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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [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: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Wu P, Chen J, Li H, Lu H, Li Y, Zhang J. Interactions between ferroptosis and tumour development mechanisms: Implications for gynaecological cancer therapy (Review). Oncol Rep 2025; 53:18. [PMID: 39635847 PMCID: PMC11638741 DOI: 10.3892/or.2024.8851] [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: 09/19/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
Ferroptosis is a form of programmed cell death that is distinct from apoptosis. The mechanism involves redox‑active metallic iron and is characterized by an abnormal increase in iron‑dependent lipid reactive oxygen species, which results in high levels of membrane lipid peroxides. The relationship between ferroptosis and gynaecological tumours is complex. Ferroptosis can regulate tumour proliferation, metastasis and chemotherapy resistance, and targeting ferroptosis is a promising antitumour approach. Ferroptosis interacts with mechanisms related to tumorigenesis and development, such as macrophage polarization, the neutrophil trap network, mitochondrial autophagy and cuproptosis. The present review examines recent information on the interaction between the molecular mechanism of ferroptosis and other tumour‑related mechanisms, as well as the involvement of ferroptosis in gynaecological tumours, to identify implications for gynaecological cancer therapy.
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Affiliation(s)
- Peiting Wu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 410013, P.R. China
| | - Jianlin Chen
- Department of Assisted Reproductive Centre, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hui Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 410013, P.R. China
| | - Haiyuan Lu
- Department of Clinical Laboratory Department, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
- Department of Hunan Vigorzoe Biotechnology Co., Ltd., Hunan 417700, P.R. China
| | - Yukun Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 410013, P.R. China
| | - Juan Zhang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan 410013, P.R. China
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Su C, Xue Y, Fan S, Sun X, Si Q, Gu Z, Wang J, Deng R. Ferroptosis and its relationship with cancer. Front Cell Dev Biol 2025; 12:1423869. [PMID: 39877159 PMCID: PMC11772186 DOI: 10.3389/fcell.2024.1423869] [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: 04/26/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Marked by iron buildup and lipid peroxidation, ferroptosis is a relatively new regulatory cell death (RCD) pathway. Many diseases like cancer, myocardial ischemia-reperfusion injury (MIRI), neurological disorders and acute renal failure (AKI) are corelated with ferroptosis. The main molecular processes of ferroptosis discovered yet will be presented here, along with the approaches in which it interacts with tumour-associated signaling pathways and its uses in systemic therapy, radiation therapy, and immunotherapy managing tumors.
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Affiliation(s)
| | | | | | | | | | | | | | - Runzhi Deng
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
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Cammisotto V, Valeriani E, Pignatelli P, Violi F. Nicotinamide Adenine Dinucleotide Phosphate Oxidases and Metabolic Dysfunction-Associated Steatotic Liver Disease. Antioxidants (Basel) 2025; 14:83. [PMID: 39857417 PMCID: PMC11763266 DOI: 10.3390/antiox14010083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/01/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by lipid accumulation in the liver due to an excess in their supplies or an impairment in their management. While some patients remain stable for years, a proportion of them progress up to steatohepatitis (MASH). MASLD links with systemic pathways being associated with metabolic and non-metabolic diseases. Although liver lipid accumulation represents the first hit for MASLD, the pathophysiology of its development and progression to MASH remains not completely understood. Oxidative stress has received particular attention in recent years, as most of the oxidative process occurs in the liver, which is also the target of oxidative stress-induced damage. Growing evidence linked the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) to the increased liver production of reactive oxygen species up to liver damage and fibrosis. NOX acts both in hepatocytes and in non-parenchymal hepatic cells, contributing to hepatocyte lipotoxicity, impaired hepatic microcirculation, hepatic stellate, and mesenchymal stem cells activation and proliferation. This review aims to summarize the current knowledge on the involvement of oxidative stress in the MASLD-MASH transition, focusing on the role of NOX isoforms, and to suggest targeting NOX as a therapeutic approach in MASLD.
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Affiliation(s)
- Vittoria Cammisotto
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Emanuele Valeriani
- Department of General Surgery and Surgical Specialty, Sapienza University of Rome, 00185 Rome, Italy
- Department of Infectious Disease, Azienda Ospedaliero-Universitaria Policlinico Umberto I, 00161 Rome, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
| | - Francesco Violi
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (V.C.); (P.P.); (F.V.)
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Yan W, Rao D, Fan F, Liang H, Zhang Z, Dong H. Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma. Front Oncol 2024; 14:1407434. [PMID: 38962270 PMCID: PMC11220127 DOI: 10.3389/fonc.2024.1407434] [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: 03/26/2024] [Accepted: 05/21/2024] [Indexed: 07/05/2024] Open
Abstract
Hepatitis B infection is substantially associated with the development of liver cancer globally, with the prevalence of hepatocellular carcinoma (HCC) cases exceeding 50%. Hepatitis B virus (HBV) encodes the Hepatitis B virus X (HBx) protein, a pleiotropic regulatory protein necessary for the transcription of the HBV covalently closed circular DNA (cccDNA) microchromosome. In previous studies, HBV-associated HCC was revealed to be affected by HBx in multiple signaling pathways, resulting in genetic mutations and epigenetic modifications in proto-oncogenes and tumor suppressor genes. In addition, transforming growth factor-β (TGF-β) has dichotomous potentials at various phases of malignancy as it is a crucial signaling pathway that regulates multiple cellular and physiological processes. In early HCC, TGF-β has a significant antitumor effect, whereas in advanced HCC, it promotes malignant progression. TGF-β interacts with the HBx protein in HCC, regulating the pathogenesis of HCC. This review summarizes the respective and combined functions of HBx and TGB-β in HCC occurrence and development.
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Affiliation(s)
- Wei Yan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Dean Rao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Feimu Fan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Zunyi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, Hubei, China
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Damerau A, Rosenow E, Alkhoury D, Buttgereit F, Gaber T. Fibrotic pathways and fibroblast-like synoviocyte phenotypes in osteoarthritis. Front Immunol 2024; 15:1385006. [PMID: 38895122 PMCID: PMC11183113 DOI: 10.3389/fimmu.2024.1385006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1─ phenotype is restricted to the synovial lining layer. In contrast, the THY1+ phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells.
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Affiliation(s)
- Alexandra Damerau
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
| | - Emely Rosenow
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Dana Alkhoury
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
| | - Timo Gaber
- Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany
- German Rheumatism Research Center Berlin, a Leibniz Institute, Glucocorticoids - Bioenergetics - 3R Research Lab, Berlin, Germany
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Salminen A, Kaarniranta K, Kauppinen A. Tissue fibroblasts are versatile immune regulators: An evaluation of their impact on the aging process. Ageing Res Rev 2024; 97:102296. [PMID: 38588867 DOI: 10.1016/j.arr.2024.102296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/26/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Fibroblasts are abundant stromal cells which not only control the integrity of extracellular matrix (ECM) but also act as immune regulators. It is known that the structural cells within tissues can establish an organ-specific immunity expressing many immune-related genes and closely interact with immune cells. In fact, fibroblasts can modify their immune properties to display both pro-inflammatory and immunosuppressive activities in a context-dependent manner. After acute insults, fibroblasts promote tissue inflammation although they concurrently recruit immunosuppressive cells to enhance the resolution of inflammation. In chronic pathological states, tissue fibroblasts, especially senescent fibroblasts, can display many pro-inflammatory and immunosuppressive properties and stimulate the activities of different immunosuppressive cells. In return, immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSC), evoke an excessive conversion of fibroblasts into myofibroblasts, thus aggravating the severity of tissue fibrosis. Single-cell transcriptome studies on fibroblasts isolated from aged tissues have confirmed that tissue fibroblasts express many genes coding for cytokines, chemokines, and complement factors, whereas they lose some fibrogenic properties. The versatile immune properties of fibroblasts and their close cooperation with immune cells indicate that tissue fibroblasts have a crucial role in the aging process and age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, KYS FI-70029, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland
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Sun C, Zhan J, Li Y, Zhou C, Huang S, Zhu X, Huang K. Non-apoptotic regulated cell death mediates reprogramming of the tumour immune microenvironment by macrophages. J Cell Mol Med 2024; 28:e18348. [PMID: 38652105 PMCID: PMC11037416 DOI: 10.1111/jcmm.18348] [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: 11/24/2023] [Revised: 02/23/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024] Open
Abstract
Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour-associated macrophages (TAMs) are the most abundant immune cells in TIME. Non-apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti-tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non-apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non-apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non-apoptotic RCD, the way in which non-apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non-apoptotic RCD and ICIs are reviewed.
