Zishen Huoxue decoction (ZSHX) enhances cardiomyocyte viability following hypoxic stress; however, its upstream therapeutic targets remain unclear. Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway. In vitro, ZSHX inhibited pathological mitochondrial fission following hypoxic stress, regulated FUN14 domain-containing protein 1 (FUNDC1)-related mitophagy, and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II (LC3II)/translocase of outer mitochondrial membrane 20 (TOM20) expression while inhibiting the over-activated mitochondrial unfolded protein response. Additionally, ZSHX regulated the stability of beta-tubulin through Sirtuin 5 (SIRT5) and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria (UPR^mt) via the SIRT5 and -β-tubulin axis. This targeting pathway may be crucial for cardiomyocytes to resist hypoxia. Collectively, these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis, which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^mt on cardiomyocytes.
Mitophagy/drug effects* ; Tubulin/genetics* ; Animals ; Myocytes, Cardiac/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Sirtuins/genetics* ; Unfolded Protein Response/drug effects* ; Myocardial Ischemia/genetics* ; Rats ; Humans ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Male

Mesenchymal stem cells (MSCs) are an effective therapeutic strategy to delay aging in dogs, they are prone to aging and have poor genetic stability when cultured for a long time in vitro. Therefore, it is of great significance to explore a method to improve the anti-aging ability of MSCs. Previous studies have shown that sirtuin 6 (SIRT6) plays an important role in anti-aging. This study constructed MSCs with overexpressed SIRT6 gene. Through Giemsa staining and senescence-associated β-galactosidase staining, it was found that SIRT6 significantly enhances the anti-aging capacity of MSCs. Transmission electron microscopy imaging and the detection of oxidative stress-related indicators revealed that SIRT6 improves the anti-aging capacity of MSCs by maintaining mitochondrial homeostasis and reducing oxidative stress levels. Transcriptome sequencing analysis revealed that SIRT6 mainly acted on phosphatidylinositol-3-kinase, mitogen-activated protein kinase and other aging and inflammation related pathways. In the establishment and verification of aging models in mice and dogs, it was found that the spatial memory ability of the model mice was significantly increased after intravenous transplantation of SIRT6 overexpression cells, the organ index was also significantly changed, and the anti-oxidative capacity of the dogs and mice blood was improved. The morphology of the spleens and livers in the SIRT6 overexpression cell treatment group could be effectively restored, and the expression levels of aging and inflammation-related proteins were significantly decreased. This study provides a new idea for the study of SIRT6-mediated anti-aging of MSCs.
Animals ; Dogs ; Mesenchymal Stem Cells/metabolism* ; Sirtuins/genetics* ; Aging/physiology* ; Mice ; Oxidative Stress ; Mesenchymal Stem Cell Transplantation

Vascular calcification significantly increases the incidence of cardiovascular disease and all-cause mortality patients with chronic kidney disease(CKD), severely affecting their health and lifespan. However, the mechanisms underlying vascular calcification in CKD remain incompletely understood, and the available therapeutic agents are limited. Research has found that the transformation of vascular smooth muscle cells(VSMCs) from a contractile phenotype to an osteoblast-like phenotype is a key step in CKD-related vascular calcification. As research on the pathogenesis of calcification progresses, it has been demonstrated that bone morphogenetic protein(BMP) and silent information regulator(SIRT) signaling pathways can participate in the process of vascular calcification by regulating the osteogenic transdifferentiation of VSMCs. Traditional Chinese medicine(TCM) has accumulated a wealth of valuable experience in the prevention and treatment of kidney diseases over centuries. Modern research indicates that TCM, with its multi-pathway, multi-target, and low-toxicity properties, has shown certain advantages in the prevention and treatment of CKD-related vascular calcification and in improving patients' quality of life. Therefore, in this study, we will introduce the latest research progress of TCM in preventing and treating CKD-related vascular calcification, particularly focusing on the BMP and SIRT signaling pathways, with the aim of providing ideas for the clinical diagnosis and treatment of CKD-related vascular calcification with TCM and related basic research.
Humans ; Vascular Calcification/genetics* ; Renal Insufficiency, Chronic/genetics* ; Signal Transduction/drug effects* ; Bone Morphogenetic Proteins/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Sirtuins/genetics* ; Medicine, Chinese Traditional

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice ; Animals ; Butyric Acid/metabolism* ; Ketone Bodies/metabolism* ; Liver/metabolism* ; Hydroxybutyrates/metabolism* ; Down-Regulation ; Sirtuins/metabolism* ; Hydroxymethylglutaryl-CoA Synthase/metabolism*

Silent information regulator 1 (SIRT1) is one of the seven mammalian proteins of the sirtuin family of NAD⁺-dependent deacetylases. SIRT1 plays a pivotal role in neuroprotection and ongoing research has uncovered a mechanism by which SIRT1 may exert a neuroprotective effect on Alzheimer's disease (AD). Growing evidence demonstrates that SIRT1 regulates many pathological processes including amyloid-β precursor protein (APP) processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. SIRT1 has recently received enormous attention, and pharmacological or transgenic approaches to activate the sirtuin pathway have shown promising results in the experimental models of AD. In the present review, we delineate the role of SIRT1 in AD from a disease-centered perspective and provides an up-to-date overview of the SIRT1 modulators and their potential as effective therapeutics in AD.
Animals ; Alzheimer Disease ; Amyloid beta-Protein Precursor ; Animals, Genetically Modified ; Sirtuin 1 ; Sirtuins ; Humans

