin resistance. On the other hand, Sirtun1 (SIRT1) and Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1alpha (PGC-1α) are known factors and related proteins involved in skeletal muscle atrophy. Therefore, the present study aimed to investigate the effect of aerobic training with resveratrol consumption on SIRT1 and PGC-1α levels in the gastrocnemius muscles of rats after spinal cord injury. Materials and methods: 36 male Wistar rats aged eight weeks were randomly placed in 4 groups including control, resveratrol, training, and resveratrol+training (each group n=9). After anesthesia, an incision was made in the midline of the back and over the vertebral ridges. The muscles and lamina of the T9 vertebra were removed without damaging the dura mater, Spinal cord injury was caused by dropping a ten-gram weight from a height of 25 mm on the spinal cord in the T10 segment. After confirmation of SCI, a Resveratrol supplement with a dose of 10 mg/kg was injected intraperitoneally and daily (every morning for 4 weeks), and the rats of other groups were injected with the same amount of saline. The aerobic training was carried out with the help of the weight support system for 4 weeks, 5 sessions per week, each session was 58 minutes and the intensity was 20 m/min. 48 hours after the last training session, the gastrocnemius muscle of right leg of all rats was removed. The SIRT1 and PGC-1α levels in the gastrocnemius muscle were measured by the ELISA method. To analyze the data, one-way analysis of variance and LSD post hoc tests were used at the significance level of P

Abstract Background Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins. Methods Rats fed with fructose in drinking water, Sirt1 −/− mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used. Results Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1 −/− mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin. Conclusions Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.

Abstract Background Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. Methods Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. Results The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. Conclusions The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery. Graphical Abstract

Abstract Acute liver injury, there is a risky neurological condition known as hepatic encephalopathy (HE). Herbacetin is a glycosylated flavonoid with many pharmacological characteristics. The purpose of this study was to assess the ability of herbacetin to protect against the cognitive deficits associated with thioacetamide (TAA) rat model and delineate the underlying behavioral and pharmacological mechanisms. Rats were pretreated with herbacetin (20 and 40 mg/kg) for 30days. On 30th day, the rats were injected with TAA (i.p. 350 mg/kg) in a single dose. In addition to a histpathological studies, ultra-structural architecture of the brain, liver functions, oxidative stress biomarkers, and behavioral tests were evaluated. Compared to the TAA-intoxicated group, herbacetin improved the locomotor and cognitive deficits, serum hepatotoxicity indices and ammonia levels. Herbacetin reduced brain levels of malodialdeyde, glutamine synthetase (GS), tumor necrosis factor- alpha (TNF-α), interleukin 1 B (IL-1β), annexin v, and increased brain GSH, Sirtuin 1 (SIRT1), and AMP-activated kinase (AMPK) expression levels. Also, herbacetin improve the histopathological changes and ultra- structure of brain tissue via attenuating the number of inflammatory and apoptotic cells. Herbacetin treatment significantly reduced the toxicity caused by TAA. These findings suggest that herbacetin might be taken into account as a possible neuroprotective and cognitive enhancing agent due to its ability to reduce oxidative stress, inflammation and apoptosis associated with TAA.

Lipid droplets (LDs) are dynamic organelles that store neutral lipids and are closely linked to obesity. Previous studies have suggested that Lycium barbarum polysaccharide (LBP) supplements can ameliorate obesity, but the underlying mechanisms remain unclear. In this study, we hypothesize that LBP alleviates LD accumulation in adipose tissue (AT) by inhibiting fat-specific protein 27 (Fsp27) through an activating transcription factor-6 (ATF6)/small-molecule sirtuin 1 (SIRT1)-dependent mechanism. LD accumulation in AT is induced in high-fat diet (HFD)-fed mice, and differentiation of 3T3-L1 preadipocytes (PAs) is induced. The ability of LBP to alleviate LD accumulation and the possible underlying mechanism are then investigated both in vivo and in vitro. The influences of LBP on the expressions of LD-associated genes ( ATF6 and Fsp27) are also detected. The results show that HFD and PA differentiation markedly increase LD accumulation in ATs and adipocytes, respectively, and these effects are markedly suppressed by LBP supplementation. Furthermore, LBP significantly activates SIRT1 and decreases ATF6 and Fsp27 expressions. Interestingly, the inhibitory effects of LBP are either abolished or exacerbated when ATF6 is overexpressed or silenced, respectively. Furthermore, SIRT1 level is transcriptionally regulated by LBP through opposite actions mediated by ATF6. Collectively, our findings suggest that LBP supplementation alleviates obesity by ameliorating LD accumulation, which might be partially mediated by an ATF6/SIRT1-dependent mechanism.