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Affiliation(s)
- Chengpeng Sun
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- HuanKui Academy, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Jianhao Zhan
- HuanKui Academy, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Yao Li
- The First Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Chulin Zhou
- The Second Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Shuo Huang
- The Second Clinical Medical College, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Xingen Zhu
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular DiseasesNanchangChina
- JXHC Key Laboratory of Neurological MedicineNanchangJiangxiP. R. China
| | - Kai Huang
- Department of NeurosurgeryThe Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiP. R. China
- Jiangxi Key Laboratory of Neurological Tumors and Cerebrovascular DiseasesNanchangChina
- JXHC Key Laboratory of Neurological MedicineNanchangJiangxiP. R. China
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9
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Bhadane D, Kamble D, Deval M, Das S, Sitasawad S. NOX4 alleviates breast cancer cell aggressiveness by co-ordinating mitochondrial turnover through PGC1α/Drp1 axis. Cell Signal 2024; 115:111008. [PMID: 38092301 DOI: 10.1016/j.cellsig.2023.111008] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 11/27/2023] [Accepted: 12/08/2023] [Indexed: 12/29/2023]
Abstract
Triple Negative Breast Cancer (TNBC) is a highly aggressive form of breast cancer, with few treatment options. This study investigates the complex molecular mechanism by which NADPH oxidase 4 (NOX4), a major ROS producer in mitochondria, affects the aggressiveness of luminal and triple-negative breast cancer cells (TNBCs). We found that NOX4 expression was differentially regulated in luminal and TNBC cells, with a positive correlation to their epithelial characteristics. Time dependent analysis revealed that TNBCs exhibits higher steady-state ROS levels than luminal cells, but NOX4 silencing increased ROS levels in luminal breast cancer cells and enhanced their ability to migrate and invade. In contrast, NOX4 over expression in TNBCs had the opposite effect. The mouse tail-vein experiment showed that the group injected with NOX4 silenced luminal cells had a higher number of lung metastases compared to the control group. Mechanistically, NOX4 enhanced PGC1α dependent mitochondrial biogenesis and attenuated Drp1-mediated mitochondrial fission in luminal breast cancer cells, leading to an increased mitochondrial mass and elongated mitochondrial morphology. Interestingly, NOX4 silencing increased mitochondrial ROS (mtROS) levels without affecting mitochondrial (Δψm) and cellular integrity. Inhibition of Drp1-dependent fission with Mdivi1 reversed the effect of NOX4-dependent mitochondrial biogenesis, dynamics, and migration of breast cancer cells. Our findings suggest that NOX4 expression diminishes from luminal to a triple negative state, accompanied by elevated ROS levels, which may modulate mitochondrial turnover to attain an aggressive phenotype. The study provides potential insights for targeted therapies for TNBCs.
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Affiliation(s)
- Deepali Bhadane
- Redox Biology Laboratory, National Centre for Cell Science (NCCS), Pune 411007, India
| | - Dinisha Kamble
- Redox Biology Laboratory, National Centre for Cell Science (NCCS), Pune 411007, India
| | - Mangesh Deval
- Redox Biology Laboratory, National Centre for Cell Science (NCCS), Pune 411007, India
| | - Subhajit Das
- Redox Biology Laboratory, National Centre for Cell Science (NCCS), Pune 411007, India
| | - Sandhya Sitasawad
- Redox Biology Laboratory, National Centre for Cell Science (NCCS), Pune 411007, India.
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Chen L, Guo W, Mao C, Shen J, Wan M. Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents. J Mater Chem B 2024; 12:1446-1466. [PMID: 38265305 DOI: 10.1039/d3tb02790b] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
Liver fibrosis is a reversible damage-repair response, the pathological features of which mainly include damage to hepatocytes, sinusoid capillarization, hepatic stellate cells activation, excessive accumulation of extracellular matrix and inflammatory response. Although some treatments (including drugs and stem cell therapy) for these pathological features have been shown to be effective, more clinical trials are needed to confirm their effectiveness. In recent years, nanomaterials-based therapies have emerged as an innovative and promising alternative to traditional drugs, being explored for the treatment of liver fibrosis diseases. Natural nanomaterials (including extracellular vesicles) and synthetic nanomaterials (including inorganic nanomaterials and organic nanomaterials) are developed to facilitate drug targeting delivery and combination therapy. In this review, the pathological features of liver fibrosis and the current anti-fibrosis drugs in clinical trials are briefly introduced, followed by a detailed introduction of the therapeutic nanoagents for the precise delivery of anti-fibrosis drugs. Finally, the future development trend in this field is discussed.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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11
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Flores-Estrada J, Cano-Martínez A, Vargas-González Á, Castrejón-Téllez V, Cornejo-Garrido J, Martínez-Rosas M, Guarner-Lans V, Rubio-Ruíz ME. Hepatoprotective Mechanisms Induced by Spinach Methanolic Extract in Rats with Hyperglycemia-An Immunohistochemical Analysis. Antioxidants (Basel) 2023; 12:2013. [PMID: 38001866 PMCID: PMC10669258 DOI: 10.3390/antiox12112013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Spinach methanolic extract (SME) has a hepatoprotective effect due to its polyphenolic antioxidants; however, its action in parenchymal (PQ) and non-parenchymal (nPQ) cells remains unknown. This study investigates the hepatoprotective effect of SME on streptozotocin-induced hyperglycemic rats (STZ), focusing on immunohistochemical analyses. Methods: The extract was prepared, and the total polyphenols and antioxidant activity were quantified. Adult male Wistar rats were divided into four groups (n = 8): normoglycemic rats (NG), STZ-induced hyperglycemic (STZ), STZ treated with 400 mg/kg SME (STZ-SME), and NG treated with SME (SME) for 12 weeks. Serum liver transaminases and lipid peroxidation levels in tissue were determined. The distribution pattern and relative levels of markers related to oxidative stress [reactive oxygen species (ROS), superoxide dismutase-1, catalase, and glutathione peroxidase-1], of cytoprotective molecules [nuclear NRF2 and heme oxygenase-1 (HO-1)], of inflammatory mediators [nuclear NF-κB, TNF-α], proliferation (PCNA), and of fibrogenesis markers [TGF-β, Smad2/3, MMP-9, and TIMP1] were evaluated. Results: SME had antioxidant capacity, and it lowered serum transaminase levels in STZ-SME compared to STZ. It reduced NOX4 staining, and lipid peroxidation levels were related to low formation of ROS. In STZ-SME, the immunostaining for antioxidant enzymes increased in nPQ cells compared to STZ. However, enzymes were also localized in extra and intracellular vesicles in STZ. Nuclear NRF2 staining and HO-1 expression in PQ and nPQ were higher in STZ-SME than in STZ. Inflammatory factors were decreased in STZ-SME and were related to the percentage decrease in NF-κB nuclear staining in nPQ cells. Similarly, TGF-β (in the sinusoids) and MMP-9 (in nPQ) were increased in the STZ-SME group compared to the other groups; however, staining for CTGF, TIMP1, and Smad2/3 was lower. Conclusions: SME treatment in hyperglycemic rats induced by STZ may have hepatoprotective properties due to its scavenger capacity and the regulation of differential expression of antioxidant enzymes between the PQ and nPQ cells, reducing inflammatory and fibrogenic biomarkers in liver tissue.
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Affiliation(s)
| | - Agustina Cano-Martínez
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
| | - Álvaro Vargas-González
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
| | - Vicente Castrejón-Téllez
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
| | - Jorge Cornejo-Garrido
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Mexico City 07320, Mexico;
| | - Martín Martínez-Rosas
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
| | - Verónica Guarner-Lans
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
| | - María Esther Rubio-Ruíz
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City 14080, Mexico; (A.C.-M.); (Á.V.-G.); (V.C.-T.); (M.M.-R.); (V.G.-L.); (M.E.R.-R.)
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12
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Lee YA, Shin MH. Involvement of NOX2-derived ROS in human hepatoma HepG2 cell death induced by Entamoeba histolytica. PARASITES, HOSTS AND DISEASES 2023; 61:388-396. [PMID: 38043534 PMCID: PMC10693973 DOI: 10.3347/phd.23094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/02/2023] [Indexed: 12/05/2023]
Abstract
Entamoeba histolytica is an enteric tissue-invasive protozoan parasite causing amoebic colitis and liver abscesses in humans. Amoebic contact with host cells activates intracellular signaling pathways that lead to host cell death via generation of caspase-3, calpain, Ca2+ elevation, and reactive oxygen species (ROS). We previously reported that various NADPH oxidases (NOXs) are responsible for ROS-dependent death of various host cells induced by amoeba. In the present study, we investigated the specific NOX isoform involved in ROS-dependent death of hepatocytes induced by amoebas. Co-incubation of hepatoma HepG2 cells with live amoebic trophozoites resulted in remarkably increased DNA fragmentation compared to cells incubated with medium alone. HepG2 cells that adhered to amoebic trophozoites showed strong dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence, suggesting intracellular ROS accumulation within host cells stimulated by amoebic trophozoites. Pretreatment of HepG2 cells with the general NOX inhibitor DPI or NOX2-specific inhibitor GSK 2795039 reduced Entamoeba-induced ROS generation. Similarly, Entamoeba-induced LDH release from HepG2 cells was effectively inhibited by pretreatment with DPI or GSK 2795039. In NOX2-silenced HepG2 cells, Entamoeba-induced LDH release was also significantly inhibited compared with controls. Taken together, the results support an important role of NOX2-derived ROS in hepatocyte death induced by E. histolytica.
