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Ye K, Zhao X, Liu L, Ge F, Zheng F, Liu Z, Tian M, Han X, Gao X, Xia Q, Wang D. Comparative Analysis of Human Brain RNA-seq Reveals the Combined Effects of Ferroptosis and Autophagy on Alzheimer's Disease in Multiple Brain Regions. Mol Neurobiol 2025; 62:6128-6149. [PMID: 39710824 DOI: 10.1007/s12035-024-04642-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024]
Abstract
Ferroptosis and autophagy are closely associated with Alzheimer's disease (AD). Elevated ferric ion levels can induce oxidative stress and chronic inflammatory responses, resulting in brain tissue damage and further neurological cell damage. Autophagy in Alzheimer's has a dual role. On one hand, it protects neurons by removing β-amyloid and cellular damage products caused by oxidative stress and inflammation. On the other hand, abnormal autophagy is linked to neuronal apoptosis and neurodegeneration. However, the intricate interplay between ferroptosis and autophagy in AD remains insufficiently explored. This study focuses on the roles of ferroptosis and autophagy in AD and their interconnection through bioinformatics analysis, shedding light on the disease. Ferroptosis and autophagy significantly correlate with the development and course of AD. Using PPI network analysis and unsupervised consistency clustering analysis, we uncovered a complex network of interactions between ferroptosis and autophagy during disease progression, demonstrating a significant congruence in their modification patterns. Functional analyses further demonstrated that ferroptosis and autophagy together affect the immunological status and synaptic regulation in hippocampal regions in patients with AD, which significantly impacts the start and progression of the disease.
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Affiliation(s)
- Ke Ye
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xue Zhao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Lulu Liu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Fangliang Ge
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Feifei Zheng
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Zijie Liu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Mengjie Tian
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xinyu Han
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
- Key Laboratory of Heilongjiang Province for Genetically Modified Animals, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150000, Heilongjiang, China.
| | - Qing Xia
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Dayong Wang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, 150000, Heilongjiang, China.
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Tian Q, Jiang H, Luan Y, Sun J, Sui Y, Chen L, Wang Y, Tan N. Vicenin-2 in Suhuang antitussive capsule attenuates mitophagy-dependent ferroptosis via LRP1 for treating post-infectious cough. JOURNAL OF ETHNOPHARMACOLOGY 2025; 349:119880. [PMID: 40288661 DOI: 10.1016/j.jep.2025.119880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 04/17/2025] [Accepted: 04/24/2025] [Indexed: 04/29/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Suhuang antitussive capsule (SH) is the only clinically approved traditional Chinese patent medicine for the treatment of post-infectious cough (PIC). During the past decade, our lab has conducted intensive researches on SH, including its efficacy and mechanism on PIC, and determined that SH has favorable anti-inflammatory, antitussive, expectorant, and anti-asthmatic pharmacological effects. Recently, we found that vicenin-2 (VIC-2) could be detected in SH and showed activity in vitro primary screening on PIC. AIM OF THE STUDY To investigate the therapeutic effects of VIC-2 on PIC and its potential mechanisms, and want to elucidate VIC-2 as one of the efficacious components of SH. MATERIALS AND METHODS The PIC mouse model was established with lipopolysaccharide (LPS)-induced combined cigarette smoke (CS)-exposed ICR mice, while the in vitro assay was constructed to induce BEAS-2B cells with cigarette smoke extract (CSE). The therapeutic effects of VIC-2 on PIC in vitro and in vivo were assessed by pathological sections, cough assay, immune cell counting, and quantitative-polymerase chain reaction (Q-PCR). The mechanisms of VIC-2 on ferroptosis and mitophagy in PIC were further explored by cell viability assay, Prussian blue staining, lipid peroxidation assessment, confocal laser scanning microscopy, and western blotting. Subsequently, virtual docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) verified the target relationship between VIC-2 and LDL receptor-related protein 1 (LRP1). In addition, the link between LRP1 and mitophagy-dependent ferroptosis was explored by knocking down LRP1. RESULTS VIC-2 significantly improved lung inflammation, oxidative stress, and airway remodeling in PIC and inhibited mitophagy-dependent ferroptosis, confirming that it is one of the antitussive components of SH for the treatment of PIC. LRP1 is one of the pharmacological targets of VIC-2, in which VIC-2 exerted the above effects through up-regulating LRP1 by influencing the LRP1-Parkin interaction. The blockade of LRP1 reversed the both in vitro and in vivo pharmacological activities of VIC-2. Furthermore, our results showed for the first time that defects in LRP1 lead to ferroptosis. CONCLUSION This study demonstrates that VIC-2 inhibits mitophagy-dependent ferroptosis via LRP1 for the treatment of PIC, constituting one of the antitussive components of SH.
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Affiliation(s)
- Qimeng Tian
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Hong Jiang
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yajun Luan
- Beijing Haiyan Pharmaceutical Co., Ltd., Yangzijiang Pharmaceutical Group, Beijing, 102206, PR China
| | - Jingge Sun
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yihang Sui
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Ling Chen
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China
| | - Yongxiang Wang
- Key Laboratory for Quality Control of Traditional Chinese Medicine of National Administration of Traditional Chinese Medicine, Institute of Chinese Medicine, Jiangsu Longfengtang Chinese Medicine Co., Ltd., Yangzijiang Pharmaceutical Group, Taizhou, 225321, PR China.
| | - Ninghua Tan
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, PR China.
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Cao R, Li H, Liu G, Yan P, Zhang J, Chen Y, Duan X, Zhao Y, Lei Y, Liu C, Guan H, Xing F, Li Y, Wang K, Kong N, Tian R, Yang P. Aging and autophagic phenotypic changes in bone marrow mesenchymal stem cells in glucocorticoid-induced osteonecrosis. Int Immunopharmacol 2025; 152:114389. [PMID: 40073811 DOI: 10.1016/j.intimp.2025.114389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 02/20/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND Glucocorticoid (GC) overuse is the main cause of osteonecrosis of the femoral head (ONFH). The dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays an important role in ONFH pathogenesis. Physiological concentrations of GCs can induce the osteogenic differentiation of BMSCs; however, intervention with high concentrations of GC may lead to changes in aging and autophagy in certain cell types. METHODS We generated an ONFH mouse model by injecting C57BL/6 J mice with MPS. BMSCs were harvested from the femora and tibiae of mice and were analyzed for osteogenesis, adipogenesis, senescence, and cell proliferation. In vitro, BMSCs were treated with different concentrations of GC for 48 h, followed by functional analyses to identify differentially expressed genes (DEGs) associated with ONFH. Additionally, various bioinformatics analyses were performed to identify differentially expressed genes in ONFH. RESULTS BMSCs from ONFH mice showed signs of aging, as indicated by increased SA-β-gal positive cells (4.4-fold) and upregulated p53 (2.6-fold) and p21 (2.0-fold) protein expression. It is also accompanied by changes in osteogenic/lipogenic differentiation ability. Bioinformatics analysis further verified these findings. High-dose GC stimulation significantly induced cellular senescence of BMSCs, as indicated by an increase in SA-β-gal positive cells (6.2-fold) and a decrease in autophagy levels. GC stimulation changes the differentiation fate of BMSCs. CONCLUSIONS Our results indicated that GC-induced ONFH was associated with changes in aging and autophagy in BMSCs. GC not only directly affected the osteogenic differentiation of BMSCs but also indirectly affected their differentiation fate through aging and autophagy changes.
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Affiliation(s)
- Ruomu Cao
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Heng Li
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Guanzhi Liu
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peng Yan
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiewen Zhang
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Chen
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xudong Duan
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yiwei Zhao
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yutian Lei
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chenkun Liu
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Huanshuai Guan
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fangze Xing
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yiyang Li
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kunzheng Wang
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ning Kong
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Run Tian
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Pei Yang
- Department of Bone and Joint Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Liu Z, Peng H, Liu P, Duan F, Yang Y, Li P, Li Z, Wu J, Chang J, Shang D, Tian Q, Zhang J, Xie Y, Liu Z, An Y. Deciphering significances of autophagy in the development and metabolism of adipose tissue. Exp Cell Res 2025; 446:114478. [PMID: 39978716 DOI: 10.1016/j.yexcr.2025.114478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/17/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
The mechanisms of adipose tissue activation and inactivation have been a hot topic of research in the last decade, from which countermeasures have been attempted to be found against obesity as well as other lipid metabolism-related diseases, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. Autophagy has been shown to be closely related to the regulation of adipocyte activity, which is involved in the whole process including white adipocyte differentiation/maturation and brown or beige adipocyte generation/activation. Dysregulation of autophagy in adipose tissue has been demonstrated to be associated with obesity. On this basis, we summarize the pathways and mechanisms of autophagy involved in the regulation of lipid metabolism and present a review of its pathophysiological roles in lipid metabolism-related diseases, in the hope of providing ideas for the treatment of these diseases.
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Affiliation(s)
- Zitao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Haoyuan Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengfei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Feiyi Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yutian Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengkun Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiaoyan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiayi Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Dandan Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Qiwen Tian
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Jiawei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Yucheng Xie
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China; Henan Provincial Research Center of Engineering Technology for Nuclear Protein Medical Detection, Zhengzhou Health College, Zhengzhou, 450064, China.
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Wang Z, Chen H, Xiong S, Chen X, Gao X, Huang P, Zou J, Cao H. Lactobacillus plantarum SMUM211204 Exopolysaccharides Have Tumor-Suppressive Effects on Colorectal Cancer by Regulating Autophagy via the mTOR Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:5931-5946. [PMID: 40017402 DOI: 10.1021/acs.jafc.4c09818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Probiotics have demonstrated their ability to suppress tumors in cell lines and mouse models. However, the precise molecules responsible for these effects remain unidentified. We focused on isolating and analyzing the exopolysaccharides (EPSs) produced by Lactobacillus plantarum (L. plantarum) SMUM211204. Our findings confirm that EPSs impair the growth of HCT116 cells and induce autophagy and apoptosis. Moreover, further experimental evidence demonstrates that EPSs diminish the expression of phosphorylation levels of PI3K, AKT, and mTOR. In contrast, they boost the expression of AMPKa, elevate the ULK1 level, and increase the protein LC3-II/I ratio. Furthermore, when rapamycin is employed to impede EPS-induced autophagy, it results in an enhancement of apoptosis and cell death in HCT116 cells. To validate these findings in vivo, we conducted an animal study using a colorectal cancer xenograft model. The results showed a significant reduction in tumor volume and weight in the EPS-treated group compared with the control group. Immunohistochemical analysis of tumors indicated increased expressions of LC3 and caspase-3, along with decreased levels of phospho-PI3Kinase, phospho-AKT, and P62, consistent with in vitro findings. Our study proved that EPSs have an inhibitory effect on colorectal cancer and can be used as a preventive and therapeutic drug for cancer.
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Affiliation(s)
- Zixuan Wang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hengqiu Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Shasha Xiong
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xiaoliang Chen
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xuefeng Gao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Pengwei Huang
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jinhu Zou
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hong Cao
- Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
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McCormick JJ, Goulet N, King KE, Fujii N, Amano T, Kenny GP. The effect of high-intensity exercise in temperate and hot ambient conditions on autophagy and the cellular stress response in young and older females. Am J Physiol Regul Integr Comp Physiol 2025; 328:R90-R101. [PMID: 39601770 DOI: 10.1152/ajpregu.00178.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/23/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024]
Abstract
The process of autophagy is vital in maintaining normal cellular function, especially during exposure to elevated states of physiological stress associated with exercise and hot ambient temperatures. Although prior observations are primarily limited to responses in males, the autophagic response to acute physiological stress in females represents a considerable knowledge gap. Therefore, we assessed autophagy and related pathways of cellular stress in peripheral blood mononuclear cells (PBMCs) from 20 healthy young [n = 10, mean (SD): aged 23 yr (3)] and older [n = 10, aged 69 yr (3)] females in response to 30 min of semi-recumbent high-intensity cycling exercise (70% of predetermined maximal oxygen consumption) in temperate (25°C) and hot (40°C) ambient conditions (15% relative humidity). Mean body temperature (rectal and skin) was measured throughout, whereas cellular responses were evaluated before and after exercise, including up to 6 h of seated recovery. Proteins associated with autophagy and related pathways were assessed via Western blot. Mean body temperature was elevated after exercise in both conditions, with significant elevations observed after exercise in the heat (all, P ≤ 0.05). Although young females displayed signs of elevated autophagic activity [elevations in microtubule-associated light chain 3B (LC3)-II and beclin-2] in response to exercise performed in both temperate and hot ambient conditions (all, P ≤ 0.05), responses were attenuated in older females. This was accompanied by elevations in chaperone-mediated autophagy in young but not in older females in response to exercise independent of ambient temperature. Our findings indicate exercise, with and without ambient heat exposure may stimulate the autophagic response in young but not in older females.NEW & NOTEWORTHY We show for the first time that an acute bout (30 min) of high-intensity intensity exercise stimulates autophagy in young females irrespective of ambient heat exposure. However, older females did not display the same increase in autophagy as their younger counterparts when high-intensity exercise was performed in temperate or hot ambient conditions. Consequently, older females may be at an elevated risk of heat-induced cellular damage during exertional heat stress.