Abstract Essential tremor (ET) is a neurological disease that impairs motor and cognitive functioning. A variant of the Lingo-1 genetic locus is associated with a heightened ET risk, and increased expression of cerebellar Lingo-1. Lingo-1 has been associated with neurodegenerative processes; however, neuroprotection from ET-associated degeneration can be conferred by the protein Sirt1. Sirt1 activity can be promoted by Resveratrol (Res) and 1,25-dihydroxyvitamin D3 (VitD3), and thus these factors may exert neuroprotective properties through a Sirt1 mechanism. As Res and VitD3 are linked to Sirt1, enhancing Sirt1 could counteract the negative effects of increased Lingo-1. Therefore, we hypothesized that a combination of Res-VitD3 in a harmaline injection model of ET would modulate Sirt1 and Lingo-1 levels. As expected, harmaline exposure (10 mg/kg/every other day; i.p.) impaired motor coordination, enhanced tremors, rearing, and cognitive dysfunction. When Res (5 mg/kg/day; i.p.) and VitD3 (0.1 mg/kg/day; i.p.) were given to adult rats (n = 8 per group) an hour before harmaline, tremor severity, rearing, and memory impairment were reduced. Individual treatment with Res and VitD3 decreased Lingo-1 gene expression levels in qPCR assays. Co-treatment with Res and VitD3 increased and decreased Sirt1 and Lingo-1 gene expression levels, respectively, and in some cases, beneficial effects on behavior were noted, which were not seen when Res or VitD3 were individually applied. Taken together, our study found that Res and VitD3 improved locomotor and cognitive deficits, modulated Sirt1 and Lingo-1. Therefore, we would recommend co-treatment of VitD3 and Res to leverage complementary effects for the management of ET symptoms.

Abstract Background Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. Methods and results T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. Conclusion This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Abstract Considering the effect of SIRT1 on improving myocardial fibrosis and GAS5 inhibiting occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating mir-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-β1 were used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with mir-217 mimics and mir-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1β and SIRT1 were conducted. The findings indicated that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1β and SIRT1 in ISO treated mice and TGF-β1 treated MCFs. However, this effect was significantly weakened after mir-217 overexpression, but was further enhanced after knockdown of mir-217. mir-217 down-regulates the expression of SIRT1, leading to increased activation of the NLRP3 inflammasome and subsequent pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced via regulating mir-217/SIRT1 pathway.

SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the K M values without significantly impacting the catalytic rate (k cat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.

Background: Hyperlipidemia is a vital etiology of acute pancreatitis (AP), 12 to 20% of which have a history of hyperlipidemia. Multiple organ failure is the major cause of the high mortality rate of AP. Liver injury has been discovered in 80% of AP patients. The relationship and role of IRF9 and SIRT1 have not been presented in AP and hyperlipidemia AP (HLAP) with liver injury. This investigation was designed to explore the function and relationship of IRF9 and SIRT1. Methods: HLAP model in vivo was performed by feeding high-fat forage and induced by peritoneal injection with 20% L-arginine. The severity of pancreas and liver tissues was assessed. Cell apoptosis in the liver was determined by the TUNEL experiment. IRF9, SIRT1, p53, and acetylated p53 (Ac-p53) expression levels in liver tissues were detected by qRT-PCR and Western blot. The association of IRF9 expression with SIRT1 levels was evaluated. The relevance of triglyceride level to tissue damage was analyzed. Results: Our observation exhibited more distinct liver damage, a large number of hepatic cell apoptosis, marked raised IRF9, Ac-p53, and sharply dropped SIRT1 in the AP and HLAP groups. Compared with other groups, HLAP showed the most significant changes in liver injury, hepatic cell apoptosis, protein, and mRNA levels. The declined expression of SIRT1 was correlated with the elevated expression of IRF9. The damage of the pancreas and liver exacerbated with the increase in triglyceride levels. Conclusion: Elevated IRF9 in pancreatitis with liver injury raised cell apoptosis and tissue damage by decreasing SIRT1 expression. [ABSTRACT FROM AUTHOR]

