Silent Information Regulator 1 Levels Research Articles

Regulation role of miR-204 on SIRT1/VEGF in metabolic memory induced by high glucose in human retinal pigment epithelial cells.

To examine the regulatory role of microRNA-204 (miR-204) on silent information regulator 1 (SIRT1) and vascular endothelial growth factor (VEGF) under high-glucose-induced metabolic memory in human retinal pigment epithelial (hRPE) cells. Cells were cultured with either normal (5 mmol/L) or high D-glucose (25 mmol/L) concentrations for 8d to establish control and high-glucose groups, respectively. To induce metabolic memory, cells were cultured with 25 mmol/L D-glucose for 4d followed by culture with 5 mmol/L D-glucose for 4d. In addition, exposed in 25 mmol/L D-glucose for 4d and then transfected with 100 nmol/L miR-204 control, miR-204 inhibitor or miR-204 mimic in 5 mmol/L D-glucose for 4d. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect miR-204 mRNA levels. SIRT1 and VEGF protein levels were assessed by immunohistochemical and Western blot. Flow cytometry was used to investigate apoptosis rate. It was found that high glucose promoted miR-204 and VEGF expression, and inhibited SIRT1 activity, even after the return to normal glucose culture conditions. Upregulation of miR-204 promoted apoptosis inhibiting SIRT1 and increasing VEGF expression. However, downregulation of miR-204 produced the opposite effects. The study identifies that miR-204 is the upstream target of SIRT1 and VEGF, and that miR-204 can protect hRPE cells from the damage caused by metabolic memory through increasing SIRT1 and inhibiting VEGF expression.

The role of the SIRT1-BMAL1 pathway in regulating oxidative stress in the early development of ischaemic stroke

Oxidative stress is the primary cause of ischaemic stroke and is closely related to circadian rhythm. However, the mechanism by which circadian rhythm regulates oxidative stress in ischaemic stroke remains elusive. The Silent Information Regulator 1 (SIRT1) controls circadian rhythm by activating the transcription of the circadian clock core protein Basic Helix-Loop-Helix ARNT Like 1 (BMAL1) through deacetylation. Studies have shown that the SIRT1-BMAL1 pathway can regulate oxidative stress. To investigate its correlation with oxidative stress, we examined the expression levels and influencing factors of SIRT1-BMAL1 at different times in ischaemic stroke patients and analyzed their clinical indexes, oxidative stress, and inflammatory factor indicators. The expression levels of oxidative stress and inflammatory factor indicators, including malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α), SIRT1, and BMAL1, were detected in ischaemic stroke patients within 4.5 h of onset and in non-stroke patients. Patients were divided into four subgroups based on onset time: subgroup 1 (0:00–05:59); subgroup 2 (06:00–11:59); subgroup 3 (12:00–17: 59); and subgroup 4 (18:00–23:59). Our results showed higher MDA, IL-6, and TNF-α levels, and lower SOD, SIRT1, and BMAL1 levels in ischaemic stroke patients compared to control patients (P < 0.05). Among the four subgroups, the content of MDA, IL-6, and TNF-α was highest in patients with ischaemic stroke onset from subgroup 2 (06:00–11:59), while the expression levels of SOD, BMAL1, and SIRT1 were lowest in patients with ischaemic stroke in subgroup 2. Additionally, myeloperoxidase (MPO) reached the highest value showing the same trends consistent with MDA, IL-6, and TNF-ɑ and opposite trends consistent with SOD, BMAL1, and SIRT1. However, triglycerides (TGs), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), immediate blood glucose, immediate diastolic blood pressure, immediate systolic blood pressure, and homocysteine (HCY) did not show any statistically significant circadian rhythm changes (P > 0.05). Our findings suggest that the SIRT1-BMAL1 pathway may be involved in early oxidative stress in ischaemic stroke, which may be related to MPO.

