FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Haitao Yang,Xinyu Zhou,Baihao Zhang,Yuzhen Shan,Yichen Jin,Enzhuang Pan,Dong Xu,Liwen Fan,Panpan Zhao,Yong Sun,Jingquan Dong
Sepsis-associated encephalopathy (SAE) is a common and serious complication of sepsis, characterized by neuroinflammation and cognitive dysfunction, yet its molecular mechanisms remain unclear. This study aimed to investigate the role of heat shock protein 90α (HSP90α) in microglial NLRP3 inflammasome activation and cognitive impairment in SAE, and to explore the therapeutic potential of a small molecule compound, nicotinamide N-oxide (NAMO). SAE models were established using cecal ligation and puncture (CLP) in mice and LPS/ATP stimulated primary microglial cells/BV-2 cells. A combination of H&E/Nissl/TUNEL staining, transcriptomics, immunoblotting, qPCR, immunofluorescence, ELISA, mtDNA release, co-immunoprecipitation, molecular docking, AAV stereotaxic delivery, and pharmacological/siRNA interventions were utilized. Results showed that HSP90α expression was significantly upregulated in microglia during SAE. HSP90α facilitated NLRP3 inflammasome activation and exacerbated cognitive dysfunction in SAE by inducing mitochondrial dysfunction and promoting the release of mitochondrial DNA (mtDNA). Mechanistically, HSP90α interacted with PPP3CA, which facilitated Drp1 dephosphorylation at Ser637, triggering mitochondrial fragmentation and mtDNA release. Importantly, we identified that NAMO binds directly to HSP90α, inhibits the HSP90α–PPP3CA–Drp1 axis, reduces mtDNA release, and suppresses NLRP3 inflammasome activation. Administration of NAMO significantly alleviated cognitive impairment in SAE mice. Collectively, our findings reveal a novel HSP90α–PPP3CA–Drp1–mtDNA–NLRP3 signaling pathway in microglial activation and cognitive injury during SAE, and propose NAMO as a promising therapeutic candidate for SAE intervention.
研究领域:
神经免疫学
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分子医学
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炎症生物学
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细胞信号转导
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重症医学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2023
·Vol. 21
·期 1
·1-17
·
IF 7.4
Zhang Yafei,Yang Bingqian,Tu Chengwei,Ping Yifan,Chen Shuhong,Wu Tong,Zhao Zheyu,Mao Yixin,Yang Zhan,Cao Zelin,Li Jianmin,Huang Kate,Ding Xi,Wu Gang,Zou Peng,Deng Zhennan,Sun Xiaoyu
Background Oral squamous cell carcinoma (OSCC) is one of the most prevalent and fatal oral cancers. Mitochondria-targeting therapies represent promising strategies against various cancers, but their applications in treating OSCC are limited. Alantolactone (ALT) possesses anticancer properties and also regulates mitochondrial events. In this study, we explored the effects of ALT on OSCC and the related mechanisms. Methods The OSCC cells were treated with varying concentrations and duration of ALT and N -Acetyl- l -cysteine (NAC). The cell viability and colony formation were assessed. The apoptotic rate was evaluated by flow cytometry with Annexin V-FITC/PI double staining. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production and DAF-FM DA to investigate reactive nitrogen species (RNS) level. Mitochondrial function was reflected by mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. KEGG enrichment analyses determined the mitochondrial-related hub genes involved in OSCC progression. Dynamin-related protein 1 (Drp1) overexpression plasmids were further transfected into the cells to analyze the role of Drp1 in OSCC progression. Immunohistochemistry staining and western blot verified the expression of the protein. Results ALT exerted anti-proliferative and pro-apoptosis effects on OSCC cells. Mechanistically, ALT elicited cell injury by promoting ROS production, mitochondrial membrane depolarization, and ATP depletion, which were reversed by NAC. Bioinformatics analysis showed that Drp1 played a crucial role in OSCC progression. OSCC patients with low Drp1 expression had a higher survival rate. The OSCC cancer tissues presented higher phosphorylated-Drp1 and Drp1 levels than the normal tissues. The results further showed that ALT suppressed Drp1 phosphorylation in OSCC cells. Moreover, Drp1 overexpression abolished the reduced Drp1 phosphorylation by ALT and promoted the cell viability of ALT-treated cells. Drp1 overexpression also reversed the mitochondrial dysfunction induced by ALT, with decreased ROS production, and increased mitochondrial membrane potential and ATP level. Conclusions ALT inhibited proliferation and promoted apoptosis of oral squamous cell carcinoma cells via impairment of mitochondrial homeostasis and regulation of Drp1. The results provide a solid basis for ALT as a therapeutic candidate for treating OSCC, with Drp1 being a novel therapeutic target in treating OSCC.
