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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.

Objectives: The study aimed to assess the role of Astaxanthin (ATX) in palmitic acid(PA) -induced bone loss in Ovariectomized(OVX) rats., Methods: In the OVX rat model, we observed that PA affects bone metabolism and accelerates bone loss. Additionally, treatment with ATX was able to suppress the deleterious effects of PA and a simultaneous decrease in serum MDA levels and an increase in SOD was observed., Results: In addition, rats treated with ATX were observed to have significantly increased bone mass and elevated activity of SIRT1 and SOD2 in bone tissue. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclast differentiation, the ATX intervention was able to significantly restore the restriction of osteogenic differentiation and the up-regulation of osteoclast differentiation with PA therapy. Furthermore, we confirm that PA damage to cells is caused by increased oxidative stress, and that ATX can target and modulate the activity of SIRT1 to regulate the levels of oxidative stress in cells., Conclusion: Summarizing, ATX may inhibit PA-induced bone loss through its antioxidant properties via the SIRT1 signaling pathway.

Liver regeneration offers a distinctive opportunity to study cell proliferation in vivo Mammalian silent information regulator 1 (SIRT1), a NAD+-dependent histone deacetylase, is an important regulator of various cellular processes, including proliferation, metabolism, and circadian rhythms. In the liver, SIRT1 coordinates the circadian oscillation of clock-controlled genes, including genes that encode enzymes involved in metabolic pathways. We performed partial hepatectomy in WT and liver-specific Sirt1-deficient mice and analyzed the expression of cell cycle regulators in liver samples taken at different times during the regenerative process, by real time PCR, Western blotting analysis, and immunohistochemistry. Lipidomic analysis was performed in the same samples by MS/HPLC. We showed that G1/S progression was significantly affected by absence of SIRT1 in the liver, as well as circadian gene expression. This was associated to lipid accumulation due to defective fatty acid beta-oxidation. Our study revealed for the first time the importance of SIRT1 in the regulation of hepatocellular proliferation, circadian rhythms, and lipid metabolism during liver regeneration in mice. These results represent an additional step toward the characterization of SIRT1 function in the liver.

Multiple myeloma is a fatal plasma cell neoplasm accounting for over 10,000 deaths in the United States each year. Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. The response to selective CDK4/6 inhibitors has been modest in multiple myeloma, potentially because of incomplete targeting of other critical myeloma oncogenic kinases. As a substantial number of multiple myeloma cell lines and primary samples were found to express AMPK-related protein kinase 5(ARK5), a member of the AMPK family associated with tumor growth and invasion, we examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 results in a better therapeutic outcome. Treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. ON123300-mediated ARK5 inhibition or ARK5-specific siRNAs resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation resulted in increased SIRT1 levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays. In addition, multiple myeloma cells sensitive to ON123300 were found to have a unique genomic signature that can guide the clinical development of ON123300. Our study provides preclinical evidence that ON123300 is unique in simultaneously inhibiting key oncogenic pathways in multiple myeloma and supports further development of ARK5 inhibition as a therapeutic approach in multiple myeloma.

Background & aimsAll-trans Retinoic acid (RA) regulates hepatic lipid and bile acid homeostasis. Similar to bile acid (BA), RA accelerates partial hepatectomy (PHx)-induced liver regeneration. Because there is a bidirectional regulatory relationship between gut microbiota and BA synthesis, we examined the effect of RA in altering the gut microbial population and BA composition and established their relationship with hepatic biological processes during the active phases of liver regeneration.MethodsC57BL/6 mice were treated with RA orally followed by 2/3 PHx. The roles of RA in shifting gut microbiota and BA profiles as well as hepatocyte metabolism and proliferation were studied.ResultsRA-primed mice exhibited accelerated hepatocyte proliferation revealed by higher numbers of Ki67-positive cells compared to untreated mice. Firmicutes and Bacteroidetes phyla dominated the gut microbial community (>85%) in both control and RA-primed mice after PHx. RA reduced the ratio of Firmicutes to Bacteroidetes, which was associated with a lean phenotype. Consistently, RA-primed mice lacked transient lipid accumulation normally found in regenerating livers. In addition, RA altered BA homeostasis and shifted BA profiles by increasing the ratio of hydrophilic to hydrophobic BAs in regenerating livers. Accordingly, metabolic regulators fibroblast growth factor 21, Sirtuin1, and their downstream targets AMPK and ERK1/2 were more robustly activated in RA-primed than unprimed regenerating livers.ConclusionsPriming mice with RA resulted in a lean microbiota composition and hydrophilic BA profiles, which were associated with facilitated metabolism and enhanced cell proliferation.

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

Hippocampus is the significant component of the limbic lobe, which is further subdivided into the dentate gyrus and parts of Cornu Ammonis. It is the crucial region for learning and memory; its sub-regions aid in the generation of episodic memory. However, the hippocampus is one of the brain areas affected by Alzheimer's (AD). In the early stages of AD, the hippocampus shows rapid loss of its tissue, which is associated with the functional disconnection with other parts of the brain. In the progression of AD, atrophy of medial temporal and hippocampal regions are the structural markers in magnetic resonance imaging (MRI). Lack of sirtuin (SIRT) expression in the hippocampal neurons will impair cognitive function, including recent memory and spatial learning. Proliferation, differentiation, and migrations are the steps involved in adult neurogenesis. The microglia in the hippocampal region are more immunologically active than the other regions of the brain. Intrinsic factors like hormones, glia, and vascular nourishment are instrumental in the neural stem cell (NSC) functions by maintaining the brain's microenvironment. Along with the intrinsic factors, many extrinsic factors like dietary intake and physical activity may also influence the NSCs. Hence, pro-neurogenic lifestyle could delay neurodegeneration. [ABSTRACT FROM AUTHOR]

Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis. [Display omitted] • ATG3 levels are elevated in the livers of mice and patients with NAFLD. • Inhibition of ATG3 in human hepatocytes and in mouse liver ameliorates steatosis by stimulating SIRT1, CPT1a, and mitochondrial function. • Hepatic knockdown of SIRT1 or CPT1a blunts the ability of ATG3 inhibition to increase mitochondrial activity and to alleviate steatosis. [ABSTRACT FROM AUTHOR]

Background: Ovarian function is closely related to the degree of vascular network development surrounding the ovary. Maternal aging-related construction defects in this vascular network can cause ovarian hypoxia, which impedes oocyte nutrient supply, leading to physiological changes in the ovaries and oocytes. The anti-aging gene Sirtuin 1 (SIRT1) senses and adapts to ambient stress and is associated with hypoxic environments and mitochondrial biogenesis. Methods: The present study is a literature review focusing on investigations involving the changes in SIRT1 and mitochondrial expression during hypoxia and the cytoprotective effects of the SIRT1 activator, resveratrol. Main findings: Hypoxia suppresses SIRT1 and mitochondrial expression. Resveratrol can reverse the hypoxia-induced decrease in mitochondrial and SIRT1 activity. Resveratrol suppresses the production of hypoxia-inducible factor-1α and vascular endothelial growth factor proteins. Conclusion: Resveratrol exhibits protective activity against hypoxic stress and may prevent hypoxia- or aging- related mitochondrial dysfunction. Resveratrol treatment may be a potential option for infertility therapy. [ABSTRACT FROM AUTHOR]