TIMELESS promotes reprogramming of glucose metabolism in oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC), the predominant malignancy of the oral cavity, is characterized by high incidence and low survival rates. Emerging evidence suggests a link between circadian rhythm disruptions and cancer development. The circadian gene TIMELESS, known for its specific expression in various tumors, has not been extensively studied in the context of OSCC. This study aims to explore the influence of TIMELESS on OSCC, focusing on cell growth and metabolic alterations.MethodsWe analyzed TIMELESS expression in OSCC using western blot, immunohistochemistry, qRT-PCR, and data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). The role of TIMELESS in OSCC was examined through clone formation, MTS, cell cycle, and EdU assays, alongside subcutaneous tumor growth experiments in nude mice. We also assessed the metabolic impact of TIMELESS by measuring glucose uptake, lactate production, oxygen consumption, and medium pH, and investigated its effect on key metabolic proteins including silent information regulator 1 (SIRT1), hexokinase 2 (HK2), pyruvate kinase isozyme type M2 (PKM2), recombinant lactate dehydrogenase A (LDHA) and glucose transporter-1 (GLUT1).ResultsElevated TIMELESS expression in OSCC tissues and cell lines was observed, correlating with reduced patient survival. TIMELESS overexpression enhanced OSCC cell proliferation, increased glycolytic activity (glucose uptake and lactate production), and suppressed oxidative phosphorylation (evidenced by reduced oxygen consumption and altered pH levels). Conversely, TIMELESS knockdown inhibited these cellular and metabolic processes, an effect mirrored by manipulating SIRT1 levels. Additionally, SIRT1 was positively associated with TIMELESS expression. The expression of SIRT1, HK2, PKM2, LDHA and GLUT1 increased with the overexpression of TIMELESS levels and decreased with the knockdown of TIMELESS.ConclusionTIMELESS exacerbates OSCC progression by modulating cellular proliferation and metabolic pathways, specifically by enhancing glycolysis and reducing oxidative phosphorylation, largely mediated through the SIRT1 pathway. This highlights TIMELESS as a potential target for OSCC therapeutic strategies.

Expression and correlation analysis of silent information regulator 1 (SIRT1), sterol regulatory element-binding protein-1 (SREBP1), and pyroptosis factor in gestational diabetes mellitus

Background and aim Globally, the prevalence of gestational diabetes mellitus (GDM) is rising each year, yet its pathophysiology is still unclear. To shed new light on the pathogenesis of gestational diabetes mellitus and perhaps uncover new therapeutic targets, this study looked at the expression levels and correlations of SIRT1, SREBP1, and pyroptosis factors like NLRP3, Caspase-1, IL-1, and IL-18 in patients with GDM. Methods This study involved a comparative analysis between two groups. The GDM group consisted of 50 GDM patients and the control group included 50 pregnant women with normal pregnancies. Detailed case data were collected for all participants. We utilized real-time quantitative PCR and Western Blot techniques to assess the expression levels of SIRT1 and SREBP1 in placental tissues from both groups. Additionally, we employed an enzyme-linked immunosorbent assay to measure the serum levels of SIRT1, SREBP1, and pyroptosis factors, namely NLRP3, Caspase-1, IL-1β, and IL-18, in the patients of both groups. Subsequently, we analyzed the correlations between these factors and clinical. Results The results showed that there were significantly lower expression levels of SIRT1 in both GDM group placental tissue and serum compared to the control group (p < 0.01). In contrast, the expression of SREBP1 was significantly higher in the GDM group than in the control group (p < 0.05). Additionally, the serum levels of NLRP3, Caspase-1, IL-1β, and IL-18 were significantly elevated in the GDM group compared to the control group (p < 0.01). The expression of SIRT1 exhibited negative correlations with the expression of FPG, OGTT-1h, FINS, HOMA-IR, SREBP1, IL-1β, and IL-18. However, there was no significant correlation between SIRT1 expression and OGTT-2h, NLRP3, or Caspase-1. On the other hand, the expression of SREBP1 was positively correlated with the expression of IL-1β, Caspase-1, and IL-18, but has no apparent correlation with NLRP3. Conclusions Low SIRT1 levels and high SREBP1 levels in placental tissue and serum, coupled with elevated levels of pyroptosis factors NLRP3, Caspase-1, IL-1β, and IL-18 in serum, may be linked to the development of gestational diabetes mellitus. Furthermore, these three factors appear to correlate with each other in the pathogenesis of GDM, offering potential directions for future research and therapeutic strategies.

Neuroprotective Effects of Oxymatrine via Triggering Autophagy and Inhibiting Apoptosis Following Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating neurological disorder characterized by high morbidity and disability. However, there is still a lack of effective treatments for it. The identification of drugs that promote autophagy and inhibit apoptosis in neurons is critical for improving patient outcomes following SCI. Previous studies have shown that increasing the activity of silent information regulator 1 (SIRT1) and downstream protein AMP-activated protein kinase (AMPK) in rat models of SCI is highly neuroprotective. Oxymatrine (OMT), a quinolizidine alkaloid, has exhibited neuroprotective effects in various central nervous system (CNS) diseases. However, its explicit effect and molecular mechanism in SCI are still unclear. Herein, we aimed to investigate the therapeutic effects of OMT and explore the potential role of autophagy regulation following SCI in rats. A modified compressive device (weight 35 g, time 5 min) was applied to induce moderate SCI in all groups except the sham group. After treatment with drugs or vehicle (saline), our results indicated that OMT treatment significantly reduced the lesion size, promoted survival of motor neurons, and subsequently attenuated motor dysfunction following SCI in rats. OMT significantly enhanced autophagy activity, inhibited apoptosis in neurons, and increased SIRT1 and p-AMPK expression levels. Interestingly, these effects of OMT on SCI were partially prevented by co-treatment with SIRT1 inhibitor EX527. Furthermore, combining OMT with the potent autophagy inhibitor chloroquine (CQ) could effectively abolish its promotion of autophagic flux. Taken together, these data revealed that OMT exerts a neuroprotective role in functional recovery against SCI in rats, and these effects are potentially associated with OMT-induced activation of autophagy via the SIRT1/AMPK signaling pathway.