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Affiliation(s)
- Young Ah Lee
- Department of Tropical Medicine and Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 03722,
Korea
| | - Myeong Heon Shin
- Department of Tropical Medicine and Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 03722,
Korea
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13
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Yu Z, Xu C, Song B, Zhang S, Chen C, Li C, Zhang S. Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances. J Transl Med 2023; 21:708. [PMID: 37814303 PMCID: PMC10563272 DOI: 10.1186/s12967-023-04554-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/22/2023] [Indexed: 10/11/2023] Open
Abstract
Cancer remains the leading cause of death around the world. In cancer treatment, over 50% of cancer patients receive radiotherapy alone or in multimodal combinations with other therapies. One of the adverse consequences after radiation exposure is the occurrence of radiation-induced tissue fibrosis (RIF), which is characterized by the abnormal activation of myofibroblasts and the excessive accumulation of extracellular matrix. This phenotype can manifest in multiple organs, such as lung, skin, liver and kidney. In-depth studies on the mechanisms of radiation-induced fibrosis have shown that a variety of extracellular signals such as immune cells and abnormal release of cytokines, and intracellular signals such as cGAS/STING, oxidative stress response, metabolic reprogramming and proteasome pathway activation are involved in the activation of myofibroblasts. Tissue fibrosis is extremely harmful to patients' health and requires early diagnosis. In addition to traditional serum markers, histologic and imaging tests, the diagnostic potential of nuclear medicine techniques is emerging. Anti-inflammatory and antioxidant therapies are the traditional treatments for radiation-induced fibrosis. Recently, some promising therapeutic strategies have emerged, such as stem cell therapy and targeted therapies. However, incomplete knowledge of the mechanisms hinders the treatment of this disease. Here, we also highlight the potential mechanistic, diagnostic and therapeutic directions of radiation-induced fibrosis.
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Affiliation(s)
- Zuxiang Yu
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Chaoyu Xu
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Bin Song
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, 621099, China
| | - Shihao Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Chong Chen
- Department of Gastroenterology, The First People's Hospital of Xuzhou, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221200, China
| | - Changlong Li
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
- Department of Molecular Biology and Biochemistry, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, China.
- NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang, 621099, China.
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14
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Loomis T, Smith LR. Thrown for a loop: fibro-adipogenic progenitors in skeletal muscle fibrosis. Am J Physiol Cell Physiol 2023; 325:C895-C906. [PMID: 37602412 PMCID: PMC11932532 DOI: 10.1152/ajpcell.00245.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/22/2023]
Abstract
Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and homeostasis. However, dysregulation of these cells leads to fibro-fatty infiltration across various muscle diseases. FAPs are the key source of extracellular matrix (ECM) deposition in muscle, and disruption to this process leads to a pathological accumulation of ECM, known as fibrosis. The replacement of contractile tissue with fibrotic ECM functionally impairs the muscle and increases muscle stiffness. FAPs and fibrotic muscle form a progressively degenerative feedback loop where, as a muscle becomes fibrotic, it induces a fibrotic FAP phenotype leading to further development of fibrosis. In this review, we summarize FAPs' role in fibrosis in terms of their activation, heterogeneity, contributions to fibrotic degeneration, and role across musculoskeletal diseases. We also discuss current research on potential therapeutic avenues to attenuate fibrosis by targeting FAPs.
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Affiliation(s)
- Taryn Loomis
- Biomedical Engineering Graduate Group, University of California, Davis, California, United States
| | - Lucas R Smith
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California, United States
- Department of Physical Medicine and Rehabilitation, University of California, Davis, California, United States
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15
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Liu WJ, Wang L, Zhou FM, Liu SW, Wang W, Zhao EJ, Yao QJ, Li W, Zhao YQ, Shi Z, Qiu JG, Jiang BH. Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC. Drug Resist Updat 2023; 70:100987. [PMID: 37392558 DOI: 10.1016/j.drup.2023.100987] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 06/20/2023] [Accepted: 06/20/2023] [Indexed: 07/03/2023]
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for human non-small-cell lung cancer (NSCLC) treatment. However, acquired resistance to EGFR-TKIs is the major barrier of treatment success, and new resistance mechanism remains to be elucidated. In this study, we found that elevated NADPH oxidase 4 (NOX4) expression was associated with acquired EGFR-TKIs resistance. Gefitinib is the first-generation FDA-approved EGFR-TKI, and osimertinib is the third-generation FDA-approved EGFR-TKI. We demonstrated that NOX4 knockdown in the EGFR-TKI resistant cells enabled the cells to become sensitive to gefitinib and osimertinib treatment, while forced expression of NOX4 in the sensitive parental cells was sufficient to induce resistance to gefitinib and osimertinib in the cells. To elucidate the mechanism of NOX4 upregulation in increasing TKIs resistance, we found that knockdown of NOX4 significantly down-regulated the expression of transcription factor YY1. YY1 bound directly to the promoter region of IL-8 to transcriptionally activate IL-8 expression. Interestingly, knockdown of NOX4 and IL-8 decreased programmed death ligand 1 (PD-L1) expression, which provide new insight on TKIs resistance and immune escape. We found that patients with higher NOX4 and IL-8 expression levels showed a shorter survival time compared to those with lower NOX4 and IL-8 expression levels in response to the anti-PD-L1 therapy. Knockdown of NOX4, YY1 or IL-8 alone inhibited angiogenesis and tumor growth. Furthermore, the combination of NOX4 inhibitor GKT137831 and gefitinib had synergistic effect to inhibit cell proliferation and tumor growth and to increase cellular apoptosis. These findings demonstrated that NOX4 and YY1 were essential for mediating the acquired EGFR-TKIs resistance. IL-8 and PD-L1 are two downstream targets of NOX4 to regulate TKIs resistance and immunotherapy. These molecules may be used as potential new biomarkers and therapeutic targets for overcoming TKIs resistance in the future.
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Affiliation(s)
- Wen-Jing Liu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Lin Wang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Feng-Mei Zhou
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Shu-Wen Liu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Wei Wang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Er-Jiang Zhao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Quan-Jun Yao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Wei Li
- Department of Pathology, Affiliated Drum Tower Hospital Nanjing University Medical School, Nanjing 210000, China
| | - Yan-Qiu Zhao
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China
| | - Zhi Shi
- Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, 510632, China
| | - Jian-Ge Qiu
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China.
| | - Bing-Hua Jiang
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, The Academy of Medical Science, Zhengzhou University, Zhengzhou 450008, China.
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16
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Espinosa-Sotelo R, Fusté NP, Peñuelas-Haro I, Alay A, Pons G, Almodóvar X, Albaladejo J, Sánchez-Vera I, Bonilla-Amadeo R, Dituri F, Serino G, Ramos E, Serrano T, Calvo M, Martínez-Chantar ML, Giannelli G, Bertran E, Fabregat I. Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma. Redox Biol 2023; 65:102818. [PMID: 37463530 PMCID: PMC10372458 DOI: 10.1016/j.redox.2023.102818] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 07/05/2023] [Accepted: 07/12/2023] [Indexed: 07/20/2023] Open
Abstract
The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-β) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-β-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-β. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-β, whereas non-canonical signals, such as the phosphorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-β-mediated inhibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-β in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-β1-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-β that may contribute to tumor progression, we found that NOX4 is also required for TGF-β-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-β-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-β-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-β signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-β pathway.
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Affiliation(s)
- Rut Espinosa-Sotelo
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBEREHD, ISCIII, Spain
| | - Noel P Fusté
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Irene Peñuelas-Haro
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBEREHD, ISCIII, Spain
| | - Ania Alay
- Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Barcelona, Spain; Preclinical and Experimental Research in Thoracic Tumors (PReTT), Oncobell Program, IDIBELL, L'Hospitalet de Llobregat, Spain
| | - Gabriel Pons
- Physiological Sciences Department, University of Barcelona, Oncobell-IDIBELL, Barcelona, Spain
| | - Xènia Almodóvar
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Júlia Albaladejo
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ismael Sánchez-Vera
- Physiological Sciences Department, University of Barcelona, Oncobell-IDIBELL, Barcelona, Spain
| | - Ricard Bonilla-Amadeo
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francesco Dituri
- National Institute of Gastroenterology, IRCCS Saverio De Bellis Research Hospital, Castellana Wrotte, Bari, Italy
| | - Grazia Serino
- National Institute of Gastroenterology, IRCCS Saverio De Bellis Research Hospital, Castellana Wrotte, Bari, Italy
| | - Emilio Ramos
- CIBEREHD, ISCIII, Spain; Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge and Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Teresa Serrano
- CIBEREHD, ISCIII, Spain; Pathological Anatomy Service, University Hospital of Bellvitge and Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mariona Calvo
- Oncología Médica, Institut Català d'Oncologia (ICO-IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
| | - María Luz Martínez-Chantar
- CIBEREHD, ISCIII, Spain; Center for Cooperative Research in Biosciences (CIC BioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Bizkaia, Spain
| | - Gianluigi Giannelli
- National Institute of Gastroenterology, IRCCS Saverio De Bellis Research Hospital, Castellana Wrotte, Bari, Italy
| | - Esther Bertran
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBEREHD, ISCIII, Spain
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBEREHD, ISCIII, Spain.
