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Ma X, Li Z, Ma H, Jiang K, Chen B, Wang W, Zhu Z, Wang J, Yang Z, Yunqing W, Dong S. Rotenone inhibited osteosarcoma metastasis by modulating ZO-2 expression and location via the ROS/Ca 2+/AMPK pathway. Redox Rep 2025; 30:2493556. [PMID: 40247635 PMCID: PMC12010658 DOI: 10.1080/13510002.2025.2493556] [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] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Pulmonary metastases in osteosarcoma (OS) are associated with a poor prognosis. Rotenone has shown anti-cancer activity. However, its effects on metastasis and the underlying mechanisms remain unknown. This study investigated the potential use of Rotenone for OS treatment. METHODS The effect of Rotenone and ROS/Ca2+/AMPK/ZO-2 pathway on metastasis and EMT was evaluated by Western blot, Transwell and Wound healing. Flow cytometer was employed to measure the intracellular Ros and Ca2+ levels. The subcellular location of ZO-2 was detected by IF, interaction between AMPK and ZO-2 were examined by Co-IP. Then, subcutaneous tumor and metastasis models were used to evaluate the function of Rotenone in OS metastasis. RESULTS Rotenone-induced ROS led to increased intracellular Ca2+, which promoted the EMT of OS cells through activation of AMPK and ZO-2 nuclear translocation. Inhibition of ROS production decreased intracellular Ca2+, restraining AMPK activity. Knock-down of ZO-2 significantly suppressed the anti-metastasis effects of Rotenone in OS cells. Moreover, Rotenone elevated p-AMPK and ZO-2 expression but inhibited EMT and lung metastasis in vivo.Conclusion These results provide evidence supporting an anti-metastatic effect of Rotenone. These findings support the use of Rotenone in the prevention of OS metastasis.
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Affiliation(s)
- Xiang Ma
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China
| | - Zhen Li
- Department of Medical Oncology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Hengwei Ma
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Kun Jiang
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Bao Chen
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Weiquan Wang
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China
| | - Ziqiang Zhu
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Jianqiang Wang
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Zuozhang Yang
- Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China
| | - Wang Yunqing
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Suwei Dong
- Department of Orthopaedics, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China
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2
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Ren X, Zhao L, Hao Y, Huang X, Lv G, Zhou X. Copper-instigated modulatory cell mortality mechanisms and progress in kidney diseases. Ren Fail 2025; 47:2431142. [PMID: 39805816 PMCID: PMC11734396 DOI: 10.1080/0886022x.2024.2431142] [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: 02/28/2024] [Revised: 06/23/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
Copper is a vital cofactor in various enzymes, plays a pivotal role in maintaining cell homeostasis. When copper metabolism is disordered and mitochondrial dysfunction is impaired, programmed cell death such as apoptosis, paraptosis, pyroptosis, ferroptosis, cuproptosis, autophagy and necroptosis can be induced. In this review, we focus on the metabolic mechanisms of copper. In addition, we discuss the mechanism by which copper induces various programmed cell deaths. Finally, this review examines copper's involvement in prevalent kidney diseases such as acute kidney injury and chronic kidney disease. The findings indicate that the use of copper chelators or plant extracts can mitigate kidney damage by reducing copper accumulation, offering novel insights into the pathogenesis and treatment strategies for kidney diseases.
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Affiliation(s)
- Xiya Ren
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Limei Zhao
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yajie Hao
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiu Huang
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guangna Lv
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoshuang Zhou
- Department of Nephrology, Shanxi Provincial People’s Hospital, The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, Shanxi, China
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3
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Zheng Q, Wang D, Lin R, Xu W. Pyroptosis, ferroptosis, and autophagy in spinal cord injury: regulatory mechanisms and therapeutic targets. Neural Regen Res 2025; 20:2787-2806. [PMID: 39101602 PMCID: PMC11826477 DOI: 10.4103/nrr.nrr-d-24-00112] [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: 01/28/2024] [Revised: 04/24/2024] [Accepted: 06/07/2024] [Indexed: 08/06/2024] Open
Abstract
Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
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Affiliation(s)
- Qingcong Zheng
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Du Wang
- Arthritis Clinical and Research Center, Peking University People’s Hospital, Beijing, China
| | - Rongjie Lin
- Department of Orthopedic Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Weihong Xu
- Department of Spinal Surgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
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4
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Qin Z, Li Y, Shao X, Li K, Bai Y, Wang B, Ma F, Shi W, Song L, Zhuang A, He F, Ding C, Yang W. HNF4A functions as a hepatocellular carcinoma oncogene or tumor suppressor depending upon the AMPK pathway activity status. Cancer Lett 2025; 623:217732. [PMID: 40254090 DOI: 10.1016/j.canlet.2025.217732] [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: 05/28/2024] [Revised: 04/10/2025] [Accepted: 04/17/2025] [Indexed: 04/22/2025]
Abstract
Cancer cells frequently undergo energy metabolic stress induced by the increased dynamics of nutrient supply. Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. However, the mechanism underlying how HNF4A functions in cancer progression remains unclear due to conflicting results observed in numerous studies. To address the roles of HNF4A in hepatocellular carcinoma (HCC), we investigated the regulatory functions of HNF4A in HCC cells under different glucose supply conditions. We found that HNF4A exhibited tumor-suppressive effects on the proliferation and migration of HCC cells in glucose-sufficient conditions and tumor-promotive effects on HCC cells in glucose-insufficient conditions. Further investigation revealed that this diverse function of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with whether the AMPKa expression levels were low or high in clinical HCC patients. Multiomics approaches consisting of proteomics and ChIP-seq revealed that key HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse function of HNF4A in HCC in response to the AMPK activity status. Specifically, HNF4A could bind to the promoter region of NEDD4 and RPS6KA2, and upregulating their expression. Our study has demonstrated the relationship between and synergism of AMPK and HNF4A in the progression of HCC under diverse nutrient conditions.
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Affiliation(s)
- Zhaoyu Qin
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yan Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Xiexiang Shao
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Kai Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Yihe Bai
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Bing Wang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fahan Ma
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Wenhao Shi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Lei Song
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Aojia Zhuang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China
| | - Fuchu He
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China; School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Chen Ding
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai 200032, China; State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing, 102206, China
| | - Wenjun Yang
- Department of Pediatric Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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5
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Peng X, Feng J, Yang H, Xia P, Pu F. Nrf2: A key regulator in chemoradiotherapy resistance of osteosarcoma. Genes Dis 2025; 12:101335. [PMID: 40242036 PMCID: PMC12000747 DOI: 10.1016/j.gendis.2024.101335] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 01/24/2024] [Accepted: 04/03/2024] [Indexed: 04/18/2025] Open
Abstract
Osteosarcoma (OS), frequently observed in children and adolescents, is one of the most common primary malignant tumors of the bone known to be associated with a high capacity for invasion and metastasis. The incidence of osteosarcoma in children and adolescents is growing annually, although improvements in survival remain limited. With the clinical application of neoadjuvant chemotherapy, chemotherapy combined with limb-preserving surgery has gained momentum as a major intervention. However, certain patients with OS experience treatment failure owing to chemoradiotherapy resistance or metastasis. Nuclear factor E2-related factor 2 (Nrf2), a key antioxidant factor in organisms, plays a crucial role in maintaining cellular physiological homeostasis; however, its overactivation in cancer cells restricts reactive oxygen species production, promotes DNA repair and drug efflux, and ultimately leads to chemoradiotherapy resistance. Recent studies have also identified the functions of Nrf2 beyond its antioxidative function, including the promotion of proliferation, metastasis, and regulation of metabolism. The current review describes the multiple mechanisms of chemoradiotherapy resistance in OS and the substantial role of Nrf2 in the signaling regulatory network to elucidate the function of Nrf2 in promoting OS chemoradiotherapy resistance and formulating relevant therapeutic strategies.
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Affiliation(s)
- Xianglin Peng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Jing Feng
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
| | - Han Yang
- Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ping Xia
- Department of Orthopedics, Wuhan Fourth Hospital, Wuhan 430030, China
| | - Feifei Pu
- Department of Orthopedics, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan 430022, China
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6
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Chen Y, Deng H, Zhang N. Autophagy-targeting modulation to promote peripheral nerve regeneration. Neural Regen Res 2025; 20:1864-1882. [PMID: 39254547 PMCID: PMC11691477 DOI: 10.4103/nrr.nrr-d-23-01948] [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: 11/27/2023] [Revised: 02/22/2024] [Accepted: 03/29/2024] [Indexed: 09/11/2024] Open
Abstract
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
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Affiliation(s)
- Yan Chen
- Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, Sichuan Province, China
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- Laboratory of Reproductive Endocrinology and Reproductive Regulation, Sichuan University, Chengdu, Sichuan Province, China
| | - Hongxia Deng
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- Laboratory of Reproductive Endocrinology and Reproductive Regulation, Sichuan University, Chengdu, Sichuan Province, China
| | - Nannan Zhang
- Key Laboratory of Birth Defects and Women and Children’s Diseases, Ministry of Education, Sichuan University, Chengdu, Sichuan Province, China
- National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, China
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7
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Takano J, Takemoto D, Tatebe H, Shoji S, Fukuda K, Kitagawa Y, Rogi T, Izumo T, Nakao Y, Ishido M, Yoshimori T. Monocatechol metabolites of sesamin and episesamin promote higher autophagy flux compared to their unmetabolized forms by mTORC1-selective inhibition. Biochem Biophys Res Commun 2025; 765:151816. [PMID: 40279799 DOI: 10.1016/j.bbrc.2025.151816] [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: 02/27/2025] [Revised: 04/04/2025] [Accepted: 04/13/2025] [Indexed: 04/29/2025]
Abstract
Sesamin and episesamin, the major lignans found in refined sesame oil, reportedly exert antioxidant, anti-inflammatory, and hypocholesterolemic effects. Sesamin has also been suggested by previous studies to promote autophagy; however, concerns have been raised regarding the use of non-physiological concentrations, inaccurate methods for evaluating autophagic activity, and incomplete understanding of underlying mechanisms. Additionally, the effects of its metabolic kinetics on autophagy remain unclear. In this study, we demonstrated that sesamin, episesamin, and their metabolites induced autophagy flux at physiological concentrations in human cell cultures expressing monomeric red fluorescent protein-green fluorescent protein tandem fluorescent-tagged microtubule-associated protein 1A/1B-light-chain 3 proteins, a robust method for monitoring autophagy flux. Notably, the monocatechol metabolites of sesamin and episesamin exhibited higher autophagy flux than their unmetabolized forms. Immunoblotting analysis revealed that sesamin and its monocatechol metabolite promoted autophagy by inhibiting mammalian target of rapamycin complex 1 (mTORC1), leading to decreased phosphorylation of unc-51 like autophagy activating kinase 1 and transcription factor EB. This suppression enhanced the isolation membrane formation and transcriptionally stimulated autophagy and lysosomal biogenesis. Importantly, mTORC1 inhibition by sesamin and its metabolites did not affect mTORC2 activity, mirroring the mTORC1-selective inhibition observed with rapamycin. These results suggest that sesamin and episesamin contribute to diverse biological activities via their metabolism in the human body, regulating autophagy and mTORC1 signaling pathways.