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高影响因子
PLoS Pathogens
·
2026
·Vol. 22
·期 2
·e1013975
·
IF 4.9
Huijie Hu,Naiyuan Jiang,Juxiong Liu,Junlong Bi,Xuanting Liu,Bin Xu,Yu Cao,Wenjin Guo,Shoupeng Fu
Staphylococcus aureus ( S. aureus )–driven senescence of bovine mammary epithelial cells is a key determinant of mammary gland health, yet its molecular basis remains poorly defined. Sirtuin 5 (SIRT5), a mitochondria-localized desuccinylase, may play an important regulatory role in this process. This study aimed to elucidate the mechanisms by which S. aureus drives cellular senescence and to define the contribution of the SIRT5–mitochondrial axis to delaying senescence. We found pronounced oxidative stress and cellular senescence in mammary tissues from cows with S. aureus mastitis, accompanied by marked downregulation of SIRT5. In an S. aureus -infected epithelial cell model, infection induced mitochondrial stress characterized by excessive mitochondrial fragmentation, loss of membrane potential, and increased mitochondrial superoxide, along with oxidative damage and cellular senescence. Mechanistically, S. aureus toxins and the toxin-induced inflammatory response cooperatively drove mitochondrial stress, which in turn increased intracellular bacterial burden and exacerbated cell death. During infection, SIRT5 protein abundance was significantly reduced. Mass spectrometry and co-immunoprecipitation analyses indicated that infection upregulated the ubiquitin-conjugating enzyme ubiquitin C (UBC), enhanced its interaction with SIRT5, and promoted ubiquitin-mediated degradation of SIRT5. Loss of SIRT5 increased succinylation of dynamin-related protein 1 (DRP1), inhibited its ubiquitin-mediated degradation, and led to its excessive accumulation on the outer mitochondrial membrane, thereby promoting excessive mitochondrial fission. Functionally, SIRT5 overexpression markedly alleviated mitochondrial stress, oxidative damage, and senescence phenotypes. When mitochondrial fission was forcibly enhanced, the cytoprotective effect of SIRT5 was substantially weakened, confirming that SIRT5 acts through a pathway dependent on mitochondrial integrity. Collectively, S. aureus infection releases toxins and induces inflammatory injury, during which UBC-mediated SIRT5 degradation activates DRP1-dependent mitochondrial hyper-fragmentation, aggravating mitochondrial stress, oxidative stress, and mammary epithelial cell senescence. These findings identify SIRT5 as a critical regulator of redox and mitochondrial homeostasis in mammary epithelial cells and a potential therapeutic target for mitigating oxidative damage associated with bovine mastitis.
