Extracellular vesicles (EVs), defined as cell-secreted nanoscale vesicles that carry bioactive molecules, have emerged as a promising therapeutic strategy in tumor and tissue regeneration. Their potential in repairing intervertebral disc degeneration (IDD) through multidimensional regulatory mechanisms is a rapidly advancing field of research. This paper provided an overview of the mechanisms of EVs in IDD repair, thoroughly reviewed recent literature on EVs for IDD, domestically and internationally, and summarized their therapeutic mechanisms. In IDD repair, EVs could act through different mechanisms at the molecular, cellular, and tissue levels. At the molecular level, EVs could treat IDD by inhibiting inflammatory reactions, suppressing oxidative stress, and regulating the synthesis and decomposition of extracellular matrix. At the cellular level, EVs could treat IDD by inhibiting cellular pyroptosis, ferroptosis, and apoptosis and promoting cell proliferation and differentiation. At the tissue level, EVs could treat IDD by inhibiting neovascularization. EVs have a strong potential for clinical application in the treatment of IDD and deserve more profound study.
Extracellular Vesicles/physiology* ; Humans ; Intervertebral Disc Degeneration/therapy* ; Apoptosis ; Cell Proliferation ; Oxidative Stress ; Cell Differentiation ; Extracellular Matrix/metabolism* ; Animals ; Pyroptosis

During the hyperacute phase of intracerebral hemorrhage (ICH), the mass effect and blood components mechanically lead to brain damage and neurotoxicity. Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake, culminating in ferroptosis in neurons. M6A (N6-methyladenosine) modification, the most prevalent mRNA modification, plays a critical role in various cell death pathways. The Fto (fat mass and obesity-associated protein) demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels. Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis. Applying nanopore direct RNA sequencing, we identified voltage-dependent anion channel 3 (Vdac3) as a potential target associated with ferroptosis. Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA. These findings elucidate the intricate interplay between Fto, Vdac3, m6A methylation, and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
Ferroptosis/physiology* ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Animals ; Neurons/metabolism* ; Transferrin/pharmacology* ; Mice ; Methylation ; Mice, Inbred C57BL ; Adenosine/metabolism* ; RNA, Messenger/metabolism* ; Male ; Oxidative Stress/physiology*

OBJECTIVES: This study aims to investigate the impact of glutathione S-transferase (GST) on the environmental adaptability of Streptococcus mutans (S. mutans). METHODS: A GST knockout strain ΔgsT was constructed. Transcriptomic sequencing was performed to analyze the gene expression differences between the wild-type S. mutans UA159 and its GST knockout strain ΔgsT. Comprehensive functional assessments, including acid tolerance assays, hydrogen peroxide challenge assays, nutrient limitation growth assays, and fluorescence in situ hybridization, were conducted to evaluate the acid tolerance, antioxidant stress resistance, growth kinetics, and interspecies competitive ability of ΔgsT within plaque biofilms. RESULTS: Compared with the wild-type S. mutans, 198 genes in ΔgsT were significantly differentially expressed and enriched in pathways related to metabolism, stress response, and energy homeostasis. The survival rate of ΔgsT in acid tolerance assays was markedly reduced (P<0.01). After 15 min of hydrogen peroxide challenge, the survival rate of ΔgsT decreased to 38.12% (wild type, 71.75%). Under nutrient-limiting conditions, ΔgsT exhibited a significantly lower final OD₆₀₀ value than the wild-type strain (P<0.05). In the biofilm competition assays, the proportion of S. mutans ΔgsT in the mixed biofilm (8.50%) was significantly lower than that of the wild type (16.89%) (P<0.05). CONCLUSIONS GST enhances the acid resistance, oxidative stress tolerance, and nutrient adaptation of S. mutans by regulating metabolism-related and stress response-related genes.
Streptococcus mutans/enzymology* ; Biofilms ; Glutathione Transferase/physiology* ; Adaptation, Physiological ; Hydrogen Peroxide/pharmacology* ; Gene Expression Regulation, Bacterial ; Oxidative Stress ; Metabolic Reprogramming

