Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses.

Maintaining metabolic homeostasis is crucial for cellular and organismal health throughout their lifespans. The intricate link between metabolism and inflammation through immunometabolism is pivotal in maintaining overall health and disease progression. The multifactorial nature of metabolic and inflammatory processes makes study of the relationship between them challenging. Homologs of Saccharomyces cerevisiae silent information regulator 2 protein, known as Sirtuins (SIRTs), have been demonstrated to promote longevity in various organisms. As nicotinamide adenine dinucleotide-dependent deacetylases, members of the Sirtuin family (SIRT1-7) regulate energy metabolism and inflammation. In this review, we provide an extensive analysis of SIRTs involved in regulating key metabolic pathways, including glucose, lipid, and amino acid metabolism. Furthermore, we systematically describe how the SIRTs influence inflammatory responses by modulating metabolic pathways, as well as inflammatory cells, mediators, and pathways. Current research findings on the preferential roles of different SIRTs in metabolic disorders and inflammation underscore the potential of SIRTs as viable pharmacological and therapeutic targets. Future research should focus on the development of promising compounds that target SIRTs, with the aim of enhancing their anti-inflammatory activity by influencing metabolic pathways within inflammatory cells.

Lidocaine inhibits the lung cancer progression through decreasing the HIST1H2BL levels via SIRT5 mediated succinylation.

Lung cancer is a malignant tumor originating from the bronchial mucosa or gland of the lung. Recently, lidocaine, a widely used amide local anesthetic, was demonstrated to inhibit many cancer progression. This research was performed to explore the specific mechanism of lidocaine in the lung cancer progression. The human normal lung epithelial cells (BEAS-2B), and NSCLC cell lines (A549 and H1299) were used and treated with lidocaine in this study. The cell biological behaviors were detected by CCK-8, wound healing and transwell assay. Besides, the mRNA and protein levels of related genes were detected by western blot. The results showed that lidocaine treatment significantly decreased the cell viability and migration of the A549 and H1299 cells. Furthermore, the lidocaine treatment significantly decreased the succinylation and protein levels of HIST1H2BL, which was reversed after SIRT5 knockdown. Additionally, HIST1H2BL knockdown decreased the cell viability and migration of the A549 and H1299 cells, while HIST1H2BL overexpression reversed the effects of lidocaine on the cell viability and migration of the A549 and H1299 cells. In conclusion, lidocaine treatment might inhibited the lung cancer progression through decreasing the SIRT5 mediated succinylation of HIST1H2BL.

Sirt6 ameliorates high glucose-induced podocyte cytoskeleton remodeling via the PI3K/AKT signaling pathway.

BACKGROUND: Podocyte injury plays an important role in the occurrence and progression of diabetic kidney disease (DKD), which leads to albuminuria. Cytoskeletal remodeling is an early manifestation of podocyte injury in DKD. However, the underlying mechanism of cytoskeletal remodeling has not been clarified. Histone deacetylase sirtuin6 (Sirt6) has been found to play a key role in DKD progression, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) pathway directly regulates the cytoskeletal structure of podocytes. Whereas, the relationship between Sirt6, the PI3K/AKT pathway and DKD progression remains unclear. METHODS: Renal injury of db/db mice was observed by PAS staining and transmission electron microscope. Expression of Sirt6 in the glomeruli of db/db mice was detected by immunofluorescence. UBCS039, a Sirt6 activator, was used to explore the renal effects of Sirt6 activation on diabetic mouse kidneys. We also downregulating Sirt6 expression in podocytes using the Sirt6 inhibitor, OSS_128167, and induced upregulation of Sirt6 using a recombinant plasmid, after which the effects of Sirt6 on high glucose (HG)-induced podocyte damage were assessed in vitro. Podocyte cytoskeletal structures were observed by phalloidin staining. The podocyte apoptotic rate was assessed by flow cytometry, and PI3K/AKT signaling activation was measured by Western blotting. RESULTS: Db/db mice exhibited renal damage including elevated urine albumin-to-creatinine ratio (ACR), increased mesangial matrix, fused podocyte foot processes, and thickened glomerular basement membrane. The expression of Sirt6 and PI3K/AKT pathway components was decreased in db/db mice. UBCS039 increased the expressions of Sirt6 and PI3K/AKT pathway components and ameliorated renal damage in db/db mice. We also observed consistent Sirt6 expression was in HG-induced podocytes in vitro. Activation of the PI3K/AKT pathway via a Sirt6 recombinant plasmid ameliorated podocyte cytoskeletal remodeling and apoptosis in HG-treated immortalized human podocytes in vitro, whereas Sirt6 inhibition by OSS_128167 accelerated HG-induced podocyte damage in vitro. CONCLUSIONS: Sirt6 protects podocytes against HG-induced cytoskeletal remodeling and apoptosis through activation of the PI3K/AKT signaling pathway. These findings provide evidence supporting the potential efficacy of Sirt6 activation as a promising therapeutic strategy for addressing podocyte injury in DKD.