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and the majority of patients have a PKD-1 or PKD-2 mutation. Sirtuin 1 (SIRT1) has roles in cellular aging, antioxidant activity, cellular proliferation. In an experimental study, inhibition of SIRT1 was found to delay renal cyst development in ADPKD. The purpose of this study is to determine the SIRT1 levels in ADPKD patients. To our knowledge, this is the first study that investigating blood and urine SIRT1 levels in ADPKD patients. Methods: Sixty-seven patients with ADPKD and 34 control cases with normal renal functions and without renal cysts were included in this study. Serum and urine SIRT1 concentrations were determined by human enzyme-linked immunosorbent assay (ELISA) kit. 24-h urine samples were used for urine SIRT1 measurements. Results: The urine SIRT1 levels were statistically significantly lower in ADPKD patients group (p < 0.001). Although blood SIRT1 levels of ADPKD patients were higher than control cases but there were no statistically significant difference between the groups in terms of blood SIRT1 levels. Urine SIRT1 levels (β = 2.452, CI 95% 1.419–4.239, p = 0.001) were found an independent factor in multivariate regression analysis for ADPKD. Conclusions: Urine SIRT1 levels were lower in ADPKD patients than control group. The low urinary SIRT1 levels despite the similar blood SIRT1 levels might be due to the impaired metabolism of SIRT1 in ADPKD patients; this state might has a role in cyst development. [ABSTRACT FROM AUTHOR]

Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson's disease (PD). Researchers have shown that fibroblast growth factor 21 (FGF21) plays multiple biological functions, including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In this study, both in vivo and in vitro models were used to investigate whether FGF21 enhances the brain function by modulating microglial polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model alongside intraperitoneally received FGF21. A behavioral test battery and tyrosine hydroxylase (TH) immunohistochemistry were conducted to evaluate the neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in mice with PD. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed M1 microglial polarization and the subsequent mRNA expression of pro-inflammatory factors while promoting M2 microglial polarization with increasing anti-inflammatory factors in mice with PD. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21-induced M2 microglial polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21-induced SIRT1 expression and M2 microglial polarization. Moreover, FGF21 pretreatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in the pathology of PD through SIRT1/NF-κB pathway-mediated microglial polarization. Given the safety record of human clinical trials, FGF21 could be a promising therapy for clinical trials to ameliorate motor and nonmotor deficits in patients with PD. [ABSTRACT FROM AUTHOR]

Oxidative stress inflicts mitochondrial dysfunction, which has been recognized as a key driver of intestinal diseases. Resveratrol (RSV) and its derivative pterostilbene (PTS) are natural antioxidants and exert a protective influence on intestinal health. However, the therapeutic effects and mechanisms of RSV and PTS on oxidative stress-induced mitochondrial dysfunction and intestinal injury remain unclear. The present study used porcine and cellular settings to compare the effects of RSV and PTS on mitochondrial redox homeostasis and function to alleviate oxidative stress-induced intestinal injury. Our results indicated that PTS was more potent than RSV in reducing oxidative stress, maintaining intestinal integrity, and preserving the mitochondrial function of diquat-challenged piglets. In the in vitro study, RSV and PTS protected against hydrogen peroxide (H 2 O 2)-induced mitochondrial dysfunction in intestinal porcine enterocyte cell line (IPEC-J2) by facilitating mitochondrial biogenesis and increasing the activities of mitochondrial complexes. In addition, both RSV and PTS efficiently mitigated mitochondrial oxidative stress by increasing sirtuin 3 protein expression and the deacetylation of superoxide dismutase 2 and peroxiredoxin 3 in H 2 O 2 -exposed IPEC-J2 cells. Furthermore, RSV and PTS preserved mitochondrial membrane potential, which restrained the release of cytochrome C from mitochondria to the cytoplasm and caspase-3 activation and further reduced apoptotic rates in H 2 O 2- exposed IPEC-J2 cells. Mechanistically, depletion of sirtuin 1 (SIRT1) abrogated RSV's and PTS's benefits against mitochondrial reactive oxygen species overproduction, mitochondrial dysfunction, and apoptosis in H 2 O 2 -exposed IPEC-J2 cells, suggesting that SIRT1 was required for RSV and PTS to protect against oxidative stress-induced intestinal injury. In conclusion, RSV and PTS improve oxidative stress-induced intestinal injury by regulating mitochondrial redox homeostasis and function via SIRT1 signaling pathway. In offering this protection, PTS is superior to RSV. [Display omitted] • SIRT1 plays a crucial role in oxidative stress-related intestinal injury. • PTS is superior to RSV in mitigating intestinal oxidative stress, mitochondrial injury and apoptosis. • RSV and PTS protect mitochondria against oxidative injury via SIRT1. • RSV and PTS improve mitochondrial biogenesis and function by SIRT1. [ABSTRACT FROM AUTHOR]

Depression is a serious and potentially life-threatening mental illness. Recently, the role of sirtuin 1 (SIRT1) in chronic unpredictable mild stress (CUMS) management has been examined. The present study explored and clarified whether microRNA (miR)-135b-5p could play a role in depression by regulating the expression of SIRT1. SIRT1 was identified as the target gene of miR-135b-5p using TargetScan and the dual luciferase reporter assay. In addition, the expression levels of SIRT1 were significantly reduced in mouse peripheral blood and hippocampal tissue samples, while the expression of miR-135b-5p exhibited the opposite effects. Subsequently, the effects of miR-135b-5p inhibition were investigated in mice with depression. The results indicated that the miR-135b-5p inhibitor significantly increased the weight loss induced by CUMS compared with the model group, while reducing the expression levels of miR-135b-5p and further alleviating the depression-like behavior induced by CUMS. Concomitantly, the results indicated that the miR-135b-5p inhibitor inhibited CUMS-induced hippocampal cell apoptosis and significantly reduced the expression levels of cleaved caspase-3 and the ratio of cleaved caspase-3/caspase-3. Moreover, the miR-135b-5p inhibitor significantly reduced the CUMS-induced increase of the inflammatory factors IL-1β, IL-6 and TNF-α in the hippocampal mouse samples, while significantly increasing the expression levels of SIRT1. Finally, the results demonstrated that all the effects of the miR-135b-5p inhibitor on CUMS-induced mice were significantly reversed by SIRT1 silencing. In conclusion, the present study indicated that the miR-135b-5p/SIRT1 pathway was a key mediator of antidepressant effects induced in depressed mice. Therefore, it could be considered a potential therapeutic target for the treatment of CUMS-induced depression. [ABSTRACT FROM AUTHOR]

Background: High expression of SIRT1 genes increases the expression of PGC1-α, which stimulates expression of GLUT4 glucose carrier in skeletal muscle. The aim of the present study was to investigate the effect of 8- week of HIIT training on the expression of SIRT1 and PGC1-α in male rats with type 2 diabetes. Methods: The research method was experimental. sixty male Wistar rats, with average weight of 250 ± 20 g, after induction of diabetes by injection of Nicotinic Amide- Streptozotocin, were randomly divided into 5 groups: Base-line control (n=12), HIIT Control (n=12), HIIT (n=12), Diabetic Control (n=12), HIIT Diabetic (n=12). The training groups performed the HIIT on a treadmill for 8- week and 5 days a week, which speeded from 16 meters per minute to the end of the eighth week to 38 meters per minute. Twenty four hours after the last training session, the rats were anesthetized. Then, soleus muscle tissue was immediately extracted, and the level of SIRT1 and PGC1-α gene expression was measured by Real Time-PCR and scale . Results: Statistical analysis of two-way ANOVA showed that the mean PGC1-α and SIRT1 indices were significantly different between the two control groups and the untrained diabetic group. Also, HIIT exercise had a significant effect on PGC1-α and SIRT1 genes (P