Staphylococcus aureus ( S. aureus ) is a leading cause of bovine mastitis, an intramammary infection that reduces milk yield, increases antibiotic use, and results in substantial economic loss. One way this bacterium damages the udder is by driving bovine mammary epithelial cells into premature senescence, but how infection triggers this process has not been fully understood. Here, we show that S. aureus infection induces an inflammatory response via its secreted toxins, which in turn provokes mitochondrial stress. We identify the mitochondrial enzyme Sirtuin 5 (SIRT5) as a key defender in this context. During infection, the host ubiquitin-conjugating enzyme ubiquitin C (UBC) targets SIRT5 for degradation. Loss of SIRT5 leads to accumulation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), causing excessive mitochondrial fragmentation, enhanced oxidative damage, increased intracellular bacterial burden, and aggravated cellular senescence. Restoring SIRT5 helps to preserve mitochondrial integrity and reduces oxidative injury and senescence; however, this protection is weakened when mitochondrial fission is forcibly maintained at a high level. Together, our findings reveal that the UBC–SIRT5–DRP1 pathway links S. aureus infection to mitochondrial damage and cellular senescence, and they highlight SIRT5 as a potential therapeutic target to protect the bovine mammary gland (S1 Fig).
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TISSUE & CELL
·
2026
·
IF 3.1
Jun Ma,Hongying Zhang,Linlong Wu,Huiyun Shen,Aifei Chen,Aiping Wu,Ying Hu
AS-IV ameliorates oxaliplatin-induced damage to DRG neurons. • AS-IV exerts neuroprotective effects by inhibiting the p53/p-Drp1 signaling pathway in OIPN. • AS-IV corrects mitochondrial dysfunction and energy metabolism disorders in OIPN. • AS-IV improves mechanical hyperalgesia and thermal hypersensitivity in OIPN rats. • AS-IV antagonizes OIPN through the p53/p-Drp1/mitochondrial axis. Objective This study targeted to explore the effect of Astragaloside IV (AS-IV) on oxaliplatin (OHP)-induced peripheral neuropathy (OIPN). Methods OHP-induced rat dorsal root ganglion (DRG) neurons were treated with AS-IV and/or p53 inhibitors or agonists. Cell viability, apoptosis, mitochondrial membrane potential, ROS, oxidative stress-related indicators, and mitochondrial complex activity were examined. The interaction between p53 and Drp1 was explored and validated. In vivo , an OIPN rat model was established via intraperitoneal injections of OHP and treated with AS-IV. Behavioral assessments were conducted, and histological examinations were performed on DRG tissues from OIPN rats. Results AS-IV significantly enhanced DRG neuronal viability following OHP induction, inhibited apoptosis, improved mitochondrial function, alleviated oxidative stress, and simultaneously suppressed OHP-induced p53 upregulation and its interaction with Drp1. p53 inhibitors mimicked these protective effects, while agonists blocked these effects. In vivo experiments demonstrated that AS-IV significantly alleviated cold, heat, and mechanical pain sensitivity in OIPN rats, reduced DRG histopathological damage and neuronal apoptosis, improved oxidative stress, and inhibited activation of the p53/p-Drp1 signaling pathway. Conclusion AS-IV protects DRG neurons from OHP-induced injury and alleviates OIPN-related symptoms by inhibiting the p53/p-Drp1 axis.
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高影响因子
Evidence-based Complementary and Alternative Medicine
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2021
·
IF 2.63
Fen Li,Dongsheng Li,Shifan Tang,Jianguang Liu,Jie Yan,Haifeng Chen,Xisheng Yan
Reperfusion of blood flow during ischemic myocardium resuscitation induces ischemia/reperfusion (I/R) injury. Oxidative stress has been identified as a major cause in this process. Quercetin (QCT) is a member of the flavonoid family that exerts antioxidant effects. The aim of this study was to investigate the preventive effects of QCT on I/R injury and its underlying mechanism. To this end, H9c2 cardiomyocytes were treated with different concentrations of QCT (10, 20, and 40 μM) and subsequently subjected to oxygen-glucose deprivation/reperfusion (OGD/R) administration. The results indicated that OGD/R-induced oxidative stress, apoptosis, and mitochondrial dysfunction in H9c2 cardiomyocytes were aggravated following 40 μM QCT treatment and alleviated following the administration of 10 and 20 μM QCT prior to OGD/R treatment. In addition, OGD/R treatment inactivated ERK1/2 signaling activation. The effect was mitigated using 10 and 20 μM QCT prior to OGD/R treatment. In conclusion, these results suggested that low concentrations of QCT might alleviate I/R injury by suppressing oxidative stress and improving mitochondrial function through the regulation of ERK1/2-DRP1 signaling, providing a potential candidate for I/R injury prevention.