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17
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Allameh A, Niayesh-Mehr R, Aliarab A, Sebastiani G, Pantopoulos K. Oxidative Stress in Liver Pathophysiology and Disease. Antioxidants (Basel) 2023; 12:1653. [PMID: 37759956 PMCID: PMC10525124 DOI: 10.3390/antiox12091653] [Citation(s) in RCA: 114] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/15/2023] [Accepted: 08/20/2023] [Indexed: 09/29/2023] Open
Abstract
The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the biotransformation of xenobiotics. The disruption of redox balance causes oxidative stress, which affects liver function, modulates inflammatory pathways and contributes to disease. Thus, oxidative stress is implicated in acute liver injury and in the pathogenesis of prevalent infectious or metabolic chronic liver diseases such as viral hepatitis B or C, alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Moreover, oxidative stress plays a crucial role in liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Herein, we provide an overview on the effects of oxidative stress on liver pathophysiology and the mechanisms by which oxidative stress promotes liver disease.
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Affiliation(s)
- Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Reyhaneh Niayesh-Mehr
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Azadeh Aliarab
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran; (A.A.); (R.N.-M.); (A.A.)
| | - Giada Sebastiani
- Chronic Viral Illness Services, McGill University Health Center, Montreal, QC H4A 3J1, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Kostas Pantopoulos
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada
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18
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Morawietz H, Brendel H, Diaba-Nuhoho P, Catar R, Perakakis N, Wolfrum C, Bornstein SR. Cross-Talk of NADPH Oxidases and Inflammation in Obesity. Antioxidants (Basel) 2023; 12:1589. [PMID: 37627585 PMCID: PMC10451527 DOI: 10.3390/antiox12081589] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.
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Affiliation(s)
- Henning Morawietz
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
| | - Heike Brendel
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
| | - Patrick Diaba-Nuhoho
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (H.B.); (P.D.-N.)
- Department of Paediatric and Adolescent Medicine, Paediatric Haematology and Oncology, University Hospital Münster, 48149 Münster, Germany
| | - Rusan Catar
- Department of Nephrology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Nikolaos Perakakis
- Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (N.P.); (S.R.B.)
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
| | - Christian Wolfrum
- Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse, 8603 Schwerzenbach, Switzerland;
| | - Stefan R. Bornstein
- Department of Medicine III, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany; (N.P.); (S.R.B.)
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany
- Diabetes and Nutritional Sciences, King’s College London, Strand, London WC2R 2LS, UK
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19
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Peñuelas‐Haro I, Espinosa‐Sotelo R, Crosas‐Molist E, Herranz‐Itúrbide M, Caballero‐Díaz D, Alay A, Solé X, Ramos E, Serrano T, Martínez‐Chantar ML, Knaus UG, Cuezva JM, Zorzano A, Bertran E, Fabregat I. The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression. Hepatology 2023; 78:416-433. [PMID: 35920301 PMCID: PMC10344438 DOI: 10.1002/hep.32702] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS The NADPH oxidase NOX4 plays a tumor-suppressor function in HCC. Silencing NOX4 confers higher proliferative and migratory capacity to HCC cells and increases their in vivo tumorigenic potential in xenografts in mice. NOX4 gene deletions are frequent in HCC, correlating with higher tumor grade and worse recurrence-free and overall survival rates. However, despite the accumulating evidence of a protective regulatory role in HCC, the cellular processes governed by NOX4 are not yet understood. Accordingly, the aim of this work was to better understand the molecular mechanisms regulated by NOX4 in HCC in order to explain its tumor-suppressor action. APPROACH AND RESULTS Experimental models: cell-based loss or gain of NOX4 function experiments, in vivo hepatocarcinogenesis induced by diethylnitrosamine in Nox4 -deficient mice, and analyses in human HCC samples. Methods include cellular and molecular biology analyses, proteomics, transcriptomics, and metabolomics, as well as histological and immunohistochemical analyses in tissues. Results identified MYC as being negatively regulated by NOX4. MYC mediated mitochondrial dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids, and an overall higher energetic capacity and ATP level. NOX4 deletion induced a redox imbalance that augmented nuclear factor erythroid 2-related factor 2 (Nrf2) activity and was responsible for MYC up-regulation. CONCLUSIONS Loss of NOX4 in HCC tumor cells induces metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression.
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Affiliation(s)
- Irene Peñuelas‐Haro
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
| | - Rut Espinosa‐Sotelo
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
| | - Eva Crosas‐Molist
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Macarena Herranz‐Itúrbide
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
| | - Daniel Caballero‐Díaz
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
| | - Ania Alay
- Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Preclinical and Experimental Research in Thoracic Tumors, Oncobell Program, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Solé
- Unit of Bioinformatics for Precision Oncology, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Preclinical and Experimental Research in Thoracic Tumors, Oncobell Program, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Molecular Biology CORE, Center for Biomedical Diagnostics, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
| | - Emilio Ramos
- CIBEREHD, ISCIII, Madrid, Spain
- Department of Surgery, Liver Transplant Unit, University Hospital of Bellvitge, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Teresa Serrano
- CIBEREHD, ISCIII, Madrid, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
- Pathological Anatomy Service, University Hospital of Bellvitge, Barcelona, Spain
| | - María L. Martínez‐Chantar
- CIBEREHD, ISCIII, Madrid, Spain
- Liver Disease Lab, Center for Cooperative Research in Biosciences, Basque Research and Technology Alliance, Bizkaia Technology Park, Spain
| | - Ulla G. Knaus
- Conway Institute, University College Dublin, Dublin, Ireland
| | - José M. Cuezva
- Center for Molecular Biology “Severo Ochoa,” Autonoma University of Madrid, Madrid, Spain
- CIBERER, ISCIII, Madrid, Spain
| | - Antonio Zorzano
- Biochemistry and Molecular Biomedicine Department, University of Barcelona, Barcelona, Spain
- Institute of Research in Biomedicine, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- CIBERDEM, ISCIII, Madrid, Spain
| | - Esther Bertran
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
| | - Isabel Fabregat
- TGF‐β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain
- CIBEREHD, ISCIII, Madrid, Spain
- Physiological Sciences Department, University of Barcelona, Barcelona, Spain
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20
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Salminen A. The plasticity of fibroblasts: A forgotten player in the aging process. Ageing Res Rev 2023; 89:101995. [PMID: 37391015 DOI: 10.1016/j.arr.2023.101995] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/15/2023] [Accepted: 06/26/2023] [Indexed: 07/02/2023]
Abstract
Tissue-resident fibroblasts are mesenchymal cells which possess an impressive plasticity in their ability to modify their properties according to the requirements of the microenvironment. There are diverse subgroups of fibroblast phenotypes associated with different tissue pathological conditions, e.g., cancers, wound healing, and many fibrotic and inflammatory conditions. The heterogeneous phenotypes can be subdivided into fibrogenic and non-fibrogenic, inflammatory and immunosuppressive subtypes as well as cellular senescent subsets. A major hallmark of activated fibroblasts is that they contain different amounts of stress fibers combined with α-smooth muscle actin (α-SMA) protein, i.e., commonly this phenotype has been called the myofibroblast. Interestingly, several stresses associated with the aging process are potent inducers of myofibroblast differentiation, e.g., oxidative and endoplasmic reticulum stresses, extracellular matrix (ECM) disorders, inflammatory mediators, and telomere shortening. Accordingly, anti-aging treatments with metformin and rapamycin inhibited the differentiation of myofibroblasts in tissues. There is evidence that the senescent phenotype induced in cultured fibroblasts does not represent the phenotype of fibroblasts in aged tissues. Considering the versatile plasticity of fibroblasts as well as their frequency and structural importance in tissues, it does seem that fibroblasts are overlooked players in the aging process.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
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21
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Sohal A, Kowdley KV. Primary Biliary Cholangitis: Promising Emerging Innovative Therapies and Their Impact on GLOBE Scores. Hepat Med 2023; 15:63-77. [PMID: 37312929 PMCID: PMC10259525 DOI: 10.2147/hmer.s361077] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.