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Affiliation(s)
- Jiro Takano
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan
| | - Daisuke Takemoto
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan.
| | | | | | | | - Yoshinori Kitagawa
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan
| | - Tomohiro Rogi
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan
| | - Takayuki Izumo
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan
| | - Yoshihiro Nakao
- Institute for Science of Life, Suntory Wellness Limited, Kyoto, 619-0284, Japan
| | | | - Tamotsu Yoshimori
- Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
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Meng Y, Zheng C, Zhang X, Gao Z, Chen H, Qi X, Li K, Liu F, Deng W, Wu Y, Liu J, Chen C, Wang C, Zhao H, Zhang H. xCT/Slc7a11 promotes pulmonary arterial hypertension by disrupting AMPKα suppression of mTOR activation. Biochem Pharmacol 2025; 236:116897. [PMID: 40147801 DOI: 10.1016/j.bcp.2025.116897] [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: 06/22/2024] [Revised: 02/19/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
While mTOR plays a key role in the development of pulmonary arterial hypertension (PAH), its suppressor, AMPKα, acts as an inhibitor. Although mTOR-driven transcriptional upregulation of the plasma membrane exchanger and amino acid transporter xCT, encoded by the Slc7a11 gene, is critical for cell proliferation and tumorigenesis, the involvement of xCT in PAH remains unexplored. In this study, we found that xCT expression was elevated in hypoxia-treated human pulmonary arterial endothelial cells (HPAECs) and the lungs of hypoxia-exposed mice and Sugen5416/hypoxia (SuHx)-induced PAH mice. Knockout of xCT prevented the development of PAH and right heart failure in SuHx-conditioned mice. The xCT inhibitor sulfasalazine prevented and reversed SuHx-induced PAH in mice. Deleting and inhibiting xCT activated AMPKα and inactivated mTOR in mouse lungs with PAH and in HPAECs. Sulfasalazine suppressed mTOR through activation of AMPKα in HPAECs. The mTOR inhibitor rapamycin reduced xCT expression, activated AMPKα, and suppressed mTOR in HPAECs. These findings suggest that xCT promotes the development of PAH, likely through suppression of AMPKα and activation of mTOR. Blockage of xCT and mTOR or activation of AMPKα by existing drugs such as sulfasalazine, sirolimus, and metformin may offer readily therapeutic strategies for PAH.
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Affiliation(s)
- Yan Meng
- Department of Pathology, Capital Medical University, Beijing, China.
| | - Cuiting Zheng
- Department of Pathology, Capital Medical University, Beijing, China; State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiyu Zhang
- Department of Pathology, Capital Medical University, Beijing, China
| | - Zhenqiang Gao
- Department of Pathology, Capital Medical University, Beijing, China
| | - Hongyu Chen
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xianmei Qi
- Department of Immunology, Capital Medical University, Beijing, China
| | - Kai Li
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fangming Liu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Weiwei Deng
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuting Wu
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Liu
- Department of Immunology, Capital Medical University, Beijing, China
| | - Chen Chen
- Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Chen Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Heng Zhao
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Joint Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
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Pandey A, Goswami A, Jithin B, Shukla S. Autophagy: The convergence point of aging and cancer. Biochem Biophys Rep 2025; 42:101986. [PMID: 40224538 PMCID: PMC11986642 DOI: 10.1016/j.bbrep.2025.101986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/10/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Autophagy, a dynamic intracellular degradation system, is critical for cellular renovation and maintaining equilibrium. By eliminating damaged components and recycling essential molecules, autophagy safeguards cellular integrity and function. The versatility of the autophagy process across various biological functions enable cells to adapt and maintain homeostasis under unfavourable conditions. Disruptions in autophagy can shift a cell from a healthy state to a disease state or, conversely, support a return to health. This review delves into the multifaceted role of autophagy during aging and age-related diseases such as cancer, highlighting its significance as a unifying target with promising therapeutic implications. Cancer development is a dynamic process characterized by the acquisition of diverse survival capabilities for proliferating at different stages. This progression unfolds over time, with cancer cells exploiting autophagy to overcome encountered stress conditions during tumor development. Notably, there are several common pathways that utilize the autophagy process during aging and cancer development. This highlights the importance of autophagy as a crucial therapeutic target, holding the potential to not only impede the growth of tumor but also enhance the patient's longevity. This review aims to simplify the intricate relationship between cancer and aging, with a particular focus on the role of autophagy.
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Affiliation(s)
- Anchala Pandey
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, 462066, India
| | | | | | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh, 462066, India
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10
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Cai J, Zhou H, Liu M, Zhang D, Lv J, Xue H, Zhou H, Zhang W. Host immunity and intracellular bacteria evasion mechanisms: Enhancing host-directed therapies with drug delivery systems. Int J Antimicrob Agents 2025; 65:107492. [PMID: 40107461 DOI: 10.1016/j.ijantimicag.2025.107492] [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: 10/31/2024] [Revised: 03/04/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025]
Abstract
Host-directed therapies (HDTs) have been investigated as a potential solution to combat intracellular and drug-resistant bacteria. HDTs stem from extensive research on the intricate interactions between the host and intracellular bacteria, leading to a treatment approach that relies on immunoregulation. To improve the bioavailability and safety of HDTs, researchers have utilized diverse drug delivery systems (DDS) to encapsulate and transport therapeutic agents to target cells. In this review, we first introduce the three mechanisms of bactericidal action and intracellular bacterial evasion: autophagy, reactive oxygen species (ROS), and inflammatory cytokines, with a particular focus on autophagy. Special attention is given to the detailed mechanism of xenophagy in clearing intracellular bacteria, a crucial selective autophagy process that specifically targets and degrades intracellular pathogens. Following this, we present the application of DDS to modulate these regulatory methods for intracellular bacteria elimination. By integrating insights from immunology and nanomedicine, this review highlights the emerging role of DDS in advancing HDTs for intracellular bacterial infections and paving the way for innovative therapeutic interventions.
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Affiliation(s)
- Jiayang Cai
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Han Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Mingwei Liu
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Dingjian Zhang
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Jingxuan Lv
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Haokun Xue
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Houcheng Zhou
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China
| | - Wenli Zhang
- Department of Pharmaceutics, China Pharmaceutical University, Jiangsu, China.
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Giroud J, Combémorel E, Pourtier A, Abbadie C, Pluquet O. Unraveling the functional and molecular interplay between cellular senescence and the unfolded protein response. Am J Physiol Cell Physiol 2025; 328:C1764-C1782. [PMID: 40257464 DOI: 10.1152/ajpcell.00091.2025] [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: 01/28/2025] [Revised: 02/12/2025] [Accepted: 04/14/2025] [Indexed: 04/22/2025]
Abstract
Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.
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Affiliation(s)
- Joëlle Giroud
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Emilie Combémorel
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Albin Pourtier
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Corinne Abbadie
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
| | - Olivier Pluquet
- CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Lille, France
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12
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Sharma RK, Sahai R, Singh NC, Maheshwari M, Yadav N, Sarkar J, Mitra K. Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells. Biochem Biophys Res Commun 2025; 759:151698. [PMID: 40153998 DOI: 10.1016/j.bbrc.2025.151698] [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: 12/10/2024] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
Ormeloxifene (ORM) is a nonsteroidal selective estrogen receptor modulator (SERM), developed by the CSIR-Central Drug Research Institute that is approved as an oral contraceptive. However, it has also shown promising anti-cancer activity, especially in breast cancer. Here, we have investigated the anti-cancer effect of ORM on colon cancer cells and show that its antiproliferative activity is mediated through mitochondrial fission and autophagy-associated cell death. We observed that ORM treatment led to an elevation in autophagy markers like LC3II, Beclin1, and Atg7. Autophagy induction and LC3II turnover were monitored by immunofluorescence staining and confocal microscopy. Transmission electron microscopy results confirmed the formation of autophagosomes and autophagolysosomes. Autophagic flux was confirmed by the increased expression of LC3II in cells co-treated with BafilomycinA1(autophagy inhibitor) and ORM. This was further corroborated using tandem mRFP-GFP-LC3 (tfLC3) transfection in DLD-1 cells. Interestingly, we observed that inhibition of autophagy reduced the apoptotic cell population, suggesting pro-death autophagy. ORM treatment caused notable ultrastructural alterations indicative of cellular stress. Notably, ORM triggered the generation of mitochondrial ROS, associated with increased levels of mitochondrial fission and a decrease in mitochondrial fusion proteins. Changes in mitochondrial dynamics were observed under the TEM, which included reduced mitochondrial size and increased mitochondrial number. Inhibition of mitochondrial fission resulted in enhanced cell survival and a concomitant decrease in the autophagic markers, implying that ORM-induced autophagy depends on mitochondrial fission. Taken together, our findings bring to light a novel mechanism where Ormeloxifene targets mitochondrial dynamics to promote autophagy-associated cell death in colon cancer cells.
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Affiliation(s)
- Rakesh Kumar Sharma
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rohit Sahai
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India
| | - Nishakumari Chentunarayan Singh
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India
| | - Mayank Maheshwari
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India
| | - Nisha Yadav
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jayanta Sarkar
- Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Kalyan Mitra
- Electron Microscopy Unit, Sophisticated Analytical Instrument Facility and Research, CSIR - Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, Uttar Pradesh, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Zhang M, Sha Y, Wang J, Qi H, Shi P, Liu Y, Jiang M, Ba L, Liu Y, Cao Y, Zhang Q, Sun H. Inhibition of ULK1 attenuates ferroptosis-mediated cardiac hypertrophy via HMGA2/METTL14/SLC7A11 axis in mice. Eur J Pharmacol 2025; 995:177416. [PMID: 39993699 DOI: 10.1016/j.ejphar.2025.177416] [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: 06/26/2024] [Revised: 01/24/2025] [Accepted: 02/19/2025] [Indexed: 02/26/2025]
Abstract
UNC-51-like kinase 1 (ULK1), a primary serine/threonine kinase, is implicated in diverse pathophysiological processes. Previous findings have linked ULK1-dependent autophagy to cardiac hypertrophy. Our study further explored the functional role and molecular mechanisms of ULK1 in non-autophagic signaling pathways. Notably, ULK1 expression was significantly elevated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-treated cardiomyocytes, suggesting an increased sensitivity to hypertrophic stimuli potentially mediated by ULK1-induced ferroptosis in hypertrophic cardiomyocytes. Treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reduced ULK1-induced cardiomyocyte hypertrophy and ferroptosis. Proteomic analysis identified the upregulation of transcription factor high mobility group A2 (HMGA2) as a key mechanism in this ferroptotic process. Elevated HMGA2 levels exacerbated ferroptosis, evidenced by increased cell death, lipid peroxidation, ROS production, and reduced GPX4 expression. Furthermore, HMGA2 was shown to promote cardiomyocyte ferroptosis via binding to methyltransferase-like 14 (METTL14), which in turn enhanced ferroptosis in cardiomyocytes through solute carrier family 7 member 11 (SLC7A11) m6A modification. In vivo, a delivery system using neutrophil membrane (NM)-coated mesoporous silica nanoparticles (MSN) was developed to inhibit cardiac hypertrophy, underscoring the therapeutic potential of targeting ULK1. Overall, this study demonstrates that ULK1 promotes cardiac hypertrophy through HMGA2/METTL14/SLC7A11 axis-mediated cardiomyocyte ferroptosis, suggesting a novel therapeutic approach for cardiac hypertrophy.
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Affiliation(s)
- Meitian Zhang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Yuetong Sha
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Jiaxin Wang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Hanping Qi
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Pilong Shi
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Yongsheng Liu
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Man Jiang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Lina Ba
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Yuhang Liu
- Department of Physiology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Yonggang Cao
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China
| | - Qianhui Zhang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China.
| | - Hongli Sun
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, 163319, China.
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14
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Liu C, Wang X, Xu S, Liu M, Cao X. Regulation of autophagy: Insights into O-GlcNAc modification mechanisms. Life Sci 2025; 369:123547. [PMID: 40058573 DOI: 10.1016/j.lfs.2025.123547] [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: 12/28/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/30/2025]
Abstract
Autophagy is a "self-eating" biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.
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Affiliation(s)
- Chengzhi Liu
- Beijing Ophthalmology & Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xinyu Wang
- Beijing Ophthalmology & Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Shengnan Xu
- College of Basic Medicine, Dalian Medical University, Dalian 116044, China
| | - Mingyue Liu
- Beijing Ophthalmology & Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
| | - Xusheng Cao
- Beijing Ophthalmology & Visual Science Key Lab, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
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15
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Ma JX, Li XJ, Li YL, Liu MC, Du RH, Cheng Y, Li LJ, Ai ZY, Jiang JT, Yan SY. Chaperonin-containing tailless complex polypeptide 1 subunit 6A negatively regulates autophagy and protects colorectal cancer cells from cisplatin-induced cytotoxicity. World J Gastroenterol 2025; 31:105729. [DOI: 10.3748/wjg.v31.i18.105729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/27/2025] [Accepted: 04/14/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND As a member of the chaperonin-containing tailless complex polypeptide 1 (TCP1) complex, which plays a pivotal role in ensuring the accurate folding of numerous proteins, chaperonin-containing TCP1 subunit 6A (CCT6A) participates in various physiological and pathological processes. However, its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer (CRC) cells.
AIM To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.
