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Background: It is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus--pituitary--testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity. Methods: A total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ. After 3 months, the rats were anesthetized and sacrificed; one testis was stored at -80°C for biochemical analysis, and the other was fixed for histological and immunofluorescence analysis. Results: The data confirmed that T1D induced oxidative stress and, consequently, alterations in both testicular somatic and germ cells. This aspect was highlighted by enhanced apoptosis, altered steroidogenesis and Leydig cell maturity, and impaired spermatogenesis. In addition, the blood--testis barrier integrity was compromised, as shown by the reduced levels of structural proteins (N-cadherin, ZO-1, occludin, connexin 43, and VANGL2) and the phosphorylation status of regulative kinases (Src and FAK). Mechanistically, the dysregulation of the SIRT1/NRF2/MAPKs signaling pathways was proven, particularly the reduced nuclear translocation of NRF2, affecting its ability to induce the transcription of genes encoding for antioxidant enzymes. Finally, the stimulation of testicular inflammation and pyroptosis was also confirmed, as highlighted by the increased levels of some markers, such as NF-kB and NLRP3. Conclusion: The combined data allowed us to confirm that T1D has detrimental effects on rat testicular activity. Moreover, a better comprehension of the molecular mechanisms underlying the association between metabolic disorders and male fertility could help to identify novel targets to prevent and treat fertility disorders related to T1D. [ABSTRACT FROM AUTHOR]

This document is an editorial published in the journal Frontiers in Endocrinology, discussing the role of autophagy in endocrine-metabolic diseases associated with aging. It explores the complex relationship between autophagy and diseases such as type 2 diabetes, thyroid dysfunctions, non-alcoholic fatty liver disease, endocrine cancer, and age-related degenerative diseases. The editorial also discusses the potential therapeutic implications of targeting autophagy in these conditions. Additionally, the document provides a list of references for two articles related to the role of sirtuins in osteoporosis and myocardial ischemia-reperfusion, offering valuable insights into mitochondrial quality control and autophagy regulation. [Extracted from the article]

BackgroundIt is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus–pituitary–testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity.MethodsA total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ. After 3 months, the rats were anesthetized and sacrificed; one testis was stored at -80°C for biochemical analysis, and the other was fixed for histological and immunofluorescence analysis.ResultsThe data confirmed that T1D induced oxidative stress and, consequently, alterations in both testicular somatic and germ cells. This aspect was highlighted by enhanced apoptosis, altered steroidogenesis and Leydig cell maturity, and impaired spermatogenesis. In addition, the blood–testis barrier integrity was compromised, as shown by the reduced levels of structural proteins (N-cadherin, ZO-1, occludin, connexin 43, and VANGL2) and the phosphorylation status of regulative kinases (Src and FAK). Mechanistically, the dysregulation of the SIRT1/NRF2/MAPKs signaling pathways was proven, particularly the reduced nuclear translocation of NRF2, affecting its ability to induce the transcription of genes encoding for antioxidant enzymes. Finally, the stimulation of testicular inflammation and pyroptosis was also confirmed, as highlighted by the increased levels of some markers, such as NF-κB and NLRP3.ConclusionThe combined data allowed us to confirm that T1D has detrimental effects on rat testicular activity. Moreover, a better comprehension of the molecular mechanisms underlying the association between metabolic disorders and male fertility could help to identify novel targets to prevent and treat fertility disorders related to T1D.

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

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

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

Autophagy is a cellular process involved in the selective degradation and recycling of dysfunctional intracellular components. It plays a crucial role in maintaining cellular homeostasis and survival by removing damaged and harmful proteins, lipids, and organelles. SIRT1, an NAD+-dependent multifunctional enzyme, is a key regulator of the autophagy process. Through its deacetylase activity, SIRT1 participates in the regulation of different steps of autophagy, from initiation to degradation. The levels and function of SIRT1 are also regulated by the autophagy process. Dysregulation in SIRT1-mediated autophagy hinders the proper functioning of the endocrine system, contributing to the onset and progression of endocrine disorders. This review provides an overview of the crosstalk between SIRT1 and autophagy and their implications in obesity, type-2 diabetes mellitus, diabetic cardiomyopathy, and hepatic steatosis. [ABSTRACT FROM AUTHOR]

The incidence and prevalence of chronic kidney disease (CKD) continue to increase worldwide remaining as a major public health burden. CKD eventually progresses to end-stage kidney failure and patients with CKD have high morbidity and mortality. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylases, has significant renal protective effects through its regulation of fibrosis, apoptosis, and senescence, oxidative stress, inflammation and aging process. The renal protective effects of Sirt1 have been described in many kidney diseases such as diabetic kidney disease and HIV-related kidney disease. SIRT1 also has protective effects against vascular calcification and therefore could be developed as a therapy for both CKD and CKD complications. In this narrative review, we will give an overview of the recent progress on the role of SIRT1 and its downstream pathways in CKD. We will also discuss potential therapeutic approach by activating SIRT1-related pathway in patients with CKD. The purpose is to hope to provide some insights on the future direction of the research in the field of SIRT1 for CKD. [ABSTRACT FROM AUTHOR]

The incidence and prevalence of chronic kidney disease (CKD) continue to increase worldwide remaining as a major public health burden. CKD eventually progresses to end-stage kidney failure and patients with CKD have high morbidity and mortality. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylases, has significant renal protective effects through its regulation of fibrosis, apoptosis, and senescence, oxidative stress, inflammation and aging process. The renal protective effects of Sirt1 have been described in many kidney diseases such as diabetic kidney disease and HIV-related kidney disease. SIRT1 also has protective effects against vascular calcification and therefore could be developed as a therapy for both CKD and CKD complications. In this narrative review, we will give an overview of the recent progress on the role of SIRT1 and its downstream pathways in CKD. We will also discuss potential therapeutic approach by activating SIRT1-related pathway in patients with CKD. The purpose is to hope to provide some insights on the future direction of the research in the field of SIRT1 for CKD.

