1
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Zhao Y, Tan F, Zhao J, Zhou S, Luo Y, Gong C. Targeting the Enhanced Sensitivity of Radiotherapy in Cancer: Mechanisms, Applications, and Challenges. MedComm (Beijing) 2025; 6:e70202. [PMID: 40384989 PMCID: PMC12079026 DOI: 10.1002/mco2.70202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 06/04/2025] Open
Abstract
Cancer is a major public health, societal, and economic challenge worldwide. According to Global Cancer Statistics 2022, it is estimated that by 2050, there will be 35 million new cancer cases globally. Although patient survival rates have improved through various therapeutic approaches, including surgery, chemotherapy, and radiotherapy, treatment efficacy remains limited once tumor metastasis occurs. Among various cancer treatment strategies, radiotherapy plays a crucial role. Along with surgery and chemotherapy, radiotherapy is a cost-effective single-modality treatment, accounting for approximately 5% of total cancer care costs. The use of radiosensitizing agents such as histone deacetylase inhibitors, 2-deoxy-d-glucose, enterolactone, and squalene epoxidase can enhance radiotherapy effectiveness. Recent radiosensitization methods involve physical stimuli and chemical radiosensitizers. However, improving their efficacy, durability, and overcoming radioresistance remain significant challenges. This review first introduces current applications of radiotherapy in cancer treatment, the molecular mechanisms underlying its anticancer effects, and its side effects. Second, it discusses the main types of radiosensitizers, their latest applications, and recent challenges in cancer treatment. Finally, it emphasizes on clinical trials of radiosensitizing agents and explores potential biomarkers for radiotherapy response in cancer. Multifunctional nanoparticles have shown greater clinical applicability than single-functional nanoparticles. Future research will focus on enhancing the drug-carrying capacity of nanomaterials to further improve radiotherapy outcomes.
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Affiliation(s)
- Yuanyuan Zhao
- Department of OncologyDepartment of RadiologyInstitute of Organ TransplantationTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of EducationNHC Key Laboratory of Organ TransplantationKey Laboratory of Organ TransplantationChinese Academy of Medical SciencesOrgan Transplantation Clinical Medical Research Center of Hubei Province WuhanWuhanChina
| | - Fangqin Tan
- Department of OncologyDepartment of RadiologyInstitute of Organ TransplantationTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jiajia Zhao
- Department of StomatologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Shuchang Zhou
- Department of OncologyDepartment of RadiologyInstitute of Organ TransplantationTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yao Luo
- Department of Laboratory MedicineSichuan Clinical Research Center for Laboratory MedicineWest China HospitalSichuan UniversityChengduChina
| | - Chen Gong
- Department of OncologyDepartment of RadiologyInstitute of Organ TransplantationTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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2
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Yan L, Quan Z, Sun T, Wang J. Autophagy signaling mediated by non-coding RNAs: Impact on breast cancer progression and treatment. Mol Aspects Med 2025; 103:101365. [PMID: 40305994 DOI: 10.1016/j.mam.2025.101365] [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: 11/26/2024] [Revised: 04/20/2025] [Accepted: 04/23/2025] [Indexed: 05/02/2025]
Abstract
Autophagy, a conserved cellular mechanism which detoxifies and degrades intracellular structures or biomolecules, has been identified as an important factor in the progression of human breast cancer and the development of treatment resistance. Non-coding RNAs (ncRNAs), a broad family of RNA, have the ability to influence various processes, including autophagy, due to their diverse downstream targets. ncRNAs play an important role in suppressing or activating autophagy by targeting autophagy-triggering components such as the ULK1 complex, Beclin1, and ATGs. Recent research has uncovered the intricate regulatory networks that govern autophagy dynamics, with ncRNAs emerging as key participants in this network. miRNAs, lncRNAs, and circRNAs are the three subfamilies of ncRNAs that have the most well-known interactions with autophagy, particularly macroautophagy. The high prevalence of breast cancer necessitates research into finding new biological processes that can help in early detection as well as enhance the effectiveness of treatment. The positive/negative link between autophagy and ncRNAs can be exploited as a supplementary therapy to improve sensitivity to treatment in breast cancer. This review investigates the regulatory roles of ncRNAs, particularly microRNAs (miRNAs), in modifying autophagy pathways in human breast cancer progression and treatment. However, future studies and clinical practice are needed to determine the most relevant microRNAs as biomarkers and also to better understand their role in breast cancer progression or treatment through modifying autophagy.
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Affiliation(s)
- Lei Yan
- Clinical Experimental Centre, Xi'an International Medical Center Hospital, No.777 Xitai Road, High-tech Zone, Xi'an, Shaanxi Province, 710100, China; Xi'an Engineering Technology Research Center for Cardiovascular Active Peptide, Xi'an, Shaanxi, 710100, China
| | - Zhuo Quan
- Clinical Experimental Centre, Xi'an International Medical Center Hospital, No.777 Xitai Road, High-tech Zone, Xi'an, Shaanxi Province, 710100, China; Xi'an Engineering Technology Research Center for Cardiovascular Active Peptide, Xi'an, Shaanxi, 710100, China
| | - Tiantian Sun
- Department of Oncology, Zibo Central Hospital, Shandong, 255036, China.
| | - Jiaju Wang
- Department of Hematology, Zibo Central Hospital, Shandong, 255036, China.
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3
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Bezrukova AI, Basharova KS, Emelyanov AK, Rybakov AV, Miliukhina IV, Pchelina SN, Usenko TS. Autophagy Process in Parkinson's Disease Depends on Mutations in the GBA1 and LRRK2 Genes. Biochem Genet 2025:10.1007/s10528-025-11125-z. [PMID: 40388077 DOI: 10.1007/s10528-025-11125-z] [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: 01/09/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and abnormal aggregation of the alpha-synuclein protein. Disruption of the autophagy-lysosomal pathway is closely associated with PD pathogenesis. Here, using western-blot analysis we assessed the level of autophagy-related proteins, including phosphorylated mTOR (p-mTOR), phosphorylated RPS6 (p-RPS6), beclin-1 (BECN1), LC3B, p62, and cathepsin D (CTSD) in macrophages derived from peripheral blood mononuclear cells (PBMC-derived macrophages) of GBA1-PD (p.N370S/N, p.L444P/N), LRRK2-PD (p.G2019S/N), idiopathic PD (iPD) patients, and healthy controls. Our findings revealed mutation-specific disruptions in autophagy pathways among PD patients. In p.N370S-GBA1-PD, PBMC-derived macrophages exhibited elevated levels of p-RPS6, BECN1, LC3B-II and decreased mature form of CTSD levels suggesting more active mTOR-dependent autophagy initiation alongside potential autophagosome accumulation that may lead to downregulation of lysosomal degradation. p.L444P-GBA1-PD PBMC-derived macrophages showed increased levels of p-RPS6 and BECN1, coupled with decreased p62 levels and stable mature form of CTSD and LC3B-II, indicative of enhanced autophagy flux driven by mTOR activity without evident lysosomal dysfunction. In p.G2019S-LRRK2-PD patients, PBMC-derived macrophages demonstrated elevated p-RPS6, LC3B-II, and mature CTSD levels, alongside reduced p62 levels. These changes suggest higher basal autophagosome abundance in steady-state autophagy and turnover, potentially driven by lysosomal alterations rather than direct mTOR dysregulation. These mutation-dependent differences highlight distinct autophagy dynamics in GBA1-PD and LRRK2-PD, underscoring the critical role of genetic mutations in modulating PD pathogenesis. Our results emphasize the necessity for subtype-specific therapeutic strategies targeting autophagy and other mTOR-regulated pathways to address the heterogeneity of PD mechanisms.
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Affiliation(s)
- A I Bezrukova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - K S Basharova
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A K Emelyanov
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - A V Rybakov
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - I V Miliukhina
- Institute of the Human Brain, Russian Academy of Sciences (RAS), 9 Akademika Pavlova Street, Saint Petersburg, Russia
| | - S N Pchelina
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia
| | - T S Usenko
- Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC «Kurchatov Institute», 1, mkr. Orlova roshcha, 188300, Gatchina, Russia.
- Pavlov First Saint Petersburg State Medical University, 6-8 Lva Tolstogo Street, 197022, Saint Petersburg, Russia.
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4
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Yousef EH, El Gayar AM, El-Magd NFA. Insights into Sorafenib resistance in hepatocellular carcinoma: Mechanisms and therapeutic aspects. Crit Rev Oncol Hematol 2025; 212:104765. [PMID: 40389183 DOI: 10.1016/j.critrevonc.2025.104765] [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: 02/05/2025] [Revised: 05/07/2025] [Accepted: 05/11/2025] [Indexed: 05/21/2025] Open
Abstract
The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.
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Affiliation(s)
- Eman H Yousef
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Pharmacology and Biochemistry department, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34511, Egypt.
| | - Amal M El Gayar
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Nada F Abo El-Magd
- Biochemistry department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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5
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He F, Nichols RM, Agosto MA, Wensel TG. Roles of class III phosphatidylinositol 3-kinase, Vps34, in phagocytosis, autophagy, and endocytosis in retinal pigmented epithelium. iScience 2025; 28:112371. [PMID: 40330883 PMCID: PMC12052997 DOI: 10.1016/j.isci.2025.112371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/17/2024] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
Phosphatidylinositol-3-phosphate (PI(3)P) is important for multiple functions of retinal pigmented epithelial (RPE) cells, but its functions in RPE have not been studied. In RPE from mouse eyes and in cultured human RPE cells, PI(3)P-enriched membranes include endosomes, the trans-Golgi network, phagosomes, and autophagophores. Mouse RPE cells lacking activity of the PI-3 kinase, Vps34, lack detectable PI(3)P and die prematurely. Phagosomes containing rod discs accumulate, as do membrane aggregates positive for autophagosome markers. These autophagy-related membranes recruit LC3/Atg8 without Vps34, but phagosomes do not. Vps34 loss leads to accumulation of lysosomes which do not fuse with phagosomes or membranes with autophagy markers. Thus, Vps34-derived PI(3)P is not needed for initiation of phagocytosis or endocytosis, nor for formation of membranes containing autophagy markers. In contrast, Vps34 and PI(3)P are essential for intermediate and later stages, including membrane fusion with lysosomes.
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Affiliation(s)
- Feng He
- Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Ralph M. Nichols
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Melina A. Agosto
- Retina and Optic Nerve Research Laboratory, Department of Physiology and Biophysics, and Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada
| | - Theodore G. Wensel
- Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
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6
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Ma Y, Yu J, Sun J, Zhu Y, Li X, Liu X, Zhang X, Liu L, Li L, Yang J, Li W, Ho KF, Shen Z, Niu X. Dust Fall Microplastics from a Megacity of China Inhibit Autophagy via the PI3K/Akt/mTOR Pathway. ENVIRONMENT & HEALTH (WASHINGTON, D.C.) 2025; 3:469-481. [PMID: 40400549 PMCID: PMC12090011 DOI: 10.1021/envhealth.4c00200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 05/23/2025]
Abstract
The problem of microplastics (MPs) pollution has caused many health risks to residents of Chinese cities. In this study, nine kinds of MPs or microrubbers (MRs) from dust fall (DF) in Xi'an, a megacity in northwestern China, were measured by pyrolysis-gas chromatography-mass spectroscopy, namely, polyethylene, polypropylene, nylon 88, polybutylene, polytetrafluorethylene, polyisoprene, polyvinyl chloride, natural rubber, and synthesis rubber. Here, 51.20% of MPs were extracted from the original DF (samples denoted DF-O). After the subtracting procedure, MPs and their residual (DF-S samples) were divided into two parts. Our results indicated that the DF-O and MPs samples exhibited higher cytotoxicity, inflammatory, and oxidative stress levels than the DF-S samples did. The DF-O and MPs samples suppressed autophagy by decreasing expression levels of microtubule-associated protein light chain 3 (LC3B), p-phosphatidylinositol 3-kinase (p-PI3K), phosphorylated AKT protein (p-Akt), and p-mammalian target of rapamycin (p-mTOR) while increasing the level of p62. Meanwhile, DF-O and MPs samples induced apoptosis through increasing levels of Bax/Bcl-2 and Cleaved Caspase-3/Caspase-3 in Raw264.7 cells. These trends could be reversed through removing half of the MPs in DF-O. Therefore, dust fall microplastics inhibited autophagy and induced apoptosis via activating the PI3K/Akt/mTOR pathway, increasing the Bax/Bcl-2 and Cleaved Caspase-3/Caspase-3 ratios. Here we provide a comprehensive perspective into the studies of atmospheric MPs pollution status and mechanisms of inhalation toxicity for health risk assessment of MPs in DF.