Study on the relationship between SlRTl and oxidative stress in aged patients undergoing in vitro fertilization and embryo transfer cycles

PurposeOxidative stress (OS) has been suggested to be involved in the pathogenesis of fertility reduction in aged patient. Silent Information Regulator 1 (SIRT1) is involved in antioxidant defense and also plays a role in regulation ovarian function. The purpose of this study was to evaluate SIRT1 and OS markers in follicular fluid (FF) and granulosa cells (GCs) for aged patient undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). MethodsThis single-center prospective cohort study was performed from May 2020 to October 2021, including 92 patients undergoing IVF/ICSI at authors’ institute. The patients were grouped by age, including group A (< 35 year, n = 28, age range 24-29), group B (35-40 year, n = 33, age range 35-40), and group C (> 40 year, n = 31, age range 41-47). The outcomes included in vitro fertilization and embryo transfer (IVF-ET) results, OS markers and SIRT1 levels. ResultsWomen in group B and group C had a significantly lower estradiol (E2) in the trigger day, retrieved oocytes, mature oocytes, two pronuclei (2PN) and Day3 available embryos than group A. Women in group C had a significantly lower implantation rate and clinical pregnancy rate than group A. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and SIRT1 levels were lower in FF of the group B and group C, whereas the malondialdehyde (MDA) level was higher than that in the group A. Moreover, the MDA levels were correlated negatively with SIRT1 (r = -0.422, P=0.001),while the SOD and GSH-Px was positively correlated with SIRT1 (r = 0.409, P = 0.001 and r = 0.526, P = 0.001). ConclusionsThe oxidative stress may be related to the decrease of SIRT1 in aged patients undergoing IVF-ET.

Sirt1 Regulates Corneal Epithelial Migration by Deacetylating Cortactin.

Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase, which plays an essential role in cellular metabolism, autophagy, and chromatin accessibility. Our study aimed to determine its role in controlling corneal epithelial wound healing (CEWH). Corneal epithelial (CE)-specific Sirt1 deletion mice were created using the Cre-lox system. CE debridement was used to create a CEWH model. Corneal epithelial cells (CECs) were collected with an Algerbrush. Western blot analysis and RT-qPCR were performed to determine protein and mRNA expression levels. SiRNA transfection technology knocked down SIRT1 and cortactin expression levels in human corneal epithelial cells. Scratch wound assay, MTS assay, and TUNEL assay determined cell migratory, proliferative, and apoptotic behavior, respectively. Co-immunoprecipitation probed for SIRT1 and cortactin interaction. Immunofluorescence staining evaluated the location and expression levels of SIRT1, cortactin, acetylated-cortactin, and F-actin. During CEWH, increases in SIRT1 mRNA and protein expression levels accompanied the downregulation of acetylated lysine in non-histone proteins. The loss of SIRT1 function reduced cell migration and, in turn, delayed CEWH. SIRT1 bound to and deacetylated cortactin in vitro and in vivo. Loss of either SIRT1 or cortactin suppressed wound edge lamellipodia formation, which is consistent with migration retardation. During CEWH, SIRT1 upregulation and its modification of cortactin boost CEC migration by increasing the development of lamellipodia at the wound edge. Therefore SIRT1 may serve as a potential target to enhance CEWH.

Effects of SIRT1 in amygdala on chronic restraint stress-induced depression-like behaviors in rats