SoxR, one of bacterial transcriptional regulators, plays a crucial role in bacterial responses to oxidative stress induced by unfavorable environmental conditions. So far, the understanding of bacterial responses to oxidative stress mainly stems from a handful model bacteria such as Escherichia coli and the studies on non-model bacterial responses to oxidative stress are limited. In this study, Citrobacter braakii JPG1, a commonly occurring strain of enterobacteria, was used as a model for the first time to explore the role of SoxR in the responses to aerobic/anaerobic-menadione stress. First, we analyzed the phylogenetic relationship of SoxR based on the whole genome and constructed the soxR-deleted strain (ΔsoxR). Then, the cell counts of the wild type (WT) and ΔsoxR were compared under aerobic/anaerobic-menadione stress. The results showed that the cell count of WT exposed to the aerobic-low concentration menadione (0.1 mmol/L) stress for 24 h increased by 4.2 times compared with that at the time point of 0 h, while that of ΔsoxR only increased by 1.3 times. The vast majority of WT and ΔsoxR cells died after exposure to the aerobic-high concentration menadione (0.3 mmol/L) stress for 24 h, with the cell counts only 29% and 0.2% of those at the time point of 0 h, respectively. Interestingly, the cell counts of WT showed no significant difference between the anaerobic-menadione stress and the control (P > 0.05), and the same was true for ΔsoxR. All these results indicated that SoxR of C. braakii JPG1 only has a regulatory effect on the redox cycling compound menadione under aerobic conditions and enhance the antioxidant capacity. Under anaerobic conditions, menadione failed to activate SoxR. The findings from this study provide new insights into understanding both the physiological responses to menadione stress and the regulatory role of SoxR under different oxygen conditions.
Bacterial Proteins/physiology* ; Anaerobiosis ; Aerobiosis ; Vitamin K 3/pharmacology* ; Citrobacter/metabolism* ; Transcription Factors/physiology* ; Oxidative Stress ; Gene Expression Regulation, Bacterial

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

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection,with a high mortality rate.Sirtuin 3,a deacetylase within mitochondria,plays an important regulatory role in cellular metabolism,oxidative stress,and inflammatory responses.In recent years,significant progress has been made in the study of the function and regulatory role of sirtuin 3 in sepsis-related diseases.Research has shown that sirtuin 3 can alleviate organ damage caused by sepsis by regulating mitochondrial function,reducing oxidative stress,and inhibiting inflammatory responses.The specific mechanisms include the regulation of mitochondrial bioenergetics,activation of antioxidant enzyme systems,and inhibition of inflammatory mediator expression.In addition,sirtuin 3 plays a protective role in the pathological process of sepsis by interacting with multiple signaling pathways.This article summarizes the functions and regulatory mechanisms of sirtuin 3 in various sepsis-related diseases,aiming to provide new targets and strategies for the prevention and treatment of sepsis in the future.
Sepsis/metabolism* ; Sirtuin 3/physiology* ; Humans ; Animals ; Oxidative Stress ; Mitochondria/metabolism* ; Signal Transduction