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Affiliation(s)
- Yajing Ma
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Jinjin Yu
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Jian Sun
- Department
of Environmental Sciences and Engineering, Xi’an Jiaotong University, Xi’an, 710049, China
| | - Yuantong Zhu
- China
Energy Engineering Group Shaanxi Electric Power Design Institute Co.,
Ltd., Xi’an 710054, China
| | - Xuan Li
- Xi’an
Ecology and Environment Bureau, Xi’an Environmental Monitoring
Station, Xi’an 710054, China
| | - Xinyao Liu
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Xinya Zhang
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Lingyi Liu
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Lingli Li
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Jiaer Yang
- Department
of Environmental Sciences and Engineering, Xi’an Jiaotong University, Xi’an, 710049, China
| | - Weifeng Li
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
| | - Kin-Fai Ho
- The
Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong 999077, Hong Kong, China
| | - Zhenxing Shen
- Department
of Environmental Sciences and Engineering, Xi’an Jiaotong University, Xi’an, 710049, China
| | - Xiaofeng Niu
- School
of Pharmacy, Xi’an Jiaotong University, Xi’an 710061, China
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7
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Kumar P, Choudhary A, Kinger S, Jagtap YA, Prajapati VK, Chitkara D, Chinnathambi S, Verma RK, Mishra A. Autophagy as a potential therapeutic target in regulating improper cellular proliferation. Front Pharmacol 2025; 16:1579183. [PMID: 40444035 PMCID: PMC12119615 DOI: 10.3389/fphar.2025.1579183] [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: 02/18/2025] [Accepted: 04/24/2025] [Indexed: 06/02/2025] Open
Abstract
Autophagy is a degradative process that makes rapid turnover of old and impaired proteins and organelles possible. It is highly instigated by stress signals, like starvation, and contributes to the cell's homeostasis. Autophagy performs a crucial function in keeping cell genomic integrity stable. Impaired autophagic flux is implicated in neurodegenerative diseases, abnormal ageing, and cancerous diseases. In diseases like cancer, autophagy performs a dualistic function; it can have both a tumor-suppressive and supportive role. Autophagy in the initial phases of tumorigenesis maintains the integrity of the genome and, if it fails, leads to cell death, thus having a tumor-suppressive role. Meanwhile, autophagy also imparts the function of the pro-survival mechanism in the latter stages of tumorigenesis and supports the cancerous cells in surviving conditions like hypoxia and increased oxidative stress. Autophagy also helps cancerous cells develop drug resistance in some cases. Thus, modulation of the autophagic mechanism is a possible therapeutic strategy in cancer therapy as its inhibition can sensitise cancer cells to anti-cancerous drugs. The promotion of autophagy, in some cases, can also safeguard cells from toxic protein aggregation and enhanced oxidative stress. Excessive autophagy can result in autophagic cell death. Autophagy also regulates several cellular processes and cell death pathways, like apoptosis. Therefore, an in-depth knowledge of the autophagy process and its regulating molecules is critically important. Pharmaceutical small molecules or cellular target modulation can help modulate the cellular autophagy process in the context of specific disease conditions.
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Affiliation(s)
- Prashant Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Akash Choudhary
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Sumit Kinger
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Yuvraj Anandrao Jagtap
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | | | - Deepak Chitkara
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, Rajasthan, India
| | - Subashchandrabose Chinnathambi
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Institute of National Importance, Bangalore, Karnataka, India
| | | | - Amit Mishra
- Department of Biosciences and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
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8
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Bi J, Sun Y, Guo M, Sun X, Sun J, Jiang R, Wang N, Huang G. Lysosomes: guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment. Cancer Cell Int 2025; 25:136. [PMID: 40205430 PMCID: PMC11984033 DOI: 10.1186/s12935-025-03771-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 03/28/2025] [Indexed: 04/11/2025] Open
Abstract
Lysosomes, as crucial organelles within cells, carry out diverse biological functions such as waste degradation, regulation of the cellular environment, and precise control of cell signaling. This paper reviews the core functions and structural characteristics of lysosomes, and delves into the current research status of lysosomes damage repair mechanisms. Subsequently, we explore in depth the close association between lysosomes and various diseases, including but not limited to age-related chronic diseases, neuro-degenerative diseases, tumors, inflammation, and immune imbalance. Additionally, we also provide a detailed discussion of the application of lysosome-targeted substances in the field of regenerative medicine, especially the enormous potential demonstrated in key areas such as stem cell regulation and therapy, and myocardial cell repair. Though the integration of multidisciplinary research efforts, we believe that lysosomes damage repair mechanisms will demonstrate even greater application value in disease treatment and regenerative medicine.
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Affiliation(s)
- Jianlei Bi
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, 116023, Liaoning, China
| | - Yincong Sun
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
- College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Meihua Guo
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Xiaoxin Sun
- College of Integrative Medicine, Dalian Medical University, Dalian, 116044, Liaoning, P.R. China
| | - Jie Sun
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Rujiao Jiang
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China
| | - Ning Wang
- Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China.
| | - Gena Huang
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian, 116023, Liaoning, China.
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9
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Nishino MS, Costa AJD, Bassani TB, Stilhano RS, Ureshino RP. Estrogen G-Protein Coupled Receptor Antagonist G15 Promotes Tau Clearance in 2D and 3D Tauopathy Models. Cell Biochem Funct 2025; 43:e70072. [PMID: 40143384 DOI: 10.1002/cbf.70072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 03/05/2025] [Accepted: 03/18/2025] [Indexed: 03/28/2025]
Abstract
Several studies have investigated the efficacy of estrogen in age-related diseases, showing promising results in several models of neurodegeneration, such as Alzheimer's disease. Animal and cellular models indicate that estrogen and related compounds can reduce the accumulation of amyloid plaques and tau protein, which are associated with Alzheimer's disease. Therefore, it is crucial to develop appropriate models to study the neuroprotective effects of estrogen, and three-dimensional (3D) models have recently emerged as a viable alternative to animal testing. This study aimed to investigate the potential of 3D tauopathy models for drug testing, focusing on estrogen-related signaling. The results demonstrate that a scaffold-free neurospheroid with inducible tau protein expression allows for the observation of tau protein distribution throughout the spheroid. Moreover, the study found that the G-protein-coupled estrogen receptor antagonist, G15, reduced tau protein concentration in both 2D and 3D models. Thus, this study highlights the importance of estrogen-related compounds in 3D cultures, which could facilitate investigations into the mechanisms of action and the neuroprotective role of estrogen in neurodegenerative diseases.
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Affiliation(s)
- Michele Sayuri Nishino
- Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil
- Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Angélica Jardim da Costa
- National Center for Energy and Materials Research, Biosciences National Laboratory, Campinas, São Paulo, Brazil
| | - Taysa Bervian Bassani
- Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil
- Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Roberta Sessa Stilhano
- Department of Physiological Sciences, Santa Casa de São Paulo School of Medical Sciences, São Paulo, São Paulo, Brazil
| | - Rodrigo Portes Ureshino
- Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil
- Laboratory of Molecular and Translational Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
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10
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Guo L, Ji K, Yin Y. SIRT5 Inhibits Mitophagy and Inflammation of Hypoxia-Induced Pulmonary Hypertension by Regulating the Desuccinylation of PDK1. Mol Biotechnol 2025:10.1007/s12033-025-01430-8. [PMID: 40169475 DOI: 10.1007/s12033-025-01430-8] [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: 04/17/2024] [Accepted: 03/07/2025] [Indexed: 04/03/2025]
Abstract
Hypoxia-induced pulmonary hypertension (HPH), a consequence of lung pathologies, is linked to changes in immune responses and inflammation. SIRT5 is recognized as the only enzyme capable of removing succinyl groups. The focus of this research was to explore the involvement of SIRT5 in HPH and to elucidate the associated mechanisms. Models simulating HPH were created in both living organisms and controlled laboratory settings under conditions of low oxygen. To investigate autophagy, transmission electron microscopy (TEM) was employed for ultrastructural analysis, while reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to measure the expression of autophagy-related genes. Cell viability was determined using the cell counting kit-8 (CCK-8) assay. The concentrations of inflammatory cytokines were quantified using ELISA, and flow cytometry was applied to evaluate reactive oxygen species (ROS) levels. To explore the interaction between PDK1 and SIRT5, co-immunoprecipitation (Co-IP) followed by Western blot analysis was conducted. Findings revealed that low oxygen conditions prompted mitophagy and elevated levels of both mRNA and proteins associated with this process in experiments conducted in organisms as well as in cellular models. Under conditions of low oxygen, the expression of SIRT5 was found to be reduced. Hypoxia enhanced cell viability, ROS level, angiogenesis-related protein levels, and inflammatory cytokine levels in pulmonary microvascular endothelial cells (PMVECs), effects that were reversed upon SIRT5 overexpression. Mechanistically, SIRT5 interacted with PDK1, desuccinylating PDK1 and thereby inhibiting mitophagy and inflammation associated with HPH. In conclusion, SIRT5 inhibited mitophagy and inflammation in HPH by regulating the desuccinylation of PDK1, potentially offering effective therapeutic strategies for treating HPH.
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Affiliation(s)
- Lin Guo
- Department of Respiratory, Yancheng City No.6 People's Hospital, No.66, Zhongting Road, Tinghu District, Yancheng, Jiangsu Province, China.
| | - Kangkang Ji
- Clinical Medical Research Centre, Binhai County People's Hospital, Yancheng, Jiangsu Province, China
| | - Yi Yin
- Dental Department, Binhai County People's Hospital, Yancheng, Jiangsu Province, China
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King CP, Chitre AS, Leal‐Gutiérrez JD, Tripi JA, Netzley AH, Horvath AP, Lamparelli AC, George A, Martin C, St. Pierre CL, Missfeldt Sanches T, Bimschleger HV, Gao J, Cheng R, Nguyen K, Holl KL, Polesskaya O, Ishiwari K, Chen H, Robinson TE, Flagel SB, Solberg Woods LC, Palmer AA, Meyer PJ. Genetic Loci Influencing Cue-Reactivity in Heterogeneous Stock Rats. GENES, BRAIN, AND BEHAVIOR 2025; 24:e70018. [PMID: 40049657 PMCID: PMC11884905 DOI: 10.1111/gbb.70018] [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: 07/17/2024] [Revised: 01/23/2025] [Accepted: 02/12/2025] [Indexed: 03/10/2025]
Abstract
Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats. Rats underwent a Pavlovian conditioned approach task that characterized the responses to food-associated stimuli ("cues"). Responses ranged from cue-directed "sign-tracking" behavior to food-cup directed "goal-tracking" behavior (12 measures, SNP heritability: 0.051-0.215). Next, rats performed novel operant responses for unrewarded presentations of the cue using the conditioned reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits across both tasks. Interval sizes of these QTLs varied widely. Seven traits shared a QTL on chromosome 1 that contained a few genes (e.g., Tenm4, Mir708) that have been associated with substance use disorders and other psychiatric disorders in humans. Other candidate genes (e.g., Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on addiction-related behaviors in HS rats and found that the QTL on chromosome 1 was also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive motivational processes and provide further support for a relationship between the attribution of incentive salience and drug abuse-related traits.
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Affiliation(s)
- Christopher P. King
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | - Apurva S. Chitre
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | | | - Jordan A. Tripi
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
| | - Alesa H. Netzley
- Department of Emergency MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Aidan P. Horvath
- Department of PsychologyUniversity of MichiganAnn ArborMichiganUSA
| | | | - Anthony George
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | - Connor Martin
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
| | | | | | | | - Jianjun Gao
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Riyan Cheng
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Khai‐Minh Nguyen
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Katie L. Holl
- Department of PhysiologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Oksana Polesskaya
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Keita Ishiwari
- Clinical and Research Institute on AddictionsBuffaloNew YorkUSA
- Department of Pharmacology and ToxicologyUniversity at BuffaloBuffaloNew YorkUSA
| | - Hao Chen
- Department of Pharmacology, Addiction Science and ToxicologyUniversity of Tennessee Health Science CenterMemphisTennesseeUSA
| | | | - Shelly B. Flagel
- Department of PsychiatryUniversity of MichiganAnn ArborMichiganUSA
- Michigan Neuroscience Institute, University of MichiganAnn ArborMichiganUSA
| | - Leah C. Solberg Woods
- Department of Internal Medicine, Molecular Medicine, Center on Diabetes, Obesity and MetabolismWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Abraham A. Palmer
- Department of PsychiatryUniversity of California San DiegoLa JollaCaliforniaUSA
- Institute for Genomic Medicine, University of California San DiegoLa JollaCaliforniaUSA
| | - Paul J. Meyer
- Department of PsychologyUniversity at BuffaloBuffaloNew YorkUSA
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12
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Tong Y, Lu Y, Li Y, Ding J, Yan C, Deng Z, Chen J, Zhang Z. Ellagic acid alleviates PM 2.5-induced senescence of lung epithelial cells by mediating autophagy. Toxicol Res (Camb) 2025; 14:tfaf055. [PMID: 40248819 PMCID: PMC12001767 DOI: 10.1093/toxres/tfaf055] [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: 02/26/2025] [Revised: 03/27/2025] [Accepted: 04/07/2025] [Indexed: 04/19/2025] Open
Abstract
Fine particulate matter (PM2.5) exposure is significantly linked to lung epithelial cell senescence, and autophagy dysfunction being a key contributor to the aging process. Although the anti-aging properties of ellagic acid (EA) are well-documented, its specific protective effect on PM2.5-induced lung epithelial cell senescence still needs to be studied in depth. To investigate the impacts of PM2.5 on autophagy and senescence in lung epithelial cells, 16HBE and A549 cells were exposed to PM2.5 suspension. Additionally, to explore the potential intervention effect of EA, cells were pretreated with EA before exposure to PM2.5 suspension. Cell morphology, proliferation, senescence-related markers, senescence-associated secretory phenotype (SASP), and autophagy-related markers were then assessed. Our results showed that the proliferation of 16HBE and A549 cells were inhibited and autophagy dysfunction and senescence were induced under PM2.5 exposure. However, pretreatment with EA can significantly improve the obstruction of autophagy flux caused by PM2.5, thereby effectively alleviating cell senescence. This study reveals the mechanism by which PM2.5 induces senescence in lung epithelial cells and confirms the protective role of ellagic acid in this process.
