Role Of Sirtuins Research Articles

Stem Cell Therapy Modulates Molecular Cues of Vasogenic Edema Following Ischemic Stroke: Role of Sirtuin-1 in Regulating Aquaporin-4 Expression.

Conventional post-stroke edema management strategies are limitedly successful as in multiple cases of hemorrhagic transformation is being reported. Clinically, acute-ischemic-stroke (AIS) intervention by endovascular mesenchymal stem cells (MSCs) have shown benefits by altering various signaling pathways. Our previous studies have reported that intra-arterial administration of 1*105 MSCs (IA-MSCs) were beneficial in alleviating post-stroke edema by modulating PKCδ/MMP9/AQP4 axis and helpful in preserving the integrity of blood-brain-barrier (BBB). However, the role of mitochondrial dysfunction and ROS generation post-AIS cannot be overlooked in context to the alteration of the BBB integrity and edema formation through the activation of inflammatory pathways. The anti-inflammatory activity of IA-MSCs in stroke has been reported to be regulated by sirtuin-1 (SIRT-1). Hence, the relationship between SIRT-1 and AQP4 towards regulation of post-stroke edema needs to be further explored. Therefore, the present study deciphers the molecular events towards AQP4 upregulation, mitochondrial dysfunction and BBB disruption in context to the modulation of SIRT-1/PKCδ/NFκB loop by IA-MSCs administration. Ovariectomized SD rats were subjected to focal ischemia. SIRT-1 activator, SIRT-1 inhibitor, NFkB inhibitor and IA-MSCs were administered at optimized dose. At 24h of reperfusion, behavioral tests were performed, and brains were harvested following euthanasia for molecular studies. IA-MSCs downregulated AQP4, PKCδ and NFkB expression, and upregulated SIRT-1 expression. SIRT-1 upregulation renders mitochondrial protection via reduction of oxidative stress resulting in BBB protection. IA-MSCs can modulate SIRT-1 mediated AQP4 expression via mitochondrial ROS reduction and modification of NFkB transcriptional regulation.

The Role of Sirtuins in Diabetic Nephropathy: A Comprehensive Review.

Diabetic nephropathy is characterized by elevated oxidative stress and chronic inflammation in the kidneys. A class of proteins called sirtuins is well-known to be important for a number of cellular functions, such as metabolism, stress tolerance, and ageing. Among them, SIRT1 is associated with the progression of diabetic nephropathy, a dangerous kidney-related consequence of diabetes mellitus. Thus, this study aims to examine the function and pathways of sirtuin that are responsible for the progression of this disease. Publications considered from the standard databases like PUBMED-MEDLINE, Google Scholar, and Scopus using standard keywords, "Sirtuin," Signalling pathway", and "Diabetic Nephropathy" well described the actual knowledge on the scientific literature indicating patient susceptibility to kidney disease that is influenced by sirtuin-1 gene variants. The research results imply that sirtuins offer enormous promise as cutting-edge therapeutic targets for kidney disease prevention and management. Renal fibrosis, metabolic disorders, renal impairment, and a possible regulation mechanism all probably entail blocking inflammation through various signalling pathways. A comprehensive understanding of the fundamental pathophysiological pathways targeting sirtuin is essential as a diagnostic tool. For the treatment of diabetic nephropathy, researchers are developing therapeutic techniques to target biological roles and functions of different types of sirtuin, processes, and signalling pathways.

Nimodipine ameliorates subarachnoid hemorrhage-induced neuroinflammation and injury by protecting mitochondrial function and regulating autophagy.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear. In this study, the in vitro cytotoxicity of neurons exposed to 2% ethanol (to stimulate oxidative stress) was assessed. An in vivo experimental SAH model was established in adult mice through internal carotid perforation. A series of in vitro and in vivo experiments were conducted to investigate the function of SIRT3 and its potential mechanisms in nimodipine-treated SAH. Nimodipine, at a concentration of 10μM within 48h of incubation, exerted significant neuroprotective effects, enhancing SIRT3 protein expression under oxidative stress. Functional in vitro studies revealed that elevated SIRT3 expression improved mitochondrial function and promoted neuronal autophagy. Additional studies unveiled that SIRT3 knockdown or inhibition of autophagosome formation using inhibitor 3-methyladenine suppressed nimodipine-induced autophagy. The absence of autophagy increased neuronal cytotoxicity and mitochondrial dysfunction, decreased the release of anti-inflammatory cytokines, and increased the release of proinflammatory cytokines. Furthermore, blocking autophagy exacerbated neuronal apoptosis worsened neurological outcomes, and nullified the neuroprotective effects of nimodipine in the SAH mouse model. These findings highlight a mechanism where SIRT3 mediates nimodipine's neuroprotective effects by regulating mitochondrial function and autophagy. This suggests that SIRT3 serves as a promising therapeutic target for SAH.