研究领域:
心脏病学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
·
IF 5.714
Shu-ping Yang,Qing Su,Ya-ru Zhang,Yun Sun,Yu-rong Chai
As the main lymphoid organ, the thymus degenerates with age. The loss of thymic epithelial cells is mainly related to thymus degeneration and reduced T cells development. As an insulin sensitizer, metformin is a first-line drug for the treatment of diabetes and has been shown to prolong the lifespan of mice, but the mechanism is still unclear. In this study, we explored the therapeutic effect of metformin on thymus degeneration in the accelerated aging mice, which was established by intraperitoneal injection D-galactose (120 mg/kg/day) for eight weeks. Metformin was intragastrically given with 100 or 300 mg/kg body weight per day, respectively, for six weeks. Histological examination showed that metformin administration could alleviate thymus atrophy caused by D-galactose. In addition, metformin therapy increased mitochondrial membrane potential, with a reduction in mitochondrial reactive oxygen species, MDA and SOD levels, and restored mitochondrial balance through enhanced expression of dynamin-related protein 1 (Drp1). Furthermore, metformin altered T lymphocyte subsets and cellular senescent cells; the expression of FoxN1, Aire and Sox2 of thymic epithelial cells also increased. Thus, metformin presented a positive effect on thymic degeneration through improving mitochondrial function. Taken together, these findings revealed an unexpected complexity in the anti-aging of this widely used drug.
研究领域:
药理学
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免疫学
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老年学
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细胞生物学
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PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
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2024
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IF 3.5
Wang Liwei,Zhang Lu,Yun Yang,Liang Tingting,Yan Chaoqun,Mao Zhuoya,Zhang Jingfang,Liu Baoshe,Zhang Jian,Liang Taigang
Occupational and unintentional exposure of zinc oxide nanoparticles (ZnONPs) raises concerns regarding their neurotoxic potential and there is an urgent need for the development of effective agents to protect against the toxic effects of ZnONPs. Astragalus memeranaceus (AM), a famous Traditional Chinese Medicine, as well as its bioactive components, showing a potential neuroprotective function. This study aims to investigate the neuroprotective effects of bioactive components of AM against ZnONPs-induced toxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. The cell apoptosis, ROS generation, MMP changes, mitochondrial fission/fusion, biogenesis, and mitophagy were assessed. In this study, AM treatment inhibited ZnONPs-induced cell apoptosis and ROS overproduction in SH-SY5Y cells. And astragaloside IV (ASIV) played a dominant role in the attenuation of cytotoxicity after ZnONPs exposure, rather than flavonoids and polysaccharides. ASIV treatment significantly reduced ROS generation and MMP collapse in ZnONPs-exposed cells. Furthermore, the protein expressions of mitochondrial biogenesis (PGC-1α), fusion (Mfn1 and Mfn2), and fission (Drp1) were markedly increased. Meanwhile, the PINK1/Parkin-mediated mitophagy was activated after ASIV administration, which ameliorated ZnONPs-induced SH-SY5Y cell death. Collectively, ASIV administration mitigated ZnONPs-induced cytotoxicity in SH-SY5Y cells through restoring mitochondrial quality control process, which hinted the protective role of ASIV in ZnONPs-induced neurotoxicity. Graphical abstract
研究领域:
药理学
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毒理学
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神经科学
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细胞生物学
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Tiancheng Li,Mengmeng Shu,Cheng Zhu,Yixin Li,Qicheng Liu,Zhiyu Zhu,Yangyang Jiang,Peng Mei,Yu Jin,Bing Fang,Lunguo Xia