BackgroundDiabetic nephropathy (DN) represents a major complication of diabetes, and podocyte injury has a critical function in DN development. TangShenWeiNing formula (TSWN) has been demonstrated to efficiently decrease proteinuria and protect podocytes in DN. This work aimed to explore the mechanism by which TSWN alleviates DN and protects podocytes.MethodsThe major bioactive components of TSWN were detected by mass spectrometry (MS) and pharmacological databases. Eight-week-old male C57BLKS/J db/m and db/db mice were provided pure water, valsartan, low dose TSWN, middle dose TSWN and high dose TSWN by gavage for 12 weeks, respectively.ResultsMS and network pharmacology analyses suggested that TSWN might prevent DN through the sirtuin (SIRT)1/hypoxia-inducible factor (HIF)-1α pathway. Diabetic mice showed elevated urinary albumin in comparison with non-diabetic mice, and TSWN decreased urinary albumin in diabetic mice. Histological injury increased in the kidney in diabetic mice, which could be improved by TSWN. Fibrosis and collagen I expression were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney; TSWN alleviated these effects. Apoptosis and cleaved caspase-3 were induced in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and TSWN blunted these effects. Podocytes were damaged in the diabetic mouse kidney, which was improved by TSWN. Podocin and nephrin amounts were decreased in the diabetic mouse kidney in comparison with the non-diabetic mouse kidney, and podocalyxin was increased in urine of diabetic animals in comparison with non-diabetic counterparts. After TSWN treatment, podocin and nephrin were raised in the diabetic mouse kidney, and urinary podocalyxin was depressed in diabetic animals. Diabetic mice had lower SIRT1 and higher HIF-1α amounts in kidney specimens in comparison with non-diabetic mice, and TSWN promoted SIRT1 and inhibited HIF-1α in the diabetic mouse kidney. Moreover, co-staining of SIRT1 and podocin revealed that SIRT1 decreased in podocytes from diabetic mice in comparison with those from non-diabetic mice, and TSWN elevated SIRT1 in podocytes.ConclusionsThis study indicated that TSWN alleviates DN by improving podocyte injury through the SIRT1/HIF-1α pathway in diabetic mouse kidneys.

The major reason of human morbidity and mortality is obesity and related diseases. Brown adipose tissue (BAT) is associated with low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Studies have shown that exercise and cold expose may induce browning. In this study, we verified (1) whether exercise and/or cold exposure can improve the expression level of ucp4c, serca, ampkα, camkII, sirt1, octβ3r , and hamlet ; (2) if these interventions can save cardiac dysfunction induced by a high-fat diet (HFD) in Drosophila. w1118 (wild-type) virgin female flies collected within 8 h after eclosion were divided into eight groups: the normal feed control group (NFD-C), the normal feed exercise group (NFD-E), the normal feed cold exposure group (NFD-CA), the normal feed exercise/cold exposure group (NFD-EC), the HFD control group (HFD-C), the HFD exercise group (HFD-E), the HFD cold exposure group (HFD-CA), and the HFD exercise/cold exposure group (HFD-EC). After exercise and/or cold exposure for 7 days, the mRNA expression levels of ucp4c, serca, ampkα, camk II, sirt1, octβ3r , and hamlet were tested by qRT-PCR, and m-mode was used to assess cardiac function. In addition, we assessed the triacylglycerol (TAG) levels, motor ability, fat mass (by Oil Red O [ORO] staining), and morphological features. The results of TAG, ORO staining, and morphological features all indicate that after interventions, body size of Drosophila was smaller compared with the control group, irrespective of the feeding patterns. The mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1 were changed to varying degrees under different intervention states (exercise and/or cold exposure). Cold exposure and exercise/cold exposure partly improved cardiac function and the normal fruit flies' cardiac function and exercise ability. However, after exercise intervention, exercise ability and heart function were improved in both HFD and normal-fat diet (NFD) fruit flies. In conclusion, different intervention states (exercise and/or cold exposure) can change the mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1. Exercise is the most effective way to restore HFD-induced cardiac dysfunction. [ABSTRACT FROM AUTHOR]

The major reason of human morbidity and mortality is obesity and related diseases. Brown adipose tissue (BAT) is associated with low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Studies have shown that exercise and cold expose may induce browning. In this study, we verified (1) whether exercise and/or cold exposure can improve the expression level of ucp4c, serca, ampkα, camkII, sirt1, octβ3r, and hamlet; (2) if these interventions can save cardiac dysfunction induced by a high-fat diet (HFD) in Drosophila. w1118 (wild-type) virgin female flies collected within 8 h after eclosion were divided into eight groups: the normal feed control group (NFD-C), the normal feed exercise group (NFD-E), the normal feed cold exposure group (NFD-CA), the normal feed exercise/cold exposure group (NFD-EC), the HFD control group (HFD-C), the HFD exercise group (HFD-E), the HFD cold exposure group (HFD-CA), and the HFD exercise/cold exposure group (HFD-EC). After exercise and/or cold exposure for 7 days, the mRNA expression levels of ucp4c, serca, ampkα, camk II, sirt1, octβ3r, and hamlet were tested by qRT-PCR, and m-mode was used to assess cardiac function. In addition, we assessed the triacylglycerol (TAG) levels, motor ability, fat mass (by Oil Red O [ORO] staining), and morphological features. The results of TAG, ORO staining, and morphological features all indicate that after interventions, body size of Drosophila was smaller compared with the control group, irrespective of the feeding patterns. The mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1 were changed to varying degrees under different intervention states (exercise and/or cold exposure). Cold exposure and exercise/cold exposure partly improved cardiac function and the normal fruit flies’ cardiac function and exercise ability. However, after exercise intervention, exercise ability and heart function were improved in both HFD and normal-fat diet (NFD) fruit flies. In conclusion, different intervention states (exercise and/or cold exposure) can change the mRNA expression levels of ucp4c, serca, octβ3r, hamlet, ampkα, camkII, and sirt1. Exercise is the most effective way to restore HFD-induced cardiac dysfunction.