Role of sirtuin 1 in depression‑induced coronary heart disease: Molecular pathways and therapeutic potential (Review).

Depression and coronary heart disease (CHD) are two interconnected diseases that profoundly impact global health. Depression is both a complex psychiatric disorder and an established risk factor for CHD. Sirtuin 1 (SIRT1) is an enzyme that requires the cofactor nicotinamide adenine dinucleotide (NAD+) to perform its deacetylation function, and its involvement is crucial in reducing cardiovascular risks that are associated with depression. SIRT1 exerts its cardioprotective effects via modulating oxidative stress, inflammation and metabolic processes, all of which are central to the pathogenesis of CHD in individuals with depression. Through influencing these pathways, SIRT1 helps to reduce endothelial dysfunction, prevent the formation of atherosclerotic plaques and stabilize existing plaques, thereby decreasing the overall risk of CHD. The present review underscores the important role of SIRT1 in serving as a therapeutic intervention molecule for tackling cardiovascular complications stemming from depression. Furthermore, it highlights the need for further studies to clarify how SIRT1 influences both depression and CHD at the molecular level. The ultimate goal of this research will be to translate these findings into practical clinical intervention strategies.

Sirtuins and Their Implications in the Physiopathology of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) imposes serious short- and long-term health problems for the mother and her child. An effective therapeutic that can reduce the incidence of GDM and improve long-term outcomes is a major research priority and is very important for public health. Unfortunately, despite numerous studies, the molecular mechanisms underlying GDM are not fully defined and require further study. Chronic low-grade inflammation, oxidative stress, and insulin resistance are central features of pregnancies complicated by GDM. There is evidence of the involvement of sirtuins, which are NAD+-dependent histone deacetylases, in energy metabolism and inflammation. Taking these facts into consideration, the role of sirtuins in the pathomechanism of GDM will be discussed.

Understanding the Role of Sirtuins in the Pathogenesis and Treatment of Oral Ulcers: A Rapid Review

Oral ulcers are a prevalent clinical condition with multifactorial etiologies, including trauma, infections, systemic diseases, and immune dysregulation. Sirtuins, particularly SIRT1, play an important role in regulating oxidative stress, inflammation, and cellular repair pathways. This rapid review, conducted using the PRISMA protocol, synthesizes current evidence on the role of sirtuins in oral ulcer pathophysiology and their potential as therapeutic targets. A comprehensive search identified 140 articles in PubMed, 41 in ScienceDirect, and 4 in the Cochrane Library, of which 1 study met the eligibility criteria. The findings indicate that SIRT1 expression in the oral ulcer rats model is significantly lower than in normal controls, whereas NF-κB and TNF-α levels are markedly elevated in the control group. Pharmacological activation of SIRT1 attenuates inflammation, highlighting its therapeutic potential. However, the limited sample sizes and the lack of clinical trials specifically addressing oral ulcers restrict the generalizability of these findings. Additional study is needed to validate these findings and investigate SIRT1-targeted treatments.

Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis

Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella’s metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.

Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis

Sirtuins are the major players in host immunometabolic regulation. However, the role of sirtuins in the modulation of the immune metabolism pertaining to salmonellosis is largely unknown. Here, our investigation focussed on the role of two important sirtuins, SIRT1 and SIRT3, shedding light on their impact on intracellular Salmonella’s metabolic switch and pathogenesis establishment. Our study indicated the ability of the live Salmonella Typhimurium to differentially regulate the levels of SIRT1 and SIRT3 for maintaining the high glycolytic metabolism and low fatty acid metabolism in Salmonella. Perturbing SIRT1 or SIRT3 through knockdown or inhibition resulted in a remarkable shift in the host metabolism to low fatty acid oxidation and high glycolysis. This switch led to decreased proliferation of Salmonella in the macrophages. Further, Salmonella-induced higher levels of SIRT1 and SIRT3 led to a skewed polarization state of the macrophages from a pro-inflammatory M1 state toward an immunosuppressive M2, making it more conducive for the intracellular life of Salmonella. Alongside, governing immunological functions by modulating p65 NF-κB acetylation, SIRT1, and SIRT3 also skew Salmonella-induced host metabolic switch by regulating the acetylation status of HIF-1α and PDHA1. Interestingly, though knockdown of SIRT1/3 attenuated Salmonella proliferation in macrophages, in in vivo mice model of infection, inhibition or knockdown of SIRT1/3 led to more dissemination and higher organ burden, which can be attributed to enhanced ROS and IL-6 production. Our study hence reports for the first time that Salmonella modulates SIRT1/3 levels to maintain its own metabolism for successful pathogenesis.