METHODS Cell proliferation was evaluated using the MTS assay, EdU staining, and colony growth assays. The expression of CCT6A was monitored by immunoblotting and quantitative PCR. CCT6A was knocked out by CRISPR-Cas9, and overexpressed by transfecting plasmids. Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay. To monitor apoptosis and necroptosis, immunoblotting, co-immunoprecipitation, and flow cytometry were employed.
RESULTS Cisplatin (DDP) exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A. Depletion of CCT6A amplified the cytotoxic effects of DDP, whereas overexpression of CCT6A attenuated these adverse effects. CCT6A suppressed autophagy, apoptosis, and necroptosis under both basal and DDP-treated conditions. Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP, whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP. Furthermore, inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.
CONCLUSION CCT6A negatively modulates autophagy, apoptosis, and necroptosis, and CCT6A confers resistance to DDP therapy in CRC, suggesting its potential as a therapeutic target.
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Affiliation(s)
- Jian-Xing Ma
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Xiao-Jun Li
- Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ya-Long Li
- Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ming-Chan Liu
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Rui-Hang Du
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Yi Cheng
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Liang-Jie Li
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Zhi-Ying Ai
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
| | - Jian-Tao Jiang
- The Second Affiliated Hospital of Xi’an Jiaotong University, Xibei Hospital, Xi’an 710000, Shaanxi Province, China
| | - Si-Yuan Yan
- Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
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16
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Dash BK, Urano Y, Mita Y, Ashida Y, Hirose R, Noguchi N. Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex. Proc Natl Acad Sci U S A 2025; 122:e2414790122. [PMID: 40327696 DOI: 10.1073/pnas.2414790122] [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: 07/23/2024] [Accepted: 03/09/2025] [Indexed: 05/08/2025] Open
Abstract
PARK7/DJ-1, a redox-sensitive protein implicated in neurodegeneration, cancer, and inflammation, exhibits increased secretion under stress. We previously demonstrated that, as a leaderless protein, PARK7 relies on an unconventional autophagy pathway for stress-induced secretion. The current study delves deeper into the mechanisms governing PARK7 secretion under oxidative stress triggered by the neurotoxin 6-hydroxydopamine (6-OHDA). Here, we revealed that 6-OHDA-induced autophagic flux is critical for PARK7 secretion. Downregulation of syntaxin 17 (STX17), a SNARE protein crucial for autophagosome-lysosome fusion and cargo degradation, hindered PARK7 secretion. Likewise, impairing lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) diminished PARK7 release, highlighting the importance of functional lysosomes, potentially in the form of secretory autolysosomes, in PARK7 release. We also found that 6-OHDA appeared to promote the unfolding of PARK7, allowing its selective recognition by the chaperone HSPA8 via KFERQ-like motifs, leading to PARK7 translocation to the lysosomal membrane through LAMP2 via chaperone-mediated autophagy (CMA). Additionally, a dedicated SNARE complex comprising Qabc-SNAREs (STX3/4, VTI1B, and STX8) and R-SNARE SEC22B mediates the fusion of PARK7-containing autolysosomes with the plasma membrane, facilitating the extracellular release of PARK7. Hence, this study uncovers a mechanism where 6-OHDA-induced autophagic flux drives the unconventional secretion of PARK7, involving CMA for PARK7 translocation to lysosomes and specialized SNARE complexes for membrane fusion events.
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Affiliation(s)
- Biplab Kumar Dash
- Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
| | - Yasuomi Urano
- Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
| | - Yuichiro Mita
- Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
| | - Yuki Ashida
- Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
| | - Ryoma Hirose
- Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
| | - Noriko Noguchi
- Systems Life Sciences Laboratory, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Kyoto, Japan
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17
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Guo Z, Chen D, Yao L, Sun Y, Li D, Le J, Dian Y, Zeng F, Chen X, Deng G. The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer. Signal Transduct Target Ther 2025; 10:149. [PMID: 40341098 PMCID: PMC12062509 DOI: 10.1038/s41392-025-02192-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/13/2024] [Accepted: 02/17/2025] [Indexed: 05/10/2025] Open
Abstract
Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.
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Affiliation(s)
- Ziyu Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Danyao Chen
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Yao
- Department of Liver Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yuming Sun
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Daishi Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Jiayuan Le
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yating Dian
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China
- Furong Laboratory, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Furong Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
| | - Guangtong Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, China.
- Furong Laboratory, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China.
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18
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Yu YS, Kim IS, Baek SH. Decoding the dual role of autophagy in cancer through transcriptional and epigenetic regulation. FEBS Lett 2025. [PMID: 40346781 DOI: 10.1002/1873-3468.70060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 05/12/2025]
Abstract
Autophagy is a conserved catabolic process that is essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy exhibits a context-dependent dual role: In early stages, autophagy acts as a tumor suppressor by preserving genomic integrity and limiting oxidative stress. In advanced stages, autophagy supports tumor progression by facilitating metabolic adaptation, therapy resistance, immune evasion, and metastasis. This review highlights the molecular mechanisms underlying this dual function and focuses on the transcriptional and epigenetic regulation of autophagy in cancer cells. Key transcription factors, including the MiT/TFE family, FOXO family, and p53, as well as additional regulators, are discussed in the context of stress-responsive pathways mediated by mTORC1 and AMPK. A deeper understanding of the transcriptional and epigenetic regulation of autophagy in cancer is crucial for developing context-specific therapeutic strategies to either promote or inhibit autophagy depending on the cancer stage, thereby improving clinical outcomes in cancer treatment.
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Affiliation(s)
- Young Suk Yu
- Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Seoul, Korea
| | - Ik Soo Kim
- Department of Microbiology, Gachon University College of Medicine, Incheon, South Korea
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Seoul, Korea
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19
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Meng XY, Li Y, Yan ZJ, Ye SZ, Wang KJ, Chen JF, Yu R, Ma Q. Sinularin induces autophagy-dependent cell death by activating ULK1 and enhancing FOXO3-ATG4A axis in prostate cancer cells. Sci Rep 2025; 15:15875. [PMID: 40335577 PMCID: PMC12059013 DOI: 10.1038/s41598-025-00909-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 05/02/2025] [Indexed: 05/09/2025] Open
Abstract
Sinularin is a natural product extracted from soft coral and is shown to exhibit antitumor effects against multiple human cancers. We previously showed that Sinularin induces apoptotic cell death via stabilizing the FOXO3 protein in prostate cancer cells. In this study, we demonstrated that Sinularin triggers autophagy via two different mechanisms in prostate cancer cells. First, Sinularin reduced the S757 phosphorylation of ULK1 protein, which was mediated by mTOR, leading to ULK1 activation and autophagy initiation. Second, Sinularin enhanced the expression of autophagic protein ATG4A, which is the key regulator in the formation of autophagosome, through a FOXO3-dependent transcriptional mechanism. Next, we identified that ATG4A is a new target gene of the transcription factor FOXO3. Additionally, we also found that Sinularin-induced autophagy promoted survivin degradation and led to cell apoptosis. Taken together, these findings suggest that Sinularin induces prostate cancer cell autophagy by promoting autophagy initiation through activation of ULK1 and formation of autophagosome through the FOXO3-ATG4A pathway.
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Affiliation(s)
- Xiang-Yu Meng
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Ningbo Top Medical and Health Research Program, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Yi Li
- Department of Urology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jiefang Road, Hangzhou, 310009, Zhejiang, China
| | - Ze-Jun Yan
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Ningbo Top Medical and Health Research Program, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Department of Urology, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Sha-Zhou Ye
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Ningbo Top Medical and Health Research Program, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Ke-Jie Wang
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Ningbo Top Medical and Health Research Program, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Jun-Feng Chen
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
- Ningbo Top Medical and Health Research Program, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China
| | - Rui Yu
- Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, #818 Fenghua Road, Ningbo, 315211, Zhejiang, China.
| | - Qi Ma
- Ningbo Clinical Research Center for Urological Disease, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
- Comprehensive Genitourinary Cancer Center, The First Affiliated Hospital of Ningbo University, #59 Liuting Street, Ningbo, 315010, Zhejiang, China.
- Yi-Huan Genitourinary Cancer Group, Ningbo, 315010, Zhejiang, China.
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20
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Peng F, Liu Z, Jiang F, Li N, Wang H, Meng N, Liu H, Ding K, Fu R. T-lymphocytes suppression by CD14 + monocytes with high expression of ULK2 in patients with multiple myeloma. J Transl Med 2025; 23:511. [PMID: 40336101 PMCID: PMC12057009 DOI: 10.1186/s12967-025-06516-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Accepted: 04/18/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Multiple myeloma (MM), a plasma cell malignancy, remains incurable and is highly prone to relapse. Immunosuppressive cells in the bone marrow environment inhibit endogenous T-lymphocytes activity and reduce the efficacy immunotherapies. Abnormal bone marrow monocytes in MM have been associated with inferior outcomes. This study explored the mechanism of T-lymphocytes suppression by bone marrow CD14+ monocytes in MM. METHODS Single-cell RNA sequence data (GSE124310) derived from MM samples were analyzed. CD14+ monocytes from the bone marrow of patients with newly-diagnosed MM were detected, and RNA sequencing was performed. Interactions between CD14+ monocytes and T-lymphocytes, as along with the corresponding downstream signaling mechanism, were assessed through in vitro and in vivo experiments. RESULTS The alterations in MHC II signaling related to outgoing interaction were decreased in CD14 + monocytes from patients with MM. Abnormal numbers, defective antigen presentation, and downregulated surface co-stimulatory molecules in bone marrow CD14+ monocytes were also observed. RNA sequencing identified upregulated expression of Unc-51 like autophagy activating kinase 2 (ULK2) in these monocytes, a protein involved in the antigen processing and presentation pathway. CD14+ monocytes from patients with NDMM suppressed T-lymphocyte activity, and treatment of CD14+ monocytes with a ULK1/ULK2 inhibitor alleviated this suppression. MM xenograft model showed that CD14+ monocytes high-expressing ULK2 suppressed T-lymphocytes and promoted tumor growth. CONCLUSION We demonstrated that CD14+ monocytes from MM can disrupt the delivery of antigenic peptides through the antigen processing and presentation pathway. This disruption affects T-lymphocytes activity and attenuates their ability to kill malignant cells and secrete cytokines. These findings lay the foundation for understanding the immuno-suppressive environment in MM, improving the efficacy of immunotherapy based on T-lymphocytes, and developing new therapeutic targets.
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Affiliation(s)
- Fengping Peng
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China.
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China.
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China.
| | - Fengjuan Jiang
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Nianbin Li
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Hao Wang
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Nanhao Meng
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Kai Ding
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, People's Republic of China.
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, People's Republic of China.
- Tianjin Institute of Hematology, Tianjin, 300052, People's Republic of China.
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21
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Xu M, Xu B. Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics. Mol Cancer 2025; 24:138. [PMID: 40335986 PMCID: PMC12057185 DOI: 10.1186/s12943-025-02309-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/18/2025] [Indexed: 05/09/2025] Open
Abstract
Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.
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Affiliation(s)
- Mengke Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Intelligent Oncology Innovation Center Designated by the Ministry of Education, Chongqing University Cancer Hospital and Chongqing University School of Medicine, Chongqing, 400030, China.
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22
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Wang T, Jiang H, Zheng R, Zhang C, Ma X, Liu Y. Trends and research focus on autophagy in Alzheimer's disease (2003-2023): A bibliometric study. J Alzheimers Dis 2025:13872877251336442. [PMID: 40329586 DOI: 10.1177/13872877251336442] [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: 05/08/2025]
Abstract
BackgroundAlzheimer's disease (AD) is characterized by amyloid-β plaques and tau aggregates, with autophagy dysfunction playing a key pathogenic role. While autophagy modulation shows therapeutic promise, comprehensive bibliometric analyses are lacking.ObjectiveThis study aims to map the research landscape of autophagy in AD through bibliometric analysis, identifying key trends, contributors, and emerging focus areas.MethodsWe analyzed 4018 publications (2003-2023) from Web of Science using VOSviewer and CiteSpace. Publication trends, influential authors, countries, institutions, and research hotspots were examined through co-occurrence, burst detection, and clustering analyses.ResultsAnnual publications have steadily increased, peaking in 2022. The US led in output and citations, with major contributions from the University of California and New York University. Ralph A. Nixon emerged as the most influential author. Early research (2003-2013) primarily focused on protein degradation mechanisms, whereas recent studies (2014-2023) emphasize mitochondrial dysfunction, apoptosis, and related pathways. Key evolving topics include endoplasmic reticulum stress and chaperone-mediated autophagy, with significant implications for therapeutic innovation.ConclusionsAutophagy plays a critical role in AD pathogenesis and represents a promising therapeutic target. Despite mechanistic advances, clinical translation remains challenging. Future research should prioritize multi-omics integration, drug delivery optimization, and managing risks associated with excessive autophagy activation. These findings provide valuable insights for developing novel AD therapies targeting autophagy.