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Affiliation(s)
- James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Nicholas Goulet
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Kelli E King
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Naoto Fujii
- Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
| | - Tatsuro Amano
- Laboratory for Exercise and Environmental Physiology, Faculty of Education, Niigata University, Niigata, Japan
| | - Glen P Kenny
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Hua X, Xiang D, Xu J, Zhang S, Wu S, Tian Z, Zhu J, Huang C. ISO-upregulated BECN1 specifically promotes LC3B-dependent autophagy and anticancer activity in invasive bladder cancer. Transl Oncol 2025; 51:102178. [PMID: 39489089 PMCID: PMC11565558 DOI: 10.1016/j.tranon.2024.102178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/18/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024] Open
Abstract
Isorhapontigenin (ISO), an active compound isolated from the Chinese herb Gnetum Cleistostachyum, exhibited strong preventive and therapeutic effects on bladder cancer (BC) both in vitro and in vivo. Our previous studies revealed that ISO-induced autophagy is crucial for its anti-cancer activity. However, the underlying mechanism remains unclear. Here, we showed that BECN1, an important autophagic protein, was induced by ISO treatment and played crucial roles in ISO-induced late phase of LC3B-dependent, and LC3A-independent autophagy, as well as anti-cancer activity. Downregulation of BECN1 was observed in human BCs and BBN-induced mouse invasive BC tissues, whereas co-treatment with ISO completely reversed BECN1 downregulation in BBN-induced mouse invasive BCs. Consistently, ISO treatment significantly increased BECN1 expression in vitro in a dose- and time-dependent manner. Depletion of BECN1 significantly impaired LC3B-dependent autophagy following ISO treatment, as well as abolished the inhibitory effect of ISO on anchorage-independent growth of human BC cells. Mechanistic studies revealed that BECN1 induction was mediated by ISO downregulation of c-Myc, which resulted in miR-613 reduction, in turn leading to increased NCL translation and further promoting NCL binding to BECN1 mRNA, subsequently stabilizing BECN1 mRNA. In conclusion, our results demonstrate that by activating c-Myc/miR-613/NCL axis, ISO treatment results in BECN1 posttranscriptional upregulation, which specifically initiates LC3B-dependent autophagy and anti-cancer activity. Our findings further strengths our application of ISO for therapy of high-grade invasive BC (HGIBC) patients.
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Affiliation(s)
- Xiaohui Hua
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China; School of Laboratory Medicine and Life Sciences, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Daimin Xiang
- Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China
| | - Jiheng Xu
- School of Laboratory Medicine and Life Sciences, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shouyue Zhang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Shuai Wu
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Zhongxian Tian
- School of Laboratory Medicine and Life Sciences, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Junlan Zhu
- School of Laboratory Medicine and Life Sciences, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuanshu Huang
- Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui, China; School of Laboratory Medicine and Life Sciences, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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Zhang Y, Zhu Y, Li F, Zhou Q, Zhou J. A Decrease in Autophagy Increases the Level of Collagen Type I Expression in Scleral Fibroblasts. Curr Eye Res 2025; 50:58-65. [PMID: 39229688 DOI: 10.1080/02713683.2024.2393370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 07/06/2024] [Accepted: 08/09/2024] [Indexed: 09/05/2024]
Abstract
PURPOSE Autophagy dysregulation triggers extracellular matrix remodeling via changes in cellular collagen levels and protease secretion. However, the effect of autophagy on scleral extracellular matrix remodeling in the context of myopia is not fully understood. In this study, we measured the level of autophagy in sclera of form deprivation myopic guinea pigs; we also sought a correlation between the level of autophagy in human scleral fibroblasts and the extent of COL1A1 synthesis. METHODS We measured the level of COL1A1 expression and the levels of autophagic protein markers in scleral tissues in vivo using a form deprivation myopic guinea pig model. Rapamycin and chloroquine were respectively used to activate and inhibit autophagy in cultured human scleral fibroblasts. COL1A1 gene and protein expression levels were analyzed via quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence. Levels of autophagy-related proteins were assessed via Western blotting. RESULTS The sclera of form deprivation myopic guinea pig eyes exhibited decreased expression of COL1A1 and increased expression level of autophagy. After chloroquine exposure, human scleral fibroblasts exhibited decreased autophagy and increased COL1A1 expression. CONCLUSION Inhibition of scleral fibroblast autophagy increased COL1A1 expression at the gene and protein levels, thus explaining the effect of autophagy on collagen synthesis by scleral fibroblasts.
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Affiliation(s)
- Yingjie Zhang
- Department of Ophthalmology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi Zhu
- Shanghai Aier Eye Hospital, Shanghai, China
- Shanghai Aier Eye Institute, Shanghai, China
| | - Fang Li
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qimin Zhou
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Jibo Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
- College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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9
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Zhang Y, Zhou J, Yang L, Xiao H, Liu D, Kang X. Ganoderma lucidum Spore Powder Alleviates Metabolic-Associated Fatty Liver Disease by Improving Lipid Accumulation and Oxidative Stress via Autophagy. Antioxidants (Basel) 2024; 13:1501. [PMID: 39765829 PMCID: PMC11673792 DOI: 10.3390/antiox13121501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/16/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
Lipid accumulation and oxidative stress, which could be improved by autophagy, are the "hits" of metabolic-associated fatty liver disease (MAFLD). Ganoderma lucidum spore powder (GLSP) has the effect of improving liver function. However, there are few reports about its effects on and mechanisms impacting MAFLD alleviation. This study investigated the effect of GLSP on hepatic lipid accumulation and oxidative stress and explored the role that autophagy played in this effect. The results showed that GLSP effectively reduced lipid accumulation and activated autophagy in the livers of mice with high-fat-diet-induced disease and palmitic acid-induced hepatocytes. GLSP reduced the lipid accumulation by reducing lipogenesis and promoting lipid oxidation in HepG2 cells. It decreased the production of ROS, increased the activity of SOD and CAT, and improved the mitochondrial membrane potential via the Keap1/Nrf2 pathway. The alleviating effects of GLSP on the lipid accumulation and oxidative stress was reversed by 3-methyladenine (3-MA), an autophagy inhibitor. GLSP activated autophagy via the AMPK pathway in HepG2 cells. In conclusion, GLSP could attenuate MAFLD by the improvement of lipid accumulation and oxidative stress via autophagy. This paper is the first to report the improvement of MAFLD through autophagy promotion. It will shed novel light on the discovery of therapeutic strategies targeting autophagy for MAFLD.
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Affiliation(s)
- Yuxuan Zhang
- Horticulture College, Hunan Agricultural University, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Hunan Agricultural University, Changsha 410128, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Hunan Agricultural University, Changsha 410128, China
| | - Jiali Zhou
- Horticulture College, Hunan Agricultural University, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Hunan Agricultural University, Changsha 410128, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Hunan Agricultural University, Changsha 410128, China
| | - Lan Yang
- Horticulture College, Hunan Agricultural University, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Hunan Agricultural University, Changsha 410128, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Hunan Agricultural University, Changsha 410128, China
- School of Pharmacy, North Sichuan Medical College, Nanchong 637000, China
| | - Hang Xiao
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
| | - Dongbo Liu
- Horticulture College, Hunan Agricultural University, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Hunan Agricultural University, Changsha 410128, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Hunan Agricultural University, Changsha 410128, China
- National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha 410128, China
| | - Xincong Kang
- Horticulture College, Hunan Agricultural University, Changsha 410128, China
- State Key Laboratory of Subhealth Intervention Technology, Hunan Agricultural University, Changsha 410128, China
- Hunan Provincial Engineering Research Center of Medical Nutrition Intervention Technology for Metabolic Diseases, Hunan Agricultural University, Changsha 410128, China
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10
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Li H, Wang S, An S, Gao B, Wu D, Li Y. Hydrogen sulphide reduces renal ischemia-reperfusion injury by enhancing autophagy and reducing oxidative stress. Nephrology (Carlton) 2024; 29:645-654. [PMID: 39075751 DOI: 10.1111/nep.14368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/11/2024] [Accepted: 07/02/2024] [Indexed: 07/31/2024]
Abstract
AIM Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury. Hydrogen sulphide (H2S) exerts a protective effect in renal IRI. The present study was carried out to investigate the effects of exogenous H2S on renal IRI by regulating autophagy in mice. METHODS Mice were randomly assigned to control, IRI and NaHS (an H2S donor, 28, 56 and 100 μmol/kg) groups. Renal IRI was induced by clamping the bilateral renal pedicles with non-traumatic arterial clamp for 45 min and then reperfused for 24 h. Mice were administered intraperitoneally with NaHS 20 min prior to renal ischemia. Sham group mice underwent the same procedures without clamping. Serum and kidney tissues were harvested 24 h after reperfusion for functional, histological, oxidative stress, and autophagic determination. RESULTS Compared with the control group, the concentrations of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), the protein levels of LC3II/I, Beclin-1 and P62, as well as the number of autophagosomes were significantly increased, but the activity of superoxide dismutase (SOD) was decreased after renal IRI. NaHS pre-treatment dramatically attenuated renal IRI-induced renal dysfunction, histological changes, MDA concentration and p62 expression in a dose-dependent manner. However, NaHS increased the SOD activity and the protein levels of LC3II/I and Beclin-1. CONCLUSION These results indicate that exogenous H2S protects the kidney from IRI through enhancement of autophagy and reduction of oxidative stress. Novel H2S donors could be developed in the treatment of renal IRI.
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Affiliation(s)
- Hui Li
- Joint National Laboratory of Antibody Drug Engineering, Henan University, Kaifeng, Henan, China
| | - Shuaiwei Wang
- International Laboratory for Sepsis Research, Huaihe Hospital, Henan University, Kaifeng, Henan, China
| | - Shuangshuang An
- Joint National Laboratory of Antibody Drug Engineering, Henan University, Kaifeng, Henan, China
| | - Biao Gao
- Kaifeng Central Hospital, Kaifeng, Henan, China
| | - Dongdong Wu
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
| | - Yanzhang Li
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
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11
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Pattoo TS, Khanday FA. Corelating the molecular structure of BAG3 to its oncogenic role. Cell Biol Int 2024; 48:1080-1096. [PMID: 38924608 DOI: 10.1002/cbin.12199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/22/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024]
Abstract
BAG3 is a multifaceted protein characterised by having WW domain, PXXP motif and BAG domain. This protein gets upregulated during malignant transformation of cells and has been associated with poorer survival of patients. Procancerous activity of BAG domain of BAG3 is well documented. BAG domain interacts with ATPase domain of Hsp-70 preventing protein delivery to proteasome. This impediment results in enhanced cell survival, proliferation, resistance to apoptosis and chemoresistance. Besides BAG domain other two domains/motifs of BAG3 are under research vigilance to explore its further oncogenic role. This review summarises the role of different structural determinants of BAG3 in elevating oncogenesis. Based on the already existing findings, more interacting partners of BAG3 are anticipated. The anticipated partners of BAG3 can shed a wealth of information into the mechanistic insights of its proproliferative role. Proper insights into the mechanistic details adopted by BAG3 to curtail/elaborate activity of anticipated interacting partners can serve as a potent target for development of therapeutic interventions.