Sirtuins as Key Regulators in Pancreatic Cancer: Insights into Signaling Mechanisms and Therapeutic Implications.

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD+-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise in curbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC's metabolic dependencies. SIRT6 and SIRT7, through their roles in angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD+-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies.

Sirtuins: Emergent Players in Tissue and Organ Regeneration

Sirtuins are a family of lysine deacetylases that regulate cellular homeostasis and energy sensing. Regeneration is the process that restores structural and functional homeostasis at the cellular, tissue, organ, and appendage levels. Several cellular processes, such as epithelial–mesenchymal transition (EMT), proliferation, migration, and differentiation, contribute to restoration after an injury. This review highlights the role of sirtuins in tissue, organ, and anatomical structure regeneration, showing how sirtuins modulate signalling pathways by deacetylating targets such as transcription factors. Furthermore, understanding the role of this protein family could help elucidate the molecular and cellular mechanisms underlying tissue regeneration, which may hold significant potential for fields such as regenerative medicine. The review compiles evidence suggesting that sirtuins are emerging factors in the regeneration of various organs (e.g., skin, liver, heart) and tissues (e.g., bone, muscle, cornea, spinal cord).

Abstract 4147602: The Paradox Role of Sirtuin 6 In Coronary Microvascular Function under Metabolic Stress

Coronary microvascular dysfunction (CMD), which is associated with diabetic cardiomyopathy, Takotsubo cardiomyopathy, andheart failure with preserved ejection fraction (HFpEF), is understudied. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. Nuclear Sirtuin 6 (SIRT6) plays essential roles in gene transcriptional, stress tolerance, DNA repair, inflammation, and aging. SIRT6 is strongly associated with cardiovascular pathologies, but how SIRT6 regulates endothelial metabolisms and homeostasis under metabolic stress and the underlying mechanism remains poorly understood. It might be because global Sirt6 knockout mice are perinatally lethal caused by hypoglycemia, suggesting the essential role of SIRT6 in glucose metabolism. In our preliminary studies, we generated inducible global Sirt6 knockout mice by crossing with Sirt6 f/f mice with CAG-cre (Sirt6 f/f, CAG ), and mice were viable with normal glucose levels. However, they showed impaired endothelial-dependent dilation (EDD) and impaired coronary flow reserve (CFR), an index clinically used to diagnose CMD. It suggests that deletion of Sirt6 might cause EC dysfunction because Sirt6 is reported to protect EC from premature senescence and oxidative stress by sustaining high eNOS levels. Surprisingly, when we studied non-inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, tie-2 cre ) and inducible Sirt6 endothelial-specific knockout (Sirt6 f/f, Cdh5-cre/ERT2 ) and wild-type (WT) mice, Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 mice do not phenocopy the inducible global SIRT6 knockout mice, they had normal EDD and CFR. When the mice were fed a high fat and high sugar (HFHS) diet, the Sirt6 f/f, Tie-2 and Sirt6 f/f, Cadh5 had impaired EDD, suggesting Sirt 6 functioned differently in the mice fed with chow diet or HFHS diet. We hypothesize Sirt 6 deficiency causes coronary endothelial dysfunction and contributes to CMD; activating Sirt6 will ameliorate CMD. EDD was assessed using myography (DMT). Myocardial blood flow (MBF) was measured by Doppler. Our preliminary data show that the mediator of coronary vasodilation switched from NO to H 2 O 2 in the Sirt6 knockout mice with impaired EDD. Interestingly, when the mice fed on HFHS were treated with Sirt 6 activator MDL-800, the coronary microvascular function was improved, and the blood glucose level was decreased. The underlying mechanism and the pathways involved will be elucidated.