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Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA
- Department of Gastroenterology and Hepatology, Elson Floyd College of Medicine, Spokane, WA, USA
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22
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Lamanilao GG, Dogan M, Patel PS, Azim S, Patel DS, Bhattacharya SK, Eason JD, Kuscu C, Kuscu C, Bajwa A. Key hepatoprotective roles of mitochondria in liver regeneration. Am J Physiol Gastrointest Liver Physiol 2023; 324:G207-G218. [PMID: 36648139 PMCID: PMC9988520 DOI: 10.1152/ajpgi.00220.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/28/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023]
Abstract
Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating their crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet massive metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions. Mitochondria are also involved in terminating the regenerative process by mediating apoptosis. Studies have shown that attenuation of mitochondrial activity results in delayed liver regeneration, and liver failure following resection is associated with mitochondrial dysfunction. Emerging mitochondria therapy (i.e., mitotherapy) strategies involve isolating healthy donor mitochondria for transplantation into diseased organs to promote regeneration. This review highlights mitochondria's inherent role in liver regeneration.
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Affiliation(s)
- Gene G Lamanilao
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Murat Dogan
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Prisha S Patel
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Shafquat Azim
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Disha S Patel
- Department of Legal Studies, Belmont University, Nashville, Tennessee, United States
| | - Syamal K Bhattacharya
- Division of Cardiovascular Diseases, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - James D Eason
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Canan Kuscu
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Cem Kuscu
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Amandeep Bajwa
- Department of Surgery, Transplant Research Institute, James D. Eason Transplant Institute, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Department of Genetics, Genomics, and Informatics, The University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee, United States
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
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23
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NOX as a Therapeutic Target in Liver Disease. Antioxidants (Basel) 2022; 11:antiox11102038. [PMID: 36290761 PMCID: PMC9598239 DOI: 10.3390/antiox11102038] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022] Open
Abstract
The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease's progression.
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24
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Chan MKK, Chung JYF, Tang PCT, Chan ASW, Ho JYY, Lin TPT, Chen J, Leung KT, To KF, Lan HY, Tang PMK. TGF-β signaling networks in the tumor microenvironment. Cancer Lett 2022; 550:215925. [DOI: 10.1016/j.canlet.2022.215925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 09/05/2022] [Accepted: 09/17/2022] [Indexed: 11/02/2022]
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25
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Nascè A, Gariani K, Jornayvaz FR, Szanto I. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook. Antioxidants (Basel) 2022; 11:antiox11061131. [PMID: 35740032 PMCID: PMC9219746 DOI: 10.3390/antiox11061131] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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Affiliation(s)
- Alberto Nascè
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
| | - Ildiko Szanto
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
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26
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Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis. Nat Commun 2022; 13:3275. [PMID: 35672400 PMCID: PMC9174232 DOI: 10.1038/s41467-022-30630-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 05/03/2022] [Indexed: 01/07/2023] Open
Abstract
Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure. Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.
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27
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Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib. Cell Death Dis 2022; 8:177. [PMID: 35396551 PMCID: PMC8990679 DOI: 10.1038/s41420-022-00994-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/19/2022] [Accepted: 03/24/2022] [Indexed: 12/02/2022]
Abstract
Advanced differentiated thyroid cancer cells are subjected to extreme nutritional starvation which contributes to develop resistance to treatments; however, the underlying mechanism remains unclear. Cells were subjected to serum deprivation by culture in medium containing 0.5% fetal bovine serum. A CCK8 assay, cell death Detection ELISAPLUS kit, and PI staining were conducted to determine cell viability, cell apoptosis, and cell cycle, respectively. NADPH oxidase 4 (NOX4) knockdown–stable cell lines were generated by lentivirus-mediated shRNA knockdown in BCPAP cells and TPC-1 cells. Etoposide and doxorubicin, two chemotherapeutic drugs, as well as lenvatinib were utilized to determine the effect of NOX4 on drug resistance. Lenvatinib-resistant BCPAP cells (LRBCs) were established to confirm this effect. The underlining mechanisms of NOX4 under starvation were explored using western blot. Finally, GLX351322, an inhibitor targeting NOX4, was used to inhibit NOX4-derived ROS in vitro and detect its effect on drug resistance of tumor cells in vivo. NOX4 is overexpressed under serum deprivation in BCPAP or TPC-1 cells. NOX4 knockdown impairs cell viability, increases cell apoptosis, extends G1 phase during cell cycle and modulates the level of energy-associated metabolites in starved cells. When the starved cells or LRBCs are treated with chemotherapeutic drugs or Lenvatinib, NOX4 knockdown inhibits cell viability and aggravates cell apoptosis depending on NOX4-derived ROS production. Mechanistically, starvation activates TGFβ1/SMAD3 signal, which mediates NOX4 upregulation. The upregulated NOX4 then triggers ERKs and PI3K/AKT pathway to influence cell apoptosis. GLX351322, a NOX4-derived ROS inhibitor, has an inhibitory effect on cell growth in vitro and the growth of BCPAP-derived even LRBCs-derived xenografts in vivo. These findings highlight NOX4 and NOX4-derived ROS as a potential therapeutic target in resistance to PTC.
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28
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Mogadem A, Naqvi A, Almamary MA, Ahmad WA, Jemon K, El-Alfy SH. Hepatoprotective effects of flexirubin, a novel pigment from Chryseobacterium artocarpi, against carbon tetrachloride-induced liver injury: An in vivo study and molecular modeling. Toxicol Appl Pharmacol 2022; 444:116022. [PMID: 35436475 DOI: 10.1016/j.taap.2022.116022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 04/02/2022] [Accepted: 04/09/2022] [Indexed: 12/31/2022]
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29
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Liu H, Chen YG. The Interplay Between TGF-β Signaling and Cell Metabolism. Front Cell Dev Biol 2022; 10:846723. [PMID: 35359452 PMCID: PMC8961331 DOI: 10.3389/fcell.2022.846723] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/14/2022] [Indexed: 12/15/2022] Open
Abstract
The transforming growth factor-β (TGF-β) signaling plays a critical role in the development and tissue homeostasis in metazoans, and deregulation of TGF-β signaling leads to many pathological conditions. Mounting evidence suggests that TGF-β signaling can actively alter metabolism in diverse cell types. Furthermore, metabolic pathways, beyond simply regarded as biochemical reactions, are closely intertwined with signal transduction. Here, we discuss the role of TGF-β in glucose, lipid, amino acid, redox and polyamine metabolism with an emphasis on how TGF-β can act as a metabolic modulator and how metabolic changes can influence TGF-β signaling. We also describe how interplay between TGF-β signaling and cell metabolism regulates cellular homeostasis as well as the progression of multiple diseases, including cancer.
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30
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Szanto I. NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation. Int J Mol Sci 2022; 23:ijms23052702. [PMID: 35269843 PMCID: PMC8910662 DOI: 10.3390/ijms23052702] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 02/21/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023] Open
Abstract
Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
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Affiliation(s)
- Ildiko Szanto
- Service of Endocrinology, Diabetology, Nutrition and Patient Education, Department of Internal Medicine, Geneva University Hospitals, Diabetes Center of the Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
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31
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García-Gómez P, Golán I, Dadras MS, Mezheyeuski A, Bellomo C, Tzavlaki K, Morén A, Carreras-Puigvert J, Caja L. NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells. Mol Oncol 2022; 16:1891-1912. [PMID: 35203105 PMCID: PMC9067149 DOI: 10.1002/1878-0261.13200] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 01/19/2022] [Accepted: 02/21/2022] [Indexed: 12/04/2022] Open
Abstract
Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
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Affiliation(s)
- Pedro García-Gómez
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden.,Brain Metastasis Group, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain
| | - Irene Golán
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden
| | - Mahsa S Dadras
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden.,Weill Cornell Medical College Brain and Mind Research Institute, New York, NY, USA, 10021-5608
| | - Artur Mezheyeuski
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, SE-75185, Uppsala, Sweden
| | - Claudia Bellomo
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden
| | - Kalliopi Tzavlaki
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden
| | - Anita Morén
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden
| | - Jordi Carreras-Puigvert
- Department of Pharmaceutical Biosciences, Box 591, Biomedical Center, Uppsala University, SE-75123, Uppsala, Sweden
| | - Laia Caja
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden. Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden
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The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14040940. [PMID: 35205692 PMCID: PMC8870127 DOI: 10.3390/cancers14040940] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the therapeutic implications. Abstract Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.
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Chung J, Huda MN, Shin Y, Han S, Akter S, Kang I, Ha J, Choe W, Choi TG, Kim SS. Correlation between Oxidative Stress and Transforming Growth Factor-Beta in Cancers. Int J Mol Sci 2021; 22:ijms222413181. [PMID: 34947978 PMCID: PMC8707703 DOI: 10.3390/ijms222413181] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/30/2021] [Accepted: 12/04/2021] [Indexed: 12/14/2022] Open
Abstract
The downregulation of reactive oxygen species (ROS) facilitates precancerous tumor development, even though increasing the level of ROS can promote metastasis. The transforming growth factor-beta (TGF-β) signaling pathway plays an anti-tumorigenic role in the initial stages of cancer development but a pro-tumorigenic role in later stages that fosters cancer metastasis. TGF-β can regulate the production of ROS unambiguously or downregulate antioxidant systems. ROS can influence TGF-β signaling by enhancing its expression and activation. Thus, TGF-β signaling and ROS might significantly coordinate cellular processes that cancer cells employ to expedite their malignancy. In cancer cells, interplay between oxidative stress and TGF-β is critical for tumorigenesis and cancer progression. Thus, both TGF-β and ROS can develop a robust relationship in cancer cells to augment their malignancy. This review focuses on the appropriate interpretation of this crosstalk between TGF-β and oxidative stress in cancer, exposing new potential approaches in cancer biology.