SIRT6 alleviates senescence induced by Porphyromonas gingivalis in human gingival fibroblasts.

OBJECTIVE: Bidirectional influences between senescence and inflammation are newly discovered. This study aimed to clarify the roles and mechanism of Porphyromonas gingivalis (P. gingivalis) in exacerbating senescence in human gingival fibroblasts (HGFs). DESIGN: Subgingival plaque and gingivae were collected from twenty-four periodontitis patients and eighteen periodontally healthy subjects. Quantities of P. gingivalis in subgingival plaque were explored using real-time PCR and the expressions of p53, p21 and SIRT6 in gingivae were detected by IHC. Moreover, senescence in HGFs was induced by P. gingivalis lipopolysaccharide (LPS) and the expressions of senescence-related ß-galactosidase (SA-ß-gal), p53, p21 and senescence-associated secretory phenotype (IL-6 and IL-8) with or without treatment by SIRT6 activator UBCS039 were explored by IHC, western blot and ELISA, respectively. In addition, the levels of SIRT6, Nrf2, HO-1 and reactive oxygen species (ROS) were examined by western blot and flow cytometry. RESULTS: Quantities of P. gingivalis in subgingival plaque and semi-quantitative scores of p53 and p21 in gingivae of periodontitis patients were increased compared with healthy controls (p < 0.05), while SIRT6 score in periodontitis patients was decreased (p < 0.001). Quantities of P. gingivalis were positively correlated with p53 and p21 scores (0.6 < r < 0.9, p < 0.01), and negatively correlated with SIRT6 score (-0.9 < r<-0.6, p < 0.01). Moreover, P. gingivalis LPS increased the levels of SA-ß-gal, p53, p21, IL-6, IL-8 and ROS and decreased the levels of SIRT6, Nrf2 and HO-1 in HGFs, which was rescued by UBCS039 (p < 0.05). CONCLUSIONS: P. gingivalis LPS could induce senescence of HGFs, which could be reversed by SIRT6 via Nrf2-HO-1 signaling pathway.

MitoAMPK inhibits the Warburg effect by MZF1-SIRT6 with glycosis related genes in NSCLC.

MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non-small-cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK-8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis-related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP-qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1-SIRT6 complex.

Sirtuin 6 inhibits group 3 innate lymphoid cell function and gut immunity by suppressing IL-22 production.

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Lock out SIRT4.

The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.

A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPß-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Inhibition of Sirtuin Deacylase Activity by Peroxynitrite.

