SHOCK
·
2023
·
IF 3.1
Luo S,Lyu Z,Ge L,Li Y,Liu Y,Yuan Y,Zhao R,Huang L,Zhao J,Huang H,Luo Y
Background Protein kinase ataxia telangiectasia mutated (ATM) regulates the function of endothelial cells and responds quickly to endotoxin. However, the function of ATM in lipopolysaccharide (LPS) -induced blood-brain barrier (BBB) disruption remains unknown. This study aimed to investigate the role and underlying mechanism of ATM in the regulation of the BBB function in sepsis. Methods We used lipopolysaccharide (LPS) to induce BBB disruption in vivo and to establish an in vitro model of cerebrovascular endothelial cells. BBB disruption was assessed by measuring Evans blue leakage and expression of vascular permeability regulators. To investigate the role of ATM, its inhibitor AZD1390 and clinically approved doxorubicin, an anthracycline that can activate ATM, were administered as scheduled. To explore the underlying mechanism, protein kinase B (AKT) inhibitor MK-2206 was administered to block the AKT/dynamin-related protein 1 (DRP1) pathway. Results LPS challenge induced significant BBB disruption, ATM activation and mitochondrial translocation. Inhibiting ATM with AZD1390 aggravated BBB permeability as well as the following neuroinflammation and neuronal injury, while activation of ATM by doxorubicin abrogated these defects. Further results obtained in brain microvascular endothelial cells showed that ATM inhibition reduced the phosphorylation of DRP1 at serine (S) 637, promoted excessive mitochondrial fission, and resulted in mitochondrial malfunction. By activating ATM, doxorubicin increased the protein binding between ATM and AKT and promoted the phosphorylated activation of AKT at S473, which could directly phosphorylate DRP1 at S637 to repress excessive mitochondrial fission. Consistently, the protective role of ATM was abolished by the AKT inhibitor MK-2206. Conclusions ATM protects against LPS-induced BBB disruption by regulating mitochondrial homeostasis, at least in part, through the AKT/DRP1 pathway.
研究领域:
神经科学
·
免疫学
·
药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Quanwei Li,Pan Guo,Shaofeng Wang,Luna Su,Wenlan Yu,Jianying Guo,Liammei Hu,Hui Zhang,Jiaqiang Pan,Zhaoxin Tang,Jianzhao Liao
As an efficient alternative copper (Cu) source, copper nanoparticles (nano-Cu) have been widely supplemented into animal-producing food. Therefore, it is necessary to assess the effect of nano-Cu exposure on the biological health risk. Recently, the toxic effects of nano-Cu have been confirmed but the underlying mechanism remains unclear. This study reveals the impact of nano-Cu on endoplasmic reticulum autophagy (ER-phagy) in chicken hepatocytes and further identifies Drp1 and its downstream gene FAM134B as crucial regulators of nano-Cu-induced hepatotoxicity. Nano-Cu exposure can induce Cu ion overaccumulation and pathological injury in the liver, trigger excessive mitochondrial fission and mitochondria-associated membrane (MAM) integrity damage, and activate ER-phagy in vivo and in vitro. Interestingly, the knockdown of Drp1 markedly decreases the expression of FAM134B induced by nano-Cu. Furthermore, the expression levels of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I induced by nano-Cu exposure are decreased by inhibiting the expression of Drp1. Simultaneously, the inhibition of FAM134B effectively alleviates nano-Cu-induced ER-phagy by downregulating the expression of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I. Overall, these results suggest that Drp1-mediated impairment of MAM integrity leads to ER-phagy as a novel molecular mechanism involved in the regulation of nano-Cu-induced hepatotoxicity. These findings provide new ideas for future research on the mechanism of nano-Cu-induced hepatotoxicity.
研究领域:
毒理学
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细胞生物学
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分子生物学
·
兽医学
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DOI
PubMed
高影响因子
POULTRY SCIENCE
·
2023
·
IF 4.4
Chen Yang,Pei Luo,You-tian Yang,Xin-liang Fu,Bing-xin Li,Xu Shen,Dan-ning Xu,Yun-mao Huang,Yun-bo Tian,Wen-jun Liu
ABSTRACT The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells’ steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro . Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.
研究领域:
细胞生物学
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内分泌学
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应激生理学
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DOI
PubMed
高影响因子
ACTA HISTOCHEMICA
·
2021
·
IF 2.479
Hongxi Wu,Guodong Li,Weiwei Chen,Wenbin Luo,Zhongyi Yang,Zhipeng You,Yuling Zou
Diabetic retinopathy (DR) is the leading clinical cause of blindness in diabetic patients. Mitophagy participates in the pathogenesis of DR. Dynamin related protein 1 (Drp1) is associated with mitophagy. Here, we investigated whether Drp1 can regulate mitophagy to affect the progression of DR. We constructed DR rat model by administration of streptozocin . Primary rat retinal endothelial cells (RECs) were treated with high glucose (HG) as a DR cell model. Drp1 was highly expressed in the retinal tissues of DR rats and HG-treated RECs. Drp1 knockdown inhibited HG-mediated increase of reactive oxygen species (ROS) levels and apoptosis in RECs. Moreover, Drp1 silencing inhibited the expression of autophagy-related proteins LC3-II/LC3–1 and Beclin-1 and reduced LC3 puncta in HG-treated RECs. The expression of mitochondrial marker Tom20 was reduced and the levels of mitophagy were increased in the HG-treated RECs, which was rescued by Drp1 silencing. Drp1 knockdown repressed LC3-II expression in HG-treated RECs, indicating that autophagy flux was inhibited. Rapamycin (autophagy activator) enhanced ROS levels and apoptosis in HG-treated RECs by activating autophagy, which was rescued by Drp1 knockdown. In conclusion, these data demonstrated that Drp1 knockdown repressed apoptosis of rat retinal endothelial cells by inhibiting mitophagy. Thus, this work suggests that targeted regulation of Drp1 may become a treatment for DR.