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Affiliation(s)
- Yuqi Tong
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Yanping Lu
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Yaqi Li
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Jiaquan Ding
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Chenxi Yan
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Zhihui Deng
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Jiekang Chen
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
| | - Zhaohui Zhang
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health, Hazards, Hengyang Medical School, University of South China, 28 West Changsheng Road, Hengyang, Hunan 421001, China
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13
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Zhang P, Jin M, Zhang L, Cui Y, Dong X, Yang J, Zhang J, Wu H. Berberine alleviates atherosclerosis by modulating autophagy and inflammation through the RAGE-NF-κB pathway. Front Pharmacol 2025; 16:1540835. [PMID: 40230688 PMCID: PMC11994719 DOI: 10.3389/fphar.2025.1540835] [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: 12/06/2024] [Accepted: 02/27/2025] [Indexed: 04/16/2025] Open
Abstract
Introduction Lipid accumulation and foam cell formation are significant features that expedite the progression of atherosclerosis (AS). Abnormal autophagy is a key factor in the development of AS. The importance of berberine (BBR) in AS has been well established. However, its exact role in regulating autophagy and alleviating atherosclerotic inflammation remains unclear. Purpose This study was aimed at exploring the role and mechanism of BBR in alleviating AS by activating autophagy and alleviating inflammation. Study design Network pharmacology predicts the potential mechanism of BBR in regulating AS and verifies this mechanism through in vivo and in vitro experiments, thereby providing new thinking for clinical treatment. Methods The potential mechanism through which BBR regulates AS was predicted by network pharmacology. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) were measured by administering BBR (100 mg/kg) via the stomach. Hematoxylin and eosin (HE) and oil red O staining were used for histological analysis. Expression levels of the RAGE and p-NF-κB pathways and autophagy-associated proteins were evaluated by immunofluorescence. The ApoE-/- mouse model was established with a high-fat diet (HFD) to verify the effect and mechanism of BBR in vivo. Results Functional and pathway enrichment analysis demonstrated that BBR significantly modulated the inflammation-related signaling pathways of AS. Additionally, in vivo experiments indicated that BBR reduced aortic lipid deposition and reduced the atherosclerotic plaque area. BBR decreased the expression levels of RAGE, p-NF-κB, TNF-α, and P62 in the aorta, and upregulated the expression levels of IL-10, CD31, VEGF, LC3B, and Beclin1. Similar results were obtained in vitro experiments, further supporting the in vivo findings. Notably, NF-κΒ activator 1 attenuated the effect of BBR. Conclusion In summary, BBR alleviated the disease progression of AS by regulating the expression of RAGE and p-NF-κB and activating autophagy.
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Affiliation(s)
- Peng Zhang
- College of traditional Chinese medicine, Binzhou Medical University, Yantai, China
| | - Meiying Jin
- Department of Geriatrics, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, China
| | - Lei Zhang
- Department of Cardiovascular, Affifiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yanjun Cui
- Department of Ultrasound, Affifiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaokang Dong
- Department of Cardiovascular, Affifiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Yang
- Department of Cardiovascular, Affifiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiayu Zhang
- College of traditional Chinese medicine, Binzhou Medical University, Yantai, China
| | - Haopeng Wu
- Department of Cardiovascular, Affifiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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14
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Liu C, Li X, Chen M, Liu Y, Li K, Wang D, Yang Z, Guo Y, Zhao Y, Zhao H, Zhang C. Characterization and neurotherapeutic evaluation of venom polypeptides identified from Vespa magnifica: The role of Mastoparan-M in Parkinson's disease intervention. JOURNAL OF ETHNOPHARMACOLOGY 2025; 343:119481. [PMID: 39947367 DOI: 10.1016/j.jep.2025.119481] [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: 09/03/2024] [Revised: 01/24/2025] [Accepted: 02/10/2025] [Indexed: 02/21/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Parkinson's disease (PD) is a common neurodegenerative disorder in the elderly, characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. Hufeng Jiu from Vespa magnifica Smith, a traditional remedy used by the Chinese Jingpo minority, is documented in the Pharmacopoeia of China (2020) for treating rheumatic arthritis. Notably, recent research suggests that components of wasp venom (WV) from Vespa magnifica Smith, particularly polypeptides such as Mastoparan-M (Mast-M) and Vespakinin-M, may have potential therapeutic effects for neurological disorders. However, the specific polypeptide components of WV and their therapeutic effects on PD models remain insufficiently understood. AIM OF THE STUDY This study aims to characterize the neuroactive polypeptides in Vespa magnifica Smith venom and investigate the therapeutic potential of Mast-M for PD. MATERIALS AND METHODS Neuroactive polypeptides in WV were identified using LC/MS, and Mast-M derived from venom of Vespa magnifica Smith was verified with HPLC. The neuroprotective effects of WV and its peptides were assessed using the CCK-8 assay in 1-methyl-4- phenylpyridinium (MPP+)-induced SH-SY5Y human neuroblastoma cells. Mast-M was identified as a potent antagonist against MPP+-induced neurotoxicity. The toxicity, hemolytic activity, and blood-brain-barrier (BBB) permeability of Mast-M were evaluated in mice, and its therapeutic effects were assessed in an MPTP-induced PD mouse model, focusing on motor function and tyrosine hydroxylase (TH) levels. Additionally, Mast-M's impact on mitochondrial membrane potential (MMP), autophagy, and the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signling pathway was investigated. RESULTS A total of 1007 peptides were identified in the WV, including 187 UniProtKB unreviewed, with 185 predicted to be BBB-permeability. Our results show that Mast-M exhibits a time-dependent distribution in mice, initially localizing in the peritoneal region and subsequently accumulating in the brain, liver, and kidney. Cellular uptake studies reveal that Mast-M penetrates cell membranes and accumulates intracellularly over time. In the MPP+-induced neurotoxicity model using SH-SY5Y cells, Mast-M significantly enhances cell viability and MMP. In vivo safety assessments indicate that Mast-M is well-tolerated at doses up to 100 μg/kg, with no significant toxicological effects observed. However, higher doses induce hepatic distress, necessitating dose optimization. Hemolysis was absent at concentrations ≤37 μg/mL, with an EC50 for hemolytic activity of 197 μg/mL. In MPTP-induced PD models, Mast-M partially ameliorates motor deficits and preserves TH expression in dopaminergic neurons, supporting its neuroprotective role. Mechanistically, Mast-M activates autophagic pathways, as evidenced by the upregulation of autophagy-related protein LC3 in MPP+-challenged SH-SY5Y cells. Furthermore, Mast-M promotes mitophagy and mitochondrial biogenesis, modulating the AMPK/mTOR signaling axis to facilitate mitochondrial turnover. CONCLUSION Mast-M emerges as a promising therapeutic candidate for PD, capable of crossing the BBB, enhancing autophagy, and providing neuroprotection in PD models. Further studies are warranted to optimize dosing and elucidate its full therapeutic potential.
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Affiliation(s)
- Chaojie Liu
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Xiaoyu Li
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Mingran Chen
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Yunyun Liu
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Kunkun Li
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Dexiao Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Zhibin Yang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | | | - Yu Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China
| | - Hairong Zhao
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
| | - Chenggui Zhang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, College of Pharmacy, Dali University, Dali, Yunnan, PR China; National-Local Joint Engineering Research Center of Entomoceutics, Dali, PR China.
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Li X, Yin J, Song Q, Yang Q, Li C, Gao H. The novel ginseng Rh2 derivative 2-deoxy-Rh2, exhibits potent anticancer effect via the AMPK/mTOR/autophagy signaling pathway against breast cancer. Chem Biol Interact 2025; 409:111422. [PMID: 39961461 DOI: 10.1016/j.cbi.2025.111422] [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: 07/28/2024] [Revised: 11/15/2024] [Accepted: 02/07/2025] [Indexed: 02/21/2025]
Abstract
Breast cancer is the most prevalent cancer and the second leading cause of cancer-related mortality among women globally, resulting in considerable psychological and physical distress for patients. Our previous study synthesized a novel derivative, 2-Deoxy-Rh2, which exhibited anticancer properties by influencing glycolysis and mitochondrial respiration. The objective of the current study was to investigate the anti-proliferative effects and underlying mechanisms of 2-Deoxy-Rh2 on human breast cancer cell lines MCF-7 and MDA-MB-231. In our experiments, we observed that 2-Deoxy-Rh2 reduced cell viability and induced cell cycle arrest, reactive oxygen species accumulation, and mitochondrial dysfunction. Furthermore, treatment with 2-Deoxy-Rh2 affected autophagic flux and induction, leading to increased expression of microtubule-associated protein light chain 3B (LC3B) and decreased expression of sequestosome 1 (P62) expression in both two breast cancer cell lines, which could be reversed by 3-Methyladenine (3-MA). Additionally, the AMPK signaling pathway plays a crucial role in 2-Deoxy-Rh2-induced autophagy. 2-Deoxy-Rh2 modulated the expression levels of mTOR and AMPK in MCF-7 and MDA-MB-231 cells, resulting in the cellular homeostasis disruption, autophagy and apoptosis, which was further corroborated by compound C (CC). Finally, the study validated the antitumor activity and mechanism of 2-Deoxy-Rh2 in vivo using Balb/c mice bearing 4T1 tumor cells. Overall, the results suggest that 2-Deoxy-Rh2 can induce apoptosis and autophagic cell death through the AMPK/mTOR signaling pathway, positioning it as a promising candidate for an antitumor agent against breast cancer.
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Affiliation(s)
- Xiaodong Li
- Department of Radiology, the First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Jianyuan Yin
- Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China
| | - Qing Song
- Department of Radiology, the First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Qi Yang
- Department of Radiology, the First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Chenchen Li
- Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China; State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510180, China.
| | - Huan Gao
- Department of Clinical Pharmacy, the First Hospital of Jilin University, Changchun, Jilin, 130021, China; Department of Natural Products Chemistry, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, 130021, China.
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Grazide MH, Ruidavets JB, Martinet W, Elbaz M, Vindis C. Circulating autophagy regulator Rubicon is linked to increased myocardial infarction risk. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2025; 11:100279. [PMID: 39802263 PMCID: PMC11708358 DOI: 10.1016/j.jmccpl.2024.100279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/14/2024] [Accepted: 12/20/2024] [Indexed: 01/16/2025]
Abstract
Background The identification of new biomarkers that improve existing cardiovascular risk prediction models for acute coronary syndrome is essential for accurately identifying high-risk patients and refining treatment strategies. Autophagy, a vital cellular degradation mechanism, is important for maintaining cardiac health. Dysregulation of autophagy has been described in cardiovascular conditions such as myocardial ischemia-reperfusion injury, a key factor in myocardial infarction (MI). Recently, Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein), a key negative regulator of autophagy, has been identified in the modulation of cardiac stress response. Objectives This study aimed to explore the relationship between circulating Rubicon levels and MI, and to evaluate the incremental predictive value of Rubicon when integrated into a clinical risk prediction model for MI. Results We analyzed plasma Rubicon concentrations in 177 participants, comprising type I MI patients and high-risk control subjects. Our results revealed significantly elevated plasma Rubicon levels in MI patients compared to the control group (126.5 pg/mL vs. 53 pg/mL, p < 0.001). Furthermore, Rubicon levels showed a positive correlation with cardiovascular risk factors such as total cholesterol and LDL cholesterol. Multivariate analysis confirmed that Rubicon levels were independently associated with an increased risk of MI. The inclusion of Rubicon in traditional cardiovascular risk models notably enhanced predictive accuracy for MI, with the area under the curve (AUC) rising from 0.868 to 0.905 (p < 0.001). Conclusions These findings suggest that Rubicon is a valuable biomarker associated with MI risk, providing additional predictive value beyond standard cardiovascular risk factors. This highlights the importance of Rubicon's critical role in the pathophysiology of CVD.
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Affiliation(s)
- Marie-Hélène Grazide
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, Toulouse, France
- University of Toulouse III, Toulouse, France
| | | | - Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium
| | - Meyer Elbaz
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, Toulouse, France
- University of Toulouse III, Toulouse, France
- Department of Cardiology, Rangueil University Hospital, Toulouse, France
| | - Cécile Vindis
- Center for Clinical Investigation (CIC1436)/CARDIOMET, Rangueil University Hospital, Toulouse, France
- University of Toulouse III, Toulouse, France
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Cabrera-Serrano AJ, Sánchez-Maldonado JM, González-Olmedo C, Carretero-Fernández M, Díaz-Beltrán L, Gutiérrez-Bautista JF, García-Verdejo FJ, Gálvez-Montosa F, López-López JA, García-Martín P, Pérez EM, Sánchez-Rovira P, Reyes-Zurita FJ, Sainz J. Crosstalk Between Autophagy and Oxidative Stress in Hematological Malignancies: Mechanisms, Implications, and Therapeutic Potential. Antioxidants (Basel) 2025; 14:264. [PMID: 40227235 PMCID: PMC11939785 DOI: 10.3390/antiox14030264] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 04/15/2025] Open
Abstract
Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged components and regulating stress responses. It plays a crucial role in cancer biology, including tumor progression, metastasis, and therapeutic resistance. Oxidative stress, similarly, is key to maintaining cellular balance by regulating oxidants and antioxidants, with its disruption leading to molecular damage. The interplay between autophagy and oxidative stress is particularly significant, as reactive oxygen species (ROS) act as both inducers and by-products of autophagy. While autophagy can function as a tumor suppressor in early cancer stages, it often shifts to a pro-tumorigenic role in advanced disease, aiding cancer cell survival under adverse conditions such as hypoxia and nutrient deprivation. This dual role is mediated by several signaling pathways, including PI3K/AKT/mTOR, AMPK, and HIF-1α, which coordinate the balance between autophagic activity and ROS production. In this review, we explore the mechanisms by which autophagy and oxidative stress interact across different hematological malignancies. We discuss how oxidative stress triggers autophagy, creating a feedback loop that promotes tumor survival, and how autophagic dysregulation leads to increased ROS accumulation, exacerbating tumorigenesis. We also examine the therapeutic implications of targeting the autophagy-oxidative stress axis in cancer. Current strategies involve modulating autophagy through specific inhibitors, enhancing ROS levels with pro-oxidant compounds, and combining these approaches with conventional therapies to overcome drug resistance. Understanding the complex relationship between autophagy and oxidative stress provides critical insights into novel therapeutic strategies aimed at improving cancer treatment outcomes.