To investigate the effects of silent information regulator 1 (SIRT1) in amygdala on depression-like behaviors in rats using chronic restraint stress (CRS) as a model of depression. Sixty male SD rats were randomly divided into six groups (n=10 per group): control group (Control), chronic restraint stress group (CRS), CRS + fluoxetine-treated group (CRS + FLU), CRS + saline-treated group (CRS + NaCl), CRS + SIRT1-overexpression group (CRS + AAV-SIRT1), and CRS + empty vector group (CRS + AAV-EGFP). Except for the control group, rats from the other groups were exposed to chronic restraint stress for 21 days. After the modeling, rats in fluoxetine-treated group and saline-treated group were, respectively, treated with fluoxetine (10 mg/kg) or saline (10 mg/kg) by gavage every day for 3 weeks; AAV-SIRT1 or AAV-EGFP was, respectively, stereotaxically injected into the amygdala of rats in SIRT1-overexpression group and empty vector group, and the virus was expressed for 3 weeks. Rats in normal control group and CRS model group were not given any drug treatment. The depression-like behaviors of rats in each group were evaluated by sugar preference test (SPT), open field test (OFT) and forced swimming test (FST). SIRT1 expression in amygdala of rats was assessed by using immunoblot blotting. The number of SIRT1-positive cells in amygdala of rats was detected by immunofluorescence technique. Compared with the normal control group, the level of SIRT1 protein and the number of SIRT1+ cells in amygdala of the CRS-exposed rats were decreased significantly (P＜0.01), and CRS-exposed rats showed a significant decrease in sucrose preference (P＜0.01), less total horizontal distance (P＜0.01) and less time entered the center field (P＜0.01) in the OFT, a significant increase in the immobility time of the FST (P＜0.01). Fluoxetine treatment (P＜0.05, P＜0.01) or SIRT1 overexpression (P＜0.01) partially reversed the down-regulation of SIRT1 protein and SIRT1+ cells in amygdala of CRS-exposed rats and significantly improved the depression-like behaviors of CRS rats. Fluoxetine treatment partially reversed the down-regulation of SIRT1 level and the number of SIRT1+ in CRS rats, and significantly improved the depression-like behaviors. The antidepressant effect of fluoxetine treatment may be related to the up-regulation of SIRT1 in the amygdala of CRS-exposed rats.

P-714 Visfatin and Silent Information Regulator 1 (SIRT1) in Pakistani infertile females

Abstract Study question What is the relationship of SIRT1 and oxidative stress markers with obesity among infertile Pakistani females? Summary answer Progressive decline in antioxidants with the increase in BMI suggests that obesity causes oxidative stress that consequently leads to infertility in females. What is known already Deficiency of Silent Information Regulator 1 (SIRT1) can trigger inflammation, mitochondrial malfunctioning and apoptosis through the hypothalamic-pituitary-ovarian axis, producing poor quality oocytes, triggering obesity and associated metabolic disorders. SIRT1 expression levels are higher in endocrine system dysfunctions. Obesity has a potential risk for subfertility, infertility, deteriorated embryo quality, decreased endometrial receptivity, implantation failure and increased miscarriage rates. Visfatin increases in response to low levels antioxidants in obese, and its expression is negatively associated with the antioxidants produced. It disturbs glucose metabolism and promotes obesity, rendering it a powerful candidate as an OS marker. Study design, size, duration This cross-sectional study was conducted from August 2017 – July 2019, at Aga Khan Hospital in collaboration with Australian Concept Infertility Medical Centre (ACIMC) on 207 fertile and 135 infertile female subjects were recruited after ethical approval from of Aga Khan Hospital (AKU-ERC-2018-0557-601). Participants/materials, setting, methods kg)/height in meters (m2). Females were categorized by South-Asian criteria of BMI (normal-weight=18.0-22.9; overweight = 23-24.9; obese &amp;gt;25.0 kg/m2). Commercially available ELISA kits were used for estimation of serum Manganese Superoxide Dismutase (MnSOD), Glutathione Reductase (GR), visfatin and SIRT1. Pearson Chi-Square test and ANOVA were applied to compare the means within BMI groups. Association of variables was observed by Spearman correlation with significance at p &amp;lt; 0.05. Main results and the role of chance The mean BMI was 25.94 ± 5.1 kg/m2; 27.5% of females were normal-weight, 22.8% overweight, while 40.9% were obese. BMI was significantly high in infertile subjects (p &amp;lt; 0.001). MnSOD, visfatin and GR were lower in infertile females, decreasing from normal-weight to obese (p &amp;lt; 0.001). Increase in BMI was associated with a decrease in SIRT1 and antioxidants levels in both fertile and infertile females. Limitations, reasons for caution The small sample size was a limitation of the current study due to financial constraints, on the basis of which measurement of other non-enzymatic antioxidants such as malondialdehyde (MDA), glutathione, total antioxidant capacity (TAC), nitric oxide (NO) and reactive oxygen species could not be made possible. Wider implications of the findings SIRT1 is a fascinating target in various disease situations due to the promise of pharmacological and/or natural modulators of SIRT1 activity within the framework of endocrine and immune-related disease models. Trial registration number non applicable

Amelioration of Renal Injury by Resveratrol in a Rat Renal Transplantation Model via Activation of the SIRT1/NF-κB Signaling Pathway.