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Affiliation(s)
- Tianyi Wang
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Haochen Jiang
- Department of Traditional Chinese Medicine, Qingdao Huangdao Central Hospital, Qingdao, Shandong, China
| | - Ruwen Zheng
- Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Chuchu Zhang
- Institute of Information on Traditional Chinese Medicine, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Xiumei Ma
- Department of Traditional Chinese and Western Medicine, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Liu
- Department of Traditional Chinese and Western Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
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23
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Park H, Heo H, Song Y, Lee MS, Cho Y, Lee JS, Chang J, Lee S. TRIM22 functions as a scaffold protein for autophagy initiation. Anim Cells Syst (Seoul) 2025; 29:296-311. [PMID: 40337095 PMCID: PMC12057787 DOI: 10.1080/19768354.2025.2498926] [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: 12/15/2024] [Revised: 04/03/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Tripartite motif (TRIM) family proteins are increasingly recognized as important regulators of autophagy under various physiological and pathological conditions. TRIM22 has been previously shown to mediate autophagosome-lysosome fusion, but its potential role in earlier stages of autophagy remained unexplored. In this study, we investigated the function of TRIM22 in autophagy initiation. Overexpression of TRIM22 increased LC3-II levels and enhanced autophagic flux without affecting mTOR and AMPK activity. We found that TRIM22 interacts with components of both the ULK1 complex and the class III PI3K complex through distinct domains, recruiting them into punctate structures that represent autophagosome formation sites. Domain mapping revealed that the SPRY domain mediates interactions with ATG13 and FIP200, while the N-terminal region interacts with ULK1 and ATG101. The B-box domain of TRIM22 was identified as crucial for its interaction with Beclin-1, a key component of the class III PI3K complex. Deletion of this domain impaired the ability of TRIM22 to assemble the class III PI3K complex and induce autophagic flux. Interestingly, competitive binding assays revealed that Beclin-1 and PLEKHM1 bind to the same region of TRIM22, suggesting a mechanism for coordinating different stages of autophagy. The Alzheimer's disease-associated TRIM22 variant R321K maintained autophagy initiation function in both cell lines and primary neurons. These findings demonstrate that TRIM22 acts as a scaffold protein to promote autophagy initiation, in addition to its previously described role in autophagosome-lysosome fusion. Our study provides new insights into the molecular mechanisms by which TRIM proteins regulate multiple stages of the autophagy process.
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Affiliation(s)
- Hyungsun Park
- Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea
| | - Hansol Heo
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Yeongseo Song
- Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea
| | - Myung Shin Lee
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Yebin Cho
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae-Seon Lee
- Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea
| | - Jaerak Chang
- Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seongju Lee
- Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea
- Department of Anatomy, College of Medicine, Inha University, Incheon, Republic of Korea
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24
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Yan JJ, Wang YY, Shi ZY, Ding YY, Wen HQ, Wu MP, Sun SC, Cai YF, Zhang Y. SIRT5 modulates mitochondria function via mitophagy and antioxidant mechanisms to facilitate oocyte maturation in mice. Int J Biol Macromol 2025; 306:141488. [PMID: 40015402 DOI: 10.1016/j.ijbiomac.2025.141488] [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: 01/03/2025] [Revised: 02/11/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Mitochondrial homeostasis, closely associated with mitophagy and antioxidant mechanisms, is essential for proper meiotic spindle assembly and chromosome segregation during oocyte maturation. SIRT5, known to modulate mitochondrial function under various conditions, has been shown to impact oocyte quality when inhibited, however, the precise mechanisms linking SIRT5 to mitochondrial homeostasis during meiotic progression remain unclear. In this study, we demonstrate that SIRT5 localizes predominantly at the periphery of the meiotic spindle and is enriched on chromosomes during oocyte maturation. Inhibition of SIRT5 led to significant meiotic defects, including disrupted spindle organization and chromosome misalignment. These defects were associated with increased histone acetylation, which impaired kinetochore-microtubule attachments. Moreover, SIRT5 inhibition resulted in mitochondrial dysfunction, subsequently elevating ROS levels and triggering oxidative stress, which further exacerbated meiotic abnormalities. Mechanistically, SIRT5 inhibition disrupted the balance of Parkin-dependent mitophagy by inducing ULK phosphorylation. Additionally, it activated the PI3K/Akt signaling pathway, which increased NADPH consumption and reduced GSH levels. Collectively, these findings reveal that SIRT5 plays dual roles in maintaining mitochondrial homeostasis during oocyte maturation: (1) by regulating Parkin-dependent mitophagy to prevent excessive mitochondrial clearance, and (2) by preserving the NADPH/GSH antioxidant system to ensure redox balance. These insights provide potential targets for improving oocyte quality and addressing mitochondrial dysfunction-related reproductive disorders in females.
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Affiliation(s)
- Jing-Jing Yan
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yan-Yu Wang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhi-Yu Shi
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yuan-Yuan Ding
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Hao-Quan Wen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Meng-Ping Wu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Shao-Chen Sun
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Ya-Fei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yu Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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25
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Oh SW, Yu E, Park SH, Kwon K, Lee JH, Ha H, Kim G, Shin HS, Min S, Song M, Cho JY, Lee J. Ammonium chloride, an environmental pollutant, disrupts melanocyte biology through the regulation of melanosome and autophagy. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 296:118214. [PMID: 40262244 DOI: 10.1016/j.ecoenv.2025.118214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 04/11/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Ammonium chloride is an indoor environmental pollutant released due to industrial emissions, concrete, indoor bacteria, or other sources. In this study, we characterized molecular mechanisms of ammonium chloride-induced cell damage in melanocyte cells, which are a critical effector for pigmentation. Specifically, we investigated the effects of ammonium chloride on pigmentation and its underlying mechanisms, including its involvement in melanogenesis and autophagy. Based on the experiments, we elucidated that ammonium chloride induced and increased melanogenesis by upregulating MITF via AKT-mediated melanogenic signaling pathways. Moreover, ammonium chloride did not exhibit lysosomotropic activity and inhibited autophagy by activating the AKT-mTOR signaling pathway, suggesting that the pigment-regulating mechanism of ammonium chloride was associated with autophagy in pigmented cells. The findings of this study offer new perspectives on the mechanisms involved in ammonium chloride-induced pigmentation and propose a potential approach to mitigate ammonium chloride-induced side effects like hyperpigmentation and hyperammonemia by employing a combined autophagy inducer.
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Affiliation(s)
- Sae Woong Oh
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Eunbi Yu
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - See-Hyoung Park
- Department of Bio and Chemical Engineering, Hongik University, Sejong City 30016, South Korea
| | - Kitae Kwon
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Jung Hyun Lee
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Heejun Ha
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Gyeonghyeon Kim
- Department of MetaBioHealth, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Hee Seon Shin
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Seokhyeon Min
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea
| | - Minkyung Song
- Integrative Research of T cells Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Department of Biopharmaceutical Convergence, Sungkyunkwan University, Gyunggi Do 16419, South Korea.
| | - Jae Youl Cho
- Molecular Immunology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea.
| | - Jongsung Lee
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon City, Gyunggi Do 16419, South Korea.
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26
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Ye C, Ning Z, Hu T, Zhao X, Mu W. Melatonin modulates autophagy, mitochondria and antioxidant in the liver and brain of Perccottus glenni during recovery from freezing. Comp Biochem Physiol A Mol Integr Physiol 2025; 303:111824. [PMID: 39947457 DOI: 10.1016/j.cbpa.2025.111824] [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: 12/13/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
The Amur sleeper (Percottus glenii), a freeze tolerant fish species, can survive being frozen in ice, survival after recovery from freezing. This study investigated the role of melatonin in the recovery of Perccottus glenni following freezing. The fish were categorized into the following groups: non-treated control (Con), pinealectomy (Px), melatonin injection (Mlt), sham control (Sham), and saline injection control (Sal). The results revealed that the melatonin levels were affected by pinealectomy and melatonin injection. The liver and brain of the Px and Mlt groups exhibited autophagy after 4 h, along with the differential expression of endoplasmic reticulum stress-related genes. Furthermore, the activities of the mitochondrial complex initially increased at 4 h and then decreased by 12 h in the Px and Mlt groups, while antioxidant enzyme activities varied across groups and time points. These findings indicated that melatonin plays a key role in the recovery of P. glenni in a time-dependent manner, affecting autophagy, mitochondrial function, and antioxidant capacity. This study is the first to demonstrate melatonin's time-dependent role in facilitating the recovery of P. glenni after freezing, highlighting its critical involvement in modulating autophagy, mitochondrial function, and antioxidant processes. These findings shed light on the physiological mechanisms underlying freeze tolerance and recovery in fish, offering valuable insights for understanding and potentially enhancing the recovery processes in other species.
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Affiliation(s)
- Cunrun Ye
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Zhaoyang Ning
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Tingting Hu
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Xiaoyu Zhao
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China
| | - Weijie Mu
- Department of Fisheries Physiology and Resources Utilization, State Key Laboratory of Life Sciences and Technologies, Harbin Normal University, Harbin 150025, PR China.
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Tiwari RK, Rawat SG, Rai S, Kumar A. Stress regulatory hormones and cancer: the contribution of epinephrine and cancer therapeutic value of beta blockers. Endocrine 2025; 88:359-386. [PMID: 39869294 DOI: 10.1007/s12020-025-04161-7] [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: 06/10/2024] [Accepted: 01/08/2025] [Indexed: 01/28/2025]
Abstract
The word "cancer" evokes myriad emotions, ranging from fear and despair to hope and determination. Cancer is aptly defined as a complex and multifaceted group of diseases that has unapologetically led to the loss of countless lives and affected innumerable families across the globe. The battle with cancer is not only a physical battle, but also an emotional, as well as a psychological skirmish for patients and for their loved ones. Cancer has been a part of our history, stories, and lives for centuries and has challenged the ingenuity of health and medical science, and the resilience of the human spirit. From the early days of surgery and radiation therapy to cutting-edge developments in chemotherapeutic agents, immunotherapy, and targeted treatments, the medical field continues to make significant headway in the fight against cancer. However, even after all these advancements, cancer is still among the leading cause of death globally. This urges us to understand the central hallmarks of neoplastic cells to identify novel molecular targets for the development of promising therapeutic approaches. Growing research suggests that stress mediators, including epinephrine, play a critical role in the development and progression of cancer by inducing neoplastic features through activating adrenergic receptors, particularly β-adrenoreceptors. Further, our experimental data has also shown that epinephrine mediates the growth of T-cell lymphoma by inducing proliferation, glycolysis, and apoptosis evasion via altering the expression levels of key regulators of these vital cellular processes. The beauty of receptor-based therapy lies in its precision and higher therapeutic value. Interestingly, the enhanced expression of β-adrenergic receptors (ADRBs), namely ADRB2 (β2-adrenoreceptor) and ADRB3 (β3-adrenoreceptor) has been noted in many cancers, such as breast, colon, gastric, pancreatic, and prostate and has been reported to play a pivotal role in facilitating cancer growth mainly by promoting proliferation, evasion of apoptosis, angiogenesis, invasion and metastasis, and chemoresistance. The present review article is an attempt to summarize the available findings which indicate a distinct relationship between stress hormones and cancer, with a special emphasis on epinephrine, considered as a key stress regulatory molecule. This article also discusses the possibility of using beta-blockers for cancer therapy.