Acute myocardial infarction (AMI) is one of the leading causes of mortality in cardiovascular diseases. The aim of this study was to investigate whether exosomes from Sirtuin 1 (SIRT1)-overexpressing adipose-derived stem cells (ADSCs) had a protective effect on AMI. The expression of C-X-C chemokine receptor type 7 (CXCR7) was significantly downregulated in peripheral blood endothelial progenitor cells (EPCs) from AMI patients (AMI-EPCs) compared with that in healthy donors, which coincided with impaired tube formation. The exosomes from SIRT1 overexpression in ADSCs (ADSCs-SIRT1-Exos) increased the expression of C-X-C motif chemokine 12 (CXCL12) and nuclear factor E2 related factor 2 (Nrf2) in AMI-EPCs, which promoted migration and tube formation of AMI-EPCs, and overexpression of CXCR7 helped AMI-EPCs to restore the function of cell migration and tube formation. Moreover, CXCR7 was downregulated in the myocardium of AMI mice, and knockout of CXCR7 exacerbated AMI-induced impairment of cardiovascular function. Injection of ADSCs-SIRT1-Exos increased the survival and promoted the recovery of myocardial function with reduced infarct size and post-AMI left ventricular remodeling, induced vasculogenesis, and decreased AMI-induced myocardial inflammation. These findings showed that ADSCs-SIRT1-Exos may recruit EPCs to the repair area and that this recruitment may be mediated by Nrf2/CXCL12/CXCR7 signaling.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver chronic disease worldwide. The pathogenesis of NAFLD is complex and involves many metabolic enzymes and multiple pathways. Posttranslational modifications of proteins (PMPs) added another layer of complexity to the pathogenesis of NAFLD. PMPs change protein properties and regulate many biological functions, including cellular localization, stability, intracellular signaling, and protein function. Lysine acetylation is a common reversible PMP that consists of the transfer of an acetyl group from acetyl-coenzyme A (CoA) to a lysine residue on targeted proteins. The deacetylation reaction is catalyzed by deacetylases called sirtuins. This review summarizes the role of acetylation in NAFLD with a focus on sirtuins 1 and 3.

BackgroundFibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.MethodsFour-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.ResultsThe results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.ConclusionTherefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Background: Brain metastasis is a major cause of cancer death in patients with lung cancer. Sirtuin 1 and hsa-miR-217 have been identified to mediate the development of non-small cell lung cancer. Aims: To investigate the roles of hsa-miR-217, its target sirtuin 1, and the P53/KAI1 axis in the brain metastasis from non-small cell lung cancer. Study Design: Cell culture study. Methods: Human pulmonary adenocarcinoma brain metastasis cell line PC-14/B were incubated and treated with constructed lentiviral plasmids expressing miR-217 and/or sirtuin 1. BEAS-2B cell line was used as a control. The targeted regulation of miR-217 to sirtuin 1was examined using a dual-luciferase reporter assay. Cell proliferation, migration, invasion, and related protein expression were detected to examine the effect of the miR-217/sirtuin 1 expression on metastasis. Results: PC-14/B cells expressed higher sirtuin 1 and lower P53 and KAI1 compared with BEAS-2B control cells (p

ABSTRACT Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible loss of cognitive function. The presence of senile plaques is one of the pathological markers of the disease and is associated with the onset of neuroinflammatory mechanisms. The exact pathophysiology of AD has not been completely understood, and there are no curative therapies yet. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol that is noted for its antioxidant and anti-inflammatory properties. Objective: To review the role of resveratrol in the pathophysiological aspects of AD. Methods: This study carried out a literature review using PubMed/Medline, Virtual Health Library (VHL), Web of Sciences, SCOPUS and the Cochrane Library databases. Original research articles, describing both in vitro and in vivo experiments, published between 2008 and 2018, were included. Results: We identified 667 articles, of which 619 were excluded because they were repeated or did not follow the inclusion criteria. The present study includes the remaining 48 articles. Discussion: Resveratrol demonstrates beneficial and protective effects in AD models and seems to provide a promising therapeutic alternative. Conclusion: Although resveratrol appears to mitigate some pathophysiological aspects of AD, further studies are needed to prove the safety and efficacy of this compound in humans.

Objective: Chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation and accelerated inflammaging of the lungs. Some studies showed that conjugated linoleic acid (CLA) has anti-inflammatory effects. The aim of the present study was to evaluate the effect of CLA supplementationon serum levels of interleukin (IL)-6 and sirtuin1 (SIRT1) in patients with COPD. Materials and Methods: 82 patients with stable COPD were enrolled in a double blind clinical trial. Subjects were randomly assigned to two groups: placebo (n=42) and 3.2 g CLA daily supplementation (n=40). Forced expiratory volume in one second (FEV1%), BODE index, and serum levels of IL-6, and SIRT1 were measured at the baseline and six weeks after the intervention. In addition, the study parameters in the two groups were compared based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Results: After supplementation with CLA, serum levels of IL-6 and BODE index significantly decreased (p Conclusion: Supplementation with CLA can modify the inflammatory markers and improve the health status of COPD patients. The results suggest that CLA supplementation in COPD patients can be useful in the management of the disease.

Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization.

Abstract Background Emerging evidence has shown that vitamin D and magnesium have anti-inflammatory and anti-depressant effects. Dietary intake of magnesium is associated with reduced body mass index, waist circumference, body fat percentage, as well as inflammatory biomarkers and depressive symptoms. Vitamin D deficiency has been linked to inflammation, obesity, and depressive symptoms. This study will test the effects of vitamin D and magnesium co-supplementation on mood, serum level of brain-derived neurotrophic factor (BDNF), inflammation, and sirtuin 1 (SIRT1) in obese women. Methods We will conduct an 8-week, double-blind, randomized, placebo-controlled clinical trial, in a factorial design, to evaluate the individual effects of vitamin D and magnesium, and co-supplementation of them, on mood, serum level of BDNF, inflammation, and SIRT1 in 108 obese women. Discussion We hypothesize that vitamin D and magnesium co-supplementation may provide a new adjuvant therapy through modulation of BDNF, inflammation, and SIRT1 in obese women. Trial registration Iranian Registry of Clinical Trials, IRCT20090822002365N23. Registered on 16 August 2019.

Melanoma remains one of the most dangerous skin cancers among fair-skinned population. the search for new effective treatments, including therapy based on the selection of molecular targets, is one of the main and difficult tasks in the study of melanoma. One of the trends in experimental oncology is the study of microRNa’s role in carcinogenesis. MicroRNas are involved in many physiological and pathological processes, including cell proliferation, differentiation, migration, invasion, and carcinogenesis. It has been previously revealed that miR-204-5p levels are reduced in malignant tumors, in particular, in skin melanoma. the aim of this study was to determine the functional role of sIRt1 as a direct target of miR-204-5p in the pathogenesis of skin melanoma. Bioinformatics analysis allowed identification of micrRNa target genes that affected apoptosis, proliferation and cell viability. the level of proliferation of melanoma cells under the influence of small interfering RNa was estimated using the Mtt test and fluorescence microscopy. Luciferase Reporter assay was performed to evaluate whether sIRt1 was a target of miR-204-5p. Relative luciferase activity was calculated 48 hours after transfection with miR-204-5p mimic. the Mtt test showed that the proliferative activity of melanoma cells decreased 72 hours after siRNa sIRt1 knockdown. Fluorescent microscope revealed the same tendency in sIRt1 siRNa transfected cells. Mechanistic studies revealed that miR-204-5p repressed the expression of sIRt1 through binding to its 3`utR. therefore, miR-204-5p can regulate melanoma cell proliferation by targeting sIRt1 which can affect intercellular signaling systems related to cell cycle.