In osteoarthritic chondrocytes, dysregulation of mitochondrial dynamics due to excessive intracellular reactive oxygen species (ROS) under inflammatory conditions is a significant contributory factor to poor treatment outcomes, because it leads to a reduced cell response to chondrogenic drugs during this state. The aim of this study was to develop a multifunctional Au@CeO 2 yolk-shell nanozyme (YSN) as a novel therapeutic nanomaterial and drug delivery system. Under photothermal conditions, Au@CeO 2 nanozymes neutralized excessive ROS, enhanced antioxidant capacity, and maintained mitochondrial homeostasis of osteoarthritic chondrocytes, thereby restoring cellular responsiveness to external stimuli. Furthermore, bioactive peptide CK2.1 loaded in YSNs (Au@CeO 2 -CK2.1) achieved ordered release under photothermal conditions, effectively promoting chondrocyte anabolic activity. In a mice osteoarthritis (OA) model, local Au@CeO 2 -CK2.1 photothermal therapy effectively enhanced cartilage repair and regeneration in vivo . Mechanically, our research uncovers that decreased chondrogenic drug response is associated with activation of extracellular regulated kinase-1 and -2 (ERK1/2) pathway, and Au@CeO 2 -CK2.1 YSNs regulates mitochondrial dynamics through inhibiting ERK1/2 and dynamin-1-like protein (DRP1) phosphorylation. The results of this study demonstrated an effective therapeutic strategy that rescued chondrogenic drug response in osteoarthritic chondrocytes, achieving anti-inflammation and cartilage regeneration.
研究领域:
纳米技术
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生物材料
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药物递送系统
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再生医学
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骨科
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细胞生物学
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高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 6
·228
·
IF 5.4
Ting Sun,Huimin Lv,Huarong Shao,Xiuhua Zhang,Anqi Wang,Wei Zhang,Fei Liu,Peixue Ling
Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal–lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development.
研究领域:
肝病学
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细胞生物学
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生物化学
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药理学
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分子生物学
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免疫学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Yue He,Man Shu,Zhimin Li,Yun Liu,Ziyang Xu,Kelie Wang,Yu Zhang,Teliang Lu
Diabetes mellitus (DM)-associated hyperglycemia disrupts vascularized bone regeneration through mitochondrial dysfunction in repair-related cells and hindering scaffold-mediated bone defect repair. To overcome this challenge, we developed an innovative 3D-printed β-tricalcium phosphate scaffold co-doped with zinc and silicon ions (Zn/Si-TCP). In vitro evaluations revealed that Zn/Si-TCP significantly enhanced cellular viability of both endothelial cells and osteoblasts under hyperglycemic conditions, achieving this through dual mechanisms: (1) effective reactive oxygen species (ROS) scavenging (35 % reduction), and (2) restoration of mitochondrial homeostasis, as demonstrated by 1.5-fold upregulation of mitochondrial fusion protein Mfn1 and 0.6-fold downregulation of fission protein Drp1. The scaffold notably improved mitochondrial function, enhancing membrane potential by 1.4-fold and boosting ATP generation by 1.2-fold. These synergistic effects translated to superior biological performance, with 1.5-fold enhancement in angiogenic capacity (tube formation assay) and 1.9-fold increase in osteogenic activity (ALP assay). In vivo studies in a diabetic rat calvarial defect model demonstrated the remarkable efficacy of Zn/Si-TCP scaffolds, which achieved a 4.6-fold increase in vascular density and a 2.0-fold improvement in bone volume fraction (BV/TV) compared to undoped TCP controls at 8 weeks post-implantation, indicating successful vascularized bone reconstruction facilitated by Zn/Si-TCP scaffolds. This study establishes a new paradigm in diabetic bone repair by developing a dual-functional scaffold that coordinately promotes angiogenesis and osteogenesis through mitochondrial homeostasis regulation.
研究领域:
生物医学工程
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组织工程
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再生医学
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骨生物学
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糖尿病研究
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线粒体生物学
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生物材料
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支架设计
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高影响因子
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