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Affiliation(s)
- Rajan Kumar Tiwari
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- School of Medicine and Health Sciences, The George Washington University, Washington DC, USA
| | - Shiv Govind Rawat
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- MD Anderson Cancer Center, The University of Texas, Texas, USA
| | - Siddharth Rai
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
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28
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Yan Z, Han J, Mi Z, Wang Z, Fu Y, Wang C, Dang N, Liu H, Zhang F. GPNMB disrupts SNARE complex assembly to maintain bacterial proliferation within macrophages. Cell Mol Immunol 2025; 22:512-526. [PMID: 40038549 PMCID: PMC12041529 DOI: 10.1038/s41423-025-01272-z] [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: 09/29/2024] [Accepted: 02/12/2025] [Indexed: 03/06/2025] Open
Abstract
Xenophagy plays a crucial role in restraining the growth of intracellular bacteria in macrophages. However, the machinery governing autophagosome‒lysosome fusion during bacterial infection remains incompletely understood. Here, we utilize leprosy, an ideal model for exploring the interactions between host defense mechanisms and bacterial infection. We highlight the glycoprotein nonmetastatic melanoma protein B (GPNMB), which is highly expressed in macrophages from lepromatous leprosy (L-Lep) patients and interferes with xenophagy during bacterial infection. Upon infection, GPNMB interacts with autophagosomal-localized STX17, leading to a reduced N-glycosylation level at N296 of GPNMB. This modification promotes the degradation of SNAP29, thus preventing the assembly of the STX17-SNAP29-VAMP8 SNARE complex. Consequently, the fusion of autophagosomes with lysosomes is disrupted, resulting in inhibited cellular autophagic flux. In addition to Mycobacterium leprae, GPNMB deficiency impairs the proliferation of various intracellular bacteria in human macrophages, suggesting a universal role of GPNMB in intracellular bacterial infection. Furthermore, compared with their counterparts, Gpnmbfl/fl Lyz2-Cre mice presented decreased Mycobacterium marinum amplification. Overall, our study reveals a previously unrecognized role of GPNMB in host antibacterial defense and provides insights into its regulatory mechanism in SNARE complex assembly.
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Affiliation(s)
- Zhenzhen Yan
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Dermatology, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Jinghong Han
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zihao Mi
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenzhen Wang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yixuan Fu
- Department of Dermatology, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Chuan Wang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ningning Dang
- Department of Dermatology, Shandong Provincial Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China
| | - Hong Liu
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Furen Zhang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Xie S, Wang Y, Zhao C, Cui Y, Gu C, Wu W. Putrescine promotes maturation of oocytes from reproductively old mice via mitochondrial autophagy. Reprod Biomed Online 2025; 50:104495. [PMID: 40068351 DOI: 10.1016/j.rbmo.2024.104495] [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: 05/17/2024] [Revised: 09/25/2024] [Accepted: 10/14/2024] [Indexed: 05/12/2025]
Abstract
RESEARCH QUESTION Does putrescine (PUT) improve oocytes from reproductively old mice by promoting mitochondrial autophagy? DESIGN Germinal vesicle stage cumulus-oocyte complexes (COCs) were obtained from 9-month old female C57BL/6N mice and divided into control, PUT and difluoromethylornithine, inhibitor (DFMO) groups. These germinal vesicle COCs underwent mouse in-vitro maturation (IVM) culture to observe the extrusion of the first polar body in each group. Using JC-1, dichloro-dihydro-fluorescein diacetate fluorescent probes and a confocal microscope, the mitochondrial membrane potential integrity and reactive oxygen species levels were measured in metaphase II stage oocytes. The expression and cellular localization of the p53 protein were examined by immunofluorescence. Reverse transcription quantitative polymerase chain reaction was used to detect the activation of mitochondrial autophagy pathways. The potential mechanisms through which PUT improves oocytes from reproductively old mice were explored by single-cell transcriptomic analysis. Autophagosomes, autolysosomes and mitochondria in different groups were directly observed using transmission electron microscopy. RESULTS The addition of exogenous PUT can promote IVM of oocytes from reproductively old mice. It reduces oxidative stress by promoting the autophagy of damaged mitochondria, decreasing the levels of reactive oxygen species and increasing mitochondrial membrane potential. It affects the expression and subcellular localization of the p53 protein, and increases the expression of transcription factor EB, which may be the potential mechanism behind its promotion of autophagy. CONCLUSION The target and regulatory pathway of PUT in oocytes was clarified. Putrescine is an effective small molecule compound with significant potential for non-invasively improving the fertility of elderly women.
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Affiliation(s)
- Siyuan Xie
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China.; School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yuyi Wang
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chenxi Zhao
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Yugui Cui
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China
| | - Chunyan Gu
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, China..
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Li K, Zheng Y, Cai S, Fan Z, Yang J, Liu Y, Liang S, Song M, Du S, Qi L. The subventricular zone structure, function and implications for neurological disease. Genes Dis 2025; 12:101398. [PMID: 39935607 PMCID: PMC11810716 DOI: 10.1016/j.gendis.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 05/28/2024] [Accepted: 07/28/2024] [Indexed: 02/13/2025] Open
Abstract
The subventricular zone (SVZ) is a region surrounding the lateral ventricles that contains neural stem cells and neural progenitor cells, which can proliferate and differentiate into various neural and glial cells. SVZ cells play important roles in neurological diseases like neurodegeneration, neural injury, and glioblastoma multiforme. Investigating the anatomy, structure, composition, physiology, disease associations, and related mechanisms of SVZ is significant for neural stem cell therapy and treatment/prevention of neurological disorders. However, challenges remain regarding the mechanisms regulating SVZ cell proliferation, differentiation, and migration, delivering cells to damaged areas, and immune responses. In-depth studies of SVZ functions and related therapeutic developments may provide new insights and approaches for treating brain injuries and degenerative diseases, as well as a scientific basis for neural stem cell therapy. This review summarizes research findings on SVZ and neurological diseases to provide references for relevant therapies.
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Affiliation(s)
- Kaishu Li
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Yin Zheng
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Shubing Cai
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Zhiming Fan
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Junyi Yang
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Yuanrun Liu
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Shengqi Liang
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Meihui Song
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Siyuan Du
- Department of Neurosurgery, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Ling Qi
- Institute of Digestive Diseases, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
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Corona A, Kenny PJ. Chronic stress drives depression by disrupting cellular housekeeping. Nature 2025; 641:317-318. [PMID: 40205096 DOI: 10.1038/d41586-025-00910-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
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Lei K, Chen Y, Wu J, Lin Y, Bai Y, Cao H, Che Q, Guo J, Su Z. Mechanism of liver x receptor alpha in intestine, liver and adipose tissues in metabolic associated fatty liver disease. Int J Biol Macromol 2025; 307:142275. [PMID: 40112983 DOI: 10.1016/j.ijbiomac.2025.142275] [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: 01/15/2025] [Revised: 03/16/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
Metabolism associated fatty liver disease (MAFLD) has emerged as a growing global health challenge with limited effective treatments. Research on nuclear receptors offers promising new therapeutic avenues for MAFLD. The liver X receptor (LXR) has gained attention for its roles in tumors and metabolic and inflammatory diseases; However, its effects on MAFLD treatment remain a subject of debate. This review explores the therapeutic role of LXRα in MAFLD, focusing on its functions in the intestine, hepatic and adipose tissue, and summarizes recent advancements in LXRα ligands over the past five years. In the intestine, LXRα activation enhances the efflux of non-biliary cholesterol and reduces inflammation in the gut-liver axis by regulating intestinal high-density lipoprotein synthesis and its interaction with lipopolysaccharide. In the liver, LXRα activation facilitates cholesterol transport, influences hepatic lipid synthesis, and exerts anti-inflammatory effects. In adipose tissue, LXRα helps delay MAFLD progression by managing lipid autophagy and insulin resistance. Ligands that modulate LXRα transcriptional activity show considerable promise for MAFLD treatment.
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Affiliation(s)
- Kaiwen Lei
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Chen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jianxing Wu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yiyu Lin
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Wang H, Ding K, He J, Wang J. Tetrahydropalmatine promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate atherosclerosis. Histol Histopathol 2025; 40:697-710. [PMID: 39359170 DOI: 10.14670/hh-18-809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
BACKGROUND Atherosclerosis (AS) is a chronic progressive arterial disease that is associated with macrophage autophagy and AMP-activated protein kinase (AMPK)/mechanistic target of the rapamycin (mTOR) pathway. Tetrahydropalmatine (THP) can activate AMPK-dependent autophagy. We aim to study the mechanism of macrophage autophagy mediated by THP in the treatment of AS via the AMPK/mTOR pathway. METHODS High-fat diet apolipoprotein E-deficient mice and ox-LDL-induced RAW264.7 cells were used to mimic the AS model, then THP was administered. Cell viability was detected by MTT. Pathological aorta lesions were detected using Hematoxylin and Eosin, Masson, and oil red staining. Lipid metabolism indices and inflammatory factors were measured using ELISA. A transmission electron microscope was used to observe autophagosomes. Autophagy and AMPK/mTOR pathway protein expression was detected by immunofluorescence and Western blot. The AMPK inhibitor 9-β-d-Arabinofuranosyl Adenine (Ara-A) was used to validate the effect of THP. The mRNA expression of Beclin-1 and MCP-1 was detected by q-PCR. RESULTS THP administration regulated lipid metabolism by lowering total cholesterol, triacylglycerol, low-density lipoprotein, and high-density lipoprotein levels, and suppressed aortic damage. THP suppressed aortic damage and regulated lipid metabolism by altering serum lipid levels. THP reduced inflammation and macrophage CD68 expression. Twenty μg/mL THP reduced cell viability. THP decreased cholesterol uptake and increased efflux, promoting autophagy. THP increased autophagosome number, LC3B expression, and autophagy markers p-AMPK/AMPK and LC3-II/LC3-I. THP also decreased p-mTOR/mTOR and P62. THP increased Beclin-1 mRNA expression and decreased MCP-1 mRNA expression. Ara-A reversed THP's effects. CONCLUSION THP promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate AS.
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Affiliation(s)
- Hui Wang
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Ke Ding
- Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Jiaqi He
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiahong Wang
- Traditional Chinese Medicine Dispensary, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Huang J, Yang J, Yang Y, Lu X, Xu J, Lu S, Pan H, Zhou W, Li W, Chen S. Mitigating Doxorubicin-Induced Cardiotoxicity and Enhancing Anti-Tumor Efficacy with a Metformin-Integrated Self-Assembled Nanomedicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2415227. [PMID: 40052211 PMCID: PMC12061326 DOI: 10.1002/advs.202415227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/06/2025] [Indexed: 05/10/2025]
Abstract
Doxorubicin (Dox) is a potent chemotherapeutic agent commonly used in cancer treatment. However, cardiotoxicity severely limited its clinical application. To address this challenge, a novel self-assembled nanomedicine platform, PMDDH, is developed for the co-delivery of Dox and metformin, an antidiabetic drug with cardioprotective and anti-tumor properties. PMDDH integrates metformin into a polyethyleneimine-based bioactive excipient (PMet), with Dox intercalated into double-stranded DNA and a hyaluronic acid (HA) coating to enhance tumor targeting. The PMDDH significantly improves the pharmacokinetics and tumor-targeting capabilities of Dox, while metformin enhances the drug's anti-tumor activity by downregulating programmed cell death ligand 1 (PD-L1) and activating the AMP-activated protein kinase (AMPK) signaling pathway. Additionally, the DNA component stimulates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which synergizes with Dox-induced immunogenic cell death (ICD) to promote a robust anti-tumor immune response. PMDDH markedly reduces Dox-induced cardiotoxicity by preserving mitochondrial function, reducing reactive oxygen species (ROS) production, and inducing protective autophagy in cardiomyocytes. These findings position PMDDH as a promising dual-function nanomedicine that enhances the anti-tumor efficacy of Dox while minimizing its systemic toxicity, offering a safer and more effective alternative for cancer therapy.