Introduction: Using transgenic collagen type II-specific Sirt1 knockout (CKO) mice we studied the role of Sirt1 in nutritional induced catch up growth (CUG) and we found that these mice have a less organized growth plate and reduced efficiency of CUG. In addition, we noted that they weigh more than control (CTL) mice. Studying the reason for the increased weigh, we found differences in activity and brain function. Methods: Several tests for behavior and activity were used: open field; elevated plus maze, Morris water maze, and home cage running wheels. The level of Glu- osteocalcin, known to connect bone and brain function, was measured by Elisa; brain Sirt1 was analyzed by western blot. Results: We found that CKO mice had increased anxiety, with less spatial memory, learning capabilities and reduced activity in their home cages. No significant differences were found between CKO and CTL mice in Glu- osteocalcin levels; nor in the level of brain SIRT1. Discussion/Conclusion: Using transgenic collagen type II-specific Sirt1 knockout (CKO) mice we found a close connection between linear growth and brain function. Using a collagen type II derived system we affected a central regulatory mechanism leading to hypo activity, increased anxiety, and slower learning, without affecting circadian period. As children with idiopathic short stature are more likely to have lower IQ, with substantial deficits in working memory than healthy controls, the results of the current study suggest that SIRT1 may be the underlying factor connecting growth and brain function. [ABSTRACT FROM AUTHOR]

IntroductionUsing transgenic collagen type II-specific Sirt1 knockout (CKO) mice we studied the role of Sirt1 in nutritional induced catch up growth (CUG) and we found that these mice have a less organized growth plate and reduced efficiency of CUG. In addition, we noted that they weigh more than control (CTL) mice. Studying the reason for the increased weigh, we found differences in activity and brain function.MethodsSeveral tests for behavior and activity were used: open field; elevated plus maze, Morris water maze, and home cage running wheels. The level of Glu- osteocalcin, known to connect bone and brain function, was measured by Elisa; brain Sirt1 was analyzed by western blot.ResultsWe found that CKO mice had increased anxiety, with less spatial memory, learning capabilities and reduced activity in their home cages. No significant differences were found between CKO and CTL mice in Glu- osteocalcin levels; nor in the level of brain SIRT1.Discussion/ConclusionUsing transgenic collagen type II-specific Sirt1 knockout (CKO) mice we found a close connection between linear growth and brain function. Using a collagen type II derived system we affected a central regulatory mechanism leading to hypo activity, increased anxiety, and slower learning, without affecting circadian period. As children with idiopathic short stature are more likely to have lower IQ, with substantial deficits in working memory than healthy controls, the results of the current study suggest that SIRT1 may be the underlying factor connecting growth and brain function.

Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis.

Saturated free fatty acid (FFA)-induced lipotoxicity plays an important role in obesity-induced kidney injury. Exenatide, a Glucagon-like peptide-1 receptor agonist(GLP-1RA), protects against high-fat diet (HFD)-induced kidney injury. The precise mechanism needs to be further explored. This study investigated whether exenatide protects against FFA-induced tubular epithelial cells (TECs) lipotoxicity and elucidated its underlying mechanisms. Here, we show that exenatide treatment reversed HFD induced TECs injuries, including TECs apoptosis and SIRT1 downregulation. The efficacy of exenatide was better than simvastatin. In palmitate (PA)-stimulated HK2 cells, exenatide treatment reversed the downregulation of SIRT1 and prevented an increase in reactive oxygen species (ROS) production, a decrease in mitochondrial membrane potential, and mitochondrial apoptosis. The renal-protective effects of exenatide on the generation of mitochondrial ROS and mitochondrial apoptosis were blocked by inhibiting SIRT1 activation. Collectively, these findings show that exenatide was superior to simvastatin in the treatment of obesity-TECs injuries, the mechanism is partially through SIRT1 restoration, which directly reverses mitochondrial dysfunction and apoptosis. [ABSTRACT FROM AUTHOR]

Sepsis is a common risk factor for acute kidney injury (AKI). Bone marrow-derived mesenchymal stem cells (BMSCs) bear multi-directional differentiation potential. This study explored the role of BMSCs in sepsis-induced AKI (SI-AKI). A rat model of SI-AKI was established through cecal ligation and perforation. The SI-AKI rats were injected with CM-DiL-labeled BMSCs, followed by evaluation of pathological injury of kidney tissues and kidney injury-related indicators and inflammatory factors. HK-2 cells were treated with lipopolysaccharide (LPS) to establish SI-SKI model in vitro. Levels of mitochondrial proteins, autophagy-related proteins, NLRP3 inflammasome-related protein, and expressions of Parkin and SIRT1 in renal tubular epithelial cells (RTECs) of kidney tissues and HK-2 cells were detected. The results showed that BMSCs could reach rat kidney tissues and alleviate pathological injury of SI-SKI rats. BMSCs inhibited inflammation and promoted mitophagy of RTECs and HK-2 cells in rats with SI-AKI. BMSCs upregulated expressions of Parkin and SIRT1 in HK-2 cells. Parkin silencing or SIRT1 inhibitor reversed the promoting effect of BMSCs on mitophagy. BMSCs inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin. In conclusion, BMSCs promoted mitophagy and inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin, thereby ameliorating SI-AKI.

Sepsis is a common risk factor for acute kidney injury (AKI). Bone marrow-derived mesenchymal stem cells (BMSCs) bear multi-directional differentiation potential. This study explored the role of BMSCs in sepsis-induced AKI (SI-AKI). A rat model of SI-AKI was established through cecal ligation and perforation. The SI-AKI rats were injected with CM-DiL-labeled BMSCs, followed by evaluation of pathological injury of kidney tissues and kidney injury-related indicators and inflammatory factors. HK-2 cells were treated with lipopolysaccharide (LPS) to establish SI-SKI model in vitro. Levels of mitochondrial proteins, autophagy-related proteins, NLRP3 inflammasome-related protein, and expressions of Parkin and SIRT1 in renal tubular epithelial cells (RTECs) of kidney tissues and HK-2 cells were detected. The results showed that BMSCs could reach rat kidney tissues and alleviate pathological injury of SI-SKI rats. BMSCs inhibited inflammation and promoted mitophagy of RTECs and HK-2 cells in rats with SI-AKI. BMSCs upregulated expressions of Parkin and SIRT1 in HK-2 cells. Parkin silencing or SIRT1 inhibitor reversed the promoting effect of BMSCs on mitophagy. BMSCs inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin. In conclusion, BMSCs promoted mitophagy and inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin, thereby ameliorating SI-AKI. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.

Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy. [ABSTRACT FROM AUTHOR]

Background: It is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus-pituitary-testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity., Methods: A total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ. After 3 months, the rats were anesthetized and sacrificed; one testis was stored at -80°C for biochemical analysis, and the other was fixed for histological and immunofluorescence analysis., Results: The data confirmed that T1D induced oxidative stress and, consequently, alterations in both testicular somatic and germ cells. This aspect was highlighted by enhanced apoptosis, altered steroidogenesis and Leydig cell maturity, and impaired spermatogenesis. In addition, the blood-testis barrier integrity was compromised, as shown by the reduced levels of structural proteins (N-cadherin, ZO-1, occludin, connexin 43, and VANGL2) and the phosphorylation status of regulative kinases (Src and FAK). Mechanistically, the dysregulation of the SIRT1/NRF2/MAPKs signaling pathways was proven, particularly the reduced nuclear translocation of NRF2, affecting its ability to induce the transcription of genes encoding for antioxidant enzymes. Finally, the stimulation of testicular inflammation and pyroptosis was also confirmed, as highlighted by the increased levels of some markers, such as NF-κB and NLRP3., Conclusion: The combined data allowed us to confirm that T1D has detrimental effects on rat testicular activity. Moreover, a better comprehension of the molecular mechanisms underlying the association between metabolic disorders and male fertility could help to identify novel targets to prevent and treat fertility disorders related to T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Venditti, Romano, Boccella, Haddadi, Biasi, Maione and Minucci.)

Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications.

The objective of this study was to investigate the protective effects of Lycium barbarum polysaccharides (LBP) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic rats. Compared to the control group, blood glucose levels were significantly increased and the insulin resistance was markedly aggravated in STZ-induced diabetic rats. Further, the weight of testis and epididymis and the sperm number and motility were decreased in diabetic rats. Pathological changes were also observed in the spermatogenic tubules, along with a decreased number of spermatogenic cells, downregulated proliferating cell nuclear antigen (PCNA) expression, and increased cell apoptosis in the testes. Compared to the saline-treated diabetic rat group, metformin and LBP treatment significantly decreased the level of blood glucose and improved insulin resistance and testicular function. After treatment with metformin and LBP, the pathological changes in the spermatogenic tubules improved significantly, with an increase in the number of spermatogenic cells, upregulation of PCNA, and suppression of apoptosis in the testes. The expressions of sirtuin 1 (SIRT1) and hypoxia-inducible factor 1-alpha (HIF-1α) in diabetic testes were also upregulated by metformin or LBP treatment. In summary, LBP exerted protective effects by increasing cell proliferation, inhibiting cell apoptosis, and regulating SIRT1/HIF-1α expression in the testes of diabetic rats.

Diabetic mellitus (DM) is a significant public health concern worldwide with an increased incidence of morbidity and mortality, which is particularly due to the diabetic vascular complications. Several pivotal underlying mechanisms are associated with vascular complications, including hyperglycemia, mitochondrial dysfunction, inflammation, and most importantly, oxidative stress. Oxidative stress triggers defective angiogenesis, activates pro-inflammatory pathways and causes long-lasting epigenetic changes to facilitate the development of vascular complications. Therefore, therapeutic interventions targeting oxidative stress are promising to manage diabetic vascular complications. Sirtuin1 (SIRT1), a class III histone deacetylase belonging to the sirtuin family, plays critical roles in regulating metabolism and ageing-related pathological conditions, such as vascular diseases. Growing evidence has indicated that SIRT1 acts as a sensing regulator in response to oxidative stress and attenuates vascular dysfunction via cooperating with adenosine-monophosphate-activated protein kinase (AMPK) to activate antioxidant signals through various downstream effectors, including peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1α), forkhead transcription factors (FOXOs), and peroxisome proliferative-activated receptor α (PPARα). In addition, SIRT1 interacts with hydrogen sulfide (H2S), regulates NADPH oxidase, endothelial NO synthase, and mechanistic target of rapamycin (mTOR) to suppress oxidative stress. Furthermore, mRNA expression of sirt1 is affected by microRNAs in DM. In the current review, we summarize recent advances illustrating the importance of SIRT1 in antagonizing oxidative stress. We also discuss whether modulation of SIRT1 can serve as a therapeutic strategy to treat diabetic vascular complications. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the protective effects of Lycium barbarum polysaccharides (LBP) on testicular spermatogenic function in streptozotocin (STZ)-induced diabetic rats. Compared to the control group, blood glucose levels were significantly increased and the insulin resistance was markedly aggravated in STZ-induced diabetic rats. Further, the weight of testis and epididymis and the sperm number and motility were decreased in diabetic rats. Pathological changes were also observed in the spermatogenic tubules, along with a decreased number of spermatogenic cells, downregulated proliferating cell nuclear antigen (PCNA) expression, and increased cell apoptosis in the testes. Compared to the saline-treated diabetic rat group, metformin and LBP treatment significantly decreased the level of blood glucose and improved insulin resistance and testicular function. After treatment with metformin and LBP, the pathological changes in the spermatogenic tubules improved significantly, with an increase in the number of spermatogenic cells, upregulation of PCNA, and suppression of apoptosis in the testes. The expressions of sirtuin 1 (SIRT1) and hypoxia-inducible factor 1-alpha (HIF-1α) in diabetic testes were also upregulated by metformin or LBP treatment. In summary, LBP exerted protective effects by increasing cell proliferation, inhibiting cell apoptosis, and regulating SIRT1/HIF-1α expression in the testes of diabetic rats. [ABSTRACT FROM AUTHOR]

Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial.Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers.Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293–1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250–2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602–4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762–4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114–1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010–1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022–2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China.Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis.