Ischemia–reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain‐intestinal peptide with anti‐inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia–reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR‐induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non‐invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 μg/kg 20 min before IIR surgery, and [D‐Lys3]‐GHRP‐6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia‐reoxygenation (HR) in Caco‐2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR‐induced oxidative stress and apoptosis by activating GHSR‐1α. Moreover, it was found that ghrelin activated the GHSR‐1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin‐mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR‐1α to further activate Sirt1. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pretreatment with moxibustion is a preventive treatment in traditional Chinese medicine. Pretreatment with moxibustion at the onset of prodromal symptoms can significantly reduce the symptoms and delay the onset of many diseases, but the exact mechanism remains to be studied. OBJECTIVE: To investigate the mechanism of SIRT1/FoxO3 pathway in moxibustion pretreatment to ameliorate oxidative stress injury in cerebral ischemiareperfusion model rats. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into sham-operated group, model group, moxibustion pretreatment group, and moxibustion pretreatment+EX527 (SIRT1 inhibitor) group, with 12 rats in each group. The moxibustion pretreatment group was given moxibustion with seedsized moxa cone at Baihui, Dazhui, and Zusanli before modeling, three moxa-cones per acupoint, once a day for 7 days. In the model group, moxibustion pretreatment group and moxibustion pretreatment+EX527 group, the rat model of middle cerebral artery occlusion was made by suturing of the middle cerebral artery 30 minutes after the last moxibustion. After 2 hours of cerebral ischemia, the middle artery suture was removed and the rats were reperfused for 12 hours. In the sham-operated group, only the common carotid artery, internal carotid artery, and external carotid artery were dissected without suturing the middle cerebral artery. In the moxibustion pretreatment+EX527 group, EX527 (15 mg/kg) was given intraperitoneally 30 minutes before each moxibustion. After 12 hours of reperfusion, the rats were scored for neurological deficits, and the cerebral infarct volume was calculated by 2,3,5-triphenyltetrazolium chloride staining method. The levels of oxidative stress factors in the infarcted tissues were detected by the kit method, and western-blot method was used to detect the expression levels of SIRT1, FoxO3, p-FoxO3 and brain-derived neurotrophic factor in the ischemic area of the cerebral cortex. RESULTS AND CONCLUSION: After 12 hours of reperfusion, the neurobehavioral score in the model group was significantly higher than that in the shamoperated group (P < 0.01), while the score in the moxibustion pretreatment group was significantly lower than that in the model group (P < 0.01) and moxibustion pretreatment+EX527 group (P < 0.05). There were no obvious infarct foci in the brain tissue of the sham-operated rats, but obvious ischemic foci were observed in the right side of the brain tissue of the rats in the model group (P < 0.01). The right infarct volume in the moxibustion pretreatment group was significantly reduced compared with the model group (P < 0.01), while the right infarct volume in the moxibustion pretreatment+EX527 group was significantly enlarged compared with the moxibustion pretreatment group. After 12 hours of reperfusion, the level of malondialdehyde was significantly elevated (P < 0.01) and the expression of superoxide dismutase was significantly decreased (P < 0.01) in the model group compared with the sham-operated group. The levels of malondialdehyde was significantly decreased (P < 0.01, P < 0.05) and the expression of superoxide dismutase was significantly increased (P < 0.01, P < 0.05) in the moxibustion pretreatment group compared with the model group and the moxibustion pretreatment+EX527 group. Western blot results showed that the expression levels of SIRT1, FoxO3, p-FoxO3, and brain-derived neurotrophic factor proteins were significantly higher in the model group compared with the sham-operated group (P < 0.01); compared with the model group, the expression levels of SIRT1, FoxO3, and brain-derived neurotrophic factor were significantly higher in the moxibustion pretreatment group (P < 0.01), and p-FoxO3 expression was significantly lower (P < 0.01); compared with the moxibustion pretreatment+EX527 group, the expression levels of SIRT1, FoxO3, and brain-derived neurotrophic factor were elevated in the moxibustion pretreatment group (P < 0.05), and no statistically significant difference was found in the p-FoxO3 expression (P > 0.05). To conclude, moxibustion pretreatment can significantly improve neurological function in rats after cerebral ischemia-reperfusion, and the mechanism may be related to the activation of SIRT1/FoxO3 pathway to reduce oxidative stress injury in the rat model of cerebral ischemia-reperfusion. [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]