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Affiliation(s)
- Jiaxin Huang
- Department of PharmacySecond Xiangya HospitalCentral South UniversityChangshaHunan410011China
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
| | - Jieru Yang
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
| | - Yuanying Yang
- Department of PharmacySecond Xiangya HospitalCentral South UniversityChangshaHunan410011China
| | - Xiaofeng Lu
- Department of CardiologyShanghai General HospitalShanghai Jiao Tong University School of MedicineNo.100, Haining RdShanghai200080China
- Department of CardiologyShanghai General Hospital Jiuquan HospitalNo. 22, West StJiuquanGansu735000China
| | - Juan Xu
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
- Department of CardiologyShanghai General HospitalShanghai Jiao Tong University School of MedicineNo.100, Haining RdShanghai200080China
| | - Shan Lu
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
| | - Hong Pan
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical SciencesCentral South UniversityChangshaHunan410013China
- Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical PreparationsSchool of Pharmaceutical ScienceChangsha Medical UniversityChangshaHunan410219China
| | - Wenqun Li
- Department of PharmacySecond Xiangya HospitalCentral South UniversityChangshaHunan410011China
| | - Songwen Chen
- Department of CardiologyShanghai General HospitalShanghai Jiao Tong University School of MedicineNo.100, Haining RdShanghai200080China
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Tian MY, Yang JQ, Hu JC, Lu S, Ji Y. Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control. Acta Pharmacol Sin 2025; 46:1250-1261. [PMID: 39856432 PMCID: PMC12032422 DOI: 10.1038/s41401-024-01448-9] [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: 08/20/2024] [Accepted: 11/27/2024] [Indexed: 01/27/2025]
Abstract
Diabetic cardiomyopathy causes end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1 receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d-1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca2+]mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.
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Affiliation(s)
- Meng-Yun Tian
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Ji-Qin Yang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Jin-Chuan Hu
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Shan Lu
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
- State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China.
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Al-Kuraishy HM, Sulaiman GM, Mohsin MH, Mohammed HA, Dawood RA, Albuhadily AK, Al-Gareeb AI, Albukhaty S, Abomughaid MM. Targeting of AMPK/MTOR signaling in the management of atherosclerosis: Outmost leveraging. Int J Biol Macromol 2025; 309:142933. [PMID: 40203916 DOI: 10.1016/j.ijbiomac.2025.142933] [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: 07/20/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
Atherosclerosis (AS) is a chronic vascular disorder that is characterized by the thickening and narrowing of arteries due to the development of atherosclerotic plaques. The traditional risk factors involved in AS are obesity, type 2 diabetes (T2D), dyslipidemia, hypertension, and smoking. Furthermore, non-traditional risk factors for AS, such as inflammation, sleep disturbances, physical inactivity, air pollution, and alterations of gut microbiota, gained attention in relation to the pathogenesis of AS. Interestingly, the pathogenesis of AS, is complex and related to different abnormalities of cellular and sub-cellular signaling pathways. It has been illustrated that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (MTOR) pathways are involved in AS pathogenesis. Mounting evidence indicated that AMPK plays a critical role in attenuating the development of AS by activating autophagy, which is impaired during atherogenesis. AMPK has a vasculoprotective effect by reducing lipid accumulation, inflammatory cell proliferation, and the release of pro-inflammatory cytokines, as well as decreasing inflammatory cell adhesion to the vascular endothelium. AMPK activation by metformin inhibits the migration of vascular smooth muscle cells (VSMCs) and AS development. However, the MTOR pathway contributes to AS by inhibiting autophagy, highlighting autophagy as a crucial link between the AMPK and MTOR pathways in AS pathogenesis. The MTOR is a key inducer of endothelial dysfunction and is involved in the development of AS. Therefore, both the AMPK and MTOR pathways play a crucial role in the pathogenesis of AS. However, the exact role of AMPK and MTOR pathways in the pathogenesis of AS is not fully clarified. Therefore, this review aims to discuss the potential role of the AMPK/MTOR signaling pathway in AS, and how AMPK activators and MTOR inhibitors influence the development and progression of AS. In conclusion, AMPK activators and MTOR inhibitors have vasculoprotective effects against the development and progression of AS.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ghassan M Sulaiman
- Department of Applied Sciences, University of Technology, Baghdad, Iraq.
| | - Mayyadah H Mohsin
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Hamdoon A Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Saudi Arabia
| | - Retaj A Dawood
- Department of Biology, College of Science, Al-Mustaqbal University, Hilla 51001, Iraq
| | - Ali K Albuhadily
- Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Jabir ibn Hayyan Medical University, Al-Ameer Qu, PO.Box13 Kufa, Najaf, Iraq
| | | | - Mosleh M Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, 255, Bisha 67714, Saudi Arabia
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Xiang X, Huang L, Luo W, Qin L, Bian M, Chen W, Han G, Wang N, Mo G, Zhang C, Zhang Y, Yang H, Lu S, Zhang J, Fu T. Neuromuscular electrical stimulation alleviates stroke-related sarcopenia by promoting satellite cells myogenic differentiation via AMPK-ULK1-Autophagy axis. J Orthop Translat 2025; 52:249-264. [PMID: 40342549 PMCID: PMC12059223 DOI: 10.1016/j.jot.2025.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/11/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Background Stroke-related sarcopenia can result in muscle mass loss and muscle fibers abnormality, significantly affecting muscle function. The clinical management of stroke-related sarcopenia still requires further research and investigation. This study aims to explore a promising therapy to restore muscle function and promote muscle regeneration in stroke-related sarcopenia, providing a new theory for stroke-related sarcopenia treatment. Methods Stroke-related sarcopenia rat model was established by using permanent middle cerebral artery occlusion (pMCAO) rat and treated with neuromuscular electrical stimulation (NMES). Electrical stimulation (ES) treatment in vitro was mimicked to test the effect of NMES on muscle regeneration in rat skeletal muscle satellite cells (MuSCs). Catwalk, H&E and Masson's trichrome staining, immunofluorescence, transcriptomic analysis, transmission electron microscopy, MuSCs transfection, autophagy flux detection, quantitative real-time PCR analysis, Co-Immunoprecipitation and Western Blot were used to investigate the role of NMES and its mechanism in stroke-related sarcopenia in vivo. Results After NMES treatment, muscle mass and myogenic differentiation were significantly increased in stroke-related sarcopenia rats. The NMES group had more stable gait, neater footprints, higher muscle wet weight, more voluminous morphology and more regenerated muscle fibers. Additionally, ES treatment induced myogenic differentiation in rat MuSCs in vitro. Transcriptomic analysis also showed that "AMPK signaling pathway" was enriched and genes upregulated in ES-treated cells, revealing ES treatment could activate the autophagy in an AMPK-ULK1-dependent mechanism in MuSCs. Besides, it was also founded that infusion of AMPK or ULK1 inhibitor, knockdown of AMPK or ULK1 in MuSCs could block the effect of myotube formation of ES. Conclusion NMES not only restores muscle function but also enhances myogenic activity and muscle regeneration via AMPK-ULK1 autophagy in stroke-related sarcopenia rats. Our study provides a promising strategy for the treatment of stroke-related sarcopenia. The translational potential of this article This study first demonstrates that NMES alleviates stroke-related sarcopenia by promoting MuSCs differentiation through AMPK-ULK1-autophagy axis. The findings reveal a novel therapeutic mechanism, suggesting that NMES can restore muscle function and enhance regeneration in stroke patients. By combining NMES with MuSCs-based therapies, this approach offers a promising strategy for clinical rehabilitation, potentially improving muscle mass and function in stroke survivors. The translational potential lies in its applicability to non-invasive, cost-effective treatments for sarcopenia, enhancing patients' quality of life.
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Affiliation(s)
- Xingdong Xiang
- Department of Rehabilitation Medicine, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Lei Huang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Wenchen Luo
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Lieyang Qin
- Department of Cardiovascular Surgery, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Mengxuan Bian
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Weisin Chen
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Guanjie Han
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Ning Wang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Guokang Mo
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Cheng Zhang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Yongxing Zhang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215123, China
| | - Shunyi Lu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215123, China
| | - Jian Zhang
- Department of Rehabilitation Medicine, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Tengfei Fu
- Department of Rehabilitation Medicine, Zhongshan Hospital Fudan University, Shanghai, 200032, China
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Shen H, Xie Y, Wang Y, Xie Y, Wang Y, Su Z, Zhao L, Yao S, Cao X, Liang J, Long J, Zhong R, Tang J, Wang S, Zhang L, Wang X, Stork B, Cui L, Wu W. The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease. Autophagy 2025; 21:1096-1115. [PMID: 39813987 PMCID: PMC12013425 DOI: 10.1080/15548627.2024.2447206] [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: 06/23/2024] [Revised: 12/15/2024] [Accepted: 12/22/2024] [Indexed: 01/18/2025] Open
Abstract
Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux. In the brains of people with AD and APP-PSEN1 mice, the interaction of CANX and ULK1 declines. In mice, the lack of CANX in hippocampal neurons causes the accumulation of autophagy receptors and neuron damage, which affects the cognitive function of C57BL/6 mice. Conversely, overexpression of CANX in hippocampal neurons enhances autophagy flux and partially contributes to improving cognitive function of APP-PSEN1 mice, but not the CANX variant lacking the interaction domain with ULK1. These findings reveal a novel role of CANX in autophagy activity and cognitive function by cooperating with ULK1.Abbreviation: AD: Alzheimer disease; APEX: ascorbate peroxidase; APP: amyloid beta precursor protein; APP-PSEN1 mice: amyloid beta precursor protein-presenilin 1 transgenic mice; ATG: autophagy related; Aβ: amyloid-β; BiFC: bimolecular fluorescence complementation; CANX: calnexin; EBSS: Earle's balanced salt solution; EM: electron microscopy; IP: immunopurification; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MWM: Morris water maze; PLA: proximity ligation assay; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62, sequestosome 1.
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Affiliation(s)
- Hongtao Shen
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Yuying Xie
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yan Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yusheng Xie
- Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yongxiang Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Rehabilitation Medicine, Pingshan General Hospital, Southern Medical University, Shenzhen, China
- Department of Rehabilitation Medicine, Pingshan District Peoples’ Hospital of Shenzhen, Shenzhen, China
| | - Zhenyan Su
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Laixi Zhao
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shi Yao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiaoling Cao
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinglan Liang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Junrui Long
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Rimei Zhong
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinfeng Tang
- Clinical Research and Experimental Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Sijie Wang
- Clinical Research and Experimental Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Liangqing Zhang
- Department of Anesthesiology, Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiaojing Wang
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Björn Stork
- Institute of Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lili Cui
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- The Marine Biomedical Research Institute of Guangdong, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Wenxian Wu
- Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Bai Y, Xi Y, Gui C, Huang G, Zhou G. Genetic Evidence Supporting a Causal Association Between mTORC1-Dependent Circulating Protein Levels and Diabetic Retinopathy. Transl Vis Sci Technol 2025; 14:4. [PMID: 40314641 PMCID: PMC12054711 DOI: 10.1167/tvst.14.5.4] [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: 11/25/2024] [Accepted: 04/06/2025] [Indexed: 05/03/2025] Open
Abstract
Purpose The mechanistic target of rapamycin (mTOR) signaling pathway is essential for the onset and progression of diabetic retinopathy (DR). Nevertheless, the impact of mTORC1 downstream proteins in DR remains uncertain. Therefore, we performed a Mendelian randomization (MR) research to assess the causal effect of downstream mTORC1 proteins on DR risk. Methods Summary statistics on mTORC1 downstream proteins and DR were obtained from the INTERVAL and FinnGen studies (14,584 patients and 176,010 controls), respectively. We used various MR techniques, including inverse-variance-weighted, weighted median, and MR-Egger. Possible pleiotropy and heterogeneity were identified through sensitivity analysis. Results Genetically predicted eIF4E was positively correlated to DR risk (odds ratio = 1.057; 95% confidence interval, 1.008-1.109; P = 0.022]. No relationship has been shown for circulating RP-S6K, eIF4G, eIF4A, eIF4E-BP and eIF4B levels with DR formation. There was no heterogeneity or unbalanced level pleiotropy identified. Conclusions Higher levels of serum eIF4E promote the progression of DR, proposing that pharmacological inhibition of eIF4E activity may be a prospective DR therapeutic strategy. Translational Relevance The present study has highlighted the role of eIF4E in the development of DR, establishing the foundation for basic research into DR targets.