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Affiliation(s)
- Antonio José Cabrera-Serrano
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
| | - José Manuel Sánchez-Maldonado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
| | - Carmen González-Olmedo
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - María Carretero-Fernández
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
| | - Leticia Díaz-Beltrán
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Juan Francisco Gutiérrez-Bautista
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Servicio de Análisis Clínicos e Inmunología, University Hospital Virgen de las Nieves, 18014 Granada, Spain
- Department of Biochemistry, Molecular Biology and Immunology III, University of Granada, 18016 Granada, Spain
| | - Francisco José García-Verdejo
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Fernando Gálvez-Montosa
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - José Antonio López-López
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Paloma García-Martín
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Campus de la Salud Hospital, PTS, 18016 Granada, Spain
| | - Eva María Pérez
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Campus de la Salud Hospital, PTS, 18016 Granada, Spain
| | - Pedro Sánchez-Rovira
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Medical Oncology Unit, University Hospital of Jaén, 23007 Jaén, Spain
| | - Fernando Jesús Reyes-Zurita
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
| | - Juan Sainz
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain; (A.J.C.-S.); (J.M.S.-M.); (C.G.-O.); (M.C.-F.); (L.D.-B.); (J.F.G.-B.); (F.J.G.-V.); (F.G.-M.); (J.A.L.-L.); (E.M.P.); (P.S.-R.)
- Instituto de Investigación Biosanitaria IBs.Granada, 18012 Granada, Spain;
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, 18012 Granada, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
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Rong B, Jiang H, Zhu W, Yang G, Zhou X, Lyu Z, Li X, Zhang J. Unraveling the role of macrophages in diabetes: Impaired phagocytic function and therapeutic prospects. Medicine (Baltimore) 2025; 104:e41613. [PMID: 39993124 PMCID: PMC11856964 DOI: 10.1097/md.0000000000041613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/28/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025] Open
Abstract
The rising aging population and changing lifestyles have led to a global increase in diabetes and its complications, making it one of the most prevalent diseases worldwide. Chronic inflammation is a key pathogenic feature of diabetes and its complications, yet the precise mechanisms remain unclear, impeding the development of targeted therapies. Recent studies have highlighted the β cell-macrophage crosstalk pathway as a crucial factor in chronic low-grade inflammation and glucose homeostasis imbalance in both type 1 and type 2 diabetes. Furthermore, impaired macrophage phagocytic functions, including pathogen phagocytosis, efferocytosis, and autophagy, play a significant role in diabetes complications. Given their high plasticity, macrophages represent a promising research target. This review summarizes recent findings on macrophage phagocytic dysfunction in diabetes and its complications, and explores emerging therapies targeting macrophage phagocytic function. We also discuss the current challenges in translating basic research to clinical practice, aiming to guide researchers in developing targeted treatments to regulate macrophage status and phagocytic function, thus preventing and treating metabolic inflammatory diseases.
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Affiliation(s)
- Bing Rong
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hailun Jiang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Weiming Zhu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH
| | - Xuancheng Zhou
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Zhongxi Lyu
- School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiangyi Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jieying Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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19
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Tao M, Zhang LL, Zhou GH, Wang C, Luo X. Inhibition of metabotropic glutamate receptor-5 alleviates hepatic steatosis by enhancing autophagy via activation of the AMPK signaling pathway. World J Gastroenterol 2025; 31:98852. [PMID: 39991675 PMCID: PMC11755260 DOI: 10.3748/wjg.v31.i7.98852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/08/2024] [Accepted: 12/26/2024] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has continued to increase annually. Recent studies have indicated that inhibition of metabotropic glutamate receptor 5 (mGluR5) may alleviate hepatic steatosis. However, the precise mechanism warrants further exploration. AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo. METHODS Free fatty acids (FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG. Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content. Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II, as well as the expression of the key signaling molecules AMPK and ULK1, in the treated cells. To further elucidate the contributions of autophagy and AMPK, we used chloroquine (CQ) to inhibit autophagy and compound C (CC) to inhibit AMPK activity. In parallel, wild-type mice and mGluR5 knockout (KO) mice fed a normal chow diet or a high-fat diet (HFD) were used to evaluate the effect of mGluR5 inhibition in vivo. RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression. The autophagy inhibitor CQ reversed the effects of MPEP. In addition, MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs. MPEP treatment led to the nuclear translocation of transcription factor EB, which is known to promote p62 expression. This effect was negated by the AMPK inhibitor CC. mGluR5 KO mice presented reduced body weight, improved glucose tolerance and reduced hyperlipidemia when fed a HFD. Additionally, the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62. CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway. These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
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Affiliation(s)
- Min Tao
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Li-Li Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Guang-Hong Zhou
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Cong Wang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
| | - Xie Luo
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
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20
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Vona R, Cittadini C, Ortona E, Matarrese P. Sex Disparity in Cancer: Role of Autophagy and Estrogen Receptors. Cells 2025; 14:273. [PMID: 39996745 PMCID: PMC11854201 DOI: 10.3390/cells14040273] [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: 12/12/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy, a cellular process essential for maintaining homeostasis, plays a fundamental role in recycling damaged components and in adapting to stress. The dysregulation of autophagy is implicated in numerous human diseases, including cancer, where it exhibits a dual role as both a suppressor and a promoter, depending on the context and the stage of tumor development. The significant sex differences observed in autophagic processes are determined by biological factors, such as genetic makeup and sex hormones. Estrogens, through their interaction with specific receptors, modulate autophagy and influence tumor progression, therapy resistance, and the immune response to tumors. In females, the escape from X inactivation and estrogen signaling may be responsible for the advantages, in terms of lower incidence and longer survival, observed in oncology. Women often show better responses to traditional chemotherapy, while men respond better to immunotherapy. The action of sex hormones on the immune system could contribute to these differences. However, women experience more severe adverse reactions to anticancer drugs. The estrogen/autophagy crosstalk-involved in multiple aspects of the tumor, i.e., development, progression and the response to therapy-deserves an in-depth study, as it could highlight sex-specific mechanisms useful for designing innovative and gender-tailored treatments from the perspective of precision medicine.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
| | | | | | - Paola Matarrese
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
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21
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Li Y, Lin H, Sun Y, Zhao R, Liu Y, Han J, Zhu Y, Jin N, Li X, Zhu G, Li Y. Platycodin D2 Mediates Incomplete Autophagy and Ferroptosis in Breast Cancer Cells by Regulating Mitochondrial ROS. Phytother Res 2025; 39:581-592. [PMID: 39581858 DOI: 10.1002/ptr.8386] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 09/26/2024] [Accepted: 10/29/2024] [Indexed: 11/26/2024]
Abstract
Platycodin D2 (PD2) is a triterpenoid saponin extracted from the root of Platycodon grandiflorum , a common source of medicine and food. Platycodon grandiflorum saponins have anti-inflammatory, antioxidative, antitumor, and immunity-promoting effects. However, the effect of PD2 on breast cancer cells has not been reported. The purpose of this study is to explore the molecular mechanism underlying the effect of PD2 on breast cancer cells. We analyzed the inhibitory effects and pathways of PD2 on breast cancer by CCK-8 assay, WB assay, and immunofluorescence assay. Subsequently, autophagy and ferroptosis were analyzed using different inhibitors. It was found that PD2 caused mitochondrial damage and promoted mitochondrial reactive oxygen species (mtROS) production, leading to autophagy flux inhibition and ferroptosis. Blockage of autophagy flux and ferroptosis promoted each other, resulting in the inhibition of breast cancer cell proliferation. Similar results were obtained in the tumor-bearing model in vivo. PD2 promoted autophagy flux blockage and ferroptosis in breast cancer cells, which induced each other under the action of mtROS, thus inhibiting the proliferation of breast cancer cells. PD2 is a potential new strategy for the treatment of breast cancer.
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Affiliation(s)
- Yaru Li
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Medical College, Yanbian University, Yanji, P. R. China
| | - Haijiao Lin
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Center of Children's Clinic, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin Changchun, P. R. China
| | - Yu Sun
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Department of Neurology, Jilin Central Hospital, Jilin, P. R. China
| | - Renshuang Zhao
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Medical College, Yanbian University, Yanji, P. R. China
| | - Yunyun Liu
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
| | - Jicheng Han
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
| | - Yilong Zhu
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
| | - Ningyi Jin
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Medical College, Yanbian University, Yanji, P. R. China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, P. R. China
| | - Xiao Li
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, P. R. China
| | - Guangze Zhu
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
- Department of Clinical Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin Changchun, P. R. China
| | - Yiquan Li
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of Integrative Medicine, Changchun University of Chinese Medicine, Changchun, P. R. China
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Yuan X, Lu Y, Zhang X, Tang Y, Wen S, Lai W, Long H. Effect of autophagy blockage on trigeminal neuropathic pain in rats: Role of microglia. Eur J Oral Sci 2025; 133:e13029. [PMID: 39628135 DOI: 10.1111/eos.13029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/12/2024] [Indexed: 02/01/2025]
Abstract
Microglia activation and autophagy changes are associated with the regulation of pain, but no study to date has been designed to address whether these features apply to trigeminal neuropathic pain. This study aimed to investigate how alterations in autophagy affect nociceptive behaviors may be associated with microglia activation in the caudal part of the spinal trigeminal nucleus (SpVC) in a rat model of trigeminal neuropathic pain. This model was established by chronic constriction injury of the infraorbital nerve. Autophagy inhibitors and agonists were injected into the lateral ventricle to regulate autophagy. The autophagy markers microtubule-associated protein light chain 3 I (LC3-I), LC3-II, sequestosome1 (p62), and LC-3 were examined by western blotting and/or immunofluorescence. The microglia marker ionized calcium binding adapter molecule 1 (Iba-1) was examined by immunohistochemistry. Nociceptive behavior changes were detected by measuring the mechanical thresholds and face-grooming duration. The results showed that microglia in SpVC were activated, and autophagy flux was blocked in the trigeminal neuropathic pain model. Autophagy agonists inhibited microglia activation and alleviated nociceptive behaviors. In contrast, autophagy inhibitors further activated microglia and exacerbated nociceptive behaviors. In a rat model of trigeminal neuropathic pain, autophagy blockage leads to microglia activation, which significantly influences nociceptive processes.
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Affiliation(s)
- Xuechun Yuan
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yanzhu Lu
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoqi Zhang
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Yufei Tang
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Shangyou Wen
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Wenli Lai
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Hu Long
- Department of Orthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China
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Lin H, Xu Y, Xiong H, Wang L, Shi Y, Wang D, Wang Z, Ren J, Wang S. Mechanism of action of Panax ginseng alcohol extract based on orexin-mediated autophagy in the treatment of sleep and cognition in aged sleep-deprived rats. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118907. [PMID: 39389397 DOI: 10.1016/j.jep.2024.118907] [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: 08/13/2024] [Revised: 09/29/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panax ginseng (P. ginseng) C. A. Meyer. has been used extensively globally as a medicine. It has a therapeutic effect on sleep and is an attractive alternative for patients with insomnia. The United States Patent of Invention has approved the use of P. ginseng alcohol extract (GAE) in nutraceuticals or food to improve sleep. It has shown promise as an effective therapeutic agent for improving sleep and cognition. However, its mechanism of action is not yet fully understood. AIM OF THE STUDY To investigate the therapeutic benefits of GAE on sleep and cognition and its underlying mechanism in aged sleep-deprived rats, with a focus on orexin-mediated autophagy function. MATERIALS AND METHODS We conducted in vivo tests in an aged sleep-deprivation rat model produced using p-chlorophenylalanine (PCPA) coupled with modified multi-platform method to examine the therapeutic effects and mechanisms of GAE. A pentobarbital sodium-induced sleep test and water maze were used to assess sleep and cognitive performance, respectively. An enzyme-linked immunosorbent assay was used to determine orexin levels and aging and sleep markers in serum and hypothalamic tissues. Hematoxylin-eosin staining and Nissl staining were used to assess histopathological changes, and autophagy levels were assessed using transmission electron microscopy, immunofluorescence. Western blot and immunohistochemical staining were performed to detect the levels of orexin, orexin-receptor proteins, and autophagy-associated proteins to study the effects of GAE on hippocampal neurons, and the underlying mechanisms. RESULTS In aged sleep-deprived rats, GAE treatment prolonged sleep duration, improved cognitive function, prevented hippocampal neuronal damage, increased the number of Nissl bodies, improved aging and sleep markers, and enhanced the LC3A/B expression in autophagosomes and neurons. The amount of orexin in serum and hypothalamic tissue and OX1R, OX2R, and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) proteins also reduced, which resulted in the inhibition of the PI3K/Akt/mTOR pathway and activation of the autophagy process. CONCLUSIONS GAE may reduce hypothalamic orexin secretion and interact with orexin receptors to inhibit the PI3K/Akt/mTOR signalling network and activate autophagy. This may be a potential mechanism of action of GAE in regulating sleep-related cognitive function.