Aging is a substantial risk factor for the development of osteoarthritis (OA) and, probably, an essential substrate for the development of neoplastic disease of the bone, such as osteosarcoma, which is the most common malignant mesenchymal primary bone tumor. Genetic studies have established that the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) signal transduction pathway is involved across species, including nematodes, fruit flies, and mammals. SIRT1, a phylogenetically-conserved family of deacetylases, seems to play pleiotropic effects in epithelial malignancies of the liver and interact with the IGF-1/PI3K/AKT signal transduction pathway. Some of the most critical processes in degenerative conditions may indeed include the insulin/IGF1R and SIRT1 signaling pathways as well as some specific transcription factors. The Forkhead box O (FOXO) transcription factors (FOXOs) control diverse cellular functions, such as metabolism, longevity, and cell death. FOXOs play a critical role in the IGF-1/PI3K/AKT signal transduction pathway. FOXOs can indeed be modulated to reduce age-related diseases. FOXOs have advantageous inhibitory effects on fibroblast and myofibroblast activation, which are accompanied by a subsequent excessive production of extracellular matrix. FOXOs can block or decrease the fibrosis levels in numerous organs. Previously, we observed a correlation between nuclear FOXO3 and high caspase-8 expression, which induces cellular apoptosis in response to harmful external stimuli. In this perspective, we emphasize the current advances and interactions involving the insulin/IGF1R, SIRT1, and FOXOs pathways in the bone and osteosarcoma for a better understanding of the mechanisms potentially underpinning tissue degeneration and tumorigenesis.

The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health concern, and novel therapeutic strategies to prevent T2DM are urgently needed worldwide. Aging is recognized as one of the risk factors for metabolic impairments, including insulin resistance and T2DM. Inflammation, oxidative stress, and mitochondrial dysfunction are closely related to both aging and metabolic disease. Calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related disorders, such as insulin resistance and diabetes. Therefore, metabolic CR mimetics may represent new therapeutic targets for insulin resistance and T2DM. Sirtuin 1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The activation of SIRT1 is closely associated with longevity under CR, and it is recognized as a CR mimetic. Currently, seven sirtuins have been identified in mammals. Among these sirtuins, SIRT1 and SIRT2 are located in the nucleus and cytoplasm, SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. These sirtuins regulate metabolism through their regulation of inflammation, oxidative stress and mitochondrial function via multiple mechanisms, resulting in the improvement of insulin resistance and T2DM. In this review, we describe the current understanding of the biological functions of sirtuins, especially SIRT1, SIRT2, SIRT3, and SIRT6, focusing on oxidative stress, inflammation, and mitochondrial function, which are closely associated with aging.

The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health concern, and novel therapeutic strategies to prevent T2DM are urgently needed worldwide. Aging is recognized as one of the risk factors for metabolic impairments, including insulin resistance and T2DM. Inflammation, oxidative stress, and mitochondrial dysfunction are closely related to both aging and metabolic disease. Calorie restriction (CR) can retard the aging process in organisms ranging from yeast to rodents and delay the onset of numerous age-related disorders, such as insulin resistance and diabetes. Therefore, metabolic CR mimetics may represent new therapeutic targets for insulin resistance and T2DM. Sirtuin 1 (SIRT1), the mammalian homolog of Sir2, was originally identified as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The activation of SIRT1 is closely associated with longevity under CR, and it is recognized as a CR mimetic. Currently, seven sirtuins have been identified in mammals. Among these sirtuins, SIRT1 and SIRT2 are located in the nucleus and cytoplasm, SIRT3 exists predominantly in mitochondria, and SIRT6 is located in the nucleus. These sirtuins regulate metabolism through their regulation of inflammation, oxidative stress and mitochondrial function via multiple mechanisms, resulting in the improvement of insulin resistance and T2DM. In this review, we describe the current understanding of the biological functions of sirtuins, especially SIRT1, SIRT2, SIRT3, and SIRT6, focusing on oxidative stress, inflammation, and mitochondrial function, which are closely associated with aging. [ABSTRACT FROM AUTHOR]

Background: Silent information regulator 2 homolog 1 (SIRT1) is an evolutionarily conserved enzymes with nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase activity. SIRT1 is involved in a large variety of cellular processes, such as genomic stability, energy metabolism, senescence, gene transcription, and oxidative stress. SIRT1 has long been recognized as both a tumor promoter and tumor suppressor. Its prognostic role in cancers remains controversial. Methods: A meta-analysis of 13,138 subjects in 63 articles from PubMed, EMBASE, and Cochrane Library was performed to evaluate survival and clinicopathological significance of SIRT1 expression in various cancers. Results: The pooled results of meta-analysis showed that elevated expression of SIRT1 implies a poor overall survival (OS) of cancer patients [Hazard Ratio (HR) = 1.566, 95% CI: 1.293–1.895, P < 0.0001], disease free survival (DFS) (HR = 1.631, 95% CI: 1.250–2.130, P = 0.0003), event free survival (EFS) (HR = 2.534, 95% CI: 1.602–4.009, P = 0.0001), and progress-free survival (PFS) (HR = 3.325 95% CI: 2.762–4.003, P < 0.0001). Elevated SIRT1 level was associated with tumor stage [Relative Risk (RR) = 1.299, 95% CI: 1.114–1.514, P = 0.0008], lymph node metastasis (RR = 1.172, 95% CI: 1.010–1.360, P = 0.0363), and distant metastasis (RR = 1.562, 95% CI: 1.022–2.387, P = 0.0392). Meta-regression and subgroup analysis revealed that ethnic background has influence on the role of SIRT1 expression in predicting survival and clinicopathological characteristics of cancers. Overexpression of SIRT1 predicted a worse OS and higher TNM stage and lymphatic metastasis in Asian population especially in China. Conclusion: Our data suggested that elevated expression of SIRT1 predicted a poor OS, DFS, EFS, PFS, but not for recurrence-free survival (RFS) and cancer-specific survival (CCS). SIRT1 overexpression was associated with higher tumor stage, lymph node metastasis, and distant metastasis. SIRT1-mediated molecular events and biological processes could be an underlying mechanism for metastasis and SIRT1 is a therapeutic target for inhibiting metastasis, leading to good prognosis. [ABSTRACT FROM AUTHOR]