Epigenetic Mechanisms of the Anti-inflammatory Action of the Opioid Peptide Leutragin: Role of Sirtuin 1

Sirtuin 1 (SIRT1) is a class III histone deacetylase that plays a key role in resolving inflammation through known epigenetic mechanisms involving histone and nuclear factor κB (NF-κB) deacetylation. Deacetylation reduces the transcriptional activity of NF-κB and the associated production of pro-inflammatory cytokines such as interleukin 1β (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). In the present study, we show for the first time that biomodeling of acute lung inflammation by a single injection of lipopolysaccharide (LPS) induces synchronous oscillations of mRNA levels of cytokines IL-1β, TNF-α, IL-6 and SIRT1 deacetylase in the lungs, the maximum amplitudes of cytokine mRNA oscillations are observed between 1.5 and 5 hours, whereas high levels of SIRT1 mRNA are observed up to 24 hours, when cytokine mRNA oscillations have already faded, which is consistent with the hypothesis about the role of SIRT1 as a factor acting in the phase of inflammation resolution. The study shows that the mechanism of anti-inflammatory action of inhaled hexapeptide Leutragin, a δ-opioid receptor agonist, is related to its ability to increase SIRT1 mRNA expression and decrease the amplitudes of IL-1β, TNF-α, and IL-6 mRNA oscillations in the lungs, which generally leads to the resolution of inflammation in the conditions of biomodeling of acute lung inflammation.

Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling.

Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl2, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl2-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.

Understanding the fundamental mechanisms and conditions of the tumor-suppressive and oncogenic roles of sirtuins in cancer: A review

Silent information regulators (SIRTs) or sirtuins represent a group of class III nicotinamide adenine dinucleotide–dependent histone deacetylases. In mammals, seven types of sirtuins are distinguished, differing in their target structures, enzymatic activities, and subcellular localization. Histone deacetylation is a form of epigenetic regulation of gene expression that can cause activation or deactivation of selected genetic targets. Activation of sirtuins is part of the response to nutritional and environmental stimuli (starvation, DNA damage, and oxidative stress). Activated sirtuins subsequently stimulate specific transcriptional programs to make mitochondrial oxidative metabolism more efficient in the fight against oxidative stress or regulate proteins responsible for DNA repair after damage. As a result of their multifunctional involvement in cellular metabolism, dysregulation and aberrant expression of sirtuins have been observed in various cancers. Sirtuins play a dual role in carcinogenesis, acting as either oncogenes or tumor suppressors and affecting the proliferation, apoptosis, and survival of cancerous cells.

Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels

BackgroundCalorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR. MethodsMice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications. ResultsIn the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number. ConclusionThis study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.

Elucidating the Role of Sirtuin 3 in Mammalian Oocyte Aging.

The field of reproductive biology has made significant progress in recent years, identifying specific molecular players that influence oocyte development and function. Among them, sirtuin 3 (SIRT3) has attracted particular attention for its central role in mediating mitochondrial function and cellular stress responses in oocytes. So far, studies have demonstrated that the knockdown of SIRT3 leads to a decrease in blastocyst formation and an increase in oxidative stress within an embryo, underscoring the importance of SIRT3 in maintaining the cellular redox balance critical for embryonic survival and growth. Furthermore, the literature reveals specific signaling pathways, such as the SIRT3- Glycogen synthase kinase-3 beta (GSK3β) deacetylation pathway, crucial for mitigating oxidative stress-related anomalies in oocyte meiosis, particularly under conditions like maternal diabetes. Overall, the emerging role of SIRT3 in regulating oocyte mitochondrial function and development highlights the critical importance of understanding the intricate connections between cellular metabolism, stress response pathways, and overall reproductive health and function. This knowledge could lead to the development of novel strategies to support oocyte quality and fertility, with far-reaching implications for assisted reproductive technologies and women's healthcare. This commentary aims to provide an overview of the importance of SIRT3 in oocytes by synthesizing results from a multitude of studies. The aim is to elucidate the role of SIRT3 in oocyte development, maturation, and aging and to identify areas where further research is needed.

Shikonin mitigates cyclophosphamide-induced cardiotoxicity in mice: the role of sirtuin-1, NLRP3 inflammasome, autophagy, and apoptosis.

The aim of this study was to elucidate the protective potential of shikonin (SHK) on cyclophosphamide (CP)-induced cardiotoxicity in Swiss albino mice. Mice received SHK in three different doses by oral gavage daily for 14 days and CP at 100 mg/kg, intraperitoneally once on the seventh day. On the 15th day, mice were euthanized, blood collected, and hearts were removed to estimate various biochemical and histopathological parameters. CP significantly increased serum lactate dehydrogenase, creatine kinase-MB, troponin I and NT pro-BNP, and cardiac malondialdehyde and decreased cardiac total antioxidant capacity and Nrf2, whereas increased inflammatory markers in the cardiac tissues. CP also caused hypertrophy and fibrosis in the cardiac tissues via activation of IL6/JAK2/STAT3 while depressed SIRT1 and PI3K/p-Akt pathway with consequent increased apoptosis and dysregulation of autophagy. SHK treatment reversed these changes in a dose-dependent manner and showed a significant protective effect against CP-induced cardiotoxicity via suppressing oxidative stress, inflammation, and apoptosis with modulation of autophagy via induction of SIRT1/PI3K/p-Akt signaling. Shikonin may be used as an adjuvant to cyclophosphamide in cancer treatment, but further research is needed to investigate its effects on cardiotoxicity in distinct animal cancer models.