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Affiliation(s)
- Haining Lin
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Yunlong Xu
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Huazhong Xiong
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Lichao Wang
- Prevention and Treatment Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Yuqing Shi
- College of Integrated Chinese and Western Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Dongyi Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Zixu Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Jixiang Ren
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China.
| | - Siming Wang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China; Key Laboratory of Ginseng Efficacy Substance Base and Biological Mechanism Research, Ministry of Education, Changchun University of Chinese Medicine, Changchun, 130117, China.
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24
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Jung YY, Hong Y, Nam D, Deivasigamani A, Narula AS, Chinnathambi A, Namjoshi OA, Blough BE, Alharbi SA, Hui KM, Sethi G, Ahn KS. TMP: A dual modulator of apoptosis and autophagy via SHP-1 regulation in hepatocellular carcinoma. Life Sci 2025; 361:123316. [PMID: 39675549 DOI: 10.1016/j.lfs.2024.123316] [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: 09/03/2024] [Revised: 12/01/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) poses a significant health burden due to its high incidence, and current treatment effectiveness is hindered by drug resistance. Thus, investigation of novel therapeutic approaches derived from natural sources is crucial for improving patient outcomes. AIMS This study aimed to explore the potential of Tetramethylpyrazine (TMP), bioactive alkaloid (ligustrazine) isolated from Chuanxiong (Ligusticum Wallichii), in targeting HCC by inducing apoptosis and enhancing autophagy. The study focused on elucidating the molecular mechanisms underlying anti-cancer effects of TMP. MAIN METHODS To determine the influence of TMP on apoptosis and autophagy, Western blot analysis, annexin V assay, cell cycle analysis, acridine orange staining, and immunocytochemistry were performed. Next, the activation of the STAT3 signaling pathway and the anti-cancer effects of TMP in vivo were examined in an orthotopic HCCLM3-Lu mouse model. KEY FINDINGS TMP treatment induced apoptosis in HCCLM3 and Hep3B cells by activating key apoptotic factors while inhibiting proteins associated with cell survival and angiogenesis. Additionally, TMP enhanced autophagy by promoting the formation of autophagosomes and stimulating autophagy-related proteins. Furthermore, TMP suppressed the activation of the STAT3 signaling pathway by upregulating SHP-1, thereby inhibiting tumorigenesis and activating cell death pathways. Additionally, our in vivo research demonstrated that TMP significantly inhibited tumor growth and triggered the activation of both apoptosis and autophagy in tumor tissues. SIGNIFICANCE Our findings of this study demonstrate that TMP exerts a dual-action mechanism by modulating both apoptosis and autophagy, thus offering a promising strategy to overcome drug resistance in HCC.
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Affiliation(s)
- Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdae-mun-gu, Seoul 02447, Republic of Korea
| | - Yejin Hong
- Department of Acupuncture and Moxibustion, Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea
| | - Dongwoo Nam
- Department of Acupuncture and Moxibustion, Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea; Department of Acupuncture and Moxibustion, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Ojas A Namjoshi
- Engine Biosciences, 733 Industrial Rd, San Carlos, CA 94070, USA
| | - Bruce E Blough
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC 27616, USA
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
| | - Kam Man Hui
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdae-mun-gu, Seoul 02447, Republic of Korea.
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25
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Yu Z, Lin S, Gong X, Zou Z, Yang X, Ruan Y, Qian L, Liu Y, Si Z. The role of macroautophagy in substance use disorders. Ann N Y Acad Sci 2025; 1543:68-78. [PMID: 39714908 DOI: 10.1111/nyas.15272] [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] [Indexed: 12/24/2024]
Abstract
Macroautophagy, a universal cellular process, sends cellular material to lysosomes for breakdown and is often activated by stressors like hypoxia or drug exposure. It is vital for protein balance, neurotransmitter release, synaptic function, and neuron survival. The role of macroautophagy in substance use disorders is dual. On one hand, substances like cocaine, methamphetamine, opiates, and alcohol can activate macroautophagy pathways to degrade various neuroinflammatory factors in neuronal cells, providing a protective function. On the other hand, long-term and excessive use of addictive substances can inhibit macroautophagy pathways, obstructing the fusion of autophagosomes with lysosomes and losing the original protective function. This review first summarizes the key proteins and signaling pathways involved in macroautophagy, including mTORC1, AMPK, and endoplasmic reticulum stress, and suggests that the regulation of macroautophagy plays a central role in drug-rewarding behavior and addiction. Second, we focus on the interactions between macroautophagy and neuroinflammation induced by drugs, evaluating the potential of macroautophagy modulators as therapeutic strategies for substance use disorder (SUD), and identifying autophagy-related biomarkers that can be used for early diagnosis and monitoring of treatment response. Our review summarizes the important scientific basis involved in macroautophagy pathways for the development of new therapies for SUD.
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Affiliation(s)
- Zhaoying Yu
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Shujun Lin
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xinshuang Gong
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Zhiting Zou
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xiangdong Yang
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Yuer Ruan
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Liyin Qian
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Yu Liu
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
| | - Zizhen Si
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
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26
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Hou M, Yue M, Han X, Sun T, Zhu Y, Li Z, Han J, Zhao B, Tu M, An Y. Comparative analysis of BAG1 and BAG2: Insights into their structures, functions and implications in disease pathogenesis. Int Immunopharmacol 2024; 143:113369. [PMID: 39405938 DOI: 10.1016/j.intimp.2024.113369] [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: 07/19/2024] [Revised: 09/22/2024] [Accepted: 10/06/2024] [Indexed: 10/30/2024]
Abstract
As BAG family members, Bcl-2 associated athanogene family protein 1 (BAG1) and 2 (BAG2) are implicated in multiple cellular processes, including apoptosis, autophagy, protein folding and homeostasis. Although structurally similar, they considerably differ in many ways. Unlike BAG2, BAG1 has four isoforms (BAG1L, BAG1M, BAG1S and BAG1 p29) displaying different expression features and functional patterns. BAG1 and BAG2 play different cellular functions by interacting with different molecules to participate in the regulation of various diseases, including cancer/tumor and neurodegenerative diseases. Commonly, BAG1 acts as a protective factor to predict a good prognosis of patients with some types of cancer or a risk factor in some other cancers, while BAG2 is regarded as a risk factor to promote cancer/tumor progression. In neurodegenerative diseases, BAG2 commonly acts as a neuroprotective factor. In this review, we summarized the differences in molacular structure and biological function between BAG1 and BAG2, as well as the influences of them on pathogenesis of diseases, and explore the prospects for their clinical therapy application by specifying the activators and inhibitors of BAG1 and BAG2, which might provide a better understanding of the underlying pathogenesis and developing the targeted therapy strategies for diseases.
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Affiliation(s)
- Mengwen Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Man Yue
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Yonghao Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng 475004, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng 475004, China.
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27
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Liu B, Zhang Y, Wang Q, Wang Q, Wang Z, Feng L. CD40 ligation-induced ERK activation leads to enhanced radiosensitivity in cervical carcinoma cells via promoting autophagy. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39696986 DOI: 10.3724/abbs.2024229] [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: 12/20/2024] Open
Abstract
CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation and consequently promotes autophagic flux in cervical cancer cells. Mechanistically, this effect relies on ERK contributing to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrate that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for the involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.
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Affiliation(s)
- Baocai Liu
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Yadong Zhang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Quan Wang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Qian Wang
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Zhixin Wang
- Department of Urology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Li Feng
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, China
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28
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Sánchez-Mendoza SE, de Deus-Wagatsuma VM, do Nascimento MC, Lima K, Machado-Neto JA, Djavaheri-Mergny M, Rego EM. All-trans retinoic acid potentiates cell death induced by quizartinib in acute myeloid leukemia with FLT3-ITD mutations. Ann Hematol 2024:10.1007/s00277-024-06089-w. [PMID: 39661129 DOI: 10.1007/s00277-024-06089-w] [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: 07/12/2024] [Accepted: 11/06/2024] [Indexed: 12/12/2024]
Abstract
Acute myeloid leukemia (AML) with FLT3-ITD mutation represents a quarter of AML patients and is associated with high relapse rate and dismal prognosis. FLT3 tyrosine kinase inhibitors (TKIs) were developed in order to target this genetic alteration and among these TKIs, AC220 (quizartinib) combined with chemotherapy has already shown an increased overall survival for patients with AML with FLT3-ITD mutation. Even though this increase in overall survival was significant, it remains discrete, and relapse rate is still high, so there is an unmet medical need. All-trans retinoic acid (ATRA) is well known for its effectiveness in acute promyelocytic leukemia (APL) treatment and has already been shown to have synergistic effects combined with another TKI, sorafenib. In this study, quizartinib, a more potent FLT3-TKI, was tested in combination with ATRA in the AML FLT3-ITD positive cell lines MOLM-13 and MV4-11. ATRA has effectively improved AC220 induced cell death via caspase activation. In addition, ATRA in combination with AC220 treatment notably enhanced BECN1 cleavage compared to AC220 treatment alone. Finally, in a xenotransplantation model ATRA plus AC220 was more efficient to reduce the leukemic burden than monotherapy with ATRA or AC220. Taken together, our results are a proof of the concept that ATRA and AC220 have synergistic anti-leukemic effects.
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Affiliation(s)
| | | | | | - Keli Lima
- Hematology Division, Faculdade de Medicina, University of São Paulo, São Paulo, SP, LIM31, Brazil
| | | | - Mojgan Djavaheri-Mergny
- Centre de Recherche des Cordeliers, Inserm UMRS 1138, Sorbonne Université, Université de Paris Cité, Équipe labellisée par la Ligue contre le Cancer, Institut Universitaire de France, Paris, 75006, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, 94805, France
| | - Eduardo Magalhães Rego
- Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, Brazil.
- Hematology Division, Faculdade de Medicina, University of São Paulo, São Paulo, SP, LIM31, Brazil.
- Hemocentro de São Paulo, Av. Dr. Enéas de Carvalho Aguiar 155, Prédio dos Ambulatórios, 1º Andar, São Paulo, SP, CEP 05403-000, Brazil.
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29
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Wu Y, Avcilar-Kücükgöze I, Santovito D, Atzler D. Amino Acid Metabolism and Autophagy in Atherosclerotic Cardiovascular Disease. Biomolecules 2024; 14:1557. [PMID: 39766264 PMCID: PMC11673637 DOI: 10.3390/biom14121557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 11/29/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Cardiovascular disease is the most common cause of mortality globally, accounting for approximately one out of three deaths. The main underlying pathology is atherosclerosis, a dyslipidemia-driven, chronic inflammatory disease. The interplay between immune cells and non-immune cells is of great importance in the complex process of atherogenesis. During atheroprogression, intracellular metabolic pathways, such as amino acid metabolism, are master switches of immune cell function. Autophagy, an important stress survival mechanism involved in maintaining (immune) cell homeostasis, is crucial during the development of atherosclerosis and is strongly regulated by the availability of amino acids. In this review, we focus on the interplay between amino acids, especially L-leucine, L-arginine, and L-glutamine, and autophagy during atherosclerosis development and progression, highlighting potential therapeutic perspectives.
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Affiliation(s)
- Yuting Wu
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
| | - Irem Avcilar-Kücükgöze
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
| | - Donato Santovito
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Institute for Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council, 20133 Milan, Italy
| | - Dorothee Atzler
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336 Munich, Germany; (Y.W.); (I.A.-K.)
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80336 Munich, Germany
- Walter Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
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30
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Huang P, Yang Z, Wang H, Wang C, Luo M, Zhou R, Pan Y. Imperatorin promotes melanin degradation in keratinocytes through facilitating autophagy via the PI3K/Akt signaling pathway. Arch Dermatol Res 2024; 317:70. [PMID: 39636461 DOI: 10.1007/s00403-024-03559-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: 08/01/2024] [Revised: 11/07/2024] [Accepted: 11/21/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE Melanin's pivotal role in skin protection and its overproduction leading to hyperpigmentation disorders highlight the necessity of regulating melanogenesis, with autophagy identified as a key degradation pathway. Imperatorin, a compound from Angelica dahurica, has been revealed to reduce melanin in epidermal keratinocytes, with the specific effects and mechanisms unknown. The purpose of this study was to investigate the mechanism by which imperatorin, reduces melanin production in HaCaT cells, with a focus on its potential role in promoting autophagy and regulating the PI3K/Akt signaling pathway. METHODS The study used HaCaT cells to investigate the effects of imperatorin on melanin production, autophagy, and PI3K/Akt signaling. Melanin content was measured using a spectrophotometric method. Protein levels of PMEL, ATG1, ATG5, and LC3B II were assessed by Western blotting. Autophagy was further visualized by GFP-LC3B puncta formation. The autophagy inhibitor 3-MA, the PI3K/Akt inhibitor LY294002 and PI3K/Akt activator 740 Y-P were used to assess the role of autophagy and PI3K/Akt signaling in imperatorin's effects. Cell viability was monitored to ensure that imperatorin's effects were not due to cytotoxicity. RESULTS Imperatorin reduced melanin content in HaCaT cells in a dose-dependent manner without compromising cell viability. This reduction in melanin was accompanied by decreased levels of PMEL protein, a key player in melanosome formation. Additionally, imperatorin promoted autophagy in HaCaT cells, as evidenced by increased levels of autophagy-associated markers ATG1, ATG5, and LC3B II, as well as an increase in GFP-LC3B puncta. The autophagy inhibitor 3-MA partially reversed the effects of imperatorin on both autophagy markers and PMEL levels, indicating that autophagy plays a crucial role in imperatorin's depigmentation action. Furthermore, imperatorin inhibited Akt and mTOR phosphorylation, which are downstream targets of PI3K/Akt signaling, enhancing autophagy and further reducing melanin levels. The PI3K/Akt inhibitor LY294002 amplified imperatorin's effects on PI3K and Akt phosphorylation, autophagy, and melanin levels. While, PI3K/Akt activator 740 Y-P reversed imperatorin's effects on these factors. CONCLUSIONS Imperatorin reduces melanin in HaCaT cells via promoting autophagy and melanin degradation, possibly via the PI3K/Akt signaling. Taken together, imperatorin has the therapeutic potential for the treatment of hyperpigmentation disorders.