Background: Central sensitization is one of the pivotal pathological mechanisms in chronic migraine (CM). Silent information regulator 1 (SIRT1) was shown to be involved in CM, but its specific mechanism is unclear. Reactive oxygen species (ROS) are increasingly regarded as important signaling molecules in several models of pain. However, studies about the role of ROS in the central sensitization of CM model are rare. We thus explored the specific process of SIRT1 involvement in the central sensitization of CM, focusing on the ROS pathway. Methods: Inflammatory soup was repeatedly administered to male Sprague-Dawley rats to establish a CM model. The SIRT1 expression level in trigeminal nucleus caudalis (TNC) tissues was assessed by qRT-PCR and Western blotting analysis. The levels of ROS were detected by a Tissue Reactive Oxygen Detection Kit, DHE staining, and the fluorescence signal intensity of 8-OHdG. A ROS scavenger (tempol), a SIRT1 activator (SRT1720), a SIRT1 inhibitor (EX527), and a mitochondrial fission inhibitor (Mdivi-1) were used to investigate the specific molecular mechanisms involved. NMDAR2B, CGRP, ERK, and mitochondrial fission-related protein were evaluated by Western blotting, and the CGRP level in frozen sections of the TNC was detected via immunofluorescence staining. Results: After repeated inflammatory soup infusion and successful establishment of the CM rat model, SIRT1 expression was found to be significantly reduced, accompanied by elevated ROS levels. Treatment with Tempol, SRT1720, or Mdivi-1 alleviated allodynia and reduced the increase in NMDAR2B phosphorylation and CGRP and ERK phosphorylation in the CM rat. In contrast, EX527 had the opposite effect in CM rat. SRT1720 and EX527 decreased and increased ROS levels, respectively, in CM rats, and tempol reversed the aggravating effect of EX527 in CM rats. Furthermore, the regulatory effect of SIRT1 on ROS may include the involvement of the mitochondrial fission protein DRP1. Conclusion: The results indicate the importance of SIRT1 in CM may be due to its role in regulating the production of ROS, which are involved in modulating central sensitization in CM. These findings could lead to new ideas for CM treatment with the use of SIRT1 agonists and antioxidants. [ABSTRACT FROM AUTHOR]

Arctigenin belongs to a major bioactive component of Fructus arctii and has been found with cardioprotective effects on rats with ischemia‒reperfusion (I/R) injury. The application of arctigenin is limited due to poor water solubility and low bioavailability. Hydrogel drug delivery systems can improve the efficacy and safety of drugs, increase drug utilization, and reduce side effects. We hypothesized that hydrogels containing arctigenin would facilitate the effect of arctigenin and alleviate I/R injury in the rat heart. Presently, adult Sprague–Dawley (SD) rats were subjected to 1 h of I/R injury, then hydrogels comprising arctigenin were implanted into the myocardium of rats. Triphenyl tetrazolium chloride staining, hematoxylin–eosin staining, and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling staining and Western blot were performed for evaluating the infarct size, histopathological, and vital protein alterations of hearts. It was discovered that the hydrogel combined with arctigenin abated apoptosis and reduced infarct size. In addition, the results of echocardiography and Masson staining suggested that the hydrogel with arctigenin improved cardiac function, restrained myocardial fibrosis, and activated AMP‐activated protein kinase (AMPK) and sirtuin 1 (SIRT1). Collectively, the injectable hydrogel delivery system enhances the effect of arctigenin, which may play a protective role in I/R injury by activating AMPK and SIRT1. [ABSTRACT FROM AUTHOR]

Objective SIRT1, an NAD+-dependent deacetylase, is upregulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in follicular helper T (Tfh) cell expansion and its potential value as a therapeutic target for SLE. Methods Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and B cell lymphoma 6 (BCL-6) were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1 -expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1 , respectively, and then cultured under Tfh-polarizing conditions to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes (including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies) were compared with those of controls. Results Expression of SIRT1 was elevated in Tfh cells from SLE patients and was positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. Conclusion SIRT1 overexpression contributed to the expansion of Tfh cells in SLE and may serve as a potential target for treatment. [ABSTRACT FROM AUTHOR]

Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol's therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis. [ABSTRACT FROM AUTHOR]

Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-β)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-β/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes. [ABSTRACT FROM AUTHOR]

Sirtuin 1 (SIRT1) participates in the initiation and evolution of hepatocellular carcinoma (HCC). However, the specific mechanism of SIRT1 in HCC remains unclear. The mRNA expression of miR-29a in HCC were identified by qRT-PCR. miR-29a mimic and inhibitor were employed. The alteration of biological behavior was evaluated by Cell Counting Kit-8 (CCK8), clone formation, transwell and wound-healing assay. SIRT1 was verified to be a target gene which directly regulated by miR-29a. Luciferase reporter assay and co-IP were employed to evaluate the direct binding of miR-29a and SIRT1. Animal model was used to evaluate its function on tumor growth and metastasis in vivo. The relationship between miR-29a/SIRT1 and prognosis of HCC patients was analyzed. SIRT1 overexpression accompanied by low expression of miR-29a were detected in HCC which was negatively correlated, and associated with overall survival, vascular invasion and TNM stage. Up-regulation of miR-29a suppressed cell growth and motility. Deprivation of miR-29a expression led to opposite effect. The direct binding of miR-29a to SIRT1 was confirmed by luciferase reporter assay and co-IP. miR-29a repressed SIRT1, DKK2 and β-catenin, but their expression was obviously elevated by miR-29a inhibitor. Animal model suggested miR-29a could reduce the expression of SIRT1, thereby inhibiting HCC growth and metastasis by inactivating Wnt/β-catenin pathway. Low expression of miR-29a and high expression of SIRT1 predicted shorter survival time in HCC patients. miR-29a had the function of tumor suppressor which directly inhibited oncogenic SIRT1. The loss of miR-29a led to up-regulation of SIRT1, aggravate malignant transformation and poor prognosis of HCC. [ABSTRACT FROM AUTHOR]