Sirtuins are a class of enzymes that deacylate protein lysine residues using NAD+ as a cosubstrate. Sirtuin deacylase activity has been historically regarded as protective; loss of sirtuin deacylase activity potentially increases susceptibility to aging-related disease development. However, which factors may inhibit sirtuins during aging or disease is largely unknown. Increased oxidant and inflammatory byproduct production damages cellular proteins. Previously, we and others found that sirtuin deacylase activity is inhibited by the nitric oxide (NO)-derived cysteine post-translational modification S-nitrosation. However, the comparative ability of the NO-derived oxidant peroxynitrite (ONOO-) to affect human sirtuin activity had not yet been assessed under uniform conditions. Here, we compare the ability of ONOO- (donated from SIN-1) to post-translationally modify and inhibit SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity. In response to SIN-1 treatment, inhibition of SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity correlated with increased tyrosine nitration. Mass spectrometry identified multiple novel tyrosine nitration sites in SIRT1, SIRT3, SIRT5, and SIRT6. As each sirtuin isoform has at least one tyrosine nitration site within the catalytic core, nitration may result in sirtuin inhibition. ONOO- can also react with cysteine residues, resulting in sulfenylation; however, only SIRT1 showed detectable peroxynitrite-mediated cysteine sulfenylation. While SIRT2, SIRT3, SIRT5, and SIRT6 showed no detectable sulfenylation, SIRT6 likely undergoes transient sulfenylation, quickly resolving into an intermolecular disulfide bond. These results suggest that the aging-related oxidant peroxynitrite can post-translationally modify and inhibit sirtuins, contributing to susceptibility to aging-related disease.

Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma.

Sirtuin 6 (SIRT6), a member of the SIRT family, plays essential roles in the regulation of metabolism, inflammation, aging, DNA repair, and cancer development, making it a promising anticancer drug target. Herein, we present our use of proteolysis-targeting chimera (PROTAC) technology to formulate a series of highly potent and selective SIRT6 degraders. One of the degraders, SZU-B6, induced the near-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell lines and more potently inhibited hepatocellular carcinoma (HCC) cell proliferation than the parental inhibitors. In preliminary mechanistic studies, SZU-B6 hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader SZU-B6 displayed promising antitumor activity, particularly when combined with the well-known kinase inhibitor sorafenib or irradiation in an SK-HEP-1 xenograft mouse model. Our results suggest that these PROTACs might constitute a potent therapeutic strategy for HCC.

Discovery of N-Aryl-N'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.

Impaired SUMOylation of FoxA1 promotes nonalcoholic fatty liver disease through down-regulation of Sirt6.

Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.

Unraveling the multifaceted role of SIRT7 and its therapeutic potential in human diseases.

Sirtuins, as NAD+-dependent deacetylases, are widely found in eubacteria, archaea, and eukaryotes, and they play key roles in regulating cellular functions. Among these, SIRT7 stands out as a member discovered relatively late and studied less extensively. It is localized within the nucleus and displays enzymatic activity as an NAD+-dependent deacetylase, targeting a diverse array of acyl groups. The role of SIRT7 in important cellular processes like gene transcription, cellular metabolism, cellular stress responses, and DNA damage repair has been documented in a number of studies conducted recently. These studies have also highlighted SIRT7's strong correlation with human diseases like aging, cancer, neurological disorders, and cardiovascular diseases. In addition, a variety of inhibitors against SIRT7 have been reported, indicating that targeting SIRT7 may be a promising strategy for inhibiting tumor growth. The purpose of this review is to thoroughly look into the structure and function of SIRT7 and to explore its potential value in clinical applications, offering an essential reference for research in related domains.

Baicalein Inhibits Cerebral Ischemia-Reperfusion Injury through SIRT6-Mediated FOXA2 Deacetylation to Promote SLC7A11 Expression.