Aging is a substantial risk factor for the development of osteoarthritis (OA) and, probably, an essential substrate for the development of neoplastic disease of the bone, such as osteosarcoma, which is the most common malignant mesenchymal primary bone tumor. Genetic studies have established that the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) signal transduction pathway is involved across species, including nematodes, fruit flies, and mammals. SIRT1, a phylogenetically-conserved family of deacetylases, seems to play pleiotropic effects in epithelial malignancies of the liver and interact with the IGF-1/PI3K/AKT signal transduction pathway. Some of the most critical processes in degenerative conditions may indeed include the insulin/IGF1R and SIRT1 signaling pathways as well as some specific transcription factors. The Forkhead box O (FOXO) transcription factors (FOXOs) control diverse cellular functions, such as metabolism, longevity, and cell death. FOXOs play a critical role in the IGF-1/PI3K/AKT signal transduction pathway. FOXOs can indeed be modulated to reduce age-related diseases. FOXOs have advantageous inhibitory effects on fibroblast and myofibroblast activation, which are accompanied by a subsequent excessive production of extracellular matrix. FOXOs can block or decrease the fibrosis levels in numerous organs. Previously, we observed a correlation between nuclear FOXO3 and high caspase-8 expression, which induces cellular apoptosis in response to harmful external stimuli. In this perspective, we emphasize the current advances and interactions involving the insulin/IGF1R, SIRT1, and FOXOs pathways in the bone and osteosarcoma for a better understanding of the mechanisms potentially underpinning tissue degeneration and tumorigenesis. [ABSTRACT FROM AUTHOR]

17β-Estradiol (E2) is the major estrogen secreted by the premenopausal ovary and shows dual effects on cell apoptosis under pathological conditions. E2 was previously shown to increase CD38 mRNA and protein expression in myometrial smooth muscle, but its function and mechanism remain largely unknown. Here we investigated the role of E2 in hypoxia-induced apoptosis in mouse airway smooth muscle cells (ASMCs) and explored the underlying mechanisms. Results showed that E2 significantly increased CD38 expression at both mRNA and protein levels, accompanied with decreased SIRT1 levels in ASMCs. By using primary ASMCs from the wild type (WT) and the smooth muscle-specific CD38 knockout (CD38 KO) mice, we found that the down-regulation of SIRT1 induced by E2 was abolished in CD38 KO AMSCs. E2 promoted the acetylation of p53 in WT cells, and this effect was also diminished in the absence of CD38. In addition, E2 further activated CD38/SIRT1/p53 signal pathway and promoted cell apoptosis during hypoxia. However, these effects were reversed in CD38 KO ASMCs and by the specific SIRT1 activator Resveratrol. We also found that E2 enhanced CD38 expression through estrogen receptor. The data suggested that CD38 is a direct target for E2 which promotes hypoxia-induced AMSC apoptosis through SIRT1/p53 signal pathway.

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a “C-pocket”-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.

Sirtuins are evolutionarily conserved proteins that use nicotinamide adenine dinucleotide (NAD+) as a co-substrate in their enzymatic reactions. There are seven proteins (SIRT1-7) in the human sirtuin family, among which SIRT1 is the most conserved and characterized. SIRT1 in the brain, in particular, within the hypothalamus, plays crucial roles in regulating systemic energy homeostasis and circadian rhythm. Apart from this, SIRT1 has also been found to mediate beneficial effects in neurological diseases. In this review, we will first summarize how SIRT1 in the brain relates to obesity, type 2 diabetes, and circadian synchronization, and then we discuss the neuroprotective roles of brain SIRT1 in the context of cerebral ischemia and neurodegenerative disorders.

Multiple studies have demonstrated a critical role of Sirtuin-1 (SIRT1) deacetylase in protecting kidney cells from cellular stresses. A protective role of SIRT1 has been reported in both podocytes and renal tubular cells in multiple kidney disease settings, including diabetic kidney disease (DKD). We and others have shown that SIRT1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as p53, FOXO, RelA/p65NF-κB, STAT3, and PGC1α/PPARγ. Recently we showed that the podocyte-specific overexpression of SIRT1 attenuated proteinuria and kidney injury in an experimental model of DKD, further confirming SIRT1 as a potential target to treat kidney disease. Known agonists of SIRT1 such as resveratrol diminished diabetic kidney injury in several animal models. Similarly, we also showed that puerarin, a Chinese herbal medicine compound, activates SIRT1 to provide renoprotection in mouse models of DKD. However, as these are non-specific SIRT1 agonists, we recently developed a more specific and potent SIRT1 agonist (BF175) that significantly attenuated diabetic kidney injury in type 1 diabetic OVE26 mice. We also previously reported that MS417, a bromodomain inhibitor that disrupts the interaction between the acetyl-residues of NF-κB and bromodomain-containing protein 4 (BRD4) also attenuates DKD. These results suggest that SIRT1 agonists and bromodomain inhibitors could be potential new therapuetic treatments against DKD progression.

The endocrine system plays an essential role in the physiological adaptation to malnutrition. The adaptive response of various hormones directs the energy utilization toward the survival functions and away from growth and reproduction. Particularly, the hypothalamic pituitary axis plays an integral and a central role in the regulation of endocrine organs. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that is activated in response to calorie restriction (CR). SIRT1 is involved in cellular processes via the deacetylation of histone as well as various transcription factors and signal transduction molecules and thereby modulates the endocrine/metabolic functions. There is much evidence to demonstrate clearly that SIRT1 in the hypothalamus, pituitary gland, and other target organs modifies the synthesis, secretion, and activities of hormones and in turn induces the adaptive responses. In this review, we discussed the role of SIRT1 in the hypothalamic pituitary axis and its pathophysiological significance.

Breast cancer remains a significant female mortality cause. It constitutes a multifactorial disease for which research on environmental factors offers little help in predicting onset or progression. The pursuit for its foundations by analyzing hormonal changes as a motive for disease development, indicates that increased exposure to estrogens associates with increased risk. A prevalent number of breast cancer cases show dependence on the increased activity of the classic nuclear estrogen receptor (ER) for cell proliferation and survival. SIRT1 is a Type III histone deacetylase which is receiving increasing attention due to its ability to perform activities over relevant non-histone proteins and transcription factors. Interestingly, concomitant SIRT1 overexpression is commonly found in ER-positive breast cancer cases. Both proteins had been shown to directly interact, in a process related to altered intracellular signaling and aberrant transcription, then promoting tumor progression. Moreover, SIRT1 activities had been also linked to estrogenic effects through interaction with the G-protein coupled membrane bound estrogen receptor (GPER). This work aims to summarize present knowledge on the interplay between SIRT1 and ER/GPER for breast cancer onset and progression. Lastly, evidences on the ability of SIRT1 to interact with TGFß signaling, a concurrent pathway significantly involved in breast cancer progression, are reported. The potential of this research field for the development of innovative strategies in the assessment of orphan breast cancer subtypes, such as triple negative breast cancer (TNBC), is discussed.