BACKGROUND: The sirtuin family is well recognized for its crucial involvement in various cellular processes. Nevertheless, studies on its role in the human endometrium are limited. This study aimed to explore the expression and localization of the sirtuin family in the human endometrium, focusing on sirtuin 3 (SIRT3) and its potential role in the oxidative imbalance of the endometrium in polycystic ovary syndrome (PCOS). METHODS: Endometrial specimens were collected from both patients with PCOS and controls undergoing hysteroscopy at the Center for Reproductive Medicine, Peking University Third Hospital, from July to August 2015 and used for cell culture. The protective effects of SIRT3 were investigated, and the mechanism of SIRT3 in improving endometrial receptivity of patients with PCOS was determined using various techniques, including cellular bioenergetic analysis, small interfering ribonucleic acid (siRNA) silencing, real-time quantitative polymerase chain reaction, Western blot, immunofluorescence, immunohistochemistry, and flow cytometry analysis. RESULTS: The sirtuin family was widely expressed in the human endometrium, with SIRT3 showing a significant increase in expression in patients with PCOS compared with controls ( P <0.05), as confirmed by protein and gene assays. Concurrently, endometrial antioxidant levels were elevated, while mitochondrial respiratory capacity was reduced, in patients with PCOS ( P <0.05). An endometrial oxidative stress (OS) model revealed that the downregulation of SIRT3 impaired the growth and proliferation status of endometrial cells and reduced their receptivity to day 4 mouse embryos. The results suggested that SIRT3 might be crucial in maintaining normal cellular state by regulating antioxidants, cell proliferation, and apoptosis, thereby contributing to enhanced endometrial receptivity. CONCLUSIONS Our findings proposed a significant role of SIRT3 in improving endometrial receptivity in patients with PCOS by alleviating OS and regulating the balance between cell proliferation and apoptosis. Therefore, SIRT3 could be a promising target for predicting and improving endometrial receptivity in this patient population.
Humans ; Female ; Polycystic Ovary Syndrome/metabolism* ; Endometrium/metabolism* ; Sirtuin 3/genetics* ; Oxidative Stress/genetics* ; Adult ; Animals ; Mice ; Apoptosis/physiology* ; Immunohistochemistry ; Cell Proliferation/physiology*

Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.
Male ; Humans ; Infertility, Male/metabolism* ; Oxidative Phosphorylation ; Mitochondria/metabolism* ; Spermatogenesis/physiology* ; Sertoli Cells/metabolism* ; Oxidative Stress/physiology* ; Animals ; Reactive Oxygen Species/metabolism*

Oxidative stress due to aberrant metabolism is considered as a crucial contributor to diabetes and its complications. Hyperglycemia and hyperlipemia boost excessive reactive oxygen species generation by elevated mitochondrial respiration, increased nicotinamide adenine dinucleotide phosphate oxidase activity, and enhanced pro-oxidative processes, including protein kinase C pathways, hexosamine, polyol, and advanced glycation endproducts, which exacerbate oxidative stress. Oxidative stress plays a significant role in the onset of diabetes and its associated complications by impairing insulin production, increasing insulin resistance, maintaining hyperglycemic memory, and inducing systemic inflammation. A more profound comprehension of the molecular processes that link oxidative stress to diabetes is crucial to new preventive and therapeutic strategies. Therefore, this review discusses the mechanisms underlying how oxidative stress contributes to diabetes mellitus and its complications. We also summarize the current approaches for prevention and treatment by targeting the oxidative stress pathways in diabetes.
Oxidative Stress/physiology* ; Humans ; Diabetes Mellitus/physiopathology* ; Diabetes Complications/metabolism* ; Reactive Oxygen Species/metabolism* ; Glycation End Products, Advanced/metabolism* ; Animals

Vascular aging (VA) is a common etiology of various chronic diseases and represents a major public health concern. Intermittent hypoxia (IH) associated with obstructive sleep apnea-hypopnea syndrome (OSAHS) is a primary pathological and physiological driver of OSAHS-induced systemic complications. A substantial proportion of OSAHS patients, estimated to be between 40% and 80%, have comorbidities such as hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, aneurysm, and stroke, all of which are closely associated with VA. This review examines the molecular and cellular features common to both OSAHS and VA, highlighting decreased melatonin secretion, impaired autophagy, increased apoptosis, increased inflammation and pyroptosis, increased oxidative stress, accelerated telomere shortening, accelerated stem cell depletion, metabolic disorders, imbalanced protein homeostasis, epigenetic alterations, and dysregulated neurohormonal signaling. The accumulation and combination of these features may underlie the pathophysiological link between OSAHS and VA, but the exact mechanisms by which OSAHS affects VA may require further investigation. Taken together, these findings suggest that OSAHS may serve as a novel risk factor for VA and related vascular disorders, and that targeting these features may offer therapeutic potential to mitigate the vascular risks associated with OSAHS.
Humans ; Sleep Apnea, Obstructive/pathology* ; Aging/physiology* ; Oxidative Stress/physiology* ; Animals