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Affiliation(s)
- Yaqi Bai
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yujia Xi
- The Second Hospital of Shanxi Medical University, Department of Urology, Taiyuan, China
| | - Chenwei Gui
- Department of Ophthalmology, Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guohai Huang
- Department of Ophthalmology, Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guohong Zhou
- Department of Ophthalmology, Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
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Li X, Chen W, Jia Z, Xiao Y, Shi A, Ma X. Mitochondrial Dysfunction as a Pathogenesis and Therapeutic Strategy for Metabolic-Dysfunction-Associated Steatotic Liver Disease. Int J Mol Sci 2025; 26:4256. [PMID: 40362504 PMCID: PMC12072025 DOI: 10.3390/ijms26094256] [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: 03/27/2025] [Revised: 04/28/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD) has emerged as a significant public health concern, attributed to its increasing prevalence and correlation with metabolic disorders, including obesity and type 2 diabetes. Recent research has highlighted that mitochondrial dysfunction can result in the accumulation of lipids in non-adipose tissues, as well as increased oxidative stress and inflammation. These factors are crucial in advancing the progression of MASLD. Despite advances in the understanding of MASLD pathophysiology, challenges remain in identifying effective therapeutic strategies targeting mitochondrial dysfunction. This review aims to consolidate current knowledge on how mitochondrial imbalance affects the development and progression of MASLD, while addressing existing research gaps and potential avenues for future research. This review was conducted after a systematic search of comprehensive academic databases such as PubMed, Embase, and Web of Science to gather information on mitochondrial dysfunction as well as mitochondrial-based treatments for MASLD.
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Affiliation(s)
- Xiangqiong Li
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Wenling Chen
- The First Clinical College of Yunnan University of Chinese Medicine, Kunming 650500, China;
| | - Zhuangzhuang Jia
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Yahui Xiao
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Anhua Shi
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
| | - Xuan Ma
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, China; (X.L.); (Y.X.); (X.M.)
- Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Kunming 650500, China
- Key Laboratory of Microcosmic Syndrome Differentiation, Education Department of Yunnan, Kunming 650500, China
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Freisem D, Hoenigsperger H, Catanese A, Sparrer KMJ. Inborn errors of canonical autophagy in neurodegenerative diseases. Hum Mol Genet 2025:ddae179. [PMID: 40304712 DOI: 10.1093/hmg/ddae179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 05/02/2025] Open
Abstract
Neurodegenerative disorders (NDDs), characterized by a progressive loss of neurons and cognitive function, are a severe burden to human health and mental fitness worldwide. A hallmark of NDDs such as Alzheimer's disease, Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases is disturbed cellular proteostasis, resulting in pathogenic deposition of aggregated protein species. Autophagy is a major cellular process maintaining proteostasis and integral to innate immune defenses that mediates lysosomal protein turnover. Defects in autophagy are thus frequently associated with NDDs. In this review, we discuss the interplay between NDDs associated proteins and autophagy and provide an overview over recent discoveries in inborn errors in canonical autophagy proteins that are associated with NDDs. While mutations in autophagy receptors seems to be associated mainly with the development of ALS, errors in mitophagy are mainly found to promote PD. Finally, we argue whether autophagy may impact progress and onset of the disease, as well as the potential of targeting autophagy as a therapeutic approach. Concludingly, understanding disorders due to inborn errors in autophagy-"autophagopathies"-will help to unravel underlying NDD pathomechanisms and provide unique insights into the neuroprotective role of autophagy, thus potentially paving the way for novel therapeutic interventions.
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Affiliation(s)
- Dennis Freisem
- Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstr. 1, Baden-Wuerttemberg, Ulm 89081, Germany
| | - Helene Hoenigsperger
- Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstr. 1, Baden-Wuerttemberg, Ulm 89081, Germany
| | - Alberto Catanese
- German Center for Neurodegenerative Diseases, Albert-Einstein-Allee 11, Baden-Wuerttemberg, Ulm 89081, Germany
- Institute of Anatomy and Cell Biology, Ulm University Medical Center, Albert-Einstein-Allee 11, Baden-Wuerttemberg, Ulm 89081, Germany
| | - Konstantin M J Sparrer
- Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstr. 1, Baden-Wuerttemberg, Ulm 89081, Germany
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Li C, Chen T, Li Y, Zhou C, Du J, Li X, Tang C, Ma C, Deng N, Cui H. Impact of diabetes and metformin on cuproptosis and ferroptosis in breast cancer patients: an immunohistochemical analysis. Discov Oncol 2025; 16:634. [PMID: 40299142 PMCID: PMC12040783 DOI: 10.1007/s12672-025-02425-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/18/2025] [Indexed: 04/30/2025] Open
Abstract
OBJECTIVES Breast cancer patients with diabetes are often associated with poor prognosis. This study aims to investigate the role of metformin in ferroptosis and cuproptosis in diabetic breast cancer patients and explore its potential impact on clinical outcomes. METHODS We retrospectively analyzed tissue samples from 16 breast cancer patients, including 5 non-diabetic and 11 diabetic patients (6 treated with metformin). Immunohistochemistry (IHC) staining was performed for cuproptosis (FDX1, DLAT), ferroptosis (ACSL4, GPX4), and glycolysis markers (LDHA, PKM2). Statistical analysis used quantitative results from immunohistochemistry. RESULTS Patients treated with metformin showed significantly higher expression of FDX1 and ACSL4, along with a significant decrease in GPX4 compared to other groups. Kaplan-Meier survival analysis revealed that high FDX1 expression was associated with longer survival in breast cancer patients. Correlation analysis showed a positive association between ACSL4 and FDX1 (R = 0.51, P = 0.045), suggesting a relationship between these markers. CONCLUSIONS Metformin may simultaneously enhance both cuproptosis and ferroptosis in breast cancer. FDX1 expression could serve as a prognostic marker for survival, especially in diabetic patients, providing insights into targeting metabolic and cell death pathways in breast cancer therapy.
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Affiliation(s)
- Changwen Li
- The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, People's Republic of China
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Tao Chen
- The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, People's Republic of China
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Yuanyuan Li
- The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, People's Republic of China
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Chunyan Zhou
- The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Jing Du
- School of Life Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, People's Republic of China
| | - Xiaoxin Li
- Department of Pathology, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Chuangang Tang
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Cheng Ma
- Department of Gastrointestinal Surgery, Xuzhou Central Hospital, Xuzhou, 221009, Jiangsu, People's Republic of China
| | - Na Deng
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China.
| | - Huaixin Cui
- The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, 221009, Jiangsu, People's Republic of China.
- Department of Breast Surgery, Xuzhou Central Hospital, No 199 South Jiefang Road, Xuzhou, 221009, Jiangsu, People's Republic of China.
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Zhang J, Cheng X, Chen G, Chen X, Zhao X, Chen W, Du W, He Z, Yao X, Han B, Yao D. Discovery of a Novel Selective PAK1/HDAC6/HDAC10 Inhibitor ZMF-25 that Induces Mitochondrial Metabolic Breakdown and Autophagy-Related Cell Death in Triple-Negative Breast Cancer. RESEARCH (WASHINGTON, D.C.) 2025; 8:0670. [PMID: 40302782 PMCID: PMC12038163 DOI: 10.34133/research.0670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/16/2025] [Accepted: 03/22/2025] [Indexed: 05/02/2025]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and addressing its intrinsic heterogeneity has emerged as a valuable avenue for novel clinical treatment strategy. Here, we put forward an innovative strategy for TNBC treatment by simultaneously suppressing both p21-activated kinase 1 (PAK1) and histone deacetylase (HDAC) class IIb (HDAC6/10). A series of pyrido [2,3-d]pyrimidin-7(8H)-one moiety derivatives was successfully designed and synthesized to target PAK1/HDAC6/HDAC10 by utilizing structure-based screening and pharmacophore integration. ZMF-25 demonstrates marked inhibitory activity against PAK1, HDAC6, and HDAC10 with respective IC50 values of 33, 64, and 41 nM, remarkable selectivity over HDACs and PAKs, as well as prominent antiproliferative efficiency in MDA-MB-231 cells. Additionally, ZMF-25 effectively suppresses TNBC proliferation and migration by inhibiting PAK1/HDAC6/HDAC10. Moreover, it was found to impair glycolysis and trigger reactive oxygen species generation, resulting in autophagy-related cell death by inhibiting the AKT/mTOR/ULK1 signaling. Furthermore, ZMF-25 exhibits remarkable therapeutic potential with no obvious toxicity in vivo and good pharmacokinetics. In summary, these observations indicate that ZMF-25 is a novel and potent triple-targeting PAK1/HDAC6/HDAC10 inhibitor, which is expected to provide a novel and effective strategy for TNBC treatment.
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Affiliation(s)
- Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
| | - Xiaoling Cheng
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
| | - Gang Chen
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
| | - Xi Zhao
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital ofChengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Weiji Chen
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
- Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences,
Macao Polytechnic University, Macao 999078, China
| | - Wei Du
- West China School of Pharmacy,
Sichuan University, Chengdu 610000, China
| | - Zhendan He
- School of Pharmaceutical Sciences, Health Science Center,
Shenzhen University, Shenzhen 518060, China
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
| | - Xiaojun Yao
- Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences,
Macao Polytechnic University, Macao 999078, China
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital ofChengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Dahong Yao
- School of Pharmaceutical Sciences,
Shenzhen Technology University, Shenzhen 518118, China
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Potokar M, Jorgačevski J. Targeting autophagy in astrocytes: a potential for neurodegenerative disease intervention. Front Cell Neurosci 2025; 19:1584767. [PMID: 40357169 PMCID: PMC12066609 DOI: 10.3389/fncel.2025.1584767] [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: 02/27/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
Autophagy contributes to cellular homeostasis by regulating the degradation and recycling of damaged organelles and misfolded proteins. In the central nervous system (CNS), impaired autophagy contributes to inflammation, disrupts cellular metabolism, and leads to the accumulation of toxic protein aggregates that accelerate the progression of neurodegenerative diseases. In addition to its role in protein and organelle turnover, autophagy facilitates the elimination of pathogenic bacteria and viruses, whose infections can also lead to neurological diseases and neuroinflammatory processes. Astrocytes, the most abundant glial cells in the CNS, play a crucial role in maintaining neuronal homeostasis by regulating neurotransmitter balance, ion exchange, and metabolic support. During neurodegeneration, they become reactive, actively participating in neuroinflammatory responses by releasing proinflammatory cytokines, activating microglia, and removing toxic aggregates. Cytokine-mediated responses and metabolic changes in astrocytes influence neuronal viability and neurotransmission. Autophagy in astrocytes plays an important role in tuning the astrocyte-dependent activity of neurons under physiological conditions and in pathological activation of astrocytes by disease, injury or pathogenic stimuli. In this review, we highlight the contribution of astrocytes to neurodegeneration from the perspective of changes in their cytoskeleton, the autophagy process in which the cytoskeleton plays a crucial role, and the metabolic support of neurons. The modulation of autophagy at different stages has the potential to serve as an additional therapeutic target in CNS diseases.
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Affiliation(s)
- Maja Potokar
- Laboratory of Neuroendocrinology—Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Celica Biomedical, Ljubljana, Slovenia
| | - Jernej Jorgačevski
- Laboratory of Neuroendocrinology—Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Celica Biomedical, Ljubljana, Slovenia
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Shaw P, Dey Bhowmik A, Gopinatha Pillai MS, Robbins N, Dwivedi SKD, Rao G. Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding. Cancer Lett 2025; 624:217750. [PMID: 40294841 DOI: 10.1016/j.canlet.2025.217750] [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: 01/21/2025] [Revised: 04/01/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.
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Affiliation(s)
- Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Nathan Robbins
- James E. Hurley School of Science and Mathematics, Oklahoma Baptist University, Shawnee, OK, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA.