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Affiliation(s)
| | - Firdous A Khanday
- Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India
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12
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Jakubek P, Pakula B, Rossmeisl M, Pinton P, Rimessi A, Wieckowski MR. Autophagy alterations in obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease: the evidence from human studies. Intern Emerg Med 2024; 19:1473-1491. [PMID: 38971910 PMCID: PMC11364608 DOI: 10.1007/s11739-024-03700-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/26/2024] [Indexed: 07/08/2024]
Abstract
Autophagy is an evolutionarily conserved process that plays a pivotal role in the maintenance of cellular homeostasis and its impairment has been implicated in the pathogenesis of various metabolic diseases including obesity, type 2 diabetes (T2D), and metabolic dysfunction-associated steatotic liver disease (MASLD). This review synthesizes the current evidence from human studies on autophagy alterations under these metabolic conditions. In obesity, most data point to autophagy upregulation during the initiation phase of autophagosome formation, potentially in response to proinflammatory conditions in the adipose tissue. Autophagosome formation appears to be enhanced under hyperglycemic or insulin-resistant conditions in patients with T2D, possibly acting as a compensatory mechanism to eliminate damaged organelles and proteins. Other studies have proposed that prolonged hyperglycemia and disrupted insulin signaling hinder autophagic flux, resulting in the accumulation of dysfunctional cellular components that can contribute to β-cell dysfunction. Evidence from patients with MASLD supports autophagy inhibition in disease progression. Nevertheless, given the available data, it is difficult to ascertain whether autophagy is enhanced or suppressed in these conditions because the levels of autophagy markers depend on the overall metabolism of specific organs, tissues, experimental conditions, or disease duration. Owing to these constraints, determining whether the observed shifts in autophagic activity precede or result from metabolic diseases remains challenging. Additionally, autophagy-modulating strategies are shortly discussed. To conclude, more studies investigating autophagy impairment are required to gain a more comprehensive understanding of its role in the pathogenesis of obesity, T2D, and MASLD and to unveil novel therapeutic strategies for these conditions.
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Affiliation(s)
- Patrycja Jakubek
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland.
| | - Barbara Pakula
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland
| | - Martin Rossmeisl
- Laboratory of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Paolo Pinton
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
- Center of Research for Innovative Therapies in Cystic Fibrosis, University of Ferrara, 44121, Ferrara, Italy
| | - Alessandro Rimessi
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
- Center of Research for Innovative Therapies in Cystic Fibrosis, University of Ferrara, 44121, Ferrara, Italy
| | - Mariusz Roman Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur St., 02-093, Warsaw, Poland.
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13
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Tao Y, Ding X, Jia C, Wang C, Li C. Using protein turnover assay to explore the drug mechanism of Carfilzomib. Acta Biochim Biophys Sin (Shanghai) 2024; 57:209-222. [PMID: 38978505 PMCID: PMC11877146 DOI: 10.3724/abbs.2024104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 05/06/2024] [Indexed: 07/10/2024] Open
Abstract
Carfilzomib (CFZ) is the second-generation proteasome inhibitor that is approved by Food and Drug Administration (FDA) of USA for the treatment of relapsed and refractory multiple myeloma. Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated. Since CFZ primarily functions as a proteasome inhibitor, profiling CFZ-induced changes in protein turnover at the systematic level is sufficient and necessary. In this study, we characterize the effects of CFZ on the stability of 15,000 human proteins using Protein Turnover Assay (ProTA). CFZ affects fundamental cellular glycolysis, nitric oxide production and proteasome subunit homeostasis in multiple myeloma cells. In addition, LY294002 or KU-0063794 has synergistic effects with CFZ in multiple myeloma treatment. A profound understanding of how cells respond to chemotherapeutic agents provides insights into the basic mechanism of drug function and the rationale for CFZ combination therapy.
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Affiliation(s)
- Yonghui Tao
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of EducationKey Laboratory of Molecular Biology in Medical SciencesZhejiang ProvinceChina)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
| | - Xinyu Ding
- Department of Thoracic SurgeryShanghai Pulmonary HospitalTongji University School of MedicineShanghai200433China
| | - Caiwei Jia
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
| | | | - Chuanyin Li
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of EducationKey Laboratory of Molecular Biology in Medical SciencesZhejiang ProvinceChina)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
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14
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Yin XM, Song YY, Jiang WY, Zhang HT, Chen JW, Murao K, Han MX, Sun WP, Zhang GX. Mitochondrial K ATP channel-mediated autophagy contributes to angiotensin II-induced vascular dysfunction in mice. Nutr Metab Cardiovasc Dis 2024; 34:1571-1580. [PMID: 38418351 DOI: 10.1016/j.numecd.2024.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 10/28/2023] [Accepted: 01/15/2024] [Indexed: 03/01/2024]
Abstract
BACKGROUND AND AIM The present study aimed to investigate whether the mitochondrial KATP channel contributes to angiotensin II (Ang II)-induced vascular dysfunction, the development of hypertension, and atherosclerosis. METHODS AND RESULTS ApoE (-/-) mice fed a high-fat diet were chronically infused with Ang II for eight weeks and concomitantly treated with losartan (ARB), apocynin, or 5-hydroxy decanoate (5-HD), or 3-methyladenine (3-MA). Systolic blood pressure was measured, and pathological changes of aortic or liver tissue were observed. Nitric oxide (NO), superoxide dismutase 2 (SOD2) levels and vasorelaxation rate were measured, and protein and mRNA expressions were examined by western blot and RT-PCR. Ang II-induced development of hypertension was suppressed not only by ARB, and apocynin but also by 5-HD or 3-MA. Ang II infusion decreased aortic NO production and relaxation, as well as SOD2 activity in liver, which were improved by all treatments. In addition, Ang II-induced activation of autophagy was suppressed by 5-HD in aortic tissue, furthermore, Ang II increases the atherosclerotic index in plasma and exacerbates the development of atherosclerosis by increases of fat deposition in the aorta and liver. Lipid metabolism-related mRNA expressions (LXR-α, LDLR, SRBI, Acca, and FASN) were changed by Ang II. Similarly, not only ARB, and apocynin, but also 5-HD and 3-MA suppressed Ang II-induced these changes. CONCLUSIONS Our present findings evidence that mitochondrial KATP channel-mediated autophagy contributes to Ang II-induced vascular dysfunction, development of hypertension, and atherosclerosis.
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Affiliation(s)
- Xue-Min Yin
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China
| | - Yi-Yi Song
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China
| | - Wen-Yi Jiang
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China
| | - Hao-Tian Zhang
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China
| | - Jing-Wei Chen
- Department of Internal Medicine, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, 18 Yang-Su Road, Suzhou 215003, PR China
| | - Koji Murao
- Department of Endocrine and Metabolism, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Meng-Xiao Han
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China.
| | - Wan-Ping Sun
- Laboratory of Molecular Diagnostics, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China.
| | - Guo-Xing Zhang
- Department of Physiology, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China; Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, PR China.
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15
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Dhas N, Kudarha R, Tiwari R, Tiwari G, Garg N, Kumar P, Kulkarni S, Kulkarni J, Soman S, Hegde AR, Patel J, Garkal A, Sami A, Datta D, Colaco V, Mehta T, Vora L, Mutalik S. Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies. Life Sci 2024; 346:122629. [PMID: 38631667 DOI: 10.1016/j.lfs.2024.122629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/04/2024] [Accepted: 04/10/2024] [Indexed: 04/19/2024]
Abstract
Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.
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Affiliation(s)
- Namdev Dhas
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Ritu Kudarha
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Ruchi Tiwari
- Pranveer Singh Institute of Technology (Pharmacy), Kalpi road, Bhauti, Kanpur 208020, Uttar Pradesh, India
| | - Gaurav Tiwari
- Pranveer Singh Institute of Technology (Pharmacy), Kalpi road, Bhauti, Kanpur 208020, Uttar Pradesh, India
| | - Neha Garg
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Praveen Kumar
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Sanjay Kulkarni
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Jahnavi Kulkarni
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Soji Soman
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Aswathi R Hegde
- Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, New BEL Road, MSR Nagar, Bangalore 560054, Karnataka, India
| | | | - Atul Garkal
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Anam Sami
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Deepanjan Datta
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Viola Colaco
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India
| | - Tejal Mehta
- Department of Pharmaceutics, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal 576104, Karnataka, India.
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16
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Han YZ, Du BX, Zhu XY, Wang YZY, Zheng HJ, Liu WJ. Lipid metabolism disorder in diabetic kidney disease. Front Endocrinol (Lausanne) 2024; 15:1336402. [PMID: 38742197 PMCID: PMC11089115 DOI: 10.3389/fendo.2024.1336402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.
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Affiliation(s)
- Yi-Zhen Han
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Bo-Xuan Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Xing-Yu Zhu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yang-Zhi-Yuan Wang
- School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
| | - Hui-Juan Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wei-Jing Liu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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17
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Song W, Zhang L, Cui X, Wang R, Ma J, Xu Y, Jin Y, Wang D, Lu Z. Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis. Sci Rep 2024; 14:7889. [PMID: 38570541 PMCID: PMC10991266 DOI: 10.1038/s41598-024-55614-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 02/26/2024] [Indexed: 04/05/2024] Open
Abstract
Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.
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Affiliation(s)
- Wenao Song
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
| | - Li Zhang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Xiaolin Cui
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
| | - Rongrong Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
| | - Jingyu Ma
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yue Xu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
| | - Yan Jin
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Dawei Wang
- Department of Orthopedic, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
| | - Zhiming Lu
- Department of Clinical Laboratory, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China.
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
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Nasr M, Fay A, Lupieri A, Malet N, Darmon A, Zahreddine R, Swiader A, Wahart A, Viaud J, Nègre-Salvayre A, Hirsch E, Monteyne D, Perez-Morgà D, Dupont N, Codogno P, Ramel D, Morel E, Laffargue M, Gayral S. PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice. Arterioscler Thromb Vasc Biol 2024; 44:620-634. [PMID: 38152888 DOI: 10.1161/atvbaha.123.319978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/12/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs. METHODS Using fluid flow system to generate forces on EC and multiscale imaging analyses on ApoE-/- mice whole arteries, we studied the cellular and molecular mechanism involved in autophagic response to LSS or HSS on the endothelium. RESULTS We found that LSS and HSS trigger autophagy activation by mobilizing specific autophagic signaling modules. Indeed, LSS-induced autophagy in endothelium was independent of the class III PI3K (phosphoinositide 3-kinase) VPS34 (vacuolar sorting protein 34) but controlled by the α isoform of class II PI3K (phosphoinositide 3-kinase class II α [PI3KCIIα]). Accordingly, reduced PI3KCIIα expression in ApoE-/- mice (ApoE-/-PI3KCIIα+/-) led to EC dysfunctions associated with increased plaque deposition in the LSS regions. Mechanistically, we revealed that PI3KCIIα inhibits mTORC1 (mammalian target of rapamycin complex 1) activation and that rapamycin treatment in ApoE-/-PI3KCIIα+/- mice specifically rescue autophagy in arterial LSS regions. Finally, we demonstrated that absence of PI3KCIIα led to decreased endothelial primary cilium biogenesis in response to LSS and that ablation of primary cilium mimics PI3KCIIα-decreased expression in EC dysfunction, suggesting that this organelle could be the mechanosensor linking PI3KCIIα and EC homeostasis. CONCLUSIONS Our data reveal that mechanical forces variability within the arterial system determines EC autophagic response and supports a central role of PI3KCIIα/mTORC1 axis to prevent EC dysfunction in LSS regions.