Aim: Whether accelerated aging, reflected by sirtuin 1 (SIRT1) expression, is implicated in bronchiectasis remains largely unknown. We sought to determine the patterns of SIRT1 and other aging markers in systemic circulation and airways and their expression levels associated with bronchiectasis severity and exacerbation.Methods: We enrolled 132 patients with bronchiectasis and 50 healthy subjects in a prospective cohort study to profile aging markers in systemic circulation and recruited 36 patients with bronchiectasis and 32 disease controls (idiopathic pulmonary fibrosis or tumors) in a cross-sectional study to profile aging markers in bronchial epithelium of both large-to-medium and small airways. We profiled aging marker expression from peripheral blood mononuclear cells and enumerated the positively stained cells for detection of aging marker expression in bronchial epithelium.Results: Compared with healthy controls, the relative telomere length (median: 0.88 vs. 0.99, p = 0.009), SIRT1 (median: 0.89 vs. 0.99, p = 0.002), and Ku80 (median: 0.87 vs. 0.96, p < 0.001) expression levels were consistently lower in the peripheral blood mononuclear cells among patients with bronchiectasis and modestly discriminated patients with bronchiectasis from healthy controls. No remarkable changes in SIRT1, telomere length, or Ku70 were identified at onset of exacerbation. Within the bronchial epithelium, the percentage of positively stained cells was lower for SIRT1 (median: 25.1 vs. 57.2%, p < 0.05) and numerically lower for p16 (median: 40.0 vs. 45.1%) and p21 (median: 28.9 vs. 35.9%) in patients with bronchiectasis than in disease controls (p > 0.05).Conclusion: SIRT1 was downregulated in systemic circulation and bronchiectatic airways, which was independent of disease severity and lung function impairment.

Sleep plays a major role in brain health, and cognition. Disrupted sleep is a well-described symptom of Alzheimer’s disease (AD). However, accumulating evidence suggests suboptimal sleep also increases AD risk. The deacetylase Sirtuin 1 (Sirt 1), encoded by the SIRT1 gene, impacts sleep via its relationship to wake-sleep neurotransmitters and somnogens. Evidence from animal and human studies supports a significant and complex relationship between sleep, Sirt 1/ SIRT1 and AD. Numerous hypotheses attempt to explain the critical impact of Sirt 1/ SIRT1 on wake- and sleep- promoting neurons, their related mechanisms and neurotransmitters. However, there is a paucity of studies assessing the interaction between sleep and Sirt 1/ SIRT1, as a principal component of sleep regulation, on AD pathology. In this review, we explore the potential association between Sirt 1/ SIRT1, sleep, and AD aetiology. Given sleep is a likely modifiable risk factor for AD, and recent studies suggest Sirt 1/ SIRT1 activation can be modulated by lifestyle or dietary approaches, further research in this area is required to explore its potential as a target for AD prevention and treatment.

Cocoa, rich in polyphenols, has been reported to provide many health benefits due to its antioxidant properties. In this study, we investigated the effect of Cocoa polyphenols extract (CPE) against oxidative stress-induced cellular senescence using a hydrogen peroxide (H2O2)-induced cellular senescence model in three auditory cells lines derived from the auditory organ of a transgenic mouse: House Ear Institute-Organ of Corti 1 (HEI-OC1), Organ of Corti-3 (OC-k3), and Stria Vascularis (SV-k1) cells. Our results showed that CPE attenuated senescent phenotypes, including senescence-associated β-galactosidase expression, cell proliferation, alterations of morphology, oxidative DNA damage, mitochondrial dysfunction by inhibiting mitochondrial reactive oxygen species (mtROS) generation, and related molecules expressions such as forkhead box O3 (FOXO3) and p53. In addition, we determined that CPE induces expression of sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), and it has a protective role against cellular senescence by upregulation of SIRT1 and SIRT3. These data indicate that CPE protects against senescence through SIRT1, SIRT3, FOXO3, and p53 in auditory cells. In conclusion, these results suggest that Cocoa has therapeutic potential against age-related hearing loss (ARHL).

Abnormal histone modifications have been recognized as an important contributing factor to the initiation and progression of osteosarcoma. Sirtuin 1 (Sirt1) up-regulation has been discovered in osteosarcoma cells. This study tested the influence of Sirt1 on histone H3 phosphorylation at threonine 3 (H3T3ph) in osteosarcoma cells, along with Sirt1-H3T3ph axis on osteosarcoma cell autophagy. Plasmids or si-RNAs transfection was carried out to alter Sirt1 or H3T3ph expressions. Co-immunoprecipitation analysis and GST pull-down assay were done to probe the relationship between Sirt1 and H3T3ph. Phosphoryltransferase activity of Sirt1 was tested by in vitro kinase activity assay. Cell autophagy was measured by a number of autophagosome, conversion of LC3-I to LC3-II, degradation of long-lived protein and ATG protein expressions. We found that Sirt1 directly interacted with H3 and phosphorylate H3T3 at threonine 3 in osteosarcoma cells. Moreover, Sirt1 facilitated osteosarcoma cell autophagy under starvation condition. H3T3ph took part in the Sirt1-facilitated osteosarcoma cell autophagy under starvation condition. Besides, Sirt1-H3T3ph axis facilitated osteosarcoma cell autophagy might be achieved through transcriptional activation of ATG genes. Sirt1 promoted osteosarcoma initiation and progression might be via phosphorylate H3T3 and then facilitate osteosarcoma cell autophagy through activating ATG genes transcription under starvation condition.

Microglial polarization and the subsequent neuroinflammatory response were identified as key contributors to the progress of Parkinson's disease (PD). Researchers have shown that fibroblast growth factor 21 (FGF21) plays multiple biological functions, including anti-inflammation and neuroprotection. However, the knowledge of FGF21 on microglial polarization in PD in vivo is far from completion. In this study, both in vivo and in vitro models were used to investigate whether FGF21 enhances the brain function by modulating microglial polarization in PD. The protective effects of FGF21 in vivo were conducted using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model alongside intraperitoneally received FGF21. A behavioral test battery and tyrosine hydroxylase (TH) immunohistochemistry were conducted to evaluate the neuronal function and nigrostriatal tract integrity. Immunofluorescence assay and Western blot were used to examine M1/M2 microglial polarization. Then, a microglia-neuron co-culture system was adopted in vitro to identify the underlying molecular mechanisms of FGF21. The results showed that FGF21 significantly alleviated motor and cognitive impairment in mice with PD. FGF21 also protected TH-positive neuron cells in the striatum and midbrain. Mechanistically, FGF21 suppressed M1 microglial polarization and the subsequent mRNA expression of pro-inflammatory factors while promoting M2 microglial polarization with increasing anti-inflammatory factors in mice with PD. Furthermore, sirtuin 1 (SIRT1) and the nuclear factor-kappa B (NF-κB) pathway were involved in the FGF21-induced M2 microglial polarization. Conversely, SIRT1 inhibitor EX527 significantly prevented both the FGF21-induced SIRT1 expression and M2 microglial polarization. Moreover, FGF21 pretreatment of microglia significantly prevented neuronal cell apoptosis in a microglia-neuron co-culture system. In conclusion, our data demonstrate that FGF21 exerted its protective effects in the pathology of PD through SIRT1/NF-κB pathway-mediated microglial polarization. Given the safety record of human clinical trials, FGF21 could be a promising therapy for clinical trials to ameliorate motor and nonmotor deficits in patients with PD.