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Affiliation(s)
- Jinwook Chung
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
| | - Md Nazmul Huda
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biochemistry and Molecular Biology, UAMS Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences UAMS, Little Rock, AR 72205, USA
| | - Yoonhwa Shin
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Sunhee Han
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Salima Akter
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
| | - Insug Kang
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Joohun Ha
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Wonchae Choe
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
| | - Tae Gyu Choi
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Correspondence: (T.G.C.); (S.S.K.); Tel.: +82-2-961-0287 (T.G.C.); +82-2-961-0524 (S.S.K.)
| | - Sung Soo Kim
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea; (J.C.); (M.N.H.); (Y.S.); (S.H.); (I.K.); (J.H.); (W.C.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea;
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
- Correspondence: (T.G.C.); (S.S.K.); Tel.: +82-2-961-0287 (T.G.C.); +82-2-961-0524 (S.S.K.)
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Yazaki K, Matsuno Y, Yoshida K, Sherpa M, Nakajima M, Matsuyama M, Kiwamoto T, Morishima Y, Ishii Y, Hizawa N. ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling. Eur J Cell Biol 2021; 100:151181. [PMID: 34763128 DOI: 10.1016/j.ejcb.2021.151181] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/05/2021] [Accepted: 11/02/2021] [Indexed: 01/06/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-β1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-β1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-β1-induced Notch signaling activation and EMT development. TGF-β1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-β1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-β1-induced EMT through the activation of Notch signaling.
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Affiliation(s)
- Kai Yazaki
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yosuke Matsuno
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
| | - Kazufumi Yoshida
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Mingma Sherpa
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masayuki Nakajima
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Masashi Matsuyama
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Takumi Kiwamoto
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuko Morishima
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yukio Ishii
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Nobuyuki Hizawa
- Department of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
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Zhu W, Zhang X, Yu M, Lin B, Yu C. Radiation-induced liver injury and hepatocyte senescence. Cell Death Discov 2021; 7:244. [PMID: 34531376 PMCID: PMC8446062 DOI: 10.1038/s41420-021-00634-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/06/2021] [Accepted: 08/26/2021] [Indexed: 12/14/2022] Open
Abstract
Radiation-induced liver injury (RILI) is a major complication of radiotherapy during treatment for liver cancer and other upper abdominal malignant tumors that has poor pharmacological therapeutic options. A series of pathological changes can be induced by radiation. However, the underlying mechanism of RILI remains unclear. Radiation can induce cell damage via direct energy deposition or reactive free radical generation. Cellular senescence can be observed due to the DNA damage response (DDR) caused by radiation. The senescence-associated secretory phenotype (SASP) secreted from senescent cells can cause chronic inflammation and aggravate liver dysfunction for a long time. Oxidative stress further activates the signaling pathway of the inflammatory response and affects cellular metabolism. miRNAs clearly have differential expression after radiation treatment and take part in RILI development. This review aims to systematically profile the overall mechanism of RILI and the effects of radiation on hepatocyte senescence, laying foundations for the development of new therapies.
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Affiliation(s)
- Wei Zhu
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaofen Zhang
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mengli Yu
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bingru Lin
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Herranz-Itúrbide M, Peñuelas-Haro I, Espinosa-Sotelo R, Bertran E, Fabregat I. The TGF-β/NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease. Cells 2021; 10:cells10092312. [PMID: 34571961 PMCID: PMC8470857 DOI: 10.3390/cells10092312] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 12/28/2022] Open
Abstract
The Transforming Growth Factor-beta (TGF-β) pathway plays essential roles in liver development and homeostasis and become a relevant factor involved in different liver pathologies, particularly fibrosis and cancer. The family of NADPH oxidases (NOXs) has emerged in recent years as targets of the TGF-β pathway mediating many of its effects on hepatocytes, stellate cells and macrophages. This review focuses on how the axis TGF-β/NOXs may regulate the biology of different liver cells and how this influences physiological situations, such as liver regeneration, and pathological circumstances, such as liver fibrosis and cancer. Finally, we discuss whether NOX inhibitors may be considered as potential therapeutic tools in liver diseases.
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Affiliation(s)
- Macarena Herranz-Itúrbide
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.)
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Irene Peñuelas-Haro
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.)
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Rut Espinosa-Sotelo
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.)
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Esther Bertran
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.)
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.H.-I.); (I.P.-H.); (R.E.-S.); (E.B.)
- Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08907 Barcelona, Spain
- Correspondence: ; Tel.: +34-932-607-828
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Gibson R, Dalvi SP, Dalvi PS. DJ-1 and Parkinson's disease. BRAIN DISORDERS 2021. [DOI: 10.1016/j.dscb.2021.100020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Ko YH, Jeong M, Jang DS, Choi JH. Gomisin L1, a Lignan Isolated from Schisandra Berries, Induces Apoptosis by Regulating NADPH Oxidase in Human Ovarian Cancer Cells. Life (Basel) 2021; 11:life11080858. [PMID: 34440602 PMCID: PMC8398161 DOI: 10.3390/life11080858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 01/06/2023] Open
Abstract
The fruits of Schisandra chinensis (Schisandra berries) are used as health food supplements and popular food ingredients in East Asia. Lignans, major and characteristic polyphenol compounds of Schisandra berries, possess various biological activities, including hepatoprotective and anticancer effects. However, the biological activities of gomisin L1, a lignan isolated from Schisandra berries, are less to be investigated. In this study, the antitumor activity of gomisin L1 and its underlying molecular mechanism in human ovarian cancer cells were investigated. Gomisin L1 exhibited potent cytotoxic activity against A2780 and SKOV3 ovarian cancer cells. Flow cytometry analysis revealed that the growth inhibitory effects of gomisin L1 were mediated by the induction of apoptosis. Furthermore, gomisin L1 induced an increase in intracellular reactive oxygen species (ROS) levels, and the antioxidant N-acetyl cysteine significantly negated gomisin L1-induced cell death. Moreover, inhibition of NADPH oxidase (NOX) using an inhibitor and siRNA attenuated gomisin L1-induced death of, and ROS production in, human ovarian cancer cells. Taken together, these data indicate that the lignan gomisin L1 from Schisandra berries induces apoptotic cell death by regulating intracellular ROS production via NOX.
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Affiliation(s)
- Young Hyun Ko
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea; (Y.H.K.); (M.J.)
| | - Miran Jeong
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea; (Y.H.K.); (M.J.)
| | - Dae Sik Jang
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Korea;
| | - Jung-Hye Choi
- Division of Molecular Biology, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea; (Y.H.K.); (M.J.)
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Korea;
- Correspondence:
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The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
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40
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Transforming Growth Factor- β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation. Cancers (Basel) 2021; 13:cancers13123093. [PMID: 34205678 PMCID: PMC8235010 DOI: 10.3390/cancers13123093] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/12/2021] [Accepted: 06/17/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Metabolic changes in tumor microenvironment play a critical role in cancer, related to the accumulated alterations in signaling pathways that control cellular metabolism. Cancer metabolic deregulation is related to specific events such as the control of oxidative stress, and in particular the redox imbalance with aberrant oxidant production and/or a deregulation of the efficacy of the antioxidant systems. In cancer cells, different cytokines are involved in the development and/or progression of cancer; among these cytokines, the transforming growth factor β (TGF-β) is central to tumorigenesis and cancer progression. In tumor cells, it has been demonstrated that there is a close correlation between oxidative stress and TGF-β; this crosstalk strongly contributes to tumorigenesis, both in tumor development and in mediating its invasiveness. This review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in an attempt to improve the pharmacological and therapeutic approach against cancer. Abstract Cancer metabolism involves different changes at a cellular level, and altered metabolic pathways have been demonstrated to be heavily involved in tumorigenesis and invasiveness. A crucial role for oxidative stress in cancer initiation and progression has been demonstrated; redox imbalance, due to aberrant reactive oxygen species (ROS) production or deregulated efficacy of antioxidant systems (superoxide dismutase, catalase, GSH), contributes to tumor initiation and progression of several types of cancer. ROS may modulate cancer cell metabolism by acting as secondary messengers in the signaling pathways (NF-kB, HIF-1α) involved in cellular proliferation and metastasis. It is known that ROS mediate many of the effects of transforming growth factor β (TGF-β), a key cytokine central in tumorigenesis and cancer progression, which in turn can modulate ROS production and the related antioxidant system activity. Thus, ROS synergize with TGF-β in cancer cell metabolism by increasing the redox imbalance in cancer cells and by inducing the epithelial mesenchymal transition (EMT), a crucial event associated with tumor invasiveness and metastases. Taken as a whole, this review is addressed to better understanding this crosstalk between TGF-β and oxidative stress in cancer cell metabolism, in the attempt to improve the pharmacological and therapeutic approach against cancer.