Mammalian silent information regulator 1 (SIRT1) is reported to play a role in cancers of the secretory organs, including thyroid, pancreatic endocrine, and ovarian tumors [1, 2, 3, 4]. A recent meta-analysis conducted on 37 selected studies of human cancers analyzed the correlations of overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) with SIRT1 expression [5]. This study reported that SIRT1 overexpression was associated with a worse OS in liver and lung cancers, while it was not correlated with OS in breast cancer, colorectal cancer, or gastric carcinoma. Collectively, the meta-analysis revealed that an unfavorable OS was associated with SIRT1 expression for solid malignancies. Given the growing importance of this class of lysine/histone deacetylases in human endocrine malignancies, a rational and focused literature assessment is desirable in light of future clinical translations.

Serine has recently been shown to reduce oxidative stress and inflammation, which, when occurring in the hypothalamus, contribute to age-related obesity. To explore whether long-term serine administration reduces oxidative stress and body weight in aging mice, various concentrations of l-serine dissolved in water were administered to 18-month-old C57BL/6J mice for 6 months. The results showed that the administration of 0.5% (w/v) l-serine significantly reduced food intake and body weight gain during the experiment. Moreover, the administration of 0.5% l-serine decreased the concentrations of leptin, malondialdehyde, interleukin-1β, and interleukin-6, while it increased those of superoxide dismutase and glutathione, in both the serum and hypothalamus. Reactive oxygen species and the activity of nicotinamide adenine dinucleotide phosphate oxidase were reduced in the hypothalamus of aging mice treated with l-serine as compared with untreated control mice. Additionally, the expression of the leptin receptor increased while the levels of neuropeptide Y and agouti-related protein decreased in mice that had been treated with 0.5% l-serine. The expression of Sirt1 and phosphorylated signal transducers and activators of transcription 3 (pSTAT3) increased, while that of phosphorylated NFκB decreased in the mice treated with 0.5% l-serine. These results indicated that long-term l-serine administration reduces body weight by decreasing orexigenic peptide expression and reduces oxidative stress and inflammation during aging in mice, possibly by modulating the Sirt1/NFκB pathway. Thus, l-serine has the potential to be used in the prevention of age-related obesity.

Sirtuins are evolutionarily conserved proteins that use nicotinamide adenine dinucleotide (NAD+) as a co-substrate in their enzymatic reactions. There are seven proteins (SIRT1-7) in the human sirtuin family, among which SIRT1 is the most conserved and characterized. SIRT1 in the brain, in particular, within the hypothalamus, plays crucial roles in regulating systemic energy homeostasis and circadian rhythm. Apart from this, SIRT1 has also been found to mediate beneficial effects in neurological diseases. In this review, we will first summarize how SIRT1 in the brain relates to obesity, type 2 diabetes, and circadian synchronization, and then we discuss the neuroprotective roles of brain SIRT1 in the context of cerebral ischemia and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline. [ABSTRACT FROM AUTHOR]

The endocrine system plays an essential role in the physiological adaptation to malnutrition. The adaptive response of various hormones directs the energy utilization toward the survival functions and away from growth and reproduction. Particularly, the hypothalamic pituitary axis plays an integral and a central role in the regulation of endocrine organs. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that is activated in response to calorie restriction (CR). SIRT1 is involved in cellular processes via the deacetylation of histone as well as various transcription factors and signal transduction molecules and thereby modulates the endocrine/metabolic functions. There is much evidence to demonstrate clearly that SIRT1 in the hypothalamus, pituitary gland, and other target organs modifies the synthesis, secretion, and activities of hormones and in turn induces the adaptive responses. In this review, we discussed the role of SIRT1 in the hypothalamic pituitary axis and its pathophysiological significance. [ABSTRACT FROM AUTHOR]

Multiple studies have demonstrated a critical role of Sirtuin-1 (SIRT1) deacetylase in protecting kidney cells from cellular stresses. A protective role of SIRT1 has been reported in both podocytes and renal tubular cells in multiple kidney disease settings, including diabetic kidney disease (DKD). We and others have shown that SIRT1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as p53, FOXO, RelA/p65NF-κB, STAT3, and PGC1α/PPARγ. Recently we showed that the podocyte-specific overexpression of SIRT1 attenuated proteinuria and kidney injury in an experimental model of DKD, further confirming SIRT1 as a potential target to treat kidney disease. Known agonists of SIRT1 such as resveratrol diminished diabetic kidney injury in several animal models. Similarly, we also showed that puerarin, a Chinese herbal medicine compound, activates SIRT1 to provide renoprotection in mouse models of DKD. However, as these are non-specific SIRT1 agonists, we recently developed a more specific and potent SIRT1 agonist (BF175) that significantly attenuated diabetic kidney injury in type 1 diabetic OVE26 mice. We also previously reported that MS417, a bromodomain inhibitor that disrupts the interaction between the acetyl-residues of NF-κB and bromodomain-containing protein 4 (BRD4) also attenuates DKD. These results suggest that SIRT1 agonists and bromodomain inhibitors could be potential new therapuetic treatments against DKD progression. [ABSTRACT FROM AUTHOR]