Purpose The improvement of the long-term survival of patients receiving kidney transplantation remains challenging. Ischemia reperfusion injury (IRI) reduces long-term renal graft survival in the early posttransplantation phase. However, few studies have investigated the effects of IRI on the pathogenesis of chronic renal graft failure. Silent information regulator 1 (SIRT1) regulates antioxidative stress and inflammatory response and protects against IRI. This study is aimed at investigating the role of resveratrol (RSV), an SIRT1 activator, in preventing renal injury in a rat renal transplantation model. Methods A classical F334-to-LEW orthotopic renal transplantation rat model was established. The experiment group was treated with RSV from three days prior to kidney transplantation and the treatment lasted until the day of harvest. Uninephrectomized F344 and Lewis rats were used as controls. After 12 weeks, the effects of RSV were evaluated according to renal function, histopathology, immunohistochemistry, and western blotting. The activities of oxidative stress-related markers and proinflammatory cytokines were also assessed. Results RSV treatment significantly ameliorated renal function and histopathological lesions in kidney-transplanted rats and increased the levels of GSH, SOD, and CAT and decreased the levels of MDA and iNOS. Furthermore, RSV also inhibited the expression of proinflammatory cytokines/chemokines such as TNF-α, CD68, and IL-6 in kidney-transplanted rats. In addition, the transplant group displayed significantly lower level of SIRT1 and higher level of Ac-NF-κBp65. RSV increased the expression of SIRT1 and decreased the expression of Ac-NF-κBp65. Conclusion SIRT1 plays an important role in the pathogenesis of chronic renal allograft dysfunction. It is a potential therapeutic agent for ameliorating inflammation and oxidative stress-induced renal injury following kidney transplantation by activating the SIRT1/NF-κB signaling pathway.

Quercetin-mediated SIRT1 activation attenuates collagen-induced mice arthritis

Ethnopharmacological relevanceHerba taxilli (HT, Sangjisheng in Chinese), which is composed of the dried stems and leaves of Taxillus chinensis (DC.) Danser, has been commonly used to treat inflammation and arthritis in traditional Chinese medicine (TCM). Quercetin (Que) is a major active flavonoid component isolated from HT and is one of the quality control indexes of HT. In the clinical practice of TCM, formulas containing HT are commonly used to treat rheumatoid arthritis (RA). Recent studies have shown that Que exerts antiarthritic effects. However, the mechanism by which Que treatment affects RA is not fully understood. Aim of the studyThis study aimed to explore the antiarthritic activity of Que in a collagen-induced arthritis (CIA) mouse model and investigate the underlying mechanisms. Materials and methodsThe antiarthritic activity of Que was evaluated in a CIA mouse model by determining the paw clinical arthritis scores and left ankle thicknesses and by conducting micro-PET imaging and histopathological analysis of ankle joint tissues. The proinflammatory cytokine (IL-6, TNF-α, IL-1β, IL-8, IL-13, IL-17) levels in the serum and ankle joint tissues were measured by ELISA. Mitochondrial oxidative stress was assessed by biochemical methods. Mitochondrial biogenesis was analysed by RT-qPCR. The protein levels of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), p38, phospho-p38, extracellular signal-regulated kinases (ERK)-1/2, phospho-ERK1/2, p65, and phospho-p65 in ankle joint tissues were detected by Western blot analysis. A total of 30 RA patients were recruited to investigate the relationship between the disease activity score (DAS28) and the SIRT1, PGC-1α, NRF1, and HMGB1 plasma levels. ResultsQue treatment decreased the clinical score and left ankle thickness of CIA mice, attenuated the synovial inflammation and hyperplasia and bone/cartilage destruction in ankle joints, and decreased the secretion of IL-6, TNF-α, IL-1β, IL-8, IL-13, and IL-17. Mechanistically, Que treatment improved impaired mitochondrial biogenesis and mitochondrial function by regulating the SIRT1/PGC-1α/NRF1/TFAM pathway and inhibited inflammation via the HMGB1/TLR4/p38/ERK1/2/NF-κB p65 pathway. Notably, epidemiological data revealed correlations between abnormal circulating levels of SIRT1, PGC-1α, NRF1, HMGB1 and RA disease activity in patients. ConclusionsOur data suggested a potential role of Que as a dietary therapeutic drug for RA treatment that may act through SIRT1 to target mitochondrial biogenesis. Additionally, the role of impaired mitochondrial biogenesis in RA was evaluated.

Suggested role of silent information regulator 1 (SIRT1) gene in female infertility: A cross-sectional study in Pakistan.