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Affiliation(s)
- Pan Huang
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Zhibo Yang
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Haizhen Wang
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Chang Wang
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Meijunzi Luo
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Rong Zhou
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China
| | - Yi Pan
- Department of Dermatology, the Second Affiliated Hospital, The Domestic First-class Discipline Construction Project of Chinese Medicine of Hunan, University of Chinese Medicine, Changsha, 410005, Hunan, China.
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31
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Khalafiyan A, Fadaie M, Khara F, Zarrabi A, Moghadam F, Khanahmad H, Cordani M, Boshtam M. Highlighting roles of autophagy in human diseases: a perspective from single-cell RNA sequencing analyses. Drug Discov Today 2024; 29:104224. [PMID: 39521332 DOI: 10.1016/j.drudis.2024.104224] [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: 07/14/2024] [Revised: 09/24/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Autophagy, the lysosome-driven breakdown of intracellular components, is pivotal in regulating eukaryotic cellular processes and maintaining homeostasis, making it physiologically important even under normal conditions. Cellular mechanisms involving autophagy include the response to nutrient deprivation, intracellular quality control, early development, and cell differentiation. Despite its established health significance, the role of autophagy in cancer and other diseases remains complex and not fully understood. A comprehensive understanding of autophagy is crucial to facilitate the development of novel therapies and drugs that can protect and improve human health. High-throughput technologies, such as single-cell RNA sequencing (scRNA-seq), have enabled researchers to study transcriptional landscapes at single-cell resolution, significantly advancing our knowledge of autophagy pathways across diverse physiological and pathological contexts. This review discusses the latest advances in scRNA-seq for autophagy research and highlights its potential in the molecular characterization of various diseases.
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Affiliation(s)
- Anis Khalafiyan
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahmood Fadaie
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Khara
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey; Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan; Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600 077, India
| | - Fariborz Moghadam
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
| | - Maryam Boshtam
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
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32
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Qian S, Long Y, Tan G, Li X, Xiang B, Tao Y, Xie Z, Zhang X. Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets. MedComm (Beijing) 2024; 5:e70024. [PMID: 39619229 PMCID: PMC11604731 DOI: 10.1002/mco2.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 11/02/2024] [Accepted: 11/11/2024] [Indexed: 01/12/2025] Open
Abstract
Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.
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Affiliation(s)
- Shen'er Qian
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Yao Long
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
- Department of PathologyXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Guolin Tan
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Xiaoguang Li
- Department of Otolaryngology Head and Neck SurgeryShanghai Ninth People's Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Ear InstituteShanghai Jiao Tong University School of Medicine, Shanghai Key LabShanghaiChina
| | - Bo Xiang
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
- Furong LaboratoryCentral South UniversityChangshaHunanChina
| | - Yongguang Tao
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
| | - Zuozhong Xie
- Department of Otolaryngology Head and Neck SurgeryThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Xiaowei Zhang
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
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33
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Li Z, Zhang Y, Lei J, Wu Y. Autophagy in oral cancer: Promises and challenges (Review). Int J Mol Med 2024; 54:116. [PMID: 39422076 PMCID: PMC11518578 DOI: 10.3892/ijmm.2024.5440] [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: 05/20/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
Autophagy captures damaged or dysfunctional proteins and organelles through the lysosomal pathway to achieve proper cellular homeostasis. Autophagy possesses distinct characteristics and is given recognized functions in numerous physiological and pathological conditions, such as cancer. Early stage cancer development can be stopped by autophagy. After tumor cells have successfully undergone transformation and progressed to a late stage, the autophagy-mediated system of dynamic degradation and recycling will support cancer cell growth and adaptation to various cellular stress responses while preserving energy homeostasis. In the present study, the dual function that autophagy plays in various oral cancer development contexts and stages, the existing arguments for and against autophagy, and the ways in which autophagy contributes to oral cancer modifications, such as carcinogenesis, drug resistance, invasion, metastasis and self-proliferation, are reviewed. Special attention is paid to the mechanisms and functions of autophagy in oral cancer processes, and the most recent findings on the application of certain conventional drugs or natural compounds as novel agents that modulate autophagy in oral cancer are discussed. Overall, further research is needed to determine the validity and reliability of autophagy promotion and inhibition while maximizing the difficult challenge of increasing cancer suppression to improve clinical outcomes.
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Affiliation(s)
- Zhou Li
- Department of Stomatology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030000, P.R. China
- Shanxi Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi 030000, P.R. China
| | - Yao Zhang
- Shanxi Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi 030000, P.R. China
| | - Jianhua Lei
- Department of Stomatology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030000, P.R. China
| | - Yunxia Wu
- Department of Stomatology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030000, P.R. China
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Zhu Z, Li L, Ye Y, Zhong Q. Integrating bulk and single-cell transcriptomics to elucidate the role and potential mechanisms of autophagy in aging tissue. Cell Oncol (Dordr) 2024; 47:2183-2199. [PMID: 39414741 DOI: 10.1007/s13402-024-00996-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2024] [Indexed: 10/18/2024] Open
Abstract
PURPOSE Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment. METHODS Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches. RESULTS Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging. CONCLUSION This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.
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Affiliation(s)
- Zhenhua Zhu
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linsen Li
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Youqiong Ye
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Qing Zhong
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Liu T, Zheng Y, Zhou S, Wang Y, Lei X, Xie L, Lin Q, Chang C, Xiao S, Qiu R, Qi H. 14-3-3 proteins inhibit autophagy by regulating SINAT-mediated proteolysis of ATG6 in Arabidopsis. BMC PLANT BIOLOGY 2024; 24:1148. [PMID: 39609744 PMCID: PMC11605875 DOI: 10.1186/s12870-024-05854-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024]
Abstract
BACKGROUND Autophagy is a conserved cellular process crucial for recycling cytoplasmic components and maintaining cellular homeostasis in eukaryotes. During autophagy, the formation of a protein complex involving AUTOPHAGY-RELATED PROTEIN 6 (ATG6) and phosphatidylinositol 3-kinase is pivotal for recruiting proteins involved in phagophore expansion. However, the intricate molecular mechanism regulating this protein complex in plants remains elusive. RESULTS Here, we aimed to unravel the molecular regulation of autophagy dynamics in Arabidopsis thaliana by investigating the involvement of the scaffold proteins 14-3-3λ and 14-3-3κ in regulating the proteolysis of ATG6. Phenotypic analyses revealed that 14-3-3λ and 14-3-3κ overexpression lines exhibited increased sensitivity to nutrient starvation, premature leaf senescence, and a decrease in starvation-induced autophagic vesicles, resembling the phenotypes of autophagy-defective mutants, suggesting the potential roles of 14-3-3 proteins in regulating autophagy in plants. Furthermore, our investigation unveiled the involvement of 14-3-3λ and 14-3-3κ in the RING finger E3 ligase SINAT1-mediated ubiquitination and destabilization of ATG6 in vivo. We also observed repressed turnover of ATG6 and translocation of GFP-ATG6 to mCherry-ATG8a-labelled punctate structures in the autophagy-defective mutant, which suggesting that ATG6 is probably a target of autophagy. Additionally, 14-3-3λ and 14-3-3κ interacted with Tumor necrosis factor Receptor Associated Factor 1a (TRAF1a) to promote the stability of TRAF1a in vivo under nutrient-rich conditions, suggesting a feedback regulation of autophagy. These findings demonstrate that 14-3-3λ and 14-3-3κ serve as scaffold proteins to regulate autophagy by facilitating the SINAT1-mediated proteolysis of ATG6, involving both direct and indirect mechanisms, in plants. CONCLUSIONS 14-3-3 proteins regulate autophagy by directly or indirectly binding to ATG6 and SINAT1 to promote ubiquitination and degradation of ATG6. 14-3-3 proteins are involved in modulating autophagy dynamics by facilitating SINAT1-mediated ubiquitination and degradation of ATG6.
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Affiliation(s)
- Ting Liu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou, 510642, China
| | - Yuping Zheng
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China
| | - Shunkang Zhou
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou, 510642, China
| | - Yao Wang
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Xue Lei
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Lijuan Xie
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China
| | - Qingqi Lin
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China
| | - Changqing Chang
- Guangdong Provincial Key Laboratory of Microbial Signals and Disease Control, Integrate Microbiology Research Center, College of Plant Protection, South China Agricultural University, Guangzhou, 510642, China
| | - Shi Xiao
- State Key Laboratory of Biocontrol, Guangdong Provincial Key Laboratory of Plant Resources, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Rongliang Qiu
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China.
| | - Hua Qi
- Guangdong Laboratory for Lingnan Modern Agriculture, Guangdong Provincial Key Laboratory of Agricultural & Rural Pollution Abatement and Environmental Safety, College of Natural Resources and Environment, South China Agricultural University, Guangzhou, 510642, China.
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Wei Z, Hu X, Wu Y, Zhou L, Zhao M, Lin Q. Molecular Mechanisms Underlying Initiation and Activation of Autophagy. Biomolecules 2024; 14:1517. [PMID: 39766224 PMCID: PMC11673044 DOI: 10.3390/biom14121517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/15/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Autophagy is an important catabolic process to maintain cellular homeostasis and antagonize cellular stresses. The initiation and activation are two of the most important aspects of the autophagic process. This review focuses on mechanisms underlying autophagy initiation and activation and signaling pathways regulating the activation of autophagy found in recent years. These findings include autophagy initiation by liquid-liquid phase separation (LLPS), autophagy initiation in the endoplasmic reticulum (ER) and Golgi apparatus, and the signaling pathways mediated by the ULK1 complex, the mTOR complex, the AMPK complex, and the PI3KC3 complex. Through the review, we attempt to present current research progress in autophagy regulation and forward our understanding of the regulatory mechanisms and signaling pathways of autophagy initiation and activation.
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Affiliation(s)
| | | | | | | | | | - Qiong Lin
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China; (Z.W.); (X.H.); (Y.W.); (L.Z.); (M.Z.)
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Yang S, Jiang L, Deng L, Luo J, Zhang X, Chen S, Dong Z. Chaperone-Mediated Autophagy Alleviates Cerebral Ischemia-Reperfusion Injury by Inhibiting P53-Mediated Mitochondria-Associated Apoptosis. Neurochem Res 2024; 50:29. [PMID: 39576398 DOI: 10.1007/s11064-024-04266-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/12/2024] [Accepted: 10/01/2024] [Indexed: 11/24/2024]
Abstract
Ischemia-reperfusion is a complex brain disease involving multiple biological processes, including autophagy, oxidative stress, and mitochondria-associated apoptosis. Chaperone-mediated autophagy (CMA), a selective autophagy, is involved in the development of various neurodegenerative diseases and acute nerve injury, but its role in ischemia-reperfusion is unclear. Here, we used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral ischemic stroke in vivo and in vitro, respectively. LAMP2A (lysosome-associated membrane protein 2A), a key molecule of CMA, was dramatically downregulated in ischemia-reperfusion. Enhancement of CMA activity by LAMP2A overexpression reduced the neurological deficit, brain infarct volume, pathological features, and neuronal apoptosis of the cortex in vivo. Concomitantly, enhanced CMA activity alleviated OGD/R-induced apoptosis and mitochondrial membrane potential decline in vitro. In addition, we found that CMA inhibited the P53(Tumor protein p53) signaling pathway and reduced P53 translocation to mitochondria. The P53 activator, Nutlin-3, not only reversed the inhibitory effect of CMA on apoptosis, but also significantly weakened the protective effect of CMA on OGD/R and MCAO/R. Taken together, these results indicate that inhibition of P53-mediated mitochondria-associated apoptosis is essential for the neuroprotective effect of CMA against ischemia-reperfusion.
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Affiliation(s)
- Shaonan Yang
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Lu Jiang
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Ling Deng
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Jingjing Luo
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaoling Zhang
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Sha Chen
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
| | - Zhi Dong
- Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
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Wang HD, Lv CL, Feng L, Guo JX, Zhao SY, Jiang P. The role of autophagy in brain health and disease: Insights into exosome and autophagy interactions. Heliyon 2024; 10:e38959. [PMID: 39524893 PMCID: PMC11546156 DOI: 10.1016/j.heliyon.2024.e38959] [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: 09/21/2023] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Effective management of cellular components is essential for maintaining brain health, and studies have identified several crucial biological processes in the brain. Among these, autophagy and the role of exosomes in cellular communication are critical for brain health and disease. The interaction between autophagy and exosomes in the nervous system, as well as their contributions to brain damage, have garnered significant attention. This review summarizes that exosomes and their cargoes have been implicated in the autophagy process in the pathophysiology of nervous system diseases. Furthermore, the onset and progression of neurological disorders may be affected by autophagy regulation of the secretion and release of exosomes. These findings may provide new insights into the potential mechanism by which autophagy mediates different exosome secretion and release, as well as the valuable biomedical applications of exosomes in the prevention and treatment of various brain diseases by targeting autophagy.