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Affiliation(s)
- Mouin Nasr
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Alexis Fay
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Adrien Lupieri
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Nicole Malet
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Anne Darmon
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Rana Zahreddine
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Audrey Swiader
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Amandine Wahart
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Julien Viaud
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Anne Nègre-Salvayre
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Emilio Hirsch
- Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy (E.H.)
| | - Daniel Monteyne
- IBMM-DBM, Department of Molecular Parasitology, University of Brussels, Gosselies, Belgium (D.M., D.P.-M.)
| | - David Perez-Morgà
- IBMM-DBM, Department of Molecular Parasitology, University of Brussels, Gosselies, Belgium (D.M., D.P.-M.)
| | - Nicolas Dupont
- Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, France (N.D., P.C., E.M.)
| | - Patrice Codogno
- Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, France (N.D., P.C., E.M.)
| | - Damien Ramel
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Etienne Morel
- Institut Necker-Enfants Malades (INEM), INSERM U1151-CNRS UMR 8253, Université Paris Descartes-Sorbonne Paris Cité, France (N.D., P.C., E.M.)
| | - Muriel Laffargue
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
| | - Stephanie Gayral
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut national de la Santé et de la Recherche (INSERM) 1297, University of Toulouse 3, France (M.N., A.F., A.L., N.M., A.D., R.Z., A.S., A.W., J.V., A.N.-S., D.R., M.L., S.G.)
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19
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McCormick JJ, McManus MK, King KE, Goulet N, Kenny GP. The intensity-dependent effects of exercise and superimposing environmental heat stress on autophagy in peripheral blood mononuclear cells from older men. Am J Physiol Regul Integr Comp Physiol 2024; 326:R29-R42. [PMID: 37955130 DOI: 10.1152/ajpregu.00163.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/14/2023]
Abstract
Autophagy is a vital cellular process, essential to maintaining cellular function during acute physiological stressors including exercise and heat stress. We previously showed that autophagy occurs during exercise in an intensity-dependent manner in peripheral blood mononuclear cells (PBMCs) from young men, with elevated responses in the heat. However, given autophagy declines with age, it is unclear whether a similar pattern of response occurs in older adults. Therefore, we evaluated autophagy and the cellular stress response [i.e., apoptosis, inflammation, and the heat shock response (HSR)] in PBMCs from 10 healthy older men [mean (SD): aged 70 yr (5)] in response to 30 min of semirecumbent cycling at low, moderate, and vigorous intensities [40, 55, and 70% maximal oxygen consumption (V̇o2max), respectively] in a temperate (25°C) environment, with an additional vigorous-intensity bout (70% of V̇o2max) performed in a hot environment (40°C). Responses were evaluated before and after exercise, as well as throughout a 6-h seated recovery period performed in the same environmental conditions as the respective exercise bout. Proteins were assessed via Western blot. Although we observed elevations in mean body temperature with each increase in exercise intensity, autophagy was only stimulated during vigorous-intensity exercise, where we observed elevations in LC3-II (P < 0.05). However, when the same exercise was performed in the heat, the LC3-II response was attenuated, which was accompanied by significant p62 accumulation (P < 0.05). Altogether, our findings demonstrate that older adults exhibit autophagic impairments when the same vigorous-intensity exercise is performed in hot environments, potentially underlying heat-induced cellular vulnerability in older men.NEW & NOTEWORTHY We demonstrate that autophagic stimulation occurs in response to short-duration (30-min) vigorous-intensity exercise in peripheral blood mononuclear cells from older adults; however, no changes in autophagy occur during low- or moderate-intensity exercise. Moreover, older adults exhibit autophagic impairments when the same vigorous-intensity exercise is performed in hot ambient conditions. When paired with an attenuated heat shock response, as well as elevated apoptotic responses, older men may exhibit greater cellular vulnerability to exertional heat stress.
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Affiliation(s)
- James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Morgan K McManus
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Kelli E King
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Nicholas Goulet
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Glen P Kenny
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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20
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Han D, Kim D, Kim H, Lee J, Lyu J, Kim JS, Shin J, Kim JS, Kim DK, Park HW. Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway. Front Pharmacol 2023; 14:1302227. [PMID: 38099147 PMCID: PMC10720622 DOI: 10.3389/fphar.2023.1302227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 11/20/2023] [Indexed: 12/17/2023] Open
Abstract
Introduction: Metabolism-associated fatty liver disease (MAFLD) is a global health concern because of its association with obesity, insulin resistance, and other metabolic abnormalities. Methylsulfonylmethane (MSM), an organic sulfur compound found in various plants and animals, exerts antioxidant and anti-inflammatory effects. Here, we aimed to assess the anti-obesity activity and autophagy-related mechanisms of Methylsulfonylmethane. Method: Human hepatoma (HepG2) cells treated with palmitic acid (PA) were used to examine the effects of MSM on autophagic clearance. To evaluate the anti-obesity effect of MSM, male C57/BL6 mice were fed a high-fat diet (HFD; 60% calories) and administered an oral dose of MSM (200 or 400 mg/kg/day). Moreover, we investigated the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex 1 (mTORC1)/UNC-51-like autophagy-activating kinase 1 (ULK1) signaling pathway to further determine the underlying action mechanism of MSM. Results: Methylsulfonylmethane treatment significantly mitigated PA-induced protein aggregation in human hepatoma HepG2 cells. Additionally, Methylsulfonylmethane treatment reversed the PA-induced impairment of autophagic flux. Methylsulfonylmethane also enhanced the insulin sensitivity and significantly suppressed the HFD-induced obesity and hepatic steatosis in mice. Western blotting revealed that Methylsulfonylmethane improved ubiquitinated protein clearance in HFD-induced fatty liver. Remarkably, Methylsulfonylmethane promoted the activation of AMPK and ULK1 and inhibited mTOR activity. Conclusion: Our study suggests that MSM ameliorates hepatic steatosis by enhancing the autophagic flux via an AMPK/mTOR/ULK1-dependent signaling pathway. These findings highlight the therapeutic potential of MSM for obesity-related MAFLD treatment.
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Affiliation(s)
- Daewon Han
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Deokryong Kim
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Haeil Kim
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Jeonga Lee
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Jungmook Lyu
- Department of Medical Science, Konyang University, Daejeon, Republic of Korea
| | - Jong-Seok Kim
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Jongdae Shin
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Jeong Sig Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Do Kyung Kim
- Department of Anatomy, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Hwan-Woo Park
- Department of Cell Biology, Konyang University College of Medicine, Daejeon, Republic of Korea
- Myunggok Medical Research Institute, Konyang University College of Medicine, Daejeon, Republic of Korea
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21
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Sberna G, Maggi F, Amendola A. Virus-Encoded Circular RNAs: Role and Significance in Viral Infections. Int J Mol Sci 2023; 24:16547. [PMID: 38003737 PMCID: PMC10671809 DOI: 10.3390/ijms242216547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/17/2023] [Accepted: 11/19/2023] [Indexed: 11/26/2023] Open
Abstract
Circular RNAs (circRNAs) have been the focus of intense scientific research to understand their biogenesis, mechanisms of action and regulatory functions. CircRNAs are single stranded, covalently closed RNA molecules lacking the 5'-terminal cap and the 3'-terminal polyadenine chain, characteristics that make them very stable and resistant. Synthesised by both cells and viruses, in the past circRNAs were considered to have no precise function. Today, increasing evidence shows that circRNAs are ubiquitous, some of them are tissue- and cell-specific, and critical in multiple regulatory processes (i.e., infections, inflammation, oncogenesis, gene expression). Moreover, circRNAs are emerging as important biomarkers of viral infection and disease progression. In this review, we provided an updated overview of current understanding of virus-encoded and cellular-encoded circRNAs and their involvement in cellular pathways during viral infection.
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Affiliation(s)
| | | | - Alessandra Amendola
- Laboratory of Virology and Biosafety Laboratories, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, 00149 Rome, Italy; (G.S.)
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22
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Qiang L, Zhao B, Ming M, Wang N, He TC, Hwang S, Thorburn A, He YY. Autophagy regulates tumor growth and metastasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.31.564991. [PMID: 37961427 PMCID: PMC10635024 DOI: 10.1101/2023.10.31.564991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
The role of autophagy in tumorigenesis and tumor metastasis remains poorly understood. Here we show that inhibition of autophagy stabilizes the transcription factor Twist1 through Sequestosome-1 (SQSTM1, also known as p62) and thus increases cell proliferation, migration, and epithelial-mesenchymal transition (EMT) in tumor development and metastasis. Inhibition of autophagy or p62 overexpression blocks Twist1 protein degradation in the proteasomes, while p62 inhibition enhances it. SQSTM1/p62 interacts with Twist1 via the UBA domain of p62, in a Twist1-ubiquitination-dependent manner. Lysine 175 in Twist1 is critical for Twist1 ubiquitination, degradation, and SQSTM1/p62 interaction. For squamous skin cancer and melanoma cells that express Twist1, SQSTM1/p62 increases tumor growth and metastasis in mice. Together, our results identified Twist1 as a key downstream protein for autophagy and suggest a critical role of the autophagy/p62/Twist1 axis in cancer development and metastasis.
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Affiliation(s)
- Lei Qiang
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA
| | - Baozhong Zhao
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA
| | - Mei Ming
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA
| | - Ning Wang
- Department of Orthopaedic Surgery & Rehabilitation Medicine, University of Chicago, Chicago, IL, USA
| | - Tong-Chuan He
- Department of Orthopaedic Surgery & Rehabilitation Medicine, University of Chicago, Chicago, IL, USA
| | - Seungmin Hwang
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Andrew Thorburn
- Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA
| | - Yu-Ying He
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA
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23
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Medras ZJH, Mostafa YM, Ahmed AAM, El‐Sayed NM. Arctigenin improves neuropathy via ameliorating apoptosis and modulating autophagy in streptozotocin-induced diabetic mice. CNS Neurosci Ther 2023; 29:3068-3080. [PMID: 37170684 PMCID: PMC10493658 DOI: 10.1111/cns.14249] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 03/11/2023] [Accepted: 03/23/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Oxidative stress mediates the pathophysiology of diabetic neuropathy (DN) with activation of apoptotic pathway and reduction of autophagy. Arctigenin (ARC) is a natural lignan isolated from some plants of the Asteraceae family that shows antioxidant property. The present study aimed to explore the mechanistic neuroprotective effect of ARC on animal model for DN. METHODS DN was induced using streptozotocin (STZ) at a dose of 45 mg/kg, i.p, for five consecutive days and ARC was administered orally (25 or 50 mg) for 3 weeks. The mechanical sensitivity and thermal latency were determined using von Frey and hotplate, respectively. Beclin, p62, and LC3 were detected as markers for autophagy by western blot. Levels of reduced glutathione, lipid peroxides, and activities of catalase and superoxide dismutase were detected as readout for oxidative stress. Apoptotic parameters and histopathological changes were revealed in all experimental groups. RESULTS The present study showed deterioration of the function and structure of neurons as a result of hyperglycemia. Oxidative stress and impaired autophagy were observed in diabetic neurons as well as the activation of apoptotic pathway. ARC improved the behavioral and histopathological changes of diabetic mice. ARC combated oxidative stress through diminishing lipid peroxidation and improving the activity of antioxidant enzymes. This was concomitant by reducing the biomarkers of apoptosis. ARC augmented the expression of Beclin and LC3 while it lessened the expression of p62 indicating the activation of autophagy. These findings suggest that ARC can ameliorate DN by combating apoptosis and oxidative stress and improving autophagy.
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Affiliation(s)
| | - Yasser M. Mostafa
- Department of Pharmacology and Toxicology, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt
- Department of Pharmacology & Toxicology, Faculty of PharmacyBadr University in CairoBadrEgypt
| | - Amal A. M. Ahmed
- Department of Cytology and Histology, Faculty of Veterinary MedicineSuez Canal UniversityIsmailiaEgypt
| | - Norhan M. El‐Sayed
- Department of Pharmacology and Toxicology, Faculty of PharmacySuez Canal UniversityIsmailiaEgypt
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Ruocco C, Malavazos AE, Ragni M, Carruba MO, Valerio A, Iacobellis G, Nisoli E. Amino acids contribute to adaptive thermogenesis. New insights into the mechanisms of action of recent drugs for metabolic disorders are emerging. Pharmacol Res 2023; 195:106892. [PMID: 37619907 DOI: 10.1016/j.phrs.2023.106892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/28/2023] [Accepted: 08/17/2023] [Indexed: 08/26/2023]
Abstract
Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes - controlling adipokines, microRNAs, extracellular vesicles, and metabolites - and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor - with never before seen weight loss and insulin-sensitizing efficacy - promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat.