Silent information regulator 1 (SIRT1) gene stimulates the expression of antioxidants and repairs damaged cells. It affects the mitochondrial activity within the oocytes to overcome the oxidant stress. We aimed to assess an association of SIRT1 polymorphism (Tag SNPs rs10509291 and rs12778366) with fertility, and assess serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, progesterone, manganese superoxide (MnSOD) and SIRT1. In this cross-sectional study, 207 fertile and 135 infertile subjects between the ages of 18-45years were recruited. Polymerase chain reaction (PCR) was performed; products were electrophoresed in a 2% agarose gel. Descriptive analysis of continuous variables was expressed as mean±standard deviation. Mann-Whitney test was performed for comparison of groups, P value <.001 was considered significant. Single Nucleotide Polymorphism (SNP) data were analysed by applying chi-squared statistics. All subjects were age matched (P=.896). SIRT1 levels were significantly lower in infertile females when compared with fertile subjects (P<.001). AA (rs10509291) and CC (rs12778366) variant frequency was higher in the infertile than fertile subjects (P<.01). Similarly, the frequency of A allele (rs10509291) and C allele (rs12778366) was higher in infertile subjects (P<.001). Infertile females (29%) showed existence of SNP rs10509291 while 49% demonstrated genetic variation of rs12778366. MnSOD and SIRT1 levels were found to be lower in these subjects. The presence of SIRT1 genetic variants (rs10509291 and rs12778366) apparently disturbs the expression of SIRT1 deteriorating mitochondrial antioxidant function within the oocytes, instigating oxidative stress within. Their probable effect on modulating oocyte maturation may be the cause of infertility in females.

The Protective Role of Bmal1-Regulated Autophagy Mediated by HDAC3/SIRT1 Pathway in Myocardial Ischemia/Reperfusion Injury of Diabetic Rats

Histone deacetylase 3 (HDAC3) and silent information regulator 1 (SIRT1) are histone deacetylases that regulate important metabolic pathways and play important roles in diabetes and myocardial ischemia/reperfusion (IR) injury. In this study, we explored the protective mechanism of Bmal1-regulated autophagy mediated by the HDAC3/SIRT1 pathway in myocardial IR injury of diabetic rats. Type 1 diabetes was established by administering an intraperitoneal injection of streptozotocin. After 8 weeks, the left anterior descending coronary artery was ligated for 30 min and reperfused for 120 min to establish a myocardial IR injury model in diabetic rats. H9c2 cardiomyocytes were exposed to high glucose concentration (30 mM) and hypoxia/reoxygenation (H/R) stimulation in vitro. The myocardial infarct size and levels of serum cTn-I, CK-MB, and LDH in diabetic rats subjected to myocardial IR injury were significantly higher. Upregulated HDAC3 and downregulated SIRT1 expression were observed in diabetic and IR hearts, along with a lower Bmal1 level. Autophagy was rapidly increased in the hearts of diabetic or non-diabetic rats in the IR group compared with the sham group, but significantly attenuated in the hearts of diabetic rats compared with the hearts of non-diabetic rats after IR insult. Consistent with decreased autophagy, we observed increased HDAC3 expression and decreased SIRT1 and Bmal1 levels in the myocardial tissue of diabetic rats after IR. Inhibition of HDAC3 by the inhibitor RGFP966 and activation of SIRT1 by the agonist SRT1720 could significantly attenuate myocardial IR injury in diabetic rats by restoring Bmal1-regulated autophagy. Based on these findings, the disordered HDAC3/SIRT1 circuit (upregulated HDAC3 and downregulated SIRT1 levels) plays an important role in aggravating myocardial IR injury in diabetic rats by downregulating Bmal1-mediated autophagy. Treatments targeting HDAC3/SIRT1 to activate the autophagy may represent a novel strategy to alleviate myocardial IR injury in diabetes.

Apigenin Alleviates Oxidative Stress-Induced Cellular Senescence via Modulation of the SIRT1-NAD+-CD38 Axis

Oxidative stress-induced cellular senescence is now regarded as an important driving mechanism in chronic lung diseases-particularly chronic obstructive pulmonary disease (COPD). 4',5,7-trihydroxyflavone (Apigenin) is a natural flavonoid product abundantly present in fruits, vegetables, and Chinese medicinal herbs. It has been known that apigenin has anti-oxidant, anti-inflammatory and liver-protecting effects. The efficacy of apigenin for lung aging, however, has not been reported. In this study, we selected the hydrogen peroxide (H2O[Formula: see text]- or doxorubicin (DOXO)-induced senescence model in WI-38 human embryonic lung fibroblast cells to determine the potential anti-aging effects of apigenin in vitro and associated molecular mechanisms. We found that apigenin reduced senescence-associated [Formula: see text]-galactosidase (SA-[Formula: see text]-gal) activity and promoted cell growth, concomitant with a decrease in levels of Acetyl (ac)-p53, p21[Formula: see text], and p16[Formula: see text] and an increase in phospho (p)-Rb. Apigenin also increased the activation ratio of silent information regulator 1 (SIRT1), nicotinamide adenine dinucleotide (NAD[Formula: see text], and NAD[Formula: see text]/NADH and inhibited cluster of differentiation 38 (CD38) activity in a concentration-dependent manner. SIRT1 inhibition by SIRT1 siRNA abolished the anti-aging effect of apigenin. In addition, CD38 inhibition by CD38 siRNA or apigenin increased the SIRT1 level and reduced H2O2-induced senescence. Our findings suggest that apigenin is a promising phytochemical for reducing the impact of senescent cells in age-related lung diseases such as COPD.