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Affiliation(s)
- Hai-Dong Wang
- Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/Nanjing Medical University Kangda College First Affiliated Hospital/The First People's Hospital of Lianyungang, Lianyungang, 222000, China
| | - Chao-Liang Lv
- Department of Spine Surgery, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
| | - Lei Feng
- Department of Neurosurgery, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
| | - Jin-Xiu Guo
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
| | - Shi-Yuan Zhao
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
| | - Pei Jiang
- Translational Pharmaceutical Laboratory, Jining First People's Hospital, Shandong First Medical University, Jining, 272000, China
- Institute of Translational Pharmacy, Jining Medical Research Academy, Jining, 272000, China
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Cristiani A, Dutta A, Poveda-Cuevas SA, Kern A, Bhaskara RM. Identification of potential selective autophagy receptors from protein-content profiling of autophagosomes. J Cell Biochem 2024; 125:e30405. [PMID: 37087736 DOI: 10.1002/jcb.30405] [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: 03/14/2023] [Accepted: 04/04/2023] [Indexed: 04/24/2023]
Abstract
Selective autophagy receptors (SARs) are central to cellular homeostatic and organellar recycling pathways. Over the last two decades, more than 30 SARs have been discovered and validated using a variety of experimental approaches ranging from cell biology to biochemistry, including high-throughput imaging and screening methods. Yet, the extent of selective autophagy pathways operating under various cellular contexts, for example, under basal and starvation conditions, remains unresolved. Currently, our knowledge of all known SARs and their associated cargo components is fragmentary and limited by experimental data with varying degrees of resolution. Here, we use classical predictive and modeling approaches to integrate high-quality autophagosome content profiling data with disparate datasets. We identify a global set of potential SARs and their associated cargo components active under basal autophagy, starvation-induced, and proteasome-inhibition conditions. We provide a detailed account of cellular components, biochemical pathways, and molecular processes that are degraded via autophagy. Our analysis yields a catalog of new potential SARs that satisfy the characteristics of bonafide, well-characterized SARs. We categorize them by the subcellular compartments they emerge from and classify them based on their likely mode of action. Our structural modeling validates a large subset of predicted interactions with the human ATG8 family of proteins and shows characteristic, conserved LC3-interacting region (LIR)-LIR docking site (LDS) and ubiquitin-interacting motif (UIM)-UIM docking site (UDS) binding modes. Our analysis also revealed the most abundant cargo molecules targeted by these new SARs. Our findings expand the repertoire of SARs and provide unprecedented details into the global autophagic state of HeLa cells. Taken together, our findings provide motivation for the design of new experiments, testing the role of these novel factors in selective autophagy.
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Affiliation(s)
- Alberto Cristiani
- Institute of Biochemistry II, School of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
| | - Arghya Dutta
- Institute of Biochemistry II, School of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
| | - Sergio Alejandro Poveda-Cuevas
- Institute of Biochemistry II, School of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
| | - Andreas Kern
- Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Ramachandra M Bhaskara
- Institute of Biochemistry II, School of Medicine, Goethe University Frankfurt, Frankfurt, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
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Liu X, Wang J, Yang Z, Xie Q, Diao X, Yao X, Huang S, Chen R, Zhao Y, Li T, Jiang M, Lou Z, Huang C. Upregulated DNMT3a coupling with inhibiting p62-dependent autophagy contributes to NNK tumorigenicity in human bronchial epithelial cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 286:117157. [PMID: 39393198 DOI: 10.1016/j.ecoenv.2024.117157] [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: 07/03/2024] [Revised: 09/27/2024] [Accepted: 10/04/2024] [Indexed: 10/13/2024]
Abstract
NNK, formally known as 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanoe, is a potent chemical carcinogen prevalent in cigarette smoke and is a key contributor to the development of human lung adenocarcinomas. On the other hand, autophagy plays a complex role in cancer development, acting as a "double-edged sword" whose impact varies depending on the cancer type and stage. Despite this, the relationship between autophagy and NNK-induced lung carcinogenesis remains largely unexplored. Our current study uncovers a marked reduction in p62 protein expression in both lung adenocarcinomas and lung tissues of mice exposed to cigarette smoke. Interestingly, this reduction appears to be contingent upon the activity of extrahepatic cytochrome P450 (CYP450), revealing that NNK metabolic activation by CYP450 enzyme escalates its potential to induce p62 downregulation. Further mechanistic investigations reveal that NNK suppresses autophagy by accelerating the degradation of p62 mRNA, thereby promoting the malignant transformation of human bronchial epithelial cells. This degradation process is facilitated by the hypermethylation of the Human antigen R (HuR) promoter, resulting in the transcriptional repression of HuR - a key regulator responsible for stabilizing p62 mRNA through direct binding. This hypermethylation is triggered by the activation of ribosomal protein S6, which is influenced by NNK exposure and subsequently amplifies the translation of DNA methyltransferase 3 alpha (DNMT3a). These findings provide crucial insights into the nature of p62 in both the development and potential treatment of tobacco-related lung cancer.
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Affiliation(s)
- Xuelei Liu
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Jingjing Wang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ziyi Yang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Qipeng Xie
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China; Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xinqi Diao
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Xiaoyan Yao
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Shirui Huang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ruifan Chen
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yunping Zhao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Tengda Li
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minghua Jiang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China; Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Zhefeng Lou
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Chuanshu Huang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China.
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Lin L, Lin Y, Han Z, Wang K, Zhou S, Wang Z, Wang S, Chen H. Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis. Front Immunol 2024; 15:1460023. [PMID: 39544928 PMCID: PMC11560454 DOI: 10.3389/fimmu.2024.1460023] [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: 07/05/2024] [Accepted: 10/07/2024] [Indexed: 11/17/2024] Open
Abstract
Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy.
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Affiliation(s)
- Lin Lin
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumeng Lin
- Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhongyu Han
- School of Medicine, Southeast University, Nanjing, China
- Science Education Department, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Ke Wang
- Department of Science and Education, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
| | - Shuwei Zhou
- Department of Radiology, Zhongda Hospital, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, School of Medicine, Southeast University, Nanjing, China
| | - Zhanzhan Wang
- Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Siyu Wang
- Department of Preventive Medicine, Kunshan Hospital of Chinese Medicine, Kunshan, China
| | - Haoran Chen
- Science Education Department, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
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Wang F, Liao Q, Qin Z, Li J, Wei Q, Li M, Deng H, Xiong W, Tan M, Zhou M. Autophagy: a critical mechanism of N 6-methyladenosine modification involved in tumor progression and therapy resistance. Cell Death Dis 2024; 15:783. [PMID: 39468015 PMCID: PMC11519594 DOI: 10.1038/s41419-024-07148-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024]
Abstract
N6-Methyladenosine (m6A) is an evolutionarily highly conserved epigenetic modification that affects eukaryotic RNAs, especially mRNAs, and m6A modification is commonly linked to tumor proliferation, progression, and therapeutic resistance by participating in RNA metabolism. Autophagy is an intracellular degradation and recycling biological process by which cells remove damaged organelles, protein aggregates, and other intracellular wastes, and release nutrients to maintain cell survival when energy is scarce. Recent studies have shown that m6A modification plays a critical role in the regulation of autophagy, affecting the initiation of autophagy, the formation and assembly of autophagosomes, and lysosomal function by regulating critical regulatory molecules involved in the process of autophagy. Moreover, autophagy can also affect the expression of the three types of regulators related to m6A, which in turn affects the levels of their target genes via m6A modification. Thus, m6A modification and autophagy form a sophisticated regulatory network through mutual regulation, which plays an important role in tumor progression and therapeutic resistance. In this manuscript, we reviewed the effects of m6A modification on autophagy as well as the effects of autophagy on m6A modification and the roles of the m6A-autophagy axis in tumor progression and therapy resistance. Additionally, we summarized the value and application prospects of key molecules in the m6A-autophagy axis in tumor diagnosis and therapy.
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Affiliation(s)
- Feiyang Wang
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Qiudi Liao
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Zihao Qin
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jingyi Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Qingqing Wei
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Mengna Li
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Hongyu Deng
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China
| | - Ming Tan
- Graduate Institute of Biomedical Sciences and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/ Hunan Cancer Hospital, Changsha, China.
- Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, China.
- The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, China.
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Lu W, Chu H, Yang C, Li X. Transcription factor EB (TFEB) promotes autophagy in early brain injury after subarachnoid hemorrhage in rats. Neurosurg Rev 2024; 47:741. [PMID: 39375262 DOI: 10.1007/s10143-024-02879-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: 02/05/2024] [Revised: 09/12/2024] [Accepted: 09/14/2024] [Indexed: 10/09/2024]
Abstract
Subarachnoid hemorrhage (SAH) has high mortality. Early brain injury (EBI) is responsible for unfavorable outcomes for patients with SAH. The protective involvement of autophagy in hemorrhagic stroke has been proposed. The transcription factor EB (TFEB) can increase autophagic flux by promoting autophagosome formation and autophagosome-lysosome fusion, and dysregulation of TFEB activity might induce the development of several diseases. However, the biological functions of TFEB in EBI after SAH remain unknown. We established an animal model of SAH by the modified endovascular perforation method. Expression of TFEB and autophagy required genes was measured by western blotting and immunofluorescence staining. SAH grading, brain water content and neurobehavioral functions were evaluated at 24 h post-SAH. Neuronal apoptosis in cerebral cortex was assessed by TUNEL staining and Fluoro Jade B staining. TFEB was downregulated in SAH rats, and its overexpression reduced brain edema and ameliorated neurological deficits of SAH rats. Additionally, the neuronal apoptosis induced by SAH was inhibited by TFEB overexpression. Moreover, TFEB overexpression promoted autophagy after SAH. TFEB overexpression promotes autophagy to inhibit neuronal apoptosis, brain edema and neurological deficits post-SAH.
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Affiliation(s)
- Wenqi Lu
- Department of Anesthesiology, The first Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
| | - Haichao Chu
- Department of Anesthesiology, The first Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
| | - Chunchen Yang
- Department of Anesthesiology, The first Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China
| | - Xiaoxu Li
- Department of Neurosurgery, The first Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.
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Xia N, Chen QH, Meng ZJ, Ma SY, Huang JL, Shen R, Dong YT, Du HW, Zhou K. Isobavachin induces autophagy-mediated cytotoxicity in AML12 cells via AMPK and PI3K/Akt/mTOR pathways. Toxicol In Vitro 2024; 100:105919. [PMID: 39154867 DOI: 10.1016/j.tiv.2024.105919] [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: 04/22/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Isobavachin (IBA) is a dihydroflavonoid compound with various pharmacological effects. However, further investigation into the hepatotoxicity of IBA is necessary. This study aims to identify the hepatotoxic effects of IBA and explore its potential mechanisms. The study assessed the impact of IBA on the viability of AML12, HepG2, LO2, rat, and mouse primary hepatocytes using MTT and LDH assays. Autophagy was detected in AML12 cells after IBA treatment using electron microscopy, MDC, and Ad-mCherry-GFP-LC3B fluorescence. The effect of IBA on autophagy-related proteins was examined using Western blot. The results showed that IBA had dose-dependent inhibitory effects on five cells, induced autophagy in AML12 cells, and promoted autophagic flux. The study found that IBA treatment inhibited phosphorylation of PI3K, Akt, and mTOR, while increasing phosphorylation levels of AMPK and ULK1. Treatment with both AMPK and PI3K inhibitors reversed the expression of AMPK and PI3K-Akt-mTOR signaling pathway proteins. These results suggest that IBA may have hepatocytotoxic effects but can also prevent IBA hepatotoxicity by inhibiting the AMPK and PI3K/Akt/mTOR signaling pathways. This provides a theoretical basis for preventing and treating IBA hepatotoxicity in clinical settings.
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Affiliation(s)
- Ning Xia
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qing-Hai Chen
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Tianjin, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
| | - Zhao-Jun Meng
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Shu-Yue Ma
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jia-Li Huang
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Rong Shen
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yu-Tong Dong
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hai-Wei Du
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Tianjin, China
| | - Kun Zhou
- Center of Drug Safety Evaluation, Tianjin University of Traditional Chinese Medicine, Tianjin, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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45
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Patel KD, Keskin-Erdogan Z, Sawadkar P, Nik Sharifulden NSA, Shannon MR, Patel M, Silva LB, Patel R, Chau DYS, Knowles JC, Perriman AW, Kim HW. Oxidative stress modulating nanomaterials and their biochemical roles in nanomedicine. NANOSCALE HORIZONS 2024; 9:1630-1682. [PMID: 39018043 DOI: 10.1039/d4nh00171k] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
Many pathological conditions are predominantly associated with oxidative stress, arising from reactive oxygen species (ROS); therefore, the modulation of redox activities has been a key strategy to restore normal tissue functions. Current approaches involve establishing a favorable cellular redox environment through the administration of therapeutic drugs and redox-active nanomaterials (RANs). In particular, RANs not only provide a stable and reliable means of therapeutic delivery but also possess the capacity to finely tune various interconnected components, including radicals, enzymes, proteins, transcription factors, and metabolites. Here, we discuss the roles that engineered RANs play in a spectrum of pathological conditions, such as cancer, neurodegenerative diseases, infections, and inflammation. We visualize the dual functions of RANs as both generator and scavenger of ROS, emphasizing their profound impact on diverse cellular functions. The focus of this review is solely on inorganic redox-active nanomaterials (inorganic RANs). Additionally, we deliberate on the challenges associated with current RANs-based approaches and propose potential research directions for their future clinical translation.