The influential responsibility of sirtuins in senescence and associated diseases: A review.

Aging is a process of time-associated depletion in the physiological functions, essential for the survival and reproducibility of living beings. Some age-related disorders can be successfully controlled with some biomedical techniques or pharmaceutical approaches. There are some precise remedies that demonstrate conspicuous promise in the preclinical and clinical setup of extending lifespan or enhancing health by altering natural senescence. The sirtuin family of proteins is one of the most favorable targets for antiaging strategies. Sirtuins were initially identified as transcription repressors in yeast, but today they are known to exist in bacteria and eukaryotes, as well as humans. The SIRT (1-7) family of proteins in humans is made up of seven members, each of which has either mono-ADP ribosyl transferase or deacetylase activity. Researchers suggest that sirtuins are essential for cell metabolism and play a major role in how cells react to various stimuli, such as oxidative or genotoxic stress. A healthy lifestyle, which includes exercise and a balanced diet, has been demonstrated to impact health span by adjusting the levels of sirtuins, suggesting the involvement of sirtuins in extending human longevity. The hunt for sirtuin activators is among the most extensive and comprehensive research subjects in the present scenario. Some optimism has been generated to investigate antiaging therapies by natural compounds, such as curcumin and others. This review article highlights the role of sirtuins in native senescence and their primordial roles in the progression of several life-threatening diseases. Further, it also provides recent information on the sirtuin activators and inhibitors and their therapeutic benefits.

The effect of weight loss therapies on sirtuin 1 regulation: a systematic review and meta-analysis of randomized controlled trials

BackgroundRecent evidence shows the role of sirtuin 1(SIRT1), a family of evolutionarily conserved proteins, as a potential therapeutic target in the prevention and treatment of obesity and metabolic diseases. Some evidence shows the moderating effects of weight loss interventions on this factor. However, the findings are contradictory. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of weight loss interventions on SIRT 1 modulation.MethodsFor this study, we searched four electronic databases using predefined keywords from inception until March 2024. We includedrandomized controlled trials that evaluated the effect of weight reduction strategies on SIRT1 levels. The random-effects model analysis was used to obtain the pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI). The meta-analysis was conducted using RevMan version 5.3 software and Stata version 12.0.ResultsTwelve studies with 627 volunteers were included. The pooled findings showed that weight loss interventions have no significant effect on the modulation of SIRT1 compared to the control group (pooled WMD of 0.58 ng/mL; 95% confidence interval [CI] -0.17 to 1.33; p = 0.130). However, subgroup analysis showed that weight loss interventions significantly modulate SIRT1 at metabolic disease (WMD: 1.2 ng/mL, 95% CI: 0.11 to 2.62, I2 = 82.9%). In addition, subgroup findings indicated health status and body mass index (BMI) as sources of high and potential heterogeneity.ConclusionsBased on the findings, weight loss therapies in individuals having a metabolic disorder appear to generate a considerable increase in SIRT1 levels.

Emerging role of sirtuins in non‑small cell lung cancer (Review).

Non‑small cell lung cancer (NSCLC) is a highly prevalent lung malignancy characterized by insidious onset, rapid progression and advanced stage at the time of diagnosis, making radical surgery impossible. Sirtuin (SIRT) is a histone deacetylase that relies on NAD+ for its function, regulating the aging process through modifications in protein activity and stability. It is intricately linked to various processes, including glycolipid metabolism, inflammation, lifespan regulation, tumor formation and stress response. An increasing number of studies indicate that SIRTs significantly contribute to the progression of NSCLC by regulating pathophysiological processes such as energy metabolism, autophagy and apoptosis in tumor cells through the deacetylation of histones or non‑histone proteins. The present review elaborates on the roles of different SIRTs and their mechanisms in NSCLC, while also summarizing novel therapeutic agents based on SIRTs. It aims to present new ideas and a theoretical basis for NSCLC treatment.