Reduced serum SIRT1 levels in patients with Parkinson's disease: a cross-sectional study in China.

Parkinson's disease (PD) is a movement disorder lacking of validated biomarkers. Experimental studies support the potential value of silent information regulator 1 (SIRT1) in neurodegeneration including PD. We aim to detect the serum levels of SIRT1 in PD patients in order to assess its value as a potential biomarker of PD. Fifty-eight PD patients and 91 healthy controls were included. Serum SIRT1 was determined by enzyme-linked immunosorbent assay (ELISA) and compared between controls and PD patients. Spearman correlation coefficient was analyzed to study the relationship between serum SIRT1 and clinical parameters in PD patients. Receiver operating characteristic (ROC) analysis was conducted to assess the diagnostic value of serum SIRT1 in PD identification. Serum SIRT1 was significantly reduced in PD patients compared with controls. According to the ROC curve, the optimal cut-off point was 0.47ng/ml with the sensitivity of 71% and specificity of 71%. Serum SIRT1 level was related to age of onset, disease duration, Hoehn-Yahr staging scale (H-Y stage), Unified Parkinson's Disease Rating Scale III (UPDRS III), and Mini-Mental State Examination (MMSE). PD patients with cognitive impairment had lower serum SIRT1 than those with normal cognitive ability. Serum SIRT1 was reduced in PD patients and associated with disease severity and cognitive function. Our results indicate that SIRT1 may be a potential biomarker for PD.

3‑N‑Butyphthalide improves learning and memory in rats with vascular cognitive impairment by activating the SIRT1/BDNF pathway.

Vascular cognitive impairment (VCI) is a type of cerebral vascular disorder that leads to learning and memory decline. VCI models can be induced by chronic cerebral hypoperfusion via permanent bilateral common carotid artery occlusion. 3-N-Butylphthalide (NBP) is a neuroprotective drug used for the treatment of ischemic cerebrovascular diseases. Silent information regulator 1 (SIRT1) plays an important role in memory formation and cognitive performance, and its abnormal reduction is associated with cognitive dysfunction in neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays critical roles in promoting neuronal growth and injury repair. The present study was performed to investigate the effects and the underlying mechanism of NBP on learning deficits in a rat model of VCI. Rats were divided into a control group, model group, low-NBP-dose group (30 mg/kg/day), high-NBP-dose group (60 mg/kg/day), NBP + SIRT1 inhibitor group and NBP + BDNF inhibitor group. Rats were then subjected to Morris water maze and T-maze tests, which identified that NBP treatment significantly attenuated memory impairments in VCI rats. Molecular examination indicated that SIRT1 and BDNF expression levels in the hippocampus were increased by NBP treatment. However, NBP failed to ameliorate cognitive function after inhibition of the SIRT1/BDNF signaling pathway. In addition, NBP in combination with a SIRT1 inhibitor suppressed BDNF protein expression, but inhibition of BDNF did not inhibit SIRT1 protein expression in rats with VCI. The present results suggested that the neuroprotective effects of NBP on learning deficits in a rat model of VCI may be via regulation of the SIRT1/BDNF signaling pathway, in which SIRT1 may be the upstream signaling molecule. Therefore, the SIRT1/BDNF pathway could be a potential therapeutic target for VCI.

Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity

Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, contributes to the neuroprotective effect. However, intracellular signaling pathways that affect SIRT1 function remain unknown. It is well known that N-methyl-D-aspartate (NMDA) receptor activation induces calcium influx which then activates PKC, and SIRT1 is a mRNA target for HuR protein. We hypothesize that Ca2+-PKC-HuR-SIRT1 pathway modulates SIRT1 function. The present study is to investigate the potential pathway of SIRT1 in the SH-SY5Y cell line as an in vitro model of NMDA-induced neurotoxicity. The results showed that: (1) SIRT1 levels were downregulated in NMDA model; (2) NMDA induced an increase in serine phosphorylation of HuR, while inhibition of serine phosphorylation of HuR increased SIRT1 levels, promoting cell survival; (3) PKC inhibitor (Gö 6976) reversed NMDA insults and also suppressed serine phosphorylation of HuR; (4) 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, fully reversed NMDA insults and also inhibited PKC activity evoked by NMDA. These results indicate that intracellular elevated Ca2+ activates PKC, which phosphorylates HuR and then promotes SIRT1 mRNA decay and subsequent neuronal death in NMDA model. Therefore, the study suggests that inhibition of Ca2+-PKC-HuR-SIRT1 pathway could be an effective strategy for preventing certain neurological diseases related to NMDA excitotoxicity.

SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of resveratrol against neurodevelopment damage by fluoride.

Rationale: Potential adverse effects of fluoride on neurodevelopment has been extensively explored and mitochondria have been recognized as critical targets. Mitochondrial biogenesis serves a crucial role in maintaining mitochondrial homeostasis and salubrious properties of resveratrol (RSV) has been well-defined. However, the molecular mechanisms governing mitochondrial biogenesis in developmental fluoride neurotoxicity remain unclear and the related therapeutic dietary agent is lacking.Methods: In vitro neuroblastoma SH-SY5Y cells and in vivo Sprague-Dawley rat model of developmental fluoride exposure were adopted. A total population of 60 children under long-term stable fluoride exposure were also recruited. This work used a combination of biochemical and behavioral techniques. Biochemical methods included analysis of mitochondrial function and mitochondrial biogenesis, as well as mRNA and protein expression of mitochondrial biogenesis signaling molecules, including silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Behavioral studies investigated spatial learning and memory ability of rats.Results: Both in vivo and in vitro experiments showed that sodium fluoride (NaF) caused mitochondrial dysfunction and impaired mitochondrial biogenesis. Also, NaF elevated SIRT1 levels and suppressed SIRT1 deacetylase activity along with decreased levels of PGC-1α, NRF1 and TFAM, suggestive of dysregulation of mitochondrial biogenesis signaling molecules. Moreover, enhancement of mitochondrial biogenesis by TFAM overexpression alleviated NaF-induced neuronal death through improving mitochondrial function in vitro. Further in vivo and in vitro studies identified RSV, the strongest specific SIRT1 activator, improved mitochondrial biogenesis and subsequent mitochondrial function to protect against developmental fluoride neurotoxicity via activating SIRT1-dependent PGC-1α/NRF1/TFAM signaling pathway. Noteworthy, epidemiological data indicated intimate correlations between disturbed circulating levels of mitochondrial biogenesis signaling molecules and fluoride-caused intellectual loss in children.Conclusions: Our data suggest the pivotal role of impaired mitochondrial biogenesis in developmental fluoride neurotoxicity and the underlying SIRT1 signaling dysfunction in such neurotoxic process, which emphasizes RSV as a potential therapeutic dietary agent for relieving developmental fluoride neurotoxicity.

XingNaoJing injection ameliorates cerebral ischaemia/reperfusion injury via SIRT1-mediated inflammatory response inhibition

Context XingNaoJing injection (XNJ), extracted from a traditional compound Chinese medicine Angong niuhuang pill, is well known for treating stroke in the clinic, but the specific effects and mechanisms remain unclear. Objective We investigated the mechanistic basis for the protective effect of XNJ on cerebral ischaemia/reperfusion (I/R) injury. Materials and methods Five groups of 10 SD rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. XNJ at 10 and 15 mL/kg was intraperitoneally administered 24 h before ischaemia and at the onset of reperfusion respectively. The silent information regulator 1 (SIRT1) inhibitor EX527 was intracerebroventricularly injected 0.5 h before reperfusion. Cerebral infarction size, neurological scores, morphological changes, and expression levels of inflammatory mediators and SIRT1 were measured. Furthermore, human brain microvascular endothelial cells (HBMECs) were subjected to 3 h oxygen and glucose deprivation (OGD) followed by 24 h reoxygenation to mimic cerebral I/R in vitro. EX527 pre-treatment occurred 1 h before OGD. SIRT1 and inflammatory mediator levels were analyzed. Results Both XNJ doses significantly decreased cerebral infarct area (40.11% vs. 19.66% and 9.87%) and improved neurological scores and morphological changes. Inflammatory mediator levels were remarkably decreased in both model systems after XNJ treatment. XNJ also enhanced SIRT1 expression. Notably, the SIRT1 inhibitor EX527 attenuated the XNJ-mediated decrease in inflammation in vivo and in vitro. Conclusions XNJ improved cerebral I/R injury through inhibiting the inflammatory response via the SIRT1 pathway, which may be a useful target in treating cerebral I/R injury.

The decreased SIRT1 level may account for the lipid profile in chronic kidney disease

Dysregulated lipid profile with hypertriglyceridemia and increased low-density lipoprotein (LDL) is common in chronic kidney disease (CKD) whereas the reason is unclear. A similar phenomenon is found in the elder population. Silent information regulator-1 (SIRT1) associates with many modulators regulating lipid metabolism and results in increased expression of sterol regulatory element-binding proteins (SREBPs), which functions as a key modulator in lipid synthesis. Since CKD is being viewed as a premature aging model and SIRT1 is known to decrease during the process of aging, we hypothesize that SIRT1 level is reduced in the liver when CKD develops and eventually result in dysregulated lipid profile.