Phosphate homeostasis is vital for many biological processes and disruptions in circulating levels can be detrimental. While the mechanisms behind FGF23 regulation have been regularly studied, the role of extracellular phosphate sensing and its impact on fibroblast growth factor 23 (FGF23) expression remains unclear. This study aimed to investigate the involvement of reactive oxygen species (ROS), silent information regulator 1 (SIRT1), and Hairy and Enhancer of Split-1 (HES1) in regulating FGF23 in FGF23 expressing MC3T3-E1 cells. MC3T3-E1 cells treated with β-glycerophosphate (BGP) resulted in increased Fgf23 expression. Inhibition of ROS formation by inhibition of NADPH oxidase, which is essential for ROS production, did not affect this response to BGP, suggesting ROS is not involved in this process. Moreover, treatment with tert-butyl hydroperoxide (TBHP), a ROS-inducing agent, did not increase Fgf23 expression. This suggests that ROS machinery is not involved in FGF23 stimulation as previously suggested. Nonetheless, inhibition of SIRT1 using Ex527 eliminated the Fgf23 response to BGP, indicating its involvement in FGF23 regulation after BGP treatment. Indeed, activation of SIRT1 using SRT1720 increased Fgf23 expression. Moreover, transcription factor Hes1 was upregulated by BGP treatment, which was diminished when cells were treated with Ex527 implying it is also regulated through SIRT1. These findings suggest the existence of an upstream SIRT1-HES1 axis in the regulation of FGF23 by phosphate, though we were unable to find a role for ROS in this process. Further research should provide insights into phosphate homeostasis and potential therapeutic targets for phosphate-related disorders., (© 2024. The Author(s).)

Purpose: To investigate the effect of nicotinamide (Nam) on diabetic kidney disease (DKD) in mice and explore its mechanism., Methods: Thirty DBA/2 J mice were randomly assigned to three groups. After 8 weeks of hyperglycemia induced by streptozocin (STZ), Nam and saline were administrated to STZ + Nam and STZ + NS mice, respectively, for 8 weeks. Non-diabetic mice (NDM) were used as control group. Twenty In2 -/- Akita mice were randomly divided into two groups. After 8 weeks of hyperglycemia, Nam and saline were administered to Akita + Nam and Akita + NS mice, respectively, for 6 weeks. Wild-type littermates were used as control group. Markers of renal injury were analyzed, and the molecular mechanisms were explored in human proximal tubular HK2 cells., Results: Urinary albumin-to-creatinine ratio (UACR) and kidney injury molecule 1 (KIM-1) decreased in the STZ + Nam and Akita + Nam groups. Pathological analysis showed that Nam improved the structure of glomerular basement membrane, ameliorated glomerular sclerosis, and decreased the accumulation of extracellular matrix and collagen. Compared to the diabetic control group, renal fibrosis, inflammation, and oxidative stress were reduced in the Nam-treated mice. The expression of sirtuin 1 (Sirt1) in human proximal tubular HK2 cells was inhibited by high glucose and Nam treatment enhanced its expression. However, in HK2 cells with Sirt1 knockdown, the protective effect of Nam was abolished, indicating that the beneficial effect of Nam was partially dependent on Sirt1., Conclusions: Nam has a renoprotective effect against renal injury caused by hyperglycemia and may be a potential target for the treatment of DKD., (© 2024. The Author(s).)

Background: Lipid accumulation and redox imbalance, resulting from dysregulation of hepatic fatty acids oxidation, contribute to the development of steatohepatitis and insulin resistance. Recently, dysregulated RNA N 6 -methyladenosine (m 6 A) methylation modification has been found involving fatty liver. However, the role of methyltransferase-like 14 (METTL14), the core component of m 6 A methylation, in the development of steatohepatitis is unknown. Herein, we aimed to explore the role of METTL14 on steatohepatitis and insulin resistance in mice with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: The liver tissues of mice and patients with MASLD were collected to detect the expression of METTL14. METTL14 overexpression and METTL14 silence were used to investigate the effect of METTL14 on lipid metabolism disorder in vivo and in vitro . Knockout of METTL14 in primary hepatocytes was used to investigate the role of Sirtuin 1 (SIRT1) on lipid accumulation induced by METTL14., Results: METTL14 was dramatically up-regulated in the livers of db/db mice, high-fat diet (HFD)-fed mice, and patients with MASLD. METTL14 overexpression exacerbated MASLD and promoted lipid metabolism disorder and insulin resistance in mice. Conversely, METTL14 knockout ameliorated lipid deposition and insulin resistance in HFD-fed mice. Furthermore, METTL14 overexpression facilitated lipid accumulation, while METTL14 knockout reduced lipid accumulation in HepG2 cells and primary hepatocytes. In addition, METTL14 lost up-regulated SIRT1 expression in hepatocytes. SIRT1 deficiency abrogated the ameliorating effects of METTL14 downregulation in MASLD mice., Conclusions: These findings suggest that dysfunction of the METTL14-SIRT1 pathway might promote hepatic steatosis and insulin resistance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes ( BMAL1 and PER2 ) and tight junctions ( OCLN , TJP1 , and CLND1 ), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression ( Clnd1 and Clnd4 ), and clock gene expression ( Bmal1 and Per2 ) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.

Purpose: Sepsis often triggers a systemic inflammatory response leading to multi-organ dysfunction, with complex and not fully understood pathogenesis. This study investigates the therapeutic effects of cimifugin on BV-2 cells under sepsis-induced stress conditions., Methods: We utilized a BV-2 microglial cell model treated with lipopolysaccharide (LPS) to mimic sepsis. Assessments included cellular vitality, inflammatory cytokine quantification (6 interleukin [6IL]-1β, interleukin 6 [IL-6], and tumor necrosis factor-α [TNF-α]) via enzyme-linked-immunosorbent serologic assay, and analysis of mRNA expression using real-time polymerase chain reaction. Oxidative stress and mitochondrial function were also evaluated to understand the cellular effects of cimifugin., Results: Cimifugin significantly attenuated LPS-induced inflammatory responses, oxidative stress, and mitochondrial dysfunction. It enhanced cell viability and modulated the secretion and gene expression of inflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, cimifugin activated the deacetylase sirtuin 1-nuclear factor erythroid 2-related factor 2 pathway, contributing to its protective effects against mitochondrial damage., Conclusion: Cimifugin demonstrates the potential of being an effective treatment for sepsis--induced neuroinflammation, warranting further investigation., Competing Interests: The authors stated that there was no conflict of interest to disclose.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN., (© 2024. The Authors.)