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Affiliation(s)
- Kapil D Patel
- John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
- Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
- School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD, UK
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea
| | - Zalike Keskin-Erdogan
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London, UK
- Department of Chemical Engineering, Imperial College London, Exhibition Rd, South Kensington, SW7 2BX, London, UK
| | - Prasad Sawadkar
- Division of Surgery and Interventional Science, UCL, London, UK
- The Griffin Institute, Northwick Park Institute for Medical Research, Northwick Park and St Mark's Hospitals, London, HA1 3UJ, UK
| | - Nik Syahirah Aliaa Nik Sharifulden
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London, UK
| | - Mark Robert Shannon
- John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
- Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
- School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD, UK
| | - Madhumita Patel
- Department of Chemistry and Nanoscience, Ewha Women University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea
| | - Lady Barrios Silva
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London, UK
| | - Rajkumar Patel
- Energy & Environment Sciences and Engineering (EESE), Integrated Sciences and Engineering Division (ISED), Underwood International College, Yonsei University, 85 Songdongwahak-ro, Yeonsungu, Incheon 21938, Republic of Korea
| | - David Y S Chau
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London, UK
| | - Jonathan C Knowles
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea
- Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London, UK
| | - Adam W Perriman
- John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
- Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
- School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD, UK
| | - Hae-Won Kim
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea
- Department of Biomaterials Science, School of Dentistry, Dankook University, Cheonan 31116, Republic of Korea
- Cell & Matter Institute, Dankook University, Cheonan 31116, Republic of Korea
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Luo P, Zhao Z, Yang F, Zhang L, Li S, Qiao Y, Zhang L, Yang M, Zhou X, Zhao L, Yang Y, Tang X, Shi C. Stress-Induced Autophagy Is Essential for Microspore Cell Fate Transition to the Initial Cell of Androgenesis. PLANT, CELL & ENVIRONMENT 2024. [PMID: 39267528 DOI: 10.1111/pce.15158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/23/2024] [Accepted: 09/02/2024] [Indexed: 09/17/2024]
Abstract
The isolated microspores can be reprogrammed towards embryogenesis via stress treatment during in vitro culture, and produce (doubled) haploid plants as a breeding source of new genetic variability. However, the mechanism underlying the cell fate transition from gametogenesis to embryogenesis remains largely unknown. Here, we report that autophagy plays a key role in cell fate transition for microspore embryogenesis (referred to as androgenesis) in Nicotiana tabacum. Immunofluorescence and transmission electronic microscopy detection unveiled that autophagy was triggered in microspores following exposure to inductive stress, and a transient wave of the numerous autophagy-related genes (ATGs) expression occurred before the initiation of microspore embryogenesis. Suppression or promotion of the original autophagy levels could inhibit microspore embryogenesis, indicating that stress-induced autophagic homeostasis is essential for cell fate transition. Furthermore, quantitative proteomics analysis revealed that autophagy might be involved in lignin biosynthesis and chromatin decondensation for promoting reprogramming for androgenesis initiation. Altogether, we reveal an essential role of autophagy in the microspore cell fate transition and androgenesis initiation, providing novel insight for understanding this critical developmental process.
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Affiliation(s)
- Pan Luo
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Zifu Zhao
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, China
| | - Fan Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Lai Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Siyuan Li
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Ying Qiao
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Liangxinyi Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Mingchun Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Xiaotong Zhou
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Linlin Zhao
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yong Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Xingchun Tang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, College of Life Science, Hubei University, Wuhan, China
| | - Ce Shi
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, China
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Li Y, Xiao P, Sun Y, Li Y, Zhao H, Sun J, Wang X, Han X, Jin N, Li X, Bao Y. Deapioplatycodin D promotes cell senescence induced by P21 through the mediation of incomplete mitophagy via BNIP3L. Biomed Pharmacother 2024; 178:117215. [PMID: 39084076 DOI: 10.1016/j.biopha.2024.117215] [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: 05/22/2024] [Revised: 07/16/2024] [Accepted: 07/26/2024] [Indexed: 08/02/2024] Open
Abstract
Deapioplatycodin D (DPD) is a triterpenoid saponin extracted from the root of Platycodon grandiflorum, which is a common source of medicine and food. Platycodon grandiflorum saponins have anti-inflammatory, antioxidative, antitumor, and immunity-promoting effects. However, the effect of DPD on hepatocellular carcinoma (HCC) cells has not been reported. The purpose of this study was to explore the cytotoxic effects and molecular mechanisms of DPD on HCC cells. Our study revealed that DPD significantly inhibits the proliferation of HCC, as demonstrated by the CCK-8 assay, and then we analyzed the inhibitory effects and pathways of DPD on HCC cells by Western blot and immunofluorescence assay, and found that DPD could increase the changes of autophagy-related protein levels, but had no significant effect on the expression of apoptosis-related proteins, and induced cell senescence. Then, transcriptomics analysis revealed that differential genes were significantly enriched in cell senescence and autophagy pathways and significant expression of mitochondrial autophagy-related gene BNIP3L and senescence-related gene P21. Subsequently, autophagy and cell senescence were analyzed using gene silencing, and it was found that DPD caused mitochondrial damage and promoted reactive oxygen species production, leading to the inhibition of autophagic fluxes and mitophagy via BNIP3L, and that DPD also mediated cell senescence via P21. Here, we found that autophagy promoted cell senescence, resulting in the inhibition of HCC cell proliferation. Similar results were obtained in the tumor-bearing model in vivo. In conclusion, DPD induces incomplete mitophagy and cell senescence in HCC cells, thereby inhibiting HCC cell proliferation. DPD is a potential new strategy for treating HCC.
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Affiliation(s)
- Yiquan Li
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, PR China; Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun 130117, PR China
| | - Pengpeng Xiao
- Wenzhou Key Laboratory for Virology and Immunology, Institute of Virology, Wenzhou University, Wenzhou, PR China.
| | - Yu Sun
- Department of Neurology, Jilin Central Hospital, Jilin 132000, PR China
| | - Yaru Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun 130117, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China
| | - Haifeng Zhao
- Jilin Institute for Drug Control, Changchun 130000, PR China
| | - Jialing Sun
- Jilin Institute for Drug Control, Changchun 130000, PR China
| | - Xue Wang
- Jilin Institute for Drug Control, Changchun 130000, PR China
| | - Xiaohong Han
- Jilin Institute for Drug Control, Changchun 130000, PR China
| | - Ningyi Jin
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun 130117, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China
| | - Xiao Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun 130117, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China.
| | - Yongli Bao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, PR China.
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Zhang Y, Wang M, Tang L, Yang W, Zhang J. FoxO1 silencing in Atp7b -/- neural stem cells attenuates high copper-induced apoptosis via regulation of autophagy. J Neurochem 2024; 168:2762-2774. [PMID: 38837406 DOI: 10.1111/jnc.16136] [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: 04/01/2023] [Revised: 04/17/2024] [Accepted: 05/07/2024] [Indexed: 06/07/2024]
Abstract
Wilson disease (WD) is a severely autosomal genetic disorder triggered by dysregulated copper metabolism. Autophagy and apoptosis share common modulators that process cellular death. Emerging evidences suggest that Forkhead Box O1 over-expression (FoxO1-OE) aggravates abnormal autophagy and apoptosis to induce neuronal injury. However, the underlying mechanisms remain undetermined. Herein, the aim of this study was to investigate how regulating FoxO1 affects cellular autophagy and apoptosis to attenuate neuronal injury in a well-established WD cell model, the high concentration copper sulfate (CuSO4, HC)-triggered Atp7b-/- (Knockout, KO) neural stem cell (NSC) lines. The FoxO1-OE plasmid, or siRNA-FoxO1 (siFoxO1) plasmid, or empty vector plasmid was stably transfected with recombinant lentiviral vectors into HC-induced Atp7b-/- NSCs. Toxic effects of excess deposited copper on wild-type (WT), Atp7b-/- WD mouse hippocampal NSCs were tested by Cell Counting Kit-8 (CCK-8). Subsequently, the FoxO1 expression was evaluated by immunofluorescence (IF) assay, western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Meanwhile, the cell autophagy and apoptosis were evaluated by flow cytometry (FC), TUNEL staining, 2,7-dichlorofluorescein diacetate (DCFH-DA), JC-1, WB, and qRT-PCR. The current study demonstrated a strong rise in FoxO1 levels in HC-treated Atp7b-/- NSCs, accompanied with dysregulated autophagy and hyperactive apoptosis. Also, it was observed that cell viability was significantly decreased with the over-expressed FoxO1 in HC-treated Atp7b-/- WD model. As intended, silencing FoxO1 effectively inhibited abnormal autophagy in HC-treated Atp7b-/- NSCs, as depicted by a decline in LC3II/I, Beclin-1, ATG3, ATG7, ATG13, and ATG16, whereas simultaneously increasing P62. In addition, silencing FoxO1 suppressed apoptosis via diminishing oxidative stress (OS), and mitochondrial dysfunction in HC-induced Atp7b-/- NSCs. Collectively, these results clearly demonstrate the silencing FoxO1 has the neuroprotective role of suppressing aberrant cellular autophagy and apoptosis, which efficiently attenuates neuronal injury in WD.
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Affiliation(s)
- Yu Zhang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Department of Graduate School, Anhui University of Chinese Medicine, Hefei, China
| | - Meixia Wang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
| | - Lulu Tang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Wenming Yang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
| | - Jing Zhang
- Department of Neurology, First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Anhui University of Chinese Medicine, Hefei, China
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Dong W, Lu J, Li Y, Zeng J, Du X, Yu A, Zhao X, Chi F, Xi Z, Cao S. SIRT1: a novel regulator in colorectal cancer. Biomed Pharmacother 2024; 178:117176. [PMID: 39059350 DOI: 10.1016/j.biopha.2024.117176] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/08/2024] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
The class-III histone deacetylase SIRT1 is the most extensively investigated sirtuin deacetylase. It is resistant to the broad deacetylase inhibitor trichostatin A and depends on oxidized nicotinamide adenine nucleotide (NAD+). SIRT1 plays a crucial role in the tumorigenesis of numerous types of cancers, including colorectal cancer (CRC). Accumulating evidence indicates that SIRT1 is a therapeutic target for CRC; however, the function and underlying mechanism of SIRT1 in CRC still need to be elucidated. Herein, we provide a detailed and updated review to illustrate that SIRT1 regulates many processes that go awry in CRC cells, such as apoptosis, autophagy, proliferation, migration, invasion, metastasis, oxidative stress, resistance to chemo-radio therapy, immune evasion, and metabolic reprogramming. Moreover, we closely link our review to the clinical practice of CRC treatment, summarizing the mechanisms and prospects of SIRT1 inhibitors in CRC therapy. SIRT1 inhibitors as monotherapy in CRC or in combination with chemotherapy, radiotherapy, and immune therapies are comprehensively discussed. From epigenetic regulation to its potential therapeutic effect, we hope to offer novel insights and a comprehensive understanding of SIRT1's role in CRC.
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Affiliation(s)
- Weiwei Dong
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Jinjing Lu
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - You Li
- Nursing Department, Liaoning Jinqiu Hospital, Shenyang, Liaoning Province 110016, China
| | - Juan Zeng
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xiaoyun Du
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Ao Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Xuechan Zhao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China
| | - Feng Chi
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Zhuo Xi
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
| | - Shuo Cao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, China.
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50
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Shen B, Wen Y, Li S, Zhou Y, Chen J, Yang J, Zhao C, Wang J. Paeonol ameliorates hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155839. [PMID: 38943694 DOI: 10.1016/j.phymed.2024.155839] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 05/31/2024] [Accepted: 06/20/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND Hyperlipidemia, inadequate diet, and excessive medication increase the risk of cardiovascular disease. Paeonl (Pae), a phenolic compound found in Peony and Angelica dahurica, can alleviate lipid metabolism disorders and lipotoxicity. However, the molecular mechanism of Pae alleviating hyperlipidemia remains unclear and needs to be further explored. PURPOSE In this study, we explored whether Pae can prevent hyperlipidemia and investigated the molecular mechanisms. METHODS The effects of Pae (30, 45, 60mg·kg-1) on hyperlipidemia in Tyloapol-induced WT mice and Nrf2 knockout mice (Pae: 60mg·kg-1) were detected by oil red O staining, HE staining, TG, TC and other indexes. The expression levels of proinflammatory mediators, key lipid proteins and autophagy signaling pathway proteins were analyzed by enzyme-linked immunosorbent assay, western blot and immunofluorescence. The molecular mechanism of Pae alleviating hyperlipidemia was explored through molecular docking technique and in vivo and in vitro experiments. RESULTS Several studies indicated that Pae effectively improved tyloxapol (Ty)-induced lipid metabolism disorder, as evidenced by decreased triglyceride content, increased carnitine palmitoyltransferase 1 (CPT1), and Sirtuin 1 (Sirt1) protein expression. In addition, Pae ameliorated hyperlipidemia by activating the AMPK/ACC and PI3K/mTOR pathways. Interestingly, the therapeutic effect of Pae on hyperlipidemia was markedly reduced in Nrf2-/- mice. Molecular docking results indicated that Pae and Nrf2 exhibited good binding ability, suggesting that Nrf2 is a core target mediating the effects of Pae in the treatment of hyperlipidemia. Taken together, Pae alleviated hyperlipidemia in vivo and ameliorated lipid accumulation in vitro by activating AMPK/ACC and PI3K/mTOR signaling pathways via Nrf2 binding. CONCLUSION Our data suggest that paeonol can ameliorate hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways, and it has potential therapeutic value in the occurrence and development of hyperlipidemia.
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Affiliation(s)
- Bingyu Shen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yongqiang Wen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shengxin Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yi Zhou
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Junlin Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jiaqi Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chenxu Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Jianguo Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
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