Cerebral ischemia-reperfusion injury(CIRI) is a complex cascade process and seriously hinders the recovery of patients with acute ischemic stroke, which has become an urgent public health issue to be addressed. Silent information regulators(SIRTs) are a family of nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, capable of deacylating the histone and non-histone lysine groups. Accumulating evidence has demonstrated that SIRTs are able to regulate the pathological processes such as oxidative stress, inflammatory response, mitochondrial dysfunction, and programmed cell death of CIRI through post-translational deacetylation, and exert the neuroprotection function. In this study, we reviewed the papers about the role and regulatory mechanisms of SIRTs in the pathological process of CIRI published in the past decade. Further, we summarized the research advance in the prevention and treatment of CIRI with Chinese medicine targeting SIRTs and the related signaling pathways. This review will provide new targets and theoretical support for the clinical application of Chinese medicine in treating CIRI during the occurrence of ischemic stroke.
Humans ; Brain Ischemia/therapy* ; Ischemic Stroke/therapy* ; Medicine, Chinese Traditional ; Oxidative Stress ; Reperfusion Injury/therapy* ; Sirtuins/metabolism*

SIRT6, a member of the silencing information regulatory protein family, is a nicotinamide adenine dinucleotide-dependent histone deacetylase and an ADP-ribose transferase enzyme. It plays an important role in fundamental physiological and pathological processes, including lipid metabolism, inflammation, oxidative stress and fibrosis, and is considered as a potential therapeutic target for metabolic syndrome. SIRT6 knockout mice displayed severe fatty liver, and the expression of SIRT6 in the liver of nonalcoholic steatohepatitis (NASH) mice was significantly lower than that of normal mice. Overexpression of SIRT6 significantly ameliorated NASH-induced liver damage. It is suggested that SIRT6 may play a key role in protecting against NASH. In this paper, we review the important regulatory functions of SIRT6 in the occurrence and development of NASH.
Animals ; Liver ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease/metabolism* ; Oxidative Stress ; Sirtuins/metabolism*

This study was aimed to determine the effect of acute cerebral ischemia on the protein expression level of silent mating type information regulator 2 homolog 3 (Sirt3) in the neurons and clarify the pathological role of Sirt3 in acute cerebral ischemia. The mice with middle cerebral artery occlusion (MCAO) and primary cultured rat hippocampal neurons with oxygen glucose deprivation (OGD) were used as acute cerebral ischemia models in vivo and in vitro, respectively. Sirt3 overexpression was induced in rat hippocampal neurons by lentivirus transfection. Western blot was utilized to measure the changes in Sirt3 protein expression level. CCK8 assay was used to detect cell viability. Immunofluorescent staining was used to detect mitochondrial function. Transmission electron microscope was used to detect mitochondrial autophagy. The results showed that, compared with the normoxia group, hippocampal neurons from OGD1 h/reoxygenation 2 h (R2 h) and OGD1 h/R12 h groups exhibited down-regulated Sirt3 protein expression levels. Compared with contralateral normal brain tissue, the ipsilateral penumbra region from MCAO1 h/reperfusion 24 h (R24 h) and MCAO1 h/R72 h groups exhibited down-regulated Sirt3 protein expression levels, while there was no significant difference between the Sirt3 protein levels on both sides of sham group. OGD1 h/R12 h treatment damaged mitochondrial function, activated mitochondrial autophagy and reduced cell viability in hippocampal neurons, whereas Sirt3 over-expression attenuated the above damage effects of OGD1 h/R12 h treatment. These results suggest that acute cerebral ischemia results in a decrease in Sirt3 protein level. Sirt3 overexpression can alleviate acute cerebral ischemia-induced neural injuries by improving the mitochondrial function. The current study sheds light on a novel strategy against neural injuries caused by acute cerebral ischemia.
Animals ; Brain Ischemia ; Down-Regulation ; Infarction, Middle Cerebral Artery ; Mice ; Mitochondria ; Neurons/metabolism* ; Rats ; Reperfusion Injury ; Sirtuin 3/metabolism* ; Sirtuins

SIRT3, SIRT4 and SIRT5 are located in mitochondria and also known as mitochondrial sirtuins. They play important roles in regulating many cellular functions including cell survival, cell cycle or apoptosis, DNA repair and metabolism. Mitochondrial sirtuins are involved in the protection of mitochondrial integrity and energy metabolism under stress regulating the expression of neurotransmitter receptors, neurotrophins, extracellular matrix proteins and various transcription factors, thus involved in epileptogenesis triggered by both genetic or acquired factors. Here we review research progress on the actions of mitochondrial sirtuin in epilepsy; and discuss the challenges and perspectives of mitochondrial sirtuin as a potential therapeutic target for epilepsy.
Apoptosis ; Epilepsy/genetics* ; Humans ; Mitochondria/genetics* ; Sirtuin 3 ; Sirtuins

Aging ; Cellular Senescence ; Heterochromatin ; Humans ; Sirtuins ; genetics ; Stem Cells