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Affiliation(s)
- Chiara Ruocco
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, via Vanvitelli, 32, 20129 Milan, Italy
| | - Alexis Elias Malavazos
- Endocrinology Unit, Clinical Nutrition and Cardiovascular Prevention Service, IRCCS Policlinico San Donato, Piazza Edmondo Malan, 2, San Donato Milanese, 20097 Milan, Italy; Department of Biomedical, Surgical and Dental Sciences, University of Milan, via della Commenda, 10, 20122 Milan, Italy
| | - Maurizio Ragni
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, via Vanvitelli, 32, 20129 Milan, Italy
| | - Michele O Carruba
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, via Vanvitelli, 32, 20129 Milan, Italy
| | - Alessandra Valerio
- Department of Molecular and Translational Medicine, University of Brescia, viale Europa, 11, 25123 Brescia, Italy
| | - Gianluca Iacobellis
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, 1400 NW 12th Ave, Miami, FL, USA
| | - Enzo Nisoli
- Center for Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, via Vanvitelli, 32, 20129 Milan, Italy.
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25
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Jin C, Wang T, Yang Y, Zhou P, Li J, Wu W, Lv X, Ma G, Wang A. Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds. ENVIRONMENTAL RESEARCH 2023; 227:115721. [PMID: 36965788 DOI: 10.1016/j.envres.2023.115721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/13/2023] [Accepted: 03/18/2023] [Indexed: 05/08/2023]
Abstract
The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.
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Affiliation(s)
- Canhui Jin
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Tianbao Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Yanhui Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, China
| | - Pin Zhou
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Juncheng Li
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Wenhao Wu
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Xin Lv
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Guoqing Ma
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China
| | - Aihong Wang
- Department of Gastrointestinal Surgery, South China Hospital, Health Science Center, Shenzhen University, Shenzhen, 518116, PR China.
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Su HY, Yang JJ, Zou R, An N, Chen XC, Yang C, Yang HJ, Yao CW, Liu HF. Autophagy in peritoneal fibrosis. Front Physiol 2023; 14:1187207. [PMID: 37256065 PMCID: PMC10226653 DOI: 10.3389/fphys.2023.1187207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/03/2023] [Indexed: 06/01/2023] Open
Abstract
Peritoneal dialysis (PD) is a widely accepted renal replacement therapy for patients with end-stage renal disease (ESRD). Morphological and functional changes occur in the peritoneal membranes (PMs) of patients undergoing long-term PD. Peritoneal fibrosis (PF) is a common PD-related complication that ultimately leads to PM injury and peritoneal ultrafiltration failure. Autophagy is a cellular process of "self-eating" wherein damaged organelles, protein aggregates, and pathogenic microbes are degraded to maintain intracellular environment homeostasis and cell survival. Growing evidence shows that autophagy is involved in fibrosis progression, including renal fibrosis and hepatic fibrosis, in various organs. Multiple risk factors, including high-glucose peritoneal dialysis solution (HGPDS), stimulate the activation of autophagy, which participates in PF progression, in human peritoneal mesothelial cells (HPMCs). Nevertheless, the underlying roles and mechanisms of autophagy in PF progression remain unclear. In this review, we discuss the key roles and potential mechanisms of autophagy in PF to offer novel perspectives on future therapy strategies for PF and their limitations.
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Műzes G, Sipos F. Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy. Biomedicines 2023; 11:1130. [PMID: 37189748 PMCID: PMC10135912 DOI: 10.3390/biomedicines11041130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023] Open
Abstract
The immune system and autophagy share a functional relationship. Both innate and adaptive immune responses involve autophagy and, depending on the disease's origin and pathophysiology, it may have a detrimental or positive role on autoimmune disorders. As a "double-edged sword" in tumors, autophagy can either facilitate or impede tumor growth. The autophagy regulatory network that influences tumor progression and treatment resistance is dependent on cell and tissue types and tumor stages. The connection between autoimmunity and carcinogenesis has not been sufficiently explored in past studies. As a crucial mechanism between the two phenomena, autophagy may play a substantial role, though the specifics remain unclear. Several autophagy modifiers have demonstrated beneficial effects in models of autoimmune disease, emphasizing their therapeutic potential as treatments for autoimmune disorders. The function of autophagy in the tumor microenvironment and immune cells is the subject of intensive study. The objective of this review is to investigate the role of autophagy in the simultaneous genesis of autoimmunity and malignancy, shedding light on both sides of the issue. We believe our work will assist in the organization of current understanding in the field and promote additional research on this urgent and crucial topic.
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Affiliation(s)
| | - Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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Jiang L, Moqbel SAA, Zhu J, Fu Q, Lai J, Lin C, Wu L. Nesfatin-1 suppresses autophagy of chondrocytes in osteoarthritis via remodeling of cytoskeleton and inhibiting RhoA/ROCK signal pathway. J Orthop Surg Res 2023; 18:153. [PMID: 36859270 PMCID: PMC9979404 DOI: 10.1186/s13018-023-03539-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 01/13/2023] [Indexed: 03/03/2023] Open
Abstract
Autophagy and cytoskeleton integrity of chondrocytes are a considered as major factors in the progression of osteoarthritis (OA) involving excessive chondrocyte apoptosis and senescence. Nesfatin-1, an adipokine, has been reported to be closely related to cell autophagy and cytoskeleton malfunction. Our previous study found that nesfatin-1 was highly correlated with OA progress in OA patient, and the expression of nesfatin-1 rises in knee articular tissue, serum and chondrocytes. In current study, we aimed to explore the therapeutic effect of nesfatin-1 on OA and its molecular mechanism related to chondrocyte autophagy and cytoskeleton malfunction. We firstly demonstrated that nesfatin-1 effectively suppressed excessive autophagy of OA chondrocytes at both gene and protein levels. Meanwhile, we also found that nesfatin-1 significantly improved cytoskeleton integrity by showing higher F-actin/G-actin ratio, as well as more organized actin fiber structure. Mechanistically, utility of RhoA activator and inhibitor revealed that regulation of autophagy and cytoskeleton integrity via nesfatin-1 was realized via RhoA/ROCK pathway. We also confirmed that nesfatin-1 significantly ameliorated IL-1β induced cartilage degeneration via destabilization of the medial meniscus (DMM) model. Overall, our study indicates that nesfatin-1 might be a promising therapeutic molecule for OA intervention.
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Affiliation(s)
- Lifeng Jiang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Orthopedics Research Institute of Zhejiang University, Hangzhou, China. .,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China. .,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China.
| | - Safwat Adel Abdo Moqbel
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedics Research Institute of Zhejiang University, Hangzhou, China.,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China.,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China
| | - Junxiong Zhu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedics Research Institute of Zhejiang University, Hangzhou, China.,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China.,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China
| | - Qiangchang Fu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedics Research Institute of Zhejiang University, Hangzhou, China.,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China.,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China
| | - Jiabin Lai
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedics Research Institute of Zhejiang University, Hangzhou, China.,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China.,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China
| | - Changjian Lin
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedics Research Institute of Zhejiang University, Hangzhou, China.,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China.,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China
| | - Lidong Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. .,Orthopedics Research Institute of Zhejiang University, Hangzhou, China. .,Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, China. .,Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, China.
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29
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Chen T, Tu S, Ding L, Jin M, Chen H, Zhou H. The role of autophagy in viral infections. J Biomed Sci 2023; 30:5. [PMID: 36653801 PMCID: PMC9846652 DOI: 10.1186/s12929-023-00899-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/10/2023] [Indexed: 01/20/2023] Open
Abstract
Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses and autophagy have armed viruses with multiple strategies to subvert the autophagic machinery and counteract cellular antiviral responses. Specifically, the host cell quickly initiates the autophagy to degrade virus particles or virus components upon a viral infection, while cooperating with anti-viral interferon response to inhibit the virus replication. Degraded virus-derived antigens can be presented to T lymphocytes to orchestrate the adaptive immune response. Nevertheless, some viruses have evolved the ability to inhibit autophagy in order to evade degradation and immune responses. Others induce autophagy, but then hijack autophagosomes as a replication site, or hijack the secretion autophagy pathway to promote maturation and egress of virus particles, thereby increasing replication and transmission efficiency. Interestingly, different viruses have unique strategies to counteract different types of selective autophagy, such as exploiting autophagy to regulate organelle degradation, metabolic processes, and immune responses. In short, this review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions.
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Affiliation(s)
- Tong Chen
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Shaoyu Tu
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Ling Ding
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Meilin Jin
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Huanchun Chen
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
| | - Hongbo Zhou
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430030 China ,grid.35155.370000 0004 1790 4137Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430030 China
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Sun Y, Wang H, Qu T, Luo J, An P, Ren F, Luo Y, Li Y. mTORC2: a multifaceted regulator of autophagy. Cell Commun Signal 2023; 21:4. [PMID: 36604720 PMCID: PMC9814435 DOI: 10.1186/s12964-022-00859-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/06/2022] [Indexed: 01/06/2023] Open
Abstract
Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. Video abstract.
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Affiliation(s)
- Yanan Sun
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Huihui Wang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, 730070 China
| | - Taiqi Qu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Junjie Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Peng An
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Fazheng Ren
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Yongting Luo
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
| | - Yixuan Li
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083 China
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31
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Yao S, Weng Q, Zhu Y, Liu J, Luo Y, Da D, Zhang Y. Excessive fluoride impairs autophagy flux in ameloblasts which is prevented by the autophagy activator rapamycin. ENVIRONMENTAL TOXICOLOGY 2023; 38:193-204. [PMID: 36190517 DOI: 10.1002/tox.23677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 08/13/2022] [Accepted: 09/17/2022] [Indexed: 06/16/2023]
Abstract
Excessive fluoride intake can cause dental fluorosis during teeth development and growth. However, the mechanisms underlying fluoride-induced enamel damage are still not fully elucidated. Previously, we observed fluoride-induced autophagy in ameloblasts, but the effects of fluoride on autophagy flux in ameloblasts remain unclear. Hence, this study aimed to clarify the effects of fluoride and rapamycin, an autophagy activator, on autophagy flux in ameloblasts. This in vitro study used the murine ameloblast-derived cell line LS8. Cells were treated with different concentrations of sodium fluoride (NaF) to evaluate NaF-induced cytotoxicity. Using transmission electron microscopy, we observed an increase in the number of autophagosomes with increasing fluoride concentrations. Western blot analyses showed increases in microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1 (p62) expression after NaF treatment and an increase in LC3II expression after bafilomycin A1 administration. Together with changes in RFP-GFP-LC3 lentivirus expression, this demonstrated that fluoride impaired autophagy flux. Furthermore, we evaluated whether rapamycin can alleviate fluoride-induced cytotoxicity by restoring autophagy flux. Compared to the NaF-treated group, LS8 cells cotreated with NaF and rapamycin grew considerably better and had significantly decreased p62 expression. Taken together, these data suggest that fluoride-induced impaired autophagosome degradation may damage ameloblasts. This provides experimental in vitro evidence and an explanation for the observed NaF-induced toxicity of ameloblasts. Rapamycin probably alleviates this impairment by decreasing the expression of p62, thereby preventing autophagy defects.
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Affiliation(s)
- Shuran Yao
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Qingqing Weng
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Yiying Zhu
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Jialiang Liu
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Yinyue Luo
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Dongxin Da
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
| | - Ying Zhang
- Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China
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32
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Lu P, Fang M, Yao L, Zhang N, Xu K, He P. Massage of Bladder Meridian Relieved Anxiety Induced by Chronic Stress in Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5639716. [PMID: 36531656 PMCID: PMC9754834 DOI: 10.1155/2022/5639716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 09/24/2022] [Accepted: 11/08/2022] [Indexed: 08/02/2024]
Abstract
The aim of this paper was to explore the mechanism of bladder meridian massage (BMM) on anxiety in rats with chronic stress. Chronic stress induced rats to establish rat anxiety model. The sugar water preference (SPF), tail suspension time (TST), and forced swimming time (FST) of rats were measured. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and inflammatory cytokines in serum and hippocampus of rats were detected. Brain neurotransmitters (dopamine (DA), 5- hydroxytryptamine (5-HT), and norepinephrine (NE)) were detected by enzyme-linked immunosorbent assay (ELISA) kits. Immunohistochemistry and western blotting were used to detect autophagy protein expression in hippocampus of rats. BMM significantly increased SPF, decreased TST and FST, increased SOD level in serum and hippocampus, and decreased MDA level and cytokine level. BMM reversed the changes of neurotransmitters. At the same time, BMM significantly decreased autophagy protein expression in hippocampus of rats. The above results show that BMM significantly relieve anxiety induced by chronic stress in rats.