Ischemic stroke (IS) poses a serious threat to patient survival. The inhibition of ferroptosis can effectively alleviate ischemia-reperfusion (I/R) injury, suggesting potential targets in the ferroptosis pathway for the treatment of IS. In this study, MCAO/R mice and OGD/R-induced HT22 cell were constructed. It was found that baicalein decreased ROS, MDA, and Fe2+ levels, upregulated GSH levels, and enhanced the expression of ferroptosis-related proteins (GPX4 and SLC7A11), downregulated the expression of proapoptotic proteins (Bax, cytochrome c, and cleaved caspase-3), and upregulated the expression of an antiapoptotic protein (Bcl-2), ameliorating cerebral I/R injury. In animal and cell models, Sirtuin6 (SIRT6) is downregulated, and Forkhead boxA2 (FOXA2) expression and acetylation levels are abnormally upregulated. SIRT6 inhibited FOXA2 expression and acetylation. Baicalein promoted FOXA2 deacetylation by upregulating SIRT6 expression. FOXA2 transcriptionally inhibits SLC7A11 expression. In conclusion, baicalein inhibited apoptosis and partially suppressed the role of ferroptosis to alleviate cerebral I/R injury via SIRT6-mediated FOXA2 deacetylation to promote SLC7A11 expression.

SIRT5 induces autophagy and alleviates myocardial infarction via desuccinylation of TOM1.

Myocardial infarction (MI) is a prevalent form of ischemic heart disease, significantly contributing to heart disease-related deaths worldwide. This condition is primarily caused by myocardial ischemic-reperfusion injury (MIRI). Sirtuin 5 (SIRT5) is a desuccinylase known for its ability to reduce protein succinylation. Recent studies have highlighted the potential role of SIRT5 in various human diseases, including MIRI. This study aims to investigate the specific role of SIRT5 in modulating autophagy and cardiomyocyte death in a MIRI model, as well as to identify the downstream protein targets of SIRT5. Initially, we established a hypoxia/reoxygenation (H/R)-induced MIRI cell model to measure SIRT5 expression and assess its functions. Our results indicated that H/R induction led to a downregulation of SIRT5 expression, decreased autophagy, and increased cell death. Notably, overexpression of SIRT5 effectively promoted autophagy and inhibited cell death in the MIRI cell model. Mechanistically, SIRT5 was found to directly interact with the target of myb1 membrane trafficking protein (TOM1) at the K48 site, inducing its desuccinylation and stabilization. Further rescue assays revealed that TOM1 knockdown reversed the changes in autophagy and apoptosis caused by SIRT5 overexpression in the MIRI cell model. In vivo experiments demonstrated that SIRT5 alleviated myocardial injury in MI models. In conclusion, this study uncovers the role of SIRT5-mediated desuccinylation of TOM1 in regulating autophagy-related cell death in MIRI, providing new insights into potential therapeutic strategies for MI.

Emerging role of sirtuins in non­small cell lung cancer (Review).

Non­small 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 non­histone 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.

Research advances on silence information regulator 6 as a potential therapeutic target for bone regeneration and repair. / æ²‰é»˜ä¿¡æ¯è°ƒèŠ‚å› å­6是骨组织再生修复的潜在作用靶点.

Segmental bone defects and nonunion of fractures caused by trauma, infection, tumor or systemic diseases with limited osteogenesis and prolonged bone healing cycles are challenging issues in orthopedic clinical practice. Therefore, identifying regulatory factors for bone tissue regeneration and metabolism is crucial for accelerating bone repair and reconstructing defective areas. Silence information regulator 6 (SIRT6), functioning as a deacetylase and nucleotide transferase, is extensively involved in the regulation of differentiation, apoptosis, metabolism, and inflammation in bone cells including osteoblasts and osteoclasts, and is considered to be an important factor in regulating bone metabolism. SIRT6 forms a complex with B lymphocyte-induced maturation protein 1 (Blimp1), down-regulates the expression of the nuclear factor κB (NF-κB) pathway, and promotes the expression of the ERα-FasL axis signal to inhibit osteoclast formation and maturation differentiation, thereby hindering bone resorption and increasing bone mass. In addition, SIRT6 activates the Akt-mTOR pathway to regulate the autophagy level and osteogenesis of bone marrow mesenchymal stem cells, inhibits glycolysis and reactive oxygen production in osteoblasts, promotes osteoblast differentiation through the CREB/CCN1/COX2 pathway and the bone morphogenetic protein (BMP) signaling pathway, enhances bone formation, and accelerates bone regeneration and repair of skeletal tissue. This article provides an overview of the research progress on SIRT6 in the pathophysiology of bone regeneration, revealing its potential as a novel therapeutic target for bone tissue repair to alleviate the progression of skeletal pathological diseases.