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Qiao Z, Feng X, Sun W, Wang F, Lu C. Independent and synergistic effects of extreme heat and NO 2 pollution on diabetic nephropathy in a type II diabetes mouse model. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 375:126321. [PMID: 40294690 DOI: 10.1016/j.envpol.2025.126321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 04/13/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
Extreme heat and traffic-related air pollution (TRAP) have been linked to worsening chronic health disorders, however, their combined effects on diabetic nephropathy (DN) are little understood. Type II diabetic mice were exposed to heat (40 °C) and NO2 (5 ppm) separately for 4 h per day over 6 weeks to investigate the synergistic effects on the progression of DN. We found that exposure to high temperature and NO2 elevated blood glucose levels and exacerbated histopathological changes. Additionally, there were increased oxidation indicators (ROS, MDA, 8-OHdG) and decreased antioxidant indicators (CAT, SOD, GSH-PX), along with elevated inflammation markers (TNF-α, IL-1β, IL-6). The expressions of transient receptor potential (TRP) ion channels (TRPV1, TRPV4, TRPA1, TRPM2) were also upregulated. Our findings suggest that simultaneous exposure to high temperature and NO2 impairs metabolic and autophagy pathways. Exposure to both high temperature and NO2 produces a synergistic effect, leading to more severe damage than exposure to either factor individually. This resulted in increased expression of APOA1, P62, and p-mTOR/mTOR while decreasing the expression of p-AMPKα/AMPKα and LC3-II/I. This disruption promoted the progression of DN. In contrast, capsazepine (CZP) reduced TRP expression, inflammatory markers, oxidative stress, metabolic and autophagy disorders, thereby mitigating renal damage and alleviating the progression of diabetic nephropathy. Our study provides some potential strategies for early prevention and effective reduction of DN.
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Affiliation(s)
- Zipeng Qiao
- XiangYa School of Public Health, Central South University, Changsha, 410013, China
| | - Xiangling Feng
- XiangYa School of Public Health, Central South University, Changsha, 410013, China
| | - Wenying Sun
- XiangYa School of Public Health, Central South University, Changsha, 410013, China
| | - Faming Wang
- Centre for Molecular Biosciences and Non-communicable Diseases, Xi'an University of Science and Technology, Xi'an, 710054, China
| | - Chan Lu
- XiangYa School of Public Health, Central South University, Changsha, 410013, China; FuRong Laboratory, Changsha, 410078, Hunan, China; Hunan Provincial Key Laboratory of Low Carbon Healthy Building, Central South University, Changsha, 410083, China.
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Seo MK, Kim H, Choi AJ, Seog DH, Kho WG, Park SW, Lee JG. Effects of tianeptine on mTORC1-mediated neuronal autophagy in primary rat hippocampal neurons under nutrient deprivation. Sci Rep 2025; 15:14488. [PMID: 40280952 PMCID: PMC12032415 DOI: 10.1038/s41598-025-92988-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 03/04/2025] [Indexed: 04/29/2025] Open
Abstract
The aim of this study was to investigate the effects of the antidepressant tianeptine on the mechanistic target of rapamycin complex 1(mTORC1)-mediated autophagy pathway in primary hippocampal neurons exposed to B27-deprived conditions. When primary hippocampal neurons were treated with tianeptine at doses of 1, 10, 50, and 100 µM for 3 days under B27-deprived conditions, we observed that it activated autophagy and increased the formation of autophagosomes through the upregulation of autophagic proteins, including autophagy-activating kinase 1 (ULK1), Beclin 1, LC3B-II/I, and p62. And at a concentration of 100 µM tianeptine, the decrease in mTORC1 phosphorylation induced by B27 deprivation was significantly reversed. Changes in the expression of autophagic proteins induced by B27 deprivation were reversed by tianeptine treatment in a concentration-dependent manner, and tianeptine significantly reduced the increase in LC3B membrane number induced by B27 deprivation, an effect that was blocked by pretreatment with rapamycin. In conclusion, tianeptine attenuated the activity of mTORC1-mediated autophagy in primary rat hippocampal neurons under B27-deprived conditions. These results may suggest a novel mechanism by which tianeptine may affect autophagy in neurons.
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Affiliation(s)
- Mi Kyoung Seo
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Hyewon Kim
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea
| | - Ah Jeong Choi
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
| | - Dae-Hyun Seog
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Department of Biochemistry, College of Medicine, Inje University, Busan, 47392, Republic of Korea
- Dementia and Neurodegenerative Disease Research Center, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Weon-Gyu Kho
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea
- Department of Parasitology, College of Medicine, Inje University, Busan, 47392, Republic of Korea
| | - Sung Woo Park
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Convergence Biomedical Science, College of Medicine, Inje University, Busan, 47392, Republic of Korea.
| | - Jung Goo Lee
- Paik Institute for Clinical Research, Inje University, Busan, 47392, Republic of Korea.
- Department of Psychiatry, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, 48108, Republic of Korea.
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Al Sayegh R, Wan J, Caër C, Azoulai M, Gasperment M, Baweja S, Chouillard MA, Kandiah J, Cadoux M, Mabire M, Pignolet C, Thibault-Sogorb T, Hammoutene A, Paradis V, Saveanu L, Nicolle R, Gilgenkrantz H, Weiss E, Lotersztajn S. Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation. Nat Commun 2025; 16:3860. [PMID: 40274816 PMCID: PMC12022296 DOI: 10.1038/s41467-025-59218-y] [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: 06/20/2024] [Accepted: 04/15/2025] [Indexed: 04/26/2025] Open
Abstract
Conventional CD4 T cells represent a major source of inflammatory mediators that drive progression of chronic liver disease to fibrosis and to end-stage cirrhosis. Identification of T cell pathways that limits the inflammatory response could thus have therapeutic relevance. Here we show, using both human samples and mouse models, that autophagy is deficient in CD4 T cells from patients with advanced fibrosis, and that loss of autophagy following genomic deletion of ATG5 in T cells is associated with the emergence of pathogenic IL-17A + IFN-γ + Th17 T cells that drive liver fibrosis in mice. Mechanistically, liver CD4 T cells lacking autophagy display a Th17 glycolytic phenotype associated with enhanced type 3 cytokine (i.e., IL-17A and GM-CSF) release, shifting hepatic myofibroblasts, hepatocytes and macrophages toward a proinflammatory phenotype. We also show that autophagy can be rescued in CD4 T cells from patients with extensive liver fibrosis, leading to decreased frequency of pathogenic Th17 cells and reduced GM-CSF levels; in addition, limited fibrosis is observed in mice in which Rubicon, a negative regulator of autophagy, is deleted specifically in their T cells. Our findings thus implicate autophagy in CD4 T cells as a key therapeutic target to control inflammation-driven fibrosis during chronic liver injury.
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Affiliation(s)
- Rola Al Sayegh
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Jinghong Wan
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Charles Caër
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Margot Azoulai
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Maxime Gasperment
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Sukriti Baweja
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Institute of Liver Biliary Sciences, Delhi, India
| | - Marc-Anthony Chouillard
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Département d'Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique- Hôpitaux de Paris, Clichy, France
| | - Janany Kandiah
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Inovarion, Paris, France
| | - Mathilde Cadoux
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Morgane Mabire
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Camille Pignolet
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Tristan Thibault-Sogorb
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Département d'Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique- Hôpitaux de Paris, Clichy, France
| | - Adel Hammoutene
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Valérie Paradis
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Département de Pathologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Loredana Saveanu
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Rémy Nicolle
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Hélène Gilgenkrantz
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Emmanuel Weiss
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Département d'Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique- Hôpitaux de Paris, Clichy, France
| | - Sophie Lotersztajn
- Université Paris Cité, INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France.
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Chen X, Weng Z, Zhang H, Jiao J, Liang J, Xu J, Wang D, Liu Q, Yan Q, Gu A. Nano-zinc oxide (nZnO) targets the AMPK-ULK1 pathway to promote bone regeneration. Stem Cell Res Ther 2025; 16:206. [PMID: 40275329 PMCID: PMC12023698 DOI: 10.1186/s13287-025-04322-5] [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: 06/10/2024] [Accepted: 04/09/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Nano-zinc oxide (nZnO) has attracted significant attention in bone tissue engineering due to its antibacterial properties, anti-inflammatory effects, biocompatibility, and chemical stability. Although numerous studies have demonstrated the enhancement of osteogenic differentiation by nZnO-modified tissue engineering materials, the underlying mechanisms remain poorly characterized. METHODS This study aimed to identify the molecular mechanisms how nZnO promoted osteogenic differentiation and bone regeneration using transcriptome analysis, drug intervention, and shRNA knockdown techniques, etc. First, the study evaluated the in vivo effects of gelatin methacryloyl (GelMA) containing nZnO on bone regeneration using a mouse calvarial defect model. The impact of nZnO exposure on the osteogenic differentiation of mesenchymal stem cells (MSCs) was then assessed. The combined treatment of nZnO and MSCs in GelMA for bone regeneration was assessed in the mouse calvarial defect model thereafter. RESULTS nZnO induced osteoblastic differentiation to promote bone regeneration. nZnO activated the AMP-dependent protein kinase (AMPK)-ULK1 signals to stimulate autophagosomes formation and facilitate autophagy flow, which was the essential pathway to induce osteogenic differentiation. The combined treatment of MSCs and nZnO significantly enhanced bone regeneration in calvarial defect mice. Conversely, AMPK inhibitor Compound C (C.C) reversed the effects on autophagy flow and osteogenic potentiality induced by nZnO. CONCLUSIONS These results highlight that nZnO can regulate bone regeneration by activating autophagy through the AMPK/ULK1 signaling pathway, which may provide a novel therapeutic strategy for addressing bone defects using nZnO.
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Affiliation(s)
- Xiu Chen
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Zhenkun Weng
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
- Changzhou Second People's Hospital, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 213004, China
| | - Hongchao Zhang
- School of Medicine, Shanghai East Hospital & Institute of Gallstone Disease, Tongji University, Shanghai, Nanjing, 200120, 211166, China
| | - Jian Jiao
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jingjia Liang
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jin Xu
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China
| | - Dongmei Wang
- Changzhou Second People's Hospital, Changzhou Medical Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, 213004, China
| | - Qian Liu
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
| | - Qing Yan
- Department of Neurosurgery, Children's Hospital of Nanjing Medical University, Nanjing, 211166, China.
| | - Aihua Gu
- State Key Laboratory of Reproductive Medicine and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
- Jiangsu Environmental Health Risk Assessment Engineering Research Center, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
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50
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Xue C, Yan Z, Cheng W, Zhang D, Zhang R, Duan H, Zhang L, Ma X, Hu J, Kang J, Ma X. Curcumin ameliorates aging-induced blood-testis barrier disruption by regulating AMPK/mTOR mediated autophagy. PLoS One 2025; 20:e0321752. [PMID: 40273194 PMCID: PMC12021166 DOI: 10.1371/journal.pone.0321752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/08/2025] [Indexed: 04/26/2025] Open
Abstract
The blood-testis barrier (BTB) is composed of tight junctions (TJ) between adjacent Sertoli cells (SCs) and is crucial for sperm growth and development. Aging-induced TJ impairment is closely related to testicular dysfunction. Curcumin, a natural compound, has been widely demonstrated to have a wide range of pharmacological activities, but its regulatory effects on tight junction damage in the testis remain unclear. We here explored the effect of curcumin on TJ function and its underlying molecular mechanism by using D-galactose (D-gal)-induced mouse testis and mouse testicular SCs (TM4) aging models in vitro. In this study, D-gal increased the expression of aging-related proteins p16 and p21, whereas significantly decreased the expression of TJ proteins (ZO-1, Claudin-4, Claudin-7, and Occludin). In addition, curcumin restored the adverse effects of D-gal in the SCs. Autophagy is a degradation system for maintaining cell renewal and homeostasis. D-gal significantly decreased the autophagy level, whereas curcumin restored the effect of D-gal. Using chloroquine (CQ), an inhibitor of autophagy, and rapamycin (RAPA), an activator of autophagy, it was demonstrated that autophagy plays a key role in curcumin amelioration of TJ injury in testicular SCs. Further studies unveiled that autophagy activation was mediated through the AMPK/mTOR pathway. In conclusion, curcumin ameliorates aging-induced TJ damage through AMPK/mTOR signaling pathway-regulated autophagy. This study thus clearly identifies a novel action mechanism of curcumin in the treatment of age-related male reproductive disorders.
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Affiliation(s)
- Chen Xue
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Zhenxing Yan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Wenjing Cheng
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Dong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Rong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Hongwei Duan
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Lihong Zhang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Xiaofei Ma
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Junjie Hu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
| | - Jian Kang
- School of Animal Science and technology, Guangdong polytechnic of science and trade, Guangzhou, Guangdong, China
| | - Xiaojun Ma
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou, Gansu, China
- Key Laboratory of Animal Reproductive Physiology and Reproductive Regulation in Gansu Province, Lanzhou, Lanzhou, Gansu, China
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