研究领域:
眼科学
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细胞生物学
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分子生物学
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糖尿病
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2025
·
IF 4
Peng Chen,Wenhao Xiao,Fanzhao Zou,Jiexin Lei,Fuchao Chen,Ruhong Zhang
This study explored the effects of methylated urolithin A (mUro A), on lipopolysaccharide (LPS)-induced cognitive impairment and anxiety- and depression-like behaviors, and their molecular mechanism. mUro A significantly mitigated cognitive dysfunction, anxiety- and depression-like behaviors. Furthermore, mUro A improved activities of antioxidative enzymes, regulated the release of inflammatory factors, inhibited the LPS-induced generation of Aβ 1 – 42 and restored the cholinergic system balance in the AD mouse brain. Additionally, mUro A markedly attenuated microglial activation by inhibiting the Drp1/HK1/NLRP3 pathway, thereby suppressing mitochondrial inflammation. This was evidenced by the downregulation of p-Drp1 (s616), VDACs, NLRP3, ASC, cleaved caspase 1, IL-18, and IL-1β, alongside the upregulation of HK1 expression. In conclusion, mUro A mitigates AD-associated cognitive deficits by inhibiting the Drp1/HK1/NLRP3 pathway and suppressing mitochondrial inflammation.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
高影响因子
EXPERIMENTAL EYE RESEARCH
·
2022
·
IF 3.77
Min Chen,Qianhui Zhang,Shun Wang,Feng Zheng
Retinal microvascular endothelial cell (RMEC) injury plays an important role in the pathophysiology diabetic retinopathy (DR). The GTPase dynamin-related protein 1 (Drp1), crucial to mitochondrial dynamics , has been implicated in hyperglycaemia-induced microvascular damage. Moreover, Drp1 can be deSUMOylated by the enzyme sentrin/SUMO-specific protease 3 (SENP3). Whether SENP3/deSUMOylated Drp1 can aggravate DR is unclear. Therefore, we designed this experiment to investigate the role of SENP3/desumoylated Drp1 in DR in vitro and in vivo. Murine RMECs (mRMECs) were classified into a control (CON), high-glucose (HG) and high-glucose + SENP3-siRNA (HG-siRNA) groups. The SENP3 and SUMOylated/deSUMOylated drp1 levels, mitochondrial morphology, mitochondrial membrane potential (MMP) and apoptosis rate were evaluated. In vivo, mice were assigned to a normal, type 2 diabetic or type 2 diabetic SENP3-siRNA mouse groups. Then, blood–retinal barrier function and retinal tissue structure were evaluated. As compared to those in the control group, the SENP3 and Drp1 levels, degree of mitochondrial fragmentation, extent of MMP loss and apoptosis rate of mRMECs were significantly increased in the HG group. However, inhibited SENP3 expression increased the level of SUMOylated Drp1 in the mRMECs and reduced the hyperglycaemia-induced mitochondrial damage and apoptosis rate. These experimental results were confirmed by diabetic animal experiments showing that inhibited SENP3 expression attenuated the increase in retinal permeability and diabetic retinopathy, suggesting that SENP3/deSUMOylated Drp1 activation aggravated DR by disrupting mitochondrial dynamics and apoptosis. Furthermore, blocking SENP3 expression significantly attenuated RMEC damage and DR.
研究领域:
糖尿病
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分子生物学
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细胞生物学
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眼科学
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病理生理学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2016
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IF 3.859
Aiyun Li,Shuihong Zhang,Jia Li,Kang Liu,Fang Huang,Baolin Liu
Objective This study was designed to investigate the hypothesis that metformin and resveratrol exhibited the same effect on inhibition of NLRP3 inflammasome activation with regulation of AMPK in adipose tissue exposed to high glucose. Methods To induce adipose tissue dysfunction, we treated epididymal adipose tissue of mice or differentiated 3T3-L1 adipocytes with high glucose (33 mM) for 24 h. Meanwhile, mice were injected with streptozotocin STZ to induce diabetes and followed by oral administration of metformin (200 mg/kg), resveratrol (50 mg/kg) or ER stress inhibitor TUDCA (50 mg/kg) for 7 days. The effects of metformin and resveratrol on ROS production, mitochondrial fission , ER stress, TXNIP/NLRP3 inflammasome activation, inflammation and apoptosis were observed. Results Metformin and resveratrol inhibited ROS-associated mitochondrial fission by upregulating Drp1 phosphorylation (Ser 637) in an AMPK-dependent manner, and then suppressed ER stress indicated by dephosphorylation of IRE1α and eIF2α in the adipose tissue. As a result from suppressing TXNIP/NLRP3 inflammasome activation, metformin and resveratrol inhibited inflammation and reduced cell apoptosis in adipose tissue or adipocytes exposed to high glucose. Conclusion Metformin and resveratrol protected mitochondrial integrity by inhibiting Drp1 activity and prevented NLRP3 inflammasome activation by suppressing ER stress, and thereby protected adipose function from high glucose insult.