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The Role of Oxidative Stress in NAFLD-NASH-HCC Transition-Focus on NADPH Oxidases. Biomedicines 2021; 9:biomedicines9060687. [PMID: 34204571 PMCID: PMC8235710 DOI: 10.3390/biomedicines9060687] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.
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Tokuc EO, Yuksel N, Rencber SF, Ozturk A, Duruksu G, Yazir Y, Ergun RE. Protective effects of citicoline-containing eye drops against UVB-Induced corneal oxidative damage in a rat model. Exp Eye Res 2021; 208:108612. [PMID: 33992625 DOI: 10.1016/j.exer.2021.108612] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 04/04/2021] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Abstract
It has been reported that citicoline increases antioxidant activity in some tissues. However, the effect of citicoline on corneal wound-healing has not yet been demonstrated. The aim was to investigate the protective effects of citicoline on ultraviolet B (UVB) radiation-induced corneal oxidative damage in a rat model. Four groups (eight animals each) were investigated: controls; UVB only; UVB/citicoline; and citicoline only. Corneal oxidative damage was induced by exposure to UVB radiation at 560 μW/cm2 for five days in the UVB-exposed groups and 1% citicoline eye drops were applied (3xday) for eight days in the two citicoline groups. Corneal surface damage was evaluated by opacity and fluorescein staining. Corneal injury was assessed biochemically by measuring the concentrations of glutathione (GSH) and malondialdehyde (MDA) and the activity of corneal superoxide dismutase (SOD) and catalase. Matrix metalloproteinase (MMP) -2 and -9 and caspase-3 were evaluated by immunofluorescent staining and microscopic examination and by Western blot analysis. Corneal gene expression analysis was performed for vascular endothelial growth factor (VEGF), interleukin-1 beta (IL-1β) and transforming growth factor-beta (TGF-β). UVB radiation caused significant epithelial damage and evident opacity in the cornea, together with a local decrease in SOD, catalase and GSH activity. Corneal MDA concentrations increased with UVB exposure. The UVB/Citicoline group had significantly less corneal damage, greater SOD, catalase and GSH activity, and decreased MDA concentrations compared to the UVB only group (p < 0.05). Expression of TGF-β, IL-1β and VEGF was significantly lower in the citicoline/UVB group compared to the UVB group (p < 0.05). Interestingly, TGF-β expression was lower in the citicoline only group compared with controls. Immunfluorescent staining and Western blot analysis showed increased MMP-2, -9 and caspase-3 in the UVB only group compared with the UVB/citicoline group. It was shown that citicoline treatment may be effective in suppressing oxidative stress and controlling inflammation in UVB corneal injury.
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Affiliation(s)
- Ecem Onder Tokuc
- Derince Training and Research Hospital, Department of Ophthalmology, Kocaeli, Turkey.
| | - Nursen Yuksel
- Kocaeli University School of Medicine, Department of Ophthalmology, Kocaeli, Turkey
| | - Selenay Furat Rencber
- Kocaeli University School of Medicine, Department of Histology and Embryology, Kocaeli, Turkey
| | - Ahmet Ozturk
- Kocaeli University, Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli, Turkey
| | - Gokhan Duruksu
- Kocaeli University, Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli, Turkey
| | - Yusufhan Yazir
- Kocaeli University School of Medicine, Department of Histology and Embryology, Kocaeli, Turkey; Kocaeli University, Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli, Turkey
| | - Rıza Emre Ergun
- Kocaeli University, Ford Otosan Ihsaniye Automotive Vocational School, Department of Motor Vehicles and Transportation Technologies, Kocaeli, Turkey
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Hakami NY, Dusting GJ, Chan EC, Shah MH, Peshavariya HM. Wound Healing After Alkali Burn Injury of the Cornea Involves Nox4-Type NADPH Oxidase. Invest Ophthalmol Vis Sci 2021; 61:20. [PMID: 33079994 PMCID: PMC7585390 DOI: 10.1167/iovs.61.12.20] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Purpose Corneal injury that occurs after burning with alkali initiates wound-healing processes, including inflammation, neovascularization, and fibrosis. Excessive reactions to injury can reduce corneal transparency and thereby compromise vision. The NADPH oxidase (Nox) enzyme complex is known to be involved in cell signaling for wound-healing angiogenesis, but its role in corneal neovascularization has been little studied. Methods The center corneas of wild-type and Nox4 knockout (KO) mice were injured with 3 µL 1 M NaOH, while the contralateral corneas remained untouched. On day 7, mRNA expression levels of NADPH oxidase isoforms, the proangiogenic factors VEGF-A and TGFβ1, and proinflammatory genes ICAM-1 and VCAM-1 were determined. Corneal neovascularization and fibrosis were visualized using PECAM-1 antibody and picrosirius red staining, respectively, on the same day. Results Expressions of both Nox2 and Nox4 gene isoforms as well as the above genes were markedly increased in the injured corneas at 7 days. Injured corneas showed neovascularization and fibrosis as well as an increase in clinical opacity score. All responses stimulated by alkali burn were abrogated in Nox4 KO mice. Conclusions Nox4 could be a new target to treat pathologic corneal wound-healing responses and such targeting might prevent blindness caused by burn injuries.
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Affiliation(s)
- Nora Y Hakami
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia.,Faculty of Applied Medical Sciences, King Abdul Aziz University, Jeddah, Saudi Arabia
| | - Gregory J Dusting
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
| | - Elsa C Chan
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
| | - Manisha H Shah
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
| | - Hitesh M Peshavariya
- Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia
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Dasgupta A, Shukla SK, Vernucci E, King RJ, Abrego J, Mulder SE, Mullen NJ, Graves G, Buettner K, Thakur R, Murthy D, Attri KS, Wang D, Chaika NV, Pacheco CG, Rai I, Engle DD, Grandgenett PM, Punsoni M, Reames BN, Teoh-Fitzgerald M, Oberley-Deegan R, Yu F, Klute KA, Hollingsworth MA, Zimmerman MC, Mehla K, Sadoshima J, Tuveson DA, Singh PK. SIRT1-NOX4 signaling axis regulates cancer cachexia. J Exp Med 2021; 217:151806. [PMID: 32441762 PMCID: PMC7336299 DOI: 10.1084/jem.20190745] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 01/31/2020] [Accepted: 04/08/2020] [Indexed: 12/21/2022] Open
Abstract
Approximately one third of cancer patients die due to complexities related to cachexia. However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell–induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell–mediated SIRT1 loss induced NF-κB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1–Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer–induced cachexia.
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Affiliation(s)
- Aneesha Dasgupta
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
| | - Surendra K Shukla
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Enza Vernucci
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Ryan J King
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Jaime Abrego
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Scott E Mulder
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
| | - Nicholas J Mullen
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Gavin Graves
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Kyla Buettner
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Ravi Thakur
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Divya Murthy
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Kuldeep S Attri
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Dezhen Wang
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Nina V Chaika
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Camila G Pacheco
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Ibha Rai
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Dannielle D Engle
- Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Paul M Grandgenett
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Michael Punsoni
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Bradley N Reames
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE
| | - Melissa Teoh-Fitzgerald
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
| | - Rebecca Oberley-Deegan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
| | - Fang Yu
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE
| | - Kelsey A Klute
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Michael A Hollingsworth
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Matthew C Zimmerman
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE
| | - Kamiya Mehla
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, Newark, NJ
| | - David A Tuveson
- Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Pankaj K Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE.,The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.,Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
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Decitabine Downregulates TIGAR to Induce Apoptosis and Autophagy in Myeloid Leukemia Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8877460. [PMID: 33532040 PMCID: PMC7836025 DOI: 10.1155/2021/8877460] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/20/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022]
Abstract
Decitabine (DAC) is a well-known DNA methyltransferase inhibitor, which has been widely used for the treatment of acute myeloid leukemia (AML). However, in addition to hypomethylation, DAC in AML is also involved in cell metabolism, apoptosis, and immunity. The TP53-induced glycolysis and apoptosis regulator (TIGAR) functions to inhabit glycolysis and protect cancer cells from reactive oxygen species- (ROS-) associated apoptosis. Our previous study revealed that TIGAR is highly expressed in myeloid leukemia cell lines and AML primary cells and associated with poor prognosis in adult patients with cytogenetically normal AML. In the present study, it was found that in a time- and concentration-dependent manner, DAC downregulates the TIGAR expression, induces ROS production, and promotes apoptosis in HL-60 and K562 cells. However, blocking the glycolytic pathway partially reversed the combined effects of DAC and TIGAR knockdown on apoptosis, ROS production, and cell cycle arrest, indicating that DAC induced apoptosis through the glycolytic pathway. Furthermore, TIGAR also has a negative impact on autophagy, while DAC treatment upregulates autophagy-related proteins LC3, Beclin-1, ATG3, and ATG-5, downregulates p62, and promotes the formation of autophagosomes, indicating that DAC may activate autophagy by downregulating TIGAR. Taken together, DAC plays an unmethylated role in inducing apoptosis and activating autophagy in myeloid leukemia by downregulating TIGAR.