Oxidative stress and regulation of adipogenic differentiation capacity by sirtuins in adipose stem cells derived from female patients of advancing age.

Patient age is critical for mesenchymal stem cell quality and differentiation capacity. We demonstrate that proliferation and adipogenic capacity of subcutaneous adipose stem cells (ASCs) from female patients declined with advanced age, associated with reduction in cell nucleus size, increase in nuclear lamina protein lamin B1/B2, and lamin A, upregulation of senescence marker p16INK4a and senescence-associated ß-galactosidase activity. Adipogenic induction resulted in differentiation of adipocytes and upregulation of adipogenic genes CCAAT enhancer binding protein alpha, fatty acid binding protein 4, lipoprotein lipase, and peroxisome proliferator-activated receptor-γ, which was not affected by the Sirt-1 activator YK-3-237 or the Sirt-1 inhibitor EX-527. Protein expression of the stem cell markers Oct4 and Sox2 was not significantly downregulated with advanced patient age. Mitochondrial reactive oxygen species were increased in ASCs from old-aged patients, whereas protein expression of NADPH oxidases NOX1 and NOX4 was downregulated, and dual oxidase isoforms remained unchanged. Generation of nitric oxide and iNOS expression was downregulated. Protein expression of Sirt-1 and Sirt-3 decreased with patient age, whereas Sirt-2 and Sirt-5 remained unchanged. Induction of adipogenesis stimulated protein expression of Sirt-1 and Sirt-3, which was not affected upon pre-incubation with the Sirt-1-activator YK-3-237 or the Sirt-1-inhibitor EX-527. The Sirt-1 inhibitor Sirtinol downregulated adiponectin protein expression and the number of adipocytes, whereas YK-3-237 exerted stimulatory effects. In summary, our data demonstrate increased oxidative stress in ASCs of aging patients, and decline of adipogenic capacity due to Sirt-1- mediated adiponectin downregulation in elderly patients.

SIRT6 prevent chronic cerebral hypoperfusion induced cognitive impairment by remodeling mitochondrial dynamics in a STAT5-PGAM5-Drp1 dependent manner.

Vascular dementia (VaD) is a prevalent form of dementia resulting from chronic cerebral hypoperfusion (CCH). However, the pathogenic mechanisms of VaD and corresponding therapeutic strategies are not well understood. Sirtuin 6 (SIRT6) has been implicated in various biological processes, including cellular metabolism, DNA repair, redox homeostasis, and aging. Nevertheless, its functional relevance in VaD remains unexplored. In this study, we utilized a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the role of SIRT6. We detected a significant decrease in neuronal SIRT6 protein expression following CCH. Intriguingly, neuron-specific ablation of Sirt6 in mice exacerbated neuronal damage and cognitive deficits after CCH. Conversely, treatment with MDL-800, an agonist of SIRT6, effectively mitigated neuronal loss and facilitated neurological recovery. Mechanistically, SIRT6 inhibited excessive mitochondrial fission by suppressing the CCH-induced STAT5-PGAM5-Drp1 signaling cascade. Additionally, the gene expression of monocyte SIRT6 in patients with asymptomatic carotid stenosis showed a correlation with cognitive outcomes, suggesting translational implications in human subjects. Our findings provide the first evidence that SIRT6 prevents cognitive impairment induced by CCH, and mechanistically, this protection is achieved through the remodeling of mitochondrial dynamics in a STAT5-PGAM5-Drp1-dependent manner.