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Affiliation(s)
- Ping Lu
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
| | - Min Fang
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
| | - Lei Yao
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
| | - Nan Zhang
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
| | - Ke Xu
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
| | - Pei He
- College of Acupuncture and Massage, Shanghai University of Chinese Medicine, China
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33
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Tang H, Qin K, Wang A, Li S, Fang S, Gao W, Lu M, Huang W, Zhang H, Yin Z. 3,3'-diindolylmethane inhibits LPS-induced human chondrocytes apoptosis and extracellular matrix degradation by activating PI3K-Akt-mTOR-mediated autophagy. Front Pharmacol 2022; 13:999851. [PMID: 36438802 PMCID: PMC9684728 DOI: 10.3389/fphar.2022.999851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/10/2022] [Indexed: 09/08/2024] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by articular cartilage destruction. The pathological mechanisms are complex; in particular, inflammation, autophagy, and apoptosis are often involved. 3,3-Diindolylmethane (DIM), a phytoconstituent extracted from cruciferous vegetables, has various effects such as anti-inflammatory, antioxidant and anti-apoptotic. However, the effects of DIM on osteoarthritic chondrocytes remain undetermined. In this study, we simulated a lipopolysaccharide (LPS)-induced osteoarthritis model in human primary chondrocytes. We found that LPS stimulation significantly inhibited autophagy, induced chondrocyte apoptosis and extracellular matrix (ECM) degradation, which could be ameliorated by DIM. DIM inhibited the expression of a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), matrix metalloproteinase 13 (MMP13), cleaved caspase-3, Bax, and p62, and increased the expression level of collagen II, aggrecan, Bcl-2, light chain 3 Ⅱ (LC3 Ⅱ), and beclin-1. Mechanistic studies showed that DIM increased chondrocyte autophagy levels by inhibiting the activation of PI3K/AKT/mTOR pathway. In mice destabilization of the medial meniscus (DMM) model, immunohistochemical analysis showed that DIM inhibited the expression of p-PI3K and cleaved caspase-3, increased the expression of LC3 Ⅱ. Furthermore, DIM relieved joint cartilage degeneration. In conclusion, our findings demonstrate for the first time that DIM inhibits LPS-induced chondrocyte apoptosis and ECM degradation by regulating the PI3K/AKT/mTOR-autophagy axis and delays OA progression in vivo.
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Affiliation(s)
- Hao Tang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- The Key Laboratory of Microbiology and Parasitology of Anhui Province, The Key Laboratory of Zoonoses of High Institutions in Anhui, Anhui Medical University, Hefei, China
| | - Kunpeng Qin
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Anquan Wang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shuang Li
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Sheng Fang
- Department of Orthopedics, The Second People’s Hospital of Hefei, Hefei, China
| | - Weilu Gao
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ming Lu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Huang
- Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hui Zhang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zongsheng Yin
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Tang TL, Yang Y, Guo L, Xia S, Zhang B, Yan M. Sunitinib induced hepatotoxicity in L02 cells via ROS-MAPKs signaling pathway. Front Pharmacol 2022; 13:1002142. [PMID: 36386201 PMCID: PMC9643779 DOI: 10.3389/fphar.2022.1002142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/13/2022] [Indexed: 10/19/2024] Open
Abstract
Sunitinib is a multi-targeted tyrosine kinase inhibitor with remarkable anticancer activity, while hepatotoxicity is a potentially fatal adverse effect of its administration. The aim of this study was to elucidate the mechanism of hepatotoxicity induced by Sunitinib and the protective effect of glycyrrhetinic acid (GA). Sunitinib significantly reduced the survival of human normal hepatocytes (L02 cells), induced the increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Chloroquine (CQ) and Z-VAD-FMK were applied to clarify the cell death patterns induced by Sunitinib. Sunitinib significantly induced L02 cells death by triggering apoptosis and autophagy acted as a self-defense mechanism to promote survival. Sunitinib exposure caused excessive ROS generation which activated mitogen-activated protein kinases (MAPKs) signaling. Mechanistically, SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor) respectively blocked apoptosis and autophagy induced by Sunitinib. And inhibition of ROS by NAC pretreatment ameliorated the effect of Sunitinib on MAPKs phosphorylation. GA alleviated Sunitinib-induced cell damage by inhibiting apoptosis and autophagy. These results suggested ROS/MAPKs signaling pathway was responsible for Sunitinib-induced hepatotoxicity and GA could be a preventive strategy to alleviate liver injury caused by Sunitinib.
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Affiliation(s)
| | | | | | | | | | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
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Li H, Zhou Y, Xu W, Liu J, Wang S, Jiang H. The role of autophagy in calcium oxalate kidney stone: A systematic review of the literature. Front Physiol 2022; 13:1008264. [PMID: 36213233 PMCID: PMC9533137 DOI: 10.3389/fphys.2022.1008264] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Calcium oxalate kidney stone is one of the common diseases in the urinary system and has a high recurrence rate. Currently, the pathogenesis of kidney stone and the methods to prevent recurrence are still being investigated. Autophagy, as an event of cellular self-repair, has received attention in the field of kidney stone in recent years. In some current studies, autophagy has shown destructiveness and protectiveness in the pathogenesis of kidney stone. The inhibition or promotion of autophagy may be a key target for future kidney stone therapy. This systematic literature review discusses the function of autophagy in kidney stone pathogenesis in the context of current research and synthesizes the evidence analysis to provide a basis for new future therapies. Method: We systematically reviewed the literature during September 2021 according to the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) guidelines. Articles on studying the role of autophagy in the pathogenesis of calcium oxalate kidney stone were extracted from PubMed, MEDLINE, Embase and Scopus, including in vivo versus in vitro experiments. The study topic, language and publication date were not restricted. Two authors (Li and Zhou) searched and screened the literature. Results: We screened 18 articles from the 33 collected articles, of which 6 conducted in vitro cellular studies, four conducted animal studies, eight conducted cellular studies with animal studies, and five studied human specimens. In early studies, the literature generally concluded that autophagy is deleterious in the development of kidney stone. In 2020, the idea of the protectiveness of autophagy associated with kidney stone was first proposed and focused on targeting transcription factor EB. In addition, the interaction of autophagy with other cellular events and the regulation of signaling molecules are focused on in this paper. Conclusion: This systematic review provides advances in research on the role of autophagy in renal calculi. The current studies suggest that both upregulation and downregulation of autophagy may ameliorate injury in kidney stone models. The authors prefer the upregulation of autophagy as a future research direction for kidney stone treatment.
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Affiliation(s)
- Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingjian Zhou
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyang Jiang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Hongyang Jiang,
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Yang R, Ma S, Zhuo R, Xu L, Jia S, Yang P, Yao Y, Cao H, Ma L, Pan J, Wang J. Suppression of endoplasmic reticulum stress-dependent autophagy enhances cynaropicrin-induced apoptosis via attenuation of the P62/Keap1/Nrf2 pathways in neuroblastoma. Front Pharmacol 2022; 13:977622. [PMID: 36188599 PMCID: PMC9523313 DOI: 10.3389/fphar.2022.977622] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/05/2022] [Indexed: 12/03/2022] Open
Abstract
Autophagy has dual roles in cancer, resulting in cellular adaptation to promote either cell survival or cell death. Modulating autophagy can enhance the cytotoxicity of many chemotherapeutic and targeted drugs and is increasingly considered to be a promising cancer treatment approach. Cynaropicrin (CYN) is a natural compound that was isolated from an edible plant (artichoke). Previous studies have shown that CYN exhibits antitumor effects in several cancer cell lines. However, it anticancer effects against neuroblastoma (NB) and the underlying mechanisms have not yet been investigated. More specifically, the regulation of autophagy in NB cells by CYN has never been reported before. In this study, we demonstrated that CYN induced apoptosis and protective autophagy. Further mechanistic studies suggested that ER stress-induced autophagy inhibited apoptosis by activating the p62/Keap1/Nrf2 pathways. Finally, in vivo data showed that CYN inhibited tumour growth in xenografted nude mice. Overall, our findings suggested that CYN may be a promising candidate for the treatment of NB, and the combination of pharmacological inhibitors of autophagy may hold novel therapeutic potential for the treatment of NB. Our paper will contribute to the rational utility and pharmacological studies of CYN in future anticancer research.
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Affiliation(s)
- Randong Yang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Shurong Ma
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Ran Zhuo
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Lingqi Xu
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Siqi Jia
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Pengcheng Yang
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Ye Yao
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Haibo Cao
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Liya Ma
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
| | - Jian Pan
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
- *Correspondence: Jian Pan, ; Jian Wang,
| | - Jian Wang
- Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, China
- Department of Pediatric Surgery, Children’s Hospital of Soochow University, Suzhou, China
- *Correspondence: Jian Pan, ; Jian Wang,
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McCormick JJ, Côté MD, King KE, McManus MK, Goulet N, Dokladny K, Moseley PL, Kenny GP. The autophagic response to exercise in peripheral blood mononuclear cells from young men is intensity-dependent and is altered by exposure to environmental heat. Am J Physiol Regul Integr Comp Physiol 2022; 323:R467-R482. [PMID: 35993558 DOI: 10.1152/ajpregu.00110.2022] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Autophagy is essential to maintaining cellular homeostasis in all eukaryotic cells and to tolerance of acute stressors such as starvation, heat, and recovery following exercise. Limited information exists regarding the exercise intensity-dependent autophagic response in humans, and it is unknown how environmental heat stress may modulate this response. Therefore, we evaluated autophagy and accompanying pathways of cellular stress (the heat shock response [HSR], apoptosis, and acute inflammation) in peripheral blood mononuclear cells (PBMCs) from 10 young men (mean [SD]; 22 [2] years) before, immediately after and up to 6h post-exercise recovery from 30 minutes of low-, moderate-, and high-intensity semi-recumbent cycling (40, 55 and 70% of maximal oxygen consumption (VO2max), respectively)in a temperate environment (25°C) and at 70% of VO2max in a hot environment (40°C). Changes in protein content were analyzed via Western blot. Each increase in exercise intensity was associated with elevations in mean body temperature. LC3-II increased following moderate-intensity exercise, with further increases following high-intensity exercise (p < 0.05). However, an increase in beclin-2 and ULK1, with a decrease in p62 was only observed after high-intensity exercise, which was paralleled by elevated TNF-α and cleaved-caspase-3, with the HSR peaking at 6h after exercise (p < 0.05). When exercise was performed in the heat, greater LC3-II and cleaved-caspase-3 accumulation was observed, however beclin-2 declined in recovery (p < 0.05). Therefore, our findings indicate that autophagy in PBMCs during exercise may be associated with greater heat strain exhibited during increasing exercise intensities, which is modulated by exposure to heat.