Vascular smooth muscle cells (VSMCs), known for their remarkable lifelong phenotypic plasticity, play a pivotal role in vascular pathologies through their ability to transition between different phenotypes. Our group discovered that the deficiency of the mitochondrial protein Poldip2 induces VSMC differentiation both in vivo and in vitro. Further comprehensive biochemical investigations revealed Poldip2's specific interaction with the mitochondrial ATPase caseinolytic protease chaperone subunit X (CLPX), which is the regulatory subunit for the caseinolytic protease proteolytic subunit (ClpP) that forms part of the ClpXP complex - a proteasome-like protease evolutionarily conserved from bacteria to humans. This interaction limits the protease's activity, and reduced Poldip2 levels lead to ClpXP complex activation. This finding prompted the hypothesis that ClpXP complex activity within the mitochondria may regulate the VSMC phenotype. Employing gain-of-function and loss-of-function strategies, we demonstrated that ClpXP activity significantly influences the VSMC phenotype. Notably, both genetic and pharmacological activation of ClpXP inhibits VSMC plasticity and fosters a quiescent, differentiated, and anti-inflammatory VSMC phenotype. The pharmacological activation of ClpP using TIC10, currently in phase III clinical trials for cancer, successfully replicates this phenotype both in vitro and in vivo and markedly reduces aneurysm development in a mouse model of elastase-induced aortic aneurysms. Our mechanistic exploration indicates that ClpP activation regulates the VSMC phenotype by modifying the cellular NAD + /NADH ratio and activating Sirtuin 1. Our findings reveal the crucial role of mitochondrial proteostasis in the regulation of the VSMC phenotype and propose the ClpP protease as a novel, actionable target for manipulating the VSMC phenotype., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The patent “Uses of Hydroimidazopyridopyrimidinone Derivatives for Managing Aneurysms or Other Vascular Conditions or Diseases” is pending to Emory University. This patent submission contains data from the current manuscript. The inventors are Felipe Paredes and Alejandra San Martin., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Gardeniae Fructus (GF, the dried ripe fruits of Gardenia jasminoides Ellis) has traditionally been used to treat various diseases in East Asian countries, such as liver disease. Silymarin is a well-known medicine used to treat numerous liver diseases globally. The present study was purposed to evaluate the synergistic effects of GF and silymarin on the thioacetamide (TAA)-induced liver fibrosis of a mouse model. Mice were orally administered with distilled water, GF (100 mg/kg, GF 100), silymarin (100 mg/kg, Sily 100), and GF and silymarin mixtures (50 and 100 mg/kg, GS 50 and 100). The GS group showed remarkable amelioration of liver injury in the serum levels and histopathology by observing the inflamed cell infiltrations and decreases in necrotic bodies through the liver tissue. TAA caused liver tissue oxidation, which was evidenced by the abnormal statuses of lipid peroxidation and deteriorations in the total glutathione in the hepatic protein levels; moreover, the immunohistochemistry supported the increases in the positive signals against 4-hydroxyneal and 8-OHdG through the liver tissue. These alterations corresponded well to hepatic inflammation by an increase in F4/80 positive cells and increases in pro-inflammatory cytokines in the hepatic protein levels; however, administration with GS, especially the high dose group, not only remarkably reduced oxidative stress and DNA damage in the liver cells but also considerably diminished pro-inflammatory cytokines, which were driven by Kupffer cell activations, as compared with each of the single treatment groups. The pharmacological properties of GS prolonged liver fibrosis by the amelioration of hepatic stellate cells’ (HSCs’) activation that is dominantly expressed by huge extracellular matrix (ECM) molecules including α-smooth muscle actin, and collagen type1 and 3, respectively. We further figured out that GS ameliorated HSCs activated by the regulation of Sirtuin 1 (Sirt1) activities in the hepatic protein levels, and this finding excellently reenacted the transforming growth factor-β-treated LX-2-cells-induced cell death signals depending on the Sirt1 activities. Future studies need to reveal the pharmacological roles of GS on the specific cell types during the liver fibrosis condition.

The sirtuin 1 (SIRT1) activator resveratrol has emerged as a promising candidate for the prevention of vascular oxidative stress, which is a trigger for endothelial dysfunction. However, its clinical use is limited by low oral bioavailability. In this work, we have applied a previously developed computational protocol to identify the most promising derivatives from our in-house chemical library of resveratrol derivatives. The most promising compounds in terms of SIRT1 activation and oral bioavailability, predicted in silico, were evaluated for their ability to activate the isolated SIRT1 enzyme. Then, we assessed the antioxidant effects of the most effective derivative, compound 3d, in human umbilical vein endothelial cells (HUVECs) injured with H2O2 100 µM. The SIRT1 activator 3d significantly preserved cell viability and prevented an intracellular reactive oxygen species increase in HUVECs exposed to the oxidative stimulus. Such effects were partially reduced in the presence of a sirtuin inhibitor, sirtinol, confirming the potential role of sirtuins in the activity of resveratrol and its derivatives. Although 3d appeared less effective than resveratrol in activating the isolated enzyme, the effects exhibited by both compounds in HUVECs were almost superimposable, suggesting a higher ability of 3d to cross cell membranes and activate the intracellular target SIRT1.

Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about the role of nucleophagy in LSEC defenestration. Herein, we aim to dissect the underlying mechanism of progerin and nucleophagy in LSEC phenotype. We found an abnormal accumulation of progerin and a loss of SIRT1 in the nucleus of intrahepatic cells in human fibrotic liver tissue. In vivo, nuclear progerin abnormally accumulated in defenestrated LSECs, along with a depletion of SIRT1 and Cav-1 during liver fibrogenesis, whereas these effects were reversed by the overexpression of SIRT1 with the adenovirus vector. In vitro, H2O2 induced the excessive accumulation of progeirn, with the depletion of Lamin B1 and Cav-1 to aggravate LSEC defenestration. NAC and mito-TEMPO, classical antioxidants, inhibited NOX2- and NOX4-dependent oxidative stress to improve the depletion of Lamin B1 and Cav-1 and promoted progerin-related nucleophagy, leading to a reverse in H2O2-induced LSEC defenestration. However, rapamycin aggravated the H2O2-induced depletion of Lamin B1 and Cav-1 due to excessive autophagy, despite promoting progerin nucleophagic degradation. In addition, overexpressing SIRT1 with the adenovirus vector inhibited oxidative stress to rescue the production of Lamin B1 and Cav-1. Moreover, the SIRT1-mediated deacetylation of nuclear LC3 promoted progerin nucleophagic degradation and subsequently inhibited the degradation of Lamin B1 and Cav-1, as well as improved F-actin remodeling, contributing to maintaining LSEC fenestrae. Hence, our findings indicate a new strategy for reversing LSEC defenestration by promoting progerin clearance via the SIRT1-mediated deacetylation of nuclear LC3.