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Herranz-Itúrbide M, López-Luque J, Gonzalez-Sanchez E, Caballero-Díaz D, Crosas-Molist E, Martín-Mur B, Gut M, Esteve-Codina A, Jaquet V, Jiang JX, Török NJ, Fabregat I. NADPH oxidase 4 (Nox4) deletion accelerates liver regeneration in mice. Redox Biol 2020; 40:101841. [PMID: 33493901 PMCID: PMC7823210 DOI: 10.1016/j.redox.2020.101841] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 12/21/2022] Open
Abstract
Liver is a unique organ in displaying a reparative and regenerative response after acute/chronic damage or partial hepatectomy, when all the cell types must proliferate to re-establish the liver mass. The NADPH oxidase NOX4 mediates Transforming Growth Factor-beta (TGF-β) actions, including apoptosis in hepatocytes and activation of stellate cells to myofibroblasts. Aim of this work was to analyze the impact of NOX4 in liver regeneration by using two mouse models where Nox4 was deleted: 1) general deletion of Nox4 (NOX4-/-) and 2) hepatocyte-specific deletion of Nox4 (NOX4hepKO). Liver regeneration was analyzed after 2/3 partial hepatectomy (PH). Results indicated an earlier recovery of the liver-to-body weight ratio in both NOX4-/- and NOX4hepKO mice and an increased survival, when compared to corresponding WT mice. The regenerative hepatocellular fat accumulation and the parenchyma organization recovered faster in NOX4 deleted livers. Hepatocyte proliferation, analyzed by Ki67 and phospho-Histone3 immunohistochemistry, was accelerated and increased in NOX4 deleted mice, coincident with an earlier and increased Myc expression. Primary hepatocytes isolated from NOX4 deleted mice showed higher proliferative capacity and increased expression of Myc and different cyclins in response to serum. Transcriptomic analysis through RNA-seq revealed significant changes after PH in NOX4-/- mice and support a relevant role for Myc in a node of regulation of proliferation-related genes. Interestingly, RNA-seq also revealed changes in the expression of genes related to activation of the TGF-β pathway. In fact, levels of active TGF-β1, phosphorylation of Smads and levels of its target p21 were lower at 24 h in NOX4 deleted mice. Nox4 did not appear to be essential for the termination of liver regeneration in vivo, neither for the in vitro hepatocyte response to TGF-β1 in terms of growth inhibition, which suggest its potential as therapeutic target to improve liver regeneration, without adverse effects.
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Affiliation(s)
- M Herranz-Itúrbide
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - J López-Luque
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - E Gonzalez-Sanchez
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain
| | - D Caballero-Díaz
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain
| | - E Crosas-Molist
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - B Martín-Mur
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - M Gut
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain
| | - A Esteve-Codina
- CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain
| | - V Jaquet
- Department of Pathology and Immunology, Medical School, University of Geneva, Geneva, Switzerland; RE.A.D.S Unit, Medical School, University of Geneva, Geneva, Switzerland
| | - J X Jiang
- Gastroenterology and Hepatology, UC Davis, Sacramento, CA, USA
| | - N J Török
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - I Fabregat
- TGF-β and Cancer Group. Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain.
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Hwang CY, Han YH, Lee SM, Cho SM, Yu DY, Kwon KS. Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression. Ann Geriatr Med Res 2020; 24:297-304. [PMID: 33227845 PMCID: PMC7781962 DOI: 10.4235/agmr.20.0051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/21/2020] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5' AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. METHODS Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20°C-22°C and 50%-60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other. RESULTS The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated β-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 (NOX4) and transforming growth factor (TGF)-β were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-β inhibitor SB431542 restored cell growth inhibited by Sesn2-KO. CONCLUSION Sesn2 attenuates cellular senescence via suppression of TGF-β- and NOX4-induced reactive oxygen species generation and subsequent inhibition of AMPK.
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Affiliation(s)
- Chae Young Hwang
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Ying-Hao Han
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Seung-Min Lee
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Sang-Mi Cho
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Dae-Yeul Yu
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.,GHBIO Inc., Daejeon, Korea
| | - Ki-Sun Kwon
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.,Aventi Inc., Daejeon, Korea
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Chakraborti S, Pramanick A, Saha S, Sarkar S, Singh LP, Stewart A, Maity B. Biphasic changes in TGF-β1 signaling drive NSAID-induced multi-organ damage. Free Radic Biol Med 2020; 160:125-140. [PMID: 32750407 DOI: 10.1016/j.freeradbiomed.2020.06.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 06/04/2020] [Accepted: 06/18/2020] [Indexed: 12/15/2022]
Abstract
The clinical utility of non-steroidal anti-inflammatory drugs (NSAIDs), used extensively worldwide, is limited by adverse cardiac events resulting from chronic drug exposure. Here, we provide evidence identifying transforming growth factor β (TGF-β1), released from multiple tissues, as a critical driver of NSAID-induced multi-organ damage. Biphasic changes in TGF-β1 levels in liver and heart were accompanied by ROS generation, cell death, fibrotic remodeling, compromised cardiac contractility and elevated liver enzymes. Pharmacological inhibition of TGF-βRI signaling markedly improved heart and liver function and increased overall survival of animals exposed to multiple NSAIDs, effects likely mediated by reductions in NOX-dependent ROS generation. Notably, the beneficial impact of TGF-βRI blockade was confined to a critical window wherein consecutive, but not concurrent, inhibitor administration improved cardiac and hepatic endpoints. Remarkably, in addition to ameliorating indomethacin-mediated myofilament disruptions, cardiac TGF-βRI knockdown lead to drastic reductions in TGF-β1 production accompanied by lessening in intestinal lesioning underscoring the importance of endocrine TGF-β1 signaling in NSAID-driven tissue injury. Indeed, gastric ulceration was associated with a higher incidence of cardiac complications in a human cohort underscoring the critical importance of circulation-facilitated peripheral organ system interconnectedness in efforts seeking to mitigate the toxic side effects of chronic NSAID use.
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Affiliation(s)
- Sreemoyee Chakraborti
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Arnab Pramanick
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India
| | - Sudipta Saha
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, Uttar Pradesh, 226025, India
| | - Subhasish Sarkar
- Department of Surgery, College of Medicine and Sagore Dutta Hospital, B.T. Road, Kamarhati, Kolkata, West Bengal, 700058, India
| | | | - Adele Stewart
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA.
| | - Biswanath Maity
- Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India.
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Zhang K, Zhang M, Luo Z, Wen Z, Yan X. The dichotomous role of TGF-β in controlling liver cancer cell survival and proliferation. J Genet Genomics 2020; 47:497-512. [PMID: 33339765 DOI: 10.1016/j.jgg.2020.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 09/14/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is the major form of primary liver cancer and one of the most prevalent and life-threatening malignancies globally. One of the hallmarks in HCC is the sustained cell survival and proliferative signals, which are determined by the balance between oncogenes and tumor suppressors. Transforming growth factor beta (TGF-β) is an effective growth inhibitor of epithelial cells including hepatocytes, through induction of cell cycle arrest, apoptosis, cellular senescence, or autophagy. The antitumorigenic effects of TGF-β are bypassed during liver tumorigenesis via multiple mechanisms. Furthermore, along with malignant progression, TGF-β switches to promote cancer cell survival and proliferation. This dichotomous nature of TGF-β is one of the barriers to therapeutic targeting in liver cancer. Thereafter, understanding the underlying molecular mechanisms is a prerequisite for discovering novel antitumor drugs that may specifically disable the growth-promoting branch of TGF-β signaling or restore its tumor-suppressive arm. This review summarizes how TGF-β inhibits or promotes liver cancer cell survival and proliferation, highlighting the functional switch mechanisms during the process.
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Affiliation(s)
- Kegui Zhang
- School of Biological Engineering, Huainan Normal University, Huainan, 232001, China
| | - Meiping Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China
| | - Zhijun Luo
- School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Zhili Wen
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Xiaohua Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China; Institute of Biomedical Sciences, Nanchang University Medical College, Nanchang, 330031, China.
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Pan MS, Wang H, Ansari KH, Li XP, Sun W, Fan YZ. Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:234. [PMID: 33153467 PMCID: PMC7643415 DOI: 10.1186/s13046-020-01742-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/18/2020] [Indexed: 01/17/2023]
Abstract
Background Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism. Methods A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (−) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway. Conclusions GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.
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Affiliation(s)
- Mu-Su Pan
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, P.R. China
| | - Hui Wang
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, P.R. China
| | - Kamar Hasan Ansari
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, P.R. China
| | - Xin-Ping Li
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, P.R. China
| | - Wei Sun
- Department of Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200072, P.R. China.
| | - Yue-Zu Fan
- Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, P.R. China.
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