研究领域:
药理学
·
内分泌学
·
分子生物学
·
糖尿病研究
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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.
研究领域:
肿瘤学
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细胞生物学
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药理学
·
分子生物学
·
生物信息学
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2022
·Vol. 17
·期 10
·e0275428
·
IF 3.752
Zhi-Bin Dong,Yu-Jia Wang,Meng-Lin Cheng,Bo-Jun Wang,Hong Lu,Hai-Li Zhu,Ling Liu,Min Xie
Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.
研究领域:
药理学
·
神经科学
·
疼痛研究
·
炎症
·
线粒体生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Jie Zhou,Xin Zheng,Chen Xi,Xinyi Tang,Yinjie Jiang,Minjuan Xie,Xiaoyi Fu
Hexavalent chromium [Cr(VI)] is a highly hazardous heavy metal with multiple toxic effects. Occupational studies indicate that its accumulation in humans can lead to liver damage. However, the exact mechanism underlying Cr(VI)-induced hepatotoxicity remains unknown. In this study, we explored the role of CTH/H 2 S/Drp1 pathway in Cr(VI)-induced oxidative stress, mitochondrial dysfunction, apoptosis, and liver injury. Our data showed that Cr(VI) triggered apoptosis, accompanied by H 2 S reduction, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction in both AML12 cells and mouse livers. Moreover, Cr(VI) reduced cystathionine γ-lyase (CTH) and dynamin related protein 1 (Drp1) S-sulfhydration levels, and elevated Drp1 phosphorylation levels at Serine 616, which promoted Drp1 mitochondrial translocation and Drp1-voltage-dependent anion channel 1 (VDAC1) interactions, ultimately leading to mitochondria-dependent apoptosis. Elevated hydrogen sulfide (H 2 S) levels eliminated Drp1 phosphorylation at Serine 616 by increasing Drp1 S-sulfhydration, thereby preventing Cr(VI)-induced Drp1-VDAC1 interaction and hepatotoxicity. These findings indicated that Cr(VI) induced mitochondrial apoptosis and hepatotoxicity by inhibiting CTH/H 2 S/Drp1 pathway and that targeting either CTH/H 2 S pathway or Drp1 S-sulfhydration could serve as a potential therapy for Cr(VI)-induced liver injury.
研究领域:
毒理学
·
细胞生物学
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 14
·期 2
·1024-1036
·
IF 6.317
Weili Li,Haiyang Li,Lujuan Zheng,Jing Xia,Xiaoxuan Yang,Shuhan Men,Ye Yuan,Yuying Fan
Skeletal muscle insulin resistance is the main cause of type 2 diabetes, and mitochondria play a key role. Ginsenoside CK is the main active compound of ginseng with a variety of therapeutic effects, but few studies have reported on its mechanism towards skeletal muscle insulin resistance. Here, we found that CK significantly increased skeletal muscle insulin sensitivity, thereby alleviating hyperglycemia and insulin resistance. Furthermore, the effects of CK on skeletal muscle were associated with an improved mitochondrial fusion/fission dynamics balance and fatty acid oxidation. In fatty acid (FA)-induced C2C12 cells, CK promoted the translocation of GLUT4 to the cell membrane to improve glucose uptake and glycogen synthesis and also enhanced the mitochondrial quality. CK ameliorated the damaged mitochondrial membrane potential (ΔΨm), which was based on mitophagy activation. After the knockdown of mitophagy-related receptors, we found that DRP1/PINK1 was the key pathway of CK-induced mitophagy. These findings indicated that ginsenoside CK is a promising lead compound against diabetes.
研究领域:
药理学
·
内分泌学
·
细胞生物学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-25
·
IF 9.3
Hua Fuzhou,Zhu Hong,Yu Wen,Zheng Qingcui,Zhang Lieliang,Liang Weidong,Lin Yue,Xiao Fan,Yi Pengcheng,Xiong Yanhong,Dong Yao,Li Hua,Fang Lanran,Liu Hailin,Ying Jun,Wang Xifeng
Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients’ brain and bio-fluids (CSF and serum), as well as in animal models for POD. β-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that β-arrestin1, one type of β-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using β-arrestin1 knockout (KO) mice, we find aggravating effect of β-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of β-arrestin1 and demonstrate that β-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. β-arrestin1 deletion cancels the combination of β-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using β-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that β-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.
研究领域:
神经科学
·
药理学
·
炎症
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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