Ethnopharmacological Relevance: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Tianma-Gouteng Pair (TGP), commonly prescribed as a pair-herbs, can be found in many Chinese medicine formulae to treat brain diseases. However, the neuroprotective effects and molecular mechanisms of TGP remained unexplored., Aim of the Study: This study investigated the difference between the TgCRND8 and 5 × FAD transgenic mice, the anti-AD effects of TGP, and underlying molecular mechanisms of TGP against AD through the two mouse models., Methods: Briefly, three-month-old TgCRND8 and 5 × FAD mice were orally administered with TGP for 4 and 6 months, respectively. Behavioral tests were carried out to determine the neuropsychological functions. Moreover, immunofluorescence and western blotting assays were undertaken to reveal the molecular mechanisms of TGP., Results: Although TgCRND8 and 5 × FAD mice had different beta-amyloid (Aβ) burdens, neuroinflammation status, and cognition impairments, TGP exerted neuroprotective effects against AD in the two models. In detail, behavioral tests revealed that TGP treatment markedly ameliorated the anxiety-like behavior, attenuated the recognition memory deficits, and increased the spatial learning ability as well as the reference memory of TgCRND8 and 5 × FAD mice. Moreover, TGP treatment could regulate the beta-amyloid precursor protein (APP) processing by inhibiting the Aβ production enzymes such as β- and γ-secretases and activating Aβ degrading enzyme to reduce Aβ accumulation. In addition, TGP reduced the Aβ 42 level, the ratio of Aβ 42 /Αβ 40 , Aβ accumulation, and tau hyperphosphorylation in both the 5 × FAD and TgCRND8 mouse models. Furthermore, TGP ameliorated neuroinflammation by decreasing the densities of activated microglia and astrocytes, and inhibiting the production of inflammatory cytokines. TGP upregulated the SIRT1 and AMPK, and downregulated sterol response element binding protein 2 (SREBP2) in the brain of TgCRND8 mice and deactivation of the EPhA4 and c-Abl in the brain tissues of 5 × FAD mice., Conclusion: Our experiments for the first time revealed the neuroprotective effects and molecular mechanism of TGP on 5 × FAD and TgCRND8 transgenic mouse models of different AD stages. TGP decreased the level of Aβ aggregates, improved the tauopathy, and reduced the neuroinflammation by regulation of the SIRT1/AMPK/SREBP2 axis and deactivation of EPhA4/c-Abl signaling pathway in the brains of TgCRND8 and 5 × FAD mice, respectively. All these findings unequivocally confirmed that the TGP would be promising in developing into an anti-AD therapeutic pharmaceutical., Competing Interests: Declaration of competing interest All authors declare that we have no financial and personal relationships with other people or organizations that can inappropriately influent our work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sirtuin 1 (SIRT1) inhibits growth hormone (GH) intracellular signaling for the insulin-like growth factor 1 (IGF-1) synthesis via the janus kinase (JAK)/signal transducer and activator of transcription proteins (STATs) pathway. The aim of this study was to compare SIRT1 concentrations in children with GH deficiency (GHD) and so-called idiopathic short stature (ISS, non-GH deficient), in order to determine the possible impact of changes in serum SIRT1 concentrations on the GH-IGF-1 axis. The study group included 100 short-stature children: 38 with GHD and 62 with ISS (maxGH in two stimulation tests <10 and ≥10 ng/mL, respectively). The control group consisted of 47 healthy, normal-height children. For each child, the concentrations of SIRT1, IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) were determined and the IGF-1/IGFBP-3 molar ratio was calculated. The level of SIRT1 was significantly higher in both groups of short children than in the controls ( p < 0.0001), but there were no differences between GHD and ISS (mean ± SD: 0.89 ± 0.45 for ISS; 1.24 ± 0, 86 for GHD; and 0.29 ± 0.21 for controls). A significant negative correlation was found between SIRT1 and height standard deviation score (SDS), IGF-1 and IGF-1/IGFBP-3, but not between SIRT1 and maxGH. Elevated SIRT1 levels may serve as one of the mechanisms through which the secretion of IGF-1 is reduced in children with short stature; however, further research is required to confirm this issue.

Dermal fibroblasts play a crucial role in skin structure and function by producing hyaluronic acid. Piceatannol (PIC), a polyphenol abundant in passion fruit seeds, has been reported to activate sirtuin 1 (SIRT1). Clinical trials have demonstrated that PIC intake improves skin moisture and maintains skin elasticity, yet the underlying mechanism remains unclear. This study aimed to investigate the effects of PIC on hyaluronic acid biosynthesis and the involvement of SIRT1 in this process. Human dermal fibroblast Hs68 cells were stimulated with PIC, and the expression levels of HAS2 and HYAL2 , key enzymes in hyaluronic acid biosynthesis, as well as SIRT1 expression, were assessed using quantitative real-time PCR. Additionally, the role of SIRT1 in the hyaluronic acid biosynthesis pathway during PIC stimulation was examined using a SIRT1 inhibitor. The results demonstrated that PIC increased HAS2 expression while decreasing HYAL2 expression in human dermal fibroblasts. Furthermore, PIC enhanced SIRT1 expression, and pre-treatment with a SIRT1 inhibitor mitigated PIC-induced upregulation of HAS2 , suggesting that PIC promotes hyaluronic acid synthesis by inducing SIRT1 . These findings suggest that PIC could serve as a beneficial food ingredient, enhancing skin structure and function by promoting hyaluronic acid biosynthesis via SIRT1 induction., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mizuki Yoshihara reports a relationship with 10.13039/100019269Morinaga & Co., Ltd. That includes: employment. Shinpei Kawakami reports a relationship with 10.13039/100019269Morinaga & Co., Ltd. That includes: employment. Yuko Matsui reports a relationship with 10.13039/100019269Morinaga & Co., Ltd. That includes: employment. Toshihiro Kawama reports a relationship with 10.13039/100019269Morinaga & Co., Ltd. That includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Hepatocellular carcinoma (HCC) remains a major global health problem with high incidence and mortality. Diagnosis of HCC at late stages and tumour heterogeneity in patients with different genetic profiles are known factors that complicate the disease treatment. HCC therapy becomes even more challenging in patients with drug resistance such as resistance to sorafenib, which is a common drug used in HCC patients. Sorafenib resistance can further aggravate HCC by regulating various oncogenic pathways such as autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling. Sirtuin 1 (SIRT1), is a nicotinamide adenosine dinucleotide (NAD)-dependent histone deacetylases that regulates various metabolic and oncogenic events such as cell survival, apoptosis, autophagy, tumourigenesis, metastasis and drug resistance in various cancers, but its role in HCC, particularly in sorafenib resistance is underexplored. In this study, we generated sorafenib-resistant HepG2 and Huh-7 liver cancer cell models to investigate the role of SIRT1 and its effect on autophagy and nuclear factor-kappa Beta (NF-ĸβ) signalling pathways. Western blot analysis showed increased SIRT1, altered autophagy pathway and activated NF-ĸβ signalling in sorafenib-resistant cells. SIRT1-silenced HCC cells demonstrated down-regulated autophagy in both parental and chemoresistant cells. This may occur through the deacetylation of key autophagy molecules such as FOXO3, beclin 1, ATGs and LC3 by SIRT1, highlighting the role of SIRT1 in autophagy induction. Silencing of SIRT1 also resulted in activated NF-ĸβ signalling. This is because SIRT1 failed to deacetylate p65 subunit of NF-κB, translocate the NF-κB from nucleus to cytoplasm, and suppress NF-κB activity due to the silencing. Hence, the NF-κB transcriptional activity was restored. These findings summarize the role of SIRT1 in autophagy/NF-ĸβ regulatory axis, with a similar trend observed in both parental and sorafenib-resistant cells. The present work promotes a better understanding of the role of SIRT1 in autophagy and NF-ĸβ signalling in HCC and sorafenib-resistant HCC. As some key proteins in these pathways are potential therapeutic targets, a better understanding of SIRT1/autophagy/NF-ĸβ axis could further improve the therapeutic strategies against HCC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250 µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8 µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Excitotoxicity, characterized by over-activation of glutamate receptors, is a major contributor to spinal cord injury (SCI) pathophysiology, resulting in neuronal death and loss of locomotor function. In our previous in vitro studies, we showed that excitotoxicity induced by the glutamate analogue kainate (KA) leads to a significant reduction in the number of neurons, providing a model for SCI. Our current objective was to assess the neuroprotective role of resveratrol (RESV), a natural polyphenol, following KA-induced SCI. In vivo excitotoxicity was induced by intraspinal injection of KA immediately followed by RESV administration to Balb/C adult male mice. In neonatal mouse spinal cord preparations, excitotoxicity was transiently induced by bath-applied KA, either with or without RESV. KA administration resulted in a significant deterioration in hindlimb motor coordination and balance during locomotion, which was partially reverted by RESV. Additionally, RESV preserved neurons in both dorsal and ventral regions. Sirtuin 2 (SIRT2) immunoreactive signal was increased by RESV, while the selective SIRT1 inhibitor 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (EX-527) attenuated RESV neuroprotective effects. These findings suggest that RESV attenuation of excitotoxic-induced neuronal loss and locomotor deficits is mediated, at least in part, through the activation of SIRT1, potentially involving SIRT2 as well. Indeed, our results highlight the potential use of RESV to enhance neuroprotective strategies for SCI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro , SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling. [ABSTRACT FROM AUTHOR]