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Affiliation(s)
- James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Melissa D Côté
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Kelli E King
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Morgan K McManus
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Nicholas Goulet
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Karol Dokladny
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Pope L Moseley
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,College of Health Solutions, Arizona State University, Phoenix, Arizona, United States
| | - Glen P Kenny
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Zhu X, Shen X, Lin B, Fang J, Jin J, He Q. Liuwei Dihuang Pills Inhibit Podocyte Injury and Alleviate IgA Nephropathy by Directly Altering Mesangial Cell-Derived Exosome Function and Secretion. Front Pharmacol 2022; 13:889008. [PMID: 35899112 PMCID: PMC9309816 DOI: 10.3389/fphar.2022.889008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/16/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide. Its pathological features include IgA immune complex deposition, accompanied by mesangial cell proliferation and mesangial matrix expansion. This study was conducted to investigate the effects of Liuwei Dihuang pills (LWDHW) on IgAN in mice and human podocytes, as well as to determine their underlying mechanisms of action. Methods: For in vitro experiments, podocytes were exposed to the human mesangial cell culture medium supernatant of glomerular cells treated with aggregated IgA1 (aIgA1) and LWDHW-containing serum. Cell viability and the proportion of positive cells were evaluated using CCK-8 and flow apoptosis kits, respectively. The cells were collected for western blot analysis. Twenty-four mice with IgAN induced by oral bovine serum albumin administration combined with tail vein injection of staphylococcal enterotoxin B were randomly divided into four groups of six mice each: untreated model group, model + LWDHW group, model + rapamycin group, and model + LWDHW + rapamycin group. The normal control group contained six mice. The red blood cell count in the urine, urine protein, blood urea nitrogen, serum creatinine, and IgA deposition were determined, and TUNEL and western blotting were performed in the mouse kidney tissues. Results:In vitro experiments showed that LWDHW promoted autophagy by regulating the PI3K/Akt/mTOR signalling pathway and improved the damage to podocytes caused by the aIgA1-treated mesangial cell supernatant. This study demonstrates the effectiveness of LWDHW for treating IgAN. In the animal experiments, LWDHW significantly reduced the urine red blood cell count, serum creatinine and urea nitrogen contents, and 24 h urinary protein function and improved IgA deposition in the kidney tissues, glomerular volume, glomerular cell proliferation and polysaccharide deposition, and glomerular cell apoptosis. The pills also reversed the changes in the LC3II/I ratio and p62 content in the kidney tissues. The combination of LWDHW and rapamycin showed stronger inhibitory effects compared to those of LWDHW or rapamycin alone. Conclusion: LWDHW may improve regulation of the PI3K-Akt-mTOR pathway and inhibit autophagy in podocytes, as well as alleviate IgA nephropathy by directly altering mesangial cell exosomes.
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Affiliation(s)
- Xiaodong Zhu
- Bengbu Medical College, Bengbu, China
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Xiaogang Shen
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Bo Lin
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jiaxi Fang
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Juan Jin
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Juan Jin, ; Qiang He,
| | - Qiang He
- Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Juan Jin, ; Qiang He,
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Li Y, Zhang Y, Walayat A, Fu Y, Liu B, Zhang L, Xiao D. The Regulatory Role of H19/miR-181a/ATG5 Signaling in Perinatal Nicotine Exposure-Induced Development of Neonatal Brain Hypoxic-Ischemic Sensitive Phenotype. Int J Mol Sci 2022; 23:6885. [PMID: 35805891 PMCID: PMC9266802 DOI: 10.3390/ijms23136885] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 12/18/2022] Open
Abstract
Nicotine exposure either from maternal cigarette smoking or e-cigarette vaping is one of the most common risk factors for neurodevelopmental disease in offspring. Previous studies revealed that perinatal nicotine exposure programs a sensitive phenotype to neonatal hypoxic-ischemic encephalopathy (HIE) in postnatal life, yet the underlying mechanisms remain undetermined. The goal of the present study was to determine the regulatory role of H19/miR-181a/ATG5 signaling in perinatal nicotine exposure-induced development of neonatal brain hypoxic-ischemic sensitive phenotype. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps. All experiments were conducted in offspring pups at postnatal day 9 (P9). Perinatal nicotine exposure significantly enhanced expression of miR-181a but attenuated autophagy-related protein 5 (ATG5) mRNA and protein levels in neonatal brains. Of interest, miR-181a mimicking administration in the absence of nicotine exposure also produced dose-dependent increased hypoxia/ischemia (H/I)-induced brain injury associated with a decreased ATG5 expression, closely resembling perinatal nicotine exposure-mediated effects. Locked nucleic acid (LNA)-miR-181a antisense reversed perinatal nicotine-mediated increase in H/I-induced brain injury and normalized aberrant ATG5 expression. In addition, nicotine exposure attenuated a long non-coding RNA (lncRNA) H19 expression level. Knockdown of H19 via siRNA increased the miR-181a level and enhanced H/I-induced neonatal brain injury. In conclusion, the present findings provide a novel mechanism that aberrant alteration of the H19/miR-181a/AGT5 axis plays a vital role in perinatal nicotine exposure-mediated ischemia-sensitive phenotype in offspring and suggests promising molecular targets for intervention and rescuing nicotine-induced adverse programming effects in offspring.
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Affiliation(s)
| | | | | | | | | | | | - Daliao Xiao
- Lawrence D. Longo MD Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; (Y.L.); (Y.Z.); (A.W.); (Y.F.); (B.L.); (L.Z.)
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Yang Z, Zhang Z, Zhao Y, Ye Q, Li X, Meng L, Long J, Zhang S, Zhang L. Organelle Interaction and Drug Discovery: Towards Correlative Nanoscopy and Molecular Dynamics Simulation. Front Pharmacol 2022; 13:935898. [PMID: 35795548 PMCID: PMC9251060 DOI: 10.3389/fphar.2022.935898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/01/2022] [Indexed: 11/23/2022] Open
Abstract
The inter-organelle interactions, including the cytomembrane, endoplasmic reticulum, mitochondrion, lysosome, dictyosome, and nucleus, play the important roles in maintaining the normal function and homeostasis of cells. Organelle dysfunction can lead to a range of diseases (e.g., Alzheimer's disease (AD), Parkinson's disease (PD), and cancer), and provide a new perspective for drug discovery. With the development of imaging techniques and functional fluorescent probes, a variety of algorithms and strategies have been developed for the ever-improving estimation of subcellular structures, organelle interaction, and organelle-related drug discovery with accounting for the dynamic structures of organelles, such as the nanoscopy technology and molecular dynamics (MD) simulations. Accordingly, this work summarizes a series of state-of-the-art examples of the recent progress in this rapidly changing field and uncovering the drug screening based on the structures and interactions of organelles. Finally, we propose the future outlook for exciting applications of organelle-related drug discovery, with the cooperation of nanoscopy and MD simulations.
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Affiliation(s)
- Zhiwei Yang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
- School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Zichen Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
| | - Yizhen Zhao
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
| | - Qiushi Ye
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
| | - Xuhua Li
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
| | - Lingjie Meng
- School of Chemistry, Xi’an Jiaotong University, Xi’an, China
- Instrumental Analysis Center, Xi’an Jiaotong University, Xi’an, China
| | - Jiangang Long
- School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China
| | - Shengli Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
| | - Lei Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi’an Jiaotong University, Xi’an, China
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41
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Khalil NM, Yousef RN, AlDeen HG, Behiry ME, Ashmawy I, Ramadan A, Awadallah E, Ali A, Alnaggar AR. Evaluation of the interaction between anti-apoptotic Bcl-2 protein family mRNA expression and autophagy gene Bcl-1 expression in Egyptian SLE patients. Lupus 2022; 31:1186-1190. [PMID: 35657769 DOI: 10.1177/09612033221106302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Autophagy is a complex cellular process that maintains homeostasis in systemic lupus erythematosus. Abnormally high expression of Bcl-2 was observed in B and T lymphocytes in the peripheral blood in SLE patients. These may be responsible for the survival of self-reactive lymphocytes and the development of lupus, and the study aims at evaluating interaction between apoptosis and autophagy in Egyptian lupus patients. METHODS Sixty patients with SLE were diagnosed by fulfilling the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE and sixty healthy age and sex matched control. All patients were subjected to full medical history and clinical examination. Activity was assessed using SLEDAI-2K score. Gene expression of Beclin-1, Bcl-2-L2, and Bcl-2 was measured. RESULTS The study revealed that the expression of anti-apoptotic Bcl-2 and Bcl-2-L2 was significantly higher in SLE patients than control subjects, as well as the major apoptotic agent (Beclin-1) mRNA, p = 0.03, < 0.001 and 0.02, respectively. The apoptotic Beclin-1 mRNA was positively correlated with SLE disease severity index, r = 0.25; p = 0.0.4; therefore, our results showed that expression of the Beclin-1 was significantly higher in SLE patients than control (p < 0.02). CONCLUSION The study showed that the mean levels of Beclin-1, LC-3, and interleukin (IL)-10 transcripts were significantly higher in SLE patients than in control.
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Affiliation(s)
- Noha M Khalil
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, KasrAlainy School of Medicine, 63527Cairo University, Egypt
| | - Rasha N Yousef
- Department of Clinical and Chemical Pathology, 68787National Research Centre, Giza, Egypt
| | - Hecham Gamal AlDeen
- Department of Clinical and Chemical Pathology, 68787National Research Centre, Giza, Egypt
| | - Mervat Essam Behiry
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, KasrAlainy School of Medicine, 63527Cairo University, Egypt
| | - Ingy Ashmawy
- Department of Clinical and Chemical Pathology, 68787National Research Centre, Giza, Egypt
| | - Abeer Ramadan
- Department of Molecular Genetics and Enzymology, National Research Centre, Giza, Egypt
| | - Eman Awadallah
- Department of Clinical and Chemical Pathology, 68787National Research Centre, Giza, Egypt
| | - Asmaa Ali
- Department of Molecular Genetics and Enzymology, National Research Centre, Giza, Egypt
| | - Alshaimaa R Alnaggar
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, KasrAlainy School of Medicine, 63527Cairo University, Egypt
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Identification of a novel autophagy-related prognostic signature and small molecule drugs for glioblastoma by bioinformatics. BMC Med Genomics 2022; 15:111. [PMID: 35550147 PMCID: PMC9097333 DOI: 10.1186/s12920-022-01261-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 04/25/2022] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To explore the autophagy-related prognostic signature (ARPs) via data mining in gene expression profiles for glioblastoma (GBM). METHODS Using the Cancer Genome Atlas (TCGA) database, we obtained 156 GBM samples and 5 adjacent normal samples, and denoted them as discovery cohort. Univariate Cox regression analysis was used to screen autophagy genes that related to GBM prognosis. Then, the least absolute shrinkage and selection operator Cox regression model was used to construct an autophagy-based ARPs, which was validated in an external cohort containing 80 GBM samples. The patients in the above-mentioned cohorts were divided into low-risk group and high-risk group according to the median prognostic risk score, and the diagnostic performance of the model was assessed by receiver operating characteristic curve analyses. The gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analyses were performed between the high-risk and low-risk patients. Additionally, the genetic features of ARPs, such as genetic variation profiles, correlations with tumor-infiltrating lymphocytes (TILs), and potential drug sensitivity, were further assessed in the TCGA-GBM data set. RESULTS A signature of ARPs including NDUFB9, BAK1, SUPT3H, GAPDH, CDKN1B, CHMP6, and EGFR were detected and validated. We identified a autophagy-related prognosis 7-gene signature correlated survival prognosis, immune infiltration, level of cytokines, and cytokine receptor in tumor microenvironment. Furthermore, the signature was tested in several pathways related to disorders of tumor microenvironment, as well as cancer-related pathways. Additionally, a range of small molecular drugs, shown to have a potential therapeutic effect on GBM. CONCLUSIONS We constructed an autophagy-based 7-gene signature, which could serve as an independent prognostic indicator for cases of GBM and sheds light on the role of autophagy as a potential therapeutic target in GBM.
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Fan S, Lin W, Huang Y, Xia J, Xu JF, Zhang J, Pi J. Advances and Potentials of Polydopamine Nanosystem in Photothermal-Based Antibacterial Infection Therapies. Front Pharmacol 2022; 13:829712. [PMID: 35321326 PMCID: PMC8937035 DOI: 10.3389/fphar.2022.829712] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/17/2022] [Indexed: 12/22/2022] Open
Abstract
Bacterial infection remains one of the most dangerous threats to human health due to the increasing cases of bacterial resistance, which is caused by the extensive use of current antibiotics. Photothermal therapy (PTT) is similar to photodynamic therapy (PDT), but PTT can generate heat energy under the excitation of light of specific wavelength, resulting in overheating and damage to target cells or sites. Polydopamine (PDA) has been proved to show plenty of advantages, such as simple preparation, good photothermal conversion effects, high biocompatibility, and easy functionalization and adhesion. Taking these advantages, dopamine is widely used to synthesize the PDA nanosystem with excellent photothermal effects, good biocompatibility, and high drug loading ability, which therefore play more and more important roles for anticancer and antibacterial treatment. PDA nanosystem-mediated PTT has been reported to induce significant tumor inhibition, as well as bacterial killings due to PTT-induced hyperthermia. Moreover, combined with other cancer or bacterial inhibition strategies, PDA nanosystem-mediated PTT can achieve more effective tumor and bacterial inhibitions. In this review, we summarized the progress of preparation methods for the PDA nanosystem, followed by advances of their biological functions and mechanisms for PTT uses, especially in the field of antibacterial treatments. We also provided advances on how to combine PDA nanosystem-mediated PTT with other antibacterial methods for synergistic bacterial killings. Moreover, we further provide some prospects of PDA nanosystem-mediated PTT against intracellular bacteria, which might be helpful to facilitate their future research progress for antibacterial therapy.