Objectives Our previous study showed that resveratrol (Res) attenuates apoptosis and mitochondrial dysfunction in alveolar epithelial cell injury induced by hyperoxia by activating the SIRT1/PGC-1α signaling pathway. In the present study, we investigated whether Res protects against hyperoxia-induced lung injury in neonatal rats by activating SIRT1/PGC-1α signaling pathway. Methods Naturally delivered neonatal rats were randomly divided into six groups: normoxia + normal saline, normoxia + dimethyl sulfoxide (DMSO), normoxia + Res, hyperoxia + normal saline, hyperoxia + DMSO, and hyperoxia + Res. Lung tissue samples were collected on postnatal days 1, 7, and 14. Hematoxylin and eosin staining was used to evaluate lung development. Dual-immunofluorescence staining, real-time polymerase chain reaction, and western blotting were used to evaluate the levels of silencing information regulator 2-related enzyme 1 (SIRT1), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), Nrf2, transcription factor A (TFAM) and citrate synthase, the number of mitochondrial DNA (mtDNA) and mitochondria, the integrity of mtDNA, and the expression of TFAM in mitochondria. Results We found that hyperoxia insulted lung development, whereas Res attenuated the hyperoxia lung injury. Res significantly upregulated the levels of SIRT1, PGC-1α, Nrf1, Nrf2, TFAM, and citrate synthase; promoted TFAM expression in the mitochondria; and increased the copy number of ND1 and the ratio of ND4/ND1. Conclusion Our data suggest that Res attenuates hyperoxia-induced lung injury in neonatal rats, and this was achieved, in part, by activating the SIRT1/PGC-1α signaling pathway to promote mitochondrial biogenesis. Key Points Hyperoxia insulted lung development in neonatal rats. Resveratrol promoted mitochondrial biogenesis to attenuate hyperoxia lung injury in neonatal rats. Resveratrol, at least in part, promoted mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Aims: Neuropathic pain is a common chronic pain disorder, which is largely attributed to spinal central sensitization. Calcium/calmodulin‐dependent protein kinase II alpha (CaMKIIα) activation in the spinal dorsal horn (SDH) is a major contributor to spinal sensitization. However, the exact way that CaMKIIα‐positive (CaMKIIα+) neurons in the SDH induce neuropathic pain is still unclear. This study aimed to explore the role of spinal CaMKIIα+ neurons in neuropathic pain caused by chronic constriction injury (CCI) and investigate the potential epigenetic mechanisms involved in CaMKIIα+ neuron activation. Methods: CCI‐induced neuropathic pain mice model, Sirt1loxP/loxP mice, and chemogenetic virus were used to investigate whether the activation of spinal CaMKIIα+ neurons is involved in neuropathic pain and its involved mechanism. Transcriptome sequence, western blotting, qRT‐PCR, and immunofluorescence analysis were performed to assay the expression of related molecules and activation of neurons. Co‐immunoprecipitation was used to observe the binding relationship of protein. Chromatin immunoprecipitation (ChIP)‐PCR was applied to analyze the acetylation of histone H3 in the Scn3a promoter region. Results: The expression of sodium channel Nav1.3 was increased and the expression of SIRT1 was decreased in the spinal CaMKIIα+ neurons of CCI mice. CaMKIIα neurons became overactive after CCI, and inhibiting their activation relieved CCI‐induced pain. Overexpression of SIRT1 reversed the increase of Nav1.3 and alleviated pain, while knockdown of SIRT1 or overexpression of Nav1.3 promoted CaMKIIα+ neuron activation and induced pain. By knocking down spinal SIRT1, the acetylation of histone H3 in the Scn3a (encoding Nav1.3) promoter region was increased, leading to an increased expression of Nav1.3. Conclusion: The findings suggest that an aberrant reduction of spinal SIRT1 after nerve injury epigenetically increases Nav1.3, subsequently activating CaMKIIα+ neurons and causing neuropathic pain. [ABSTRACT FROM AUTHOR]