Background and Objectives: Osteoarthritis (OA) is one of the most common and highly prevalent types of arthritis, also considered a multi phenotypic disease with a strong metabolic component. Ageing is the primary risk factor for OA, while the age-related decline in autophagic activity affects cell function and chondrocyte homeostasis. The aim of this study was to investigate the role of sirtuin 1 (SIRT1) in autophagy dysregulation and lipid metabolism in human OA chondrocytes. Materials and Methods: OA chondrocytes were treated with Resveratrol, Hydroxycloroquine (HCQ) or 3-Methyladenine (3-MA) and HCQ or 3-MA followed by siRNA against SIRT1 (siSIRT1). Then, SIRT1, AcNF-κBp65, LOX-1 and autophagy-related proteins ATG5, ATG13, PI3K class III, Beclin-1, LC3 and ULK protein levels were evaluated using Western blot. Normal articular chondrocytes were treated under serum starvation and/or siSIRT1, and the protein expression levels of the above autophagy-related proteins were evaluated. The staining patterns of LC3/p62 and LOX-1 were analyzed microscopically by immunofluorescence. SIRT1/LC3 complex formation was analyzed by immunoprecipitation. Results: SIRT1 and LOX-1 protein expression were negatively correlated in OA chondrocytes. SIRT1 regulated LOX-1 expression via NF-κB deacetylation, while treatment with Resveratrol enhanced SIRT1 enzymatic activity, resulting in LOX-1 downregulation and autophagy induction. In OA chondrocytes, SIRT1 was recognized as an autophagy substrate, formed a complex with LC3 and was consequently subjected to cytoplasmic autophagosome-lysosome degradation. Moreover, siSIRT1-treated normal chondrocytes showed decreased autophagic activity, while double-treated (siSIRT1 and serum starvation) cells showed no induction of autophagy. Conclusions: Our results suggest that SIRT1 regulates lipid homeostasis through LOX-1 expression regulation. Additionally, we indicate that the necessity of SIRT1 for autophagy induction in normal chondrocytes, together with its selective autophagic degradation in OA chondrocytes, could contribute to autophagy dysregulation in OA. We, therefore, suggest a novel regulatory scheme that functionally connects lipid metabolism and autophagy in late-stage OA. [ABSTRACT FROM AUTHOR]

Emphysema is one of the most important phenotypes for chronic obstructive pulmonary disease (COPD). Apoptosis in alveolar epithelial cells (AECs) causes the emphysematous alterations in the smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to attenuate mitochondrial dysfunction, oxidative stress, and to modulate apoptosis. It has been shown that sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, protects against cigarette smoke (CS)-induced emphysema/COPD in mice. However, the mechanisms underlying these findings remain unclear. Here, we investigate whether and how STS attenuates AEC apoptosis via a SIRT1-dependent mechanism. We found that STS treatment decreased CS extract (CSE)-induced apoptosis in human alveolar epithelial A549 cells. STS reduced oxidative stress, improved mitochondrial function and mitochondrial membrane potential (ΔΨm), and restored mitochondrial dynamics-related protein expression. Moreover, STS promoted mitophagy, and increased oxidative phosphorylation protein levels (complexes I–IV) in CSE-stimulated A549 cells. The protective effects of STS were associated with SIRT1 upregulation, because SIRT1 inhibition by EX 527 significantly attenuated or abolished the ability of STS to reverse the CSE-induced mitochondrial damage, oxidative stress, and apoptosis in A549 cells. In conclusion, STS ameliorates CSE-induced AEC apoptosis by improving mitochondrial function and reducing oxidative stress via enhancing SIRT1 pathway. These findings provide novel mechanisms underlying the protection of STS against CS-induced COPD. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is a new and effective method of nonpharmacological treatment in psychiatry, with multiple indications. Beyond clinical efficacy, TMS brings a clear benefit in understanding the intracellular mechanisms involved in the pathophysiology of mental disorders. Studies on repetitive transcranial magnetic stimulation (rTMS) have confirmed the role of intracellular signalling pathways involved in mental disorders. rTMS activates the endocannabinoid system, increases the synaptic plasticity and neurogenesis by activating BDNF (which in turn activates the Bcl2 antiapoptotic proteins and inhibits proapoptotic factors Bax), increases monoamine transmission by suppressing the BDNF, activates the cytosolic antiinflammatory protein Nrf2, and activates the Ras/MAPK/P3K/ Akt signaling pathway. Transcranial magnetic stimulation, a noninvasive method with confirmed clinical efficacy, coupled with the identification of parts of the molecular puzzle, constitutes a therapeutic alternative in psychiatry. Transcranial magnetic stimulation is therefore a new and effective method of treatment in psychiatry. In addition to its clinical effectiveness, it gives us a better understanding of synaptic connectivity and the multiple cellular mechanisms involved in the pathophysiology of mental disorders. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is the main aetiology of coronary heart disease, cerebral infarction and peripheral vascular disease in humans. Long‐noncoding RNA (LincRNA)‐p21 has been reported to participate in the development of AS. Therefore, this study was designed to investigate the mechanism of LincRNA‐p21 on suppressing the development of AS. We fed ApoE−/− mice with a high‐fat diet to induce an AS mouse model where the lesion area of AS and the extent of lipid deposition were measured. The binding of LincRNA‐p21 and miR‐221 or miR‐221 and SIRT1 was measured using a dual luciferase reporter gene assay and RIP. Following loss‐ and gain‐ function assays, CCK8, EdU, Transwell assay and scratch test were performed to determine the biological processes of human aortic endothelial cells (HAECs). miR‐221 was highly expressed while SIRT1 was poorly expressed in AS. LincRNA‐p21 acted as a sponge for miR‐221. miR‐221 targeted and negatively regulated the expression of SIRT1. LincRNA‐p21 promoted the deacetylation of Pcsk9 by SIRT1 by competitively binding to miR‐221, whereby promoting HAEC proliferation, migration and tube formation. In conclusion, LincRNA‐p21 acted as a molecular sponge for miR‐221 to promote deacetylation of the promoter region of Pcsk9 by SIRT1, therefore preventing the development of AS. [ABSTRACT FROM AUTHOR]