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Affiliation(s)
| | | | | | | | - Jun-Fa Xu
- *Correspondence: Jun-Fa Xu, ; Junai Zhang, ; Jiang Pi,
| | - Junai Zhang
- *Correspondence: Jun-Fa Xu, ; Junai Zhang, ; Jiang Pi,
| | - Jiang Pi
- *Correspondence: Jun-Fa Xu, ; Junai Zhang, ; Jiang Pi,
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McCormick JJ, King KE, Rutherford MM, Meade RD, Notley SR, Akerman AP, Dokladny K, Kenny GP. Effect of extracellular hyperosmolality during normothermia and hyperthermia on the autophagic response in peripheral blood mononuclear cells from young men. J Appl Physiol (1985) 2022; 132:995-1004. [PMID: 35238651 DOI: 10.1152/japplphysiol.00661.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Heat-stress induced dehydration is associated with extracellular hyperosmolality. To counteract the associated stress, cells employ cytoprotective mechanisms, including autophagy, however, the autophagic response to hyperosmotic stress has yet to be evaluated in humans. Thus, we investigated autophagy and associated cellular stress pathways (the heat shock response [HSR], apoptosis, and the acute inflammatory response) to isosmotic and hyperosmotic conditions with and without hyperthermia in twelve young men (mean [SD]; 25 [5] years). Participants received a 90-min intravenous infusion of either isosmotic (ISO; 0.9% NaCl; serum osmolality of 293 [4] mOsm/kg) or hyperosmotic (HYP; 3.0% NaCl; 300 [6] mOsm/kg) saline, followed by passive whole-body heating using a water perfused suit to increase esophageal temperature by ~0.8⁰C. Peripheral blood mononuclear cells were harvested at baseline (pre-infusion), post-infusion, and after heating, and changes in protein content were analyzed via Western blotting. Post-infusion, the LC3-II/I ratio was higher in HYP compared to ISO infusion (p<0.001), although no other protein changes were observed (all p>0.050). Following passive heating, autophagy increased in HYP, as demonstrated by an increase in LC3-II from baseline (p=0.004) and an elevated LC3-II/I ratio compared to ISO (p=0.035), and a decrease in p62 when compared to the ISO condition (p=0.019). This was accompanied by an elevation in cleaved caspase-3 following heating in the HYP condition (p<0.010), however, the HSR and acute inflammatory response did not change under any condition (all p>0.050). Taken together, our findings indicate that serum hyperosmolality induces autophagy and apoptotic signaling during mild hyperthermia with minimal autophagic activation during normothermia.
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Affiliation(s)
- James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Kelli E King
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Maura M Rutherford
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Robert D Meade
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada.,Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Sean R Notley
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Ashley P Akerman
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada
| | - Karol Dokladny
- Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States
| | - Glen P Kenny
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Zhang C, Wang Y. KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter influence the drug resistance to L-OHP. Aging (Albany NY) 2022; 14:1836-1847. [PMID: 35193115 PMCID: PMC8908920 DOI: 10.18632/aging.203906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 12/25/2021] [Indexed: 12/24/2022]
Abstract
Background: LncRNA potassium voltage-gated channel subfamily Q member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported to promote resistance to chemotherapy in colon cancer by inhibiting the expression of miR-34a. And the methylation of KCNQ1OT1 was also reported in the pathogenesis of various diseases. In this study, we aimed to study the combined effect of allele variation of KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter in the treatment of colon cancer. Methods: The expression levels of KCNQ1OT1, miR-34a, and ATG4B mRNA were assessed by qRT-PCR. ATG4B protein expression was analyzed by Western blot analysis. TUNEL and MTT assay were performed to examine the cell apoptosis and viability. Luciferase assays revealed the relationship between KCNQ1OT1, miR-34a and ATG4B. Results: Carrier of allele 10 and methylated promoter in KCNQ1OT1 was associated with decreased KCNQ1OT1/ATG4B expression, increased miR-34a expression and enhanced apoptosis in colon cancer tissue samples. And subsequent luciferase assay showed that miR-34a could bind to KCNQ1OT1 and ATG4B at specific binding sites. The knockdown of KCNQ1OT1 significantly suppressed the KCNQ1OT1/ATG4B expression, improved the miR-34a expression and reduced the viability of HCT116 and SW480 cells. The over-expression of ATG4B notably restored the cell viability loss and apoptosis increase induced by the knockdown of KCNQ1OT1. Moreover, oxaliplatin (L-OHP) treatment elevated the apoptosis of HCT116 and SW480 cells. Conclusions: The drug resistance in the treatment of colon cancer is most reduced in patients carrying allele 10 and methylated in KCNQ1OT1 promoter. This function is accomplished by the signaling pathway of KCNQ1OT1/miR-34a/ATG4B.
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Affiliation(s)
- Caihong Zhang
- Proctology Department, Xing Yuan Hospital of Yulin, Yulin 719000, Shaanxi, China
| | - Yonglin Wang
- Pharmacy Department, Yangling Demonstration Zone Hospital, Xianyang 712100, Shaanxi, China
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Zhou HL, Premont RT, Stamler JS. The manifold roles of protein S-nitrosylation in the life of insulin. Nat Rev Endocrinol 2022; 18:111-128. [PMID: 34789923 PMCID: PMC8889587 DOI: 10.1038/s41574-021-00583-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/08/2021] [Indexed: 02/04/2023]
Abstract
Insulin, which is released by pancreatic islet β-cells in response to elevated levels of glucose in the blood, is a critical regulator of metabolism. Insulin triggers the uptake of glucose and fatty acids into the liver, adipose tissue and muscle, and promotes the storage of these nutrients in the form of glycogen and lipids. Dysregulation of insulin synthesis, secretion, transport, degradation or signal transduction all cause failure to take up and store nutrients, resulting in type 1 diabetes mellitus, type 2 diabetes mellitus and metabolic dysfunction. In this Review, we make the case that insulin signalling is intimately coupled to protein S-nitrosylation, in which nitric oxide groups are conjugated to cysteine thiols to form S-nitrosothiols, within effectors of insulin action. We discuss the role of S-nitrosylation in the life cycle of insulin, from its synthesis and secretion in pancreatic β-cells, to its signalling and degradation in target tissues. Finally, we consider how aberrant S-nitrosylation contributes to metabolic diseases, including the roles of human genetic mutations and cellular events that alter S-nitrosylation of insulin-regulating proteins. Given the growing influence of S-nitrosylation in cellular metabolism, the field of metabolic signalling could benefit from renewed focus on S-nitrosylation in type 2 diabetes mellitus and insulin-related disorders.
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Affiliation(s)
- Hua-Lin Zhou
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Richard T Premont
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Jonathan S Stamler
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
- Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
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Autophagic Flux Unleashes GATA4-NF- κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2021:8189485. [PMID: 34987705 PMCID: PMC8720590 DOI: 10.1155/2021/8189485] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/22/2021] [Indexed: 12/30/2022]
Abstract
Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.
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Tian Z, Zhang X, Sun M. Phytochemicals Mediate Autophagy Against Osteoarthritis by Maintaining Cartilage Homeostasis. Front Pharmacol 2022; 12:795058. [PMID: 34987406 PMCID: PMC8722717 DOI: 10.3389/fphar.2021.795058] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoarthritis (OA) is a common degenerative joint disease and is a leading cause of disability and reduced quality of life worldwide. There are currently no clinical treatments that can stop or slow down OA. Drugs have pain-relieving effects, but they do not slow down the course of OA and their long-term use can lead to serious side effects. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Autophagy is an intracellular protective mechanism, and targeting autophagy-related pathways has been found to prevent and treat various diseases. Attenuation of the autophagic pathway has now been found to disrupt cartilage homeostasis and plays an important role in the development of OA. Therefore, modulation of autophagic signaling pathways mediating cartilage homeostasis has been considered as a potential therapeutic option for OA. Phytochemicals are active ingredients from plants that have recently been found to reduce inflammatory factor levels in cartilage as well as attenuate chondrocyte apoptosis by modulating autophagy-related signaling pathways, which are not only widely available but also have the potential to alleviate the symptoms of OA. We reviewed preclinical studies and clinical studies of phytochemicals mediating autophagy to regulate cartilage homeostasis for the treatment of OA. The results suggest that phytochemicals derived from plant extracts can target relevant autophagic pathways as complementary and alternative agents for the treatment of OA if subjected to rigorous clinical trials and pharmacological tests.
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Affiliation(s)
- Zheng Tian
- School of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Xinan Zhang
- School of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Mingli Sun
- School of Kinesiology, Shenyang Sport University, Shenyang, China
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Leng Y, Zhang Y, Li X, Wang Z, Zhuang Q, Lu Y. Receptor Interacting Protein Kinases 1/3: The Potential Therapeutic Target for Cardiovascular Inflammatory Diseases. Front Pharmacol 2021; 12:762334. [PMID: 34867386 PMCID: PMC8637748 DOI: 10.3389/fphar.2021.762334] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
The receptor interacting protein kinases 1/3 (RIPK1/3) have emerged as the key mediators in cell death pathways and inflammatory signaling, whose ubiquitination, phosphorylation, and inhibition could regulate the necroptosis and apoptosis effectually. Recently, more and more studies show great interest in the mechanisms and the regulator of RIPK1/3-mediated inflammatory response and in the physiopathogenesis of cardiovascular diseases. The crosstalk of autophagy and necroptosis in cardiomyocyte death is a nonnegligible conversation of cell death. We elaborated on RIPK1/3-mediated necroptosis, pathways involved, the latest regulatory molecules and therapeutic targets in terms of ischemia reperfusion, myocardial remodeling, myocarditis, atherosclerosis, abdominal aortic aneurysm, and cardiovascular transplantation, etc.
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Affiliation(s)
- Yiming Leng
- Clinical Research Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Ying Zhang
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Xinyu Li
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zeyu Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Quan Zhuang
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Yao Lu
- Clinical Research Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
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Zhang XM, Tao YH, Zhou XL, Shang XL, Gong XB, Liu YC, Huang YY, Chen G, Yu ZY, Wang JT, Du ZG, Wu GF, Zhang Y, Guo JC, Zhou HG. The role of carbonic anhydrase III and autophagy in type 2 diabetes with cardio-cerebrovascular disease. Metab Brain Dis 2021; 36:2329-2341. [PMID: 34665375 PMCID: PMC8580918 DOI: 10.1007/s11011-021-00839-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/06/2021] [Indexed: 01/10/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db-/- mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db-/- mice' carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db-/- mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db-/- mice' cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db-/- mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db-/- mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery' vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.
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Affiliation(s)
- Xiao-Ming Zhang
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China
| | - Ying-Hong Tao
- Department of Medical Examination Center, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xiu-Ling Zhou
- Department of Ultrasonics, Huashan Hospital, Fudan Univesity, Shanghai, 200040, China
| | - Xi-Liang Shang
- Department of Sport Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xiao-Bo Gong
- Department of Engineering Mechanics, School of Naval Architecture, Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ying-Chao Liu
- Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Yan-Yan Huang
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China
| | - Gang Chen
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China
| | - Zhong-Yu Yu
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China
| | - Jian-Tao Wang
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China
| | - Zun-Guo Du
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Guo-Feng Wu
- Department of Emergency Neurology, Guiyang Medical University, Guiyang, 550004, China
| | - Yu Zhang
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China.
| | - Jing-Chun Guo
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China.
| | - Hou-Guang Zhou
- Geriatrics Department and National Clinical Research Center for Aging and Medicine, Huashan Hospital, and Institutes of Brain Science, Fudan University, Shanghai, 200040, China.
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