Breast cancer remains a significant female mortality cause. It constitutes a multifactorial disease for which research on environmental factors offers little help in predicting onset or progression. The pursuit for its foundations by analyzing hormonal changes as a motive for disease development, indicates that increased exposure to estrogens associates with increased risk. A prevalent number of breast cancer cases show dependence on the increased activity of the classic nuclear estrogen receptor (ER) for cell proliferation and survival. SIRT1 is a Type III histone deacetylase which is receiving increasing attention due to its ability to perform activities over relevant non-histone proteins and transcription factors. Interestingly, concomitant SIRT1 overexpression is commonly found in ER-positive breast cancer cases. Both proteins had been shown to directly interact, in a process related to altered intracellular signaling and aberrant transcription, then promoting tumor progression. Moreover, SIRT1 activities had been also linked to estrogenic effects through interaction with the G-protein coupled membrane bound estrogen receptor (GPER). This work aims to summarize present knowledge on the interplay between SIRT1 and ER/GPER for breast cancer onset and progression. Lastly, evidences on the ability of SIRT1 to interact with TGFß signaling, a concurrent pathway significantly involved in breast cancer progression, are reported. The potential of this research field for the development of innovative strategies in the assessment of orphan breast cancer subtypes, such as triple negative breast cancer (TNBC), is discussed. [ABSTRACT FROM AUTHOR]

Mammalian silent information regulator 1 (SIRT1) is reported to play a role in cancers of the secretory organs, including thyroid, pancreatic endocrine, and ovarian tumors [1, 2, 3, 4]. A recent meta-analysis conducted on 37 selected studies of human cancers analyzed the correlations of overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) with SIRT1 expression [5]. This study reported that SIRT1 overexpression was associated with a worse OS in liver and lung cancers, while it was not correlated with OS in breast cancer, colorectal cancer, or gastric carcinoma. Collectively, the meta-analysis revealed that an unfavorable OS was associated with SIRT1 expression for solid malignancies. Given the growing importance of this class of lysine/histone deacetylases in human endocrine malignancies, a rational and focused literature assessment is desirable in light of future clinical translations. [ABSTRACT FROM AUTHOR]

Serine has recently been shown to reduce oxidative stress and inflammation, which, when occurring in the hypothalamus, contribute to age-related obesity. To explore whether long-term serine administration reduces oxidative stress and body weight in aging mice, various concentrations of l-serine dissolved in water were administered to 18-month-old C57BL/6J mice for 6 months. The results showed that the administration of 0.5% (w/v) l-serine significantly reduced food intake and body weight gain during the experiment. Moreover, the administration of 0.5% l-serine decreased the concentrations of leptin, malondialdehyde, interleukin-1β, and interleukin-6, while it increased those of superoxide dismutase and glutathione, in both the serum and hypothalamus. Reactive oxygen species and the activity of nicotinamide adenine dinucleotide phosphate oxidase were reduced in the hypothalamus of aging mice treated with l-serine as compared with untreated control mice. Additionally, the expression of the leptin receptor increased while the levels of neuropeptide Y and agouti-related protein decreased in mice that had been treated with 0.5% l-serine. The expression of Sirt1 and phosphorylated signal transducers and activators of transcription 3 (pSTAT3) increased, while that of phosphorylated NFκB decreased in the mice treated with 0.5% l-serine. These results indicated that long-term l-serine administration reduces body weight by decreasing orexigenic peptide expression and reduces oxidative stress and inflammation during aging in mice, possibly by modulating the Sirt1/NFκB pathway. Thus, l-serine has the potential to be used in the prevention of age-related obesity. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to investigate the effect of running exercise on improving bone health in aging mice and explore the role of the SIRT1 in regulating autophagy and osteogenic differentiation of Bone marrow Mesenchymal Stem Cells (BMSCs)., Methods: Twelve-month-old male C57BL/6J mice were used in this study as the aging model and were assigned to treadmill running exercise for eight weeks. Non-exercise male C57BL/6J mice of the same old were used as aging control and five-month-old mice were used as young controls. BMSCs were isolated from mice and subjected to mechanical stretching stimulation in vitro., Results: The results showed that aging mice had lower bone mass, bone mineral density (BMD), and autophagy than young mice, while running exercise improved BMD and bone mass as well as upregulated autophagy in bone cells. Mechanical loading increased osteogenic differentiation and autophagy in BMSCs, and knockdown of SIRT1 in BMSCs demonstrated that SIRT1-regulated autophagy involved the mechanical loading activation of osteogenic differentiation., Conclusion: Taken together, this study revealed that exercise improved bone health during aging by activating bone formation, which can be attributed to osteogenic differentiation of BMSCs through the activation of SIRT1-mediated autophagy. The mechanisms underlying this effect may involve mechanical loading., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Ding, Shi, Zhang, Tong, Huang, Liu, Guan, Zou, Yuan and Chen.)

Background: Non-alcoholic steatohepatitis (NASH) is becoming more widespread, and some similarities exist between its etiology and ferroptosis. However, there are limited investigations on which ferroptosis-related genes (FRGs) are regulated in NASH and how to regulate them. We screened and validated the pivotal genes linked to ferroptosis in NASH to comprehend the function of ferroptosis in the development of NASH., Methods: Two mRNA expression data were obtained from the Gene Expression Omnibus (GEO) as the training set and validation set respectively. FRGs were downloaded from FerrDb. The candidate genes were obtained from the intersection between differentially expressed genes (DEGs) and FRGs, and further analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The hub genes were identified by the protein-protein interaction (PPI) network and Cytoscape. Then, FRGs closely related to the severity of NASH were identified and further confirmed using the validation set and mouse models. Ultimately, based on these genes, a diagnostic model was established to differentiate NASH from normal tissues using another data set from GEO., Results: A total of 327 FRGs in NASH were acquired and subjected to GSEA. And 42 candidate genes were attained by overlapping the 585 FRGs with 2823 DEGs, and enrichment analysis revealed that these genes were primarily engaged in the fatty acid metabolic, inflammatory response, and oxidative stress. A total of 10 hub genes ( PTGS2、IL1B、IL6、NQO1、ZFP36、SIRT1、ATF3、CDKN1A、EGR1、NOX4 ) were then screened by PPI network. The association between the expression of 10 hub genes and the progress of NASH was subsequently evaluated by a training set and verified by a validation set and mouse models. CDKN1A was up-regulated along with the development of NASH while SIRT1 was negatively correlated with the course of the disease. And the diagnostic model based on CDKN1A and SIRT1 successfully distinguished NASH from normal samples., Conclusion: In summary, our findings provide a new approach for the diagnosis, prognosis, and treatment of NASH based on FRGs, while advancing our understanding of ferroptosis in NASH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Wang, Tao, Zhu, Li and Ning.)