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Wyant GA, Jiang Q, Singh M, Qayyum S, Levrero C, Maron BA, Kaelin WG. Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy. Circulation 2024; 150:770-786. [PMID: 38881449 PMCID: PMC11361356 DOI: 10.1161/circulationaha.123.066628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 05/22/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
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Affiliation(s)
- Gregory A. Wyant
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.A.W., Q.J., C.L., W.G.K.)
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (G.A.W., M.S., S.Q.)
| | - Qinqin Jiang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.A.W., Q.J., C.L., W.G.K.)
| | - Madhu Singh
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (G.A.W., M.S., S.Q.)
| | - Shariq Qayyum
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA (G.A.W., M.S., S.Q.)
| | - Clara Levrero
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.A.W., Q.J., C.L., W.G.K.)
| | - Bradley A. Maron
- Department of Cardiovascular Medicine (B.A.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - William G. Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.A.W., Q.J., C.L., W.G.K.)
- Department of Medicine (W.G.K.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.)
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Song Z, Gao M, Li T, Zhang Y, Chen Z, Hu L, Liu J, Li Y, Wang X, Liu Y, Mo R, Xiang R, Hua D, Chen H, Zhao M, Chen X, Yao X, Yang Y. TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis. J Invest Dermatol 2024:S0022-202X(24)00384-1. [PMID: 38823435 DOI: 10.1016/j.jid.2024.04.020] [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: 11/08/2023] [Revised: 03/27/2024] [Accepted: 04/12/2024] [Indexed: 06/03/2024]
Abstract
TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.
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Affiliation(s)
- Zhongya Song
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Meng Gao
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Tianxiao Li
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yi Zhang
- Department of Plastic and Reconstructive Surgery, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Zhiming Chen
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Linghan Hu
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Juan Liu
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingshi Li
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xi Wang
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yihe Liu
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Ran Mo
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Ruiyu Xiang
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Di Hua
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Hao Chen
- Department of Pathology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Ming Zhao
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xu Chen
- Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Xu Yao
- Department of Allergy and Rheumatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yong Yang
- Genetic Skin Disease Center, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
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Fang W, Xie S, Deng W. Ferroptosis mechanisms and regulations in cardiovascular diseases in the past, present, and future. Cell Biol Toxicol 2024; 40:17. [PMID: 38509409 PMCID: PMC10955039 DOI: 10.1007/s10565-024-09853-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/27/2024] [Indexed: 03/22/2024]
Abstract
Cardiovascular diseases (CVDs) are the main diseases that endanger human health, and their risk factors contribute to high morbidity and a high rate of hospitalization. Cell death is the most important pathophysiology in CVDs. As one of the cell death mechanisms, ferroptosis is a new form of regulated cell death (RCD) that broadly participates in CVDs (such as myocardial infarction, heart transplantation, atherosclerosis, heart failure, ischaemia/reperfusion (I/R) injury, atrial fibrillation, cardiomyopathy (radiation-induced cardiomyopathy, diabetes cardiomyopathy, sepsis-induced cardiac injury, doxorubicin-induced cardiac injury, iron overload cardiomyopathy, and hypertrophic cardiomyopathy), and pulmonary arterial hypertension), involving in iron regulation, metabolic mechanism and lipid peroxidation. This article reviews recent research on the mechanism and regulation of ferroptosis and its relationship with the occurrence and treatment of CVDs, aiming to provide new ideas and treatment targets for the clinical diagnosis and treatment of CVDs by clarifying the latest progress in CVDs research.
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Affiliation(s)
- Wenxi Fang
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China
| | - Saiyang Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, People's Republic of China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.
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Şingar E, Akbulut A, Koca G, Yazihan N, Atilgan Hİ, Yumuşak N, Demir A, Burcu A, Korkmaz M. The influencer effect of Dexmedetomidine on radioiodine relevant to lacrimal gland impairment. Int Ophthalmol 2024; 44:115. [PMID: 38411703 DOI: 10.1007/s10792-024-03052-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 02/16/2024] [Indexed: 02/28/2024]
Abstract
PURPOSE To assess the potential influencing effects of Dexmedetomidine on impaired lacrimal glands after high-dose radioiodine treatment (RAI). METHODS Thirty-six rats were arbitrarily separated into 3 groups: Sham, RAI, and Dexmedetomidine. Dexmedetomidine group was given Dexmedetomidine and RAI, the Sham group was given the same millimeters of saline, and the RAI group was given RAI only. All forms of lacrimal glands, including harderian glands (HG), extraorbital (EG), and intraorbital (IG) lacrimal glands, were evaluated for immunohistochemical, histopathologic assessments and also for tissue cytokines, oxidant and antioxidant levels. RESULTS Dexmedetomidine significantly ameliorated histopathologic changes such as periacinar fibrosis, acinar atrophy, lymphocytic infiltration, ductal proliferation, lipofuscin-like accumulation, and nucleus changes caused by RAI in all lacrimal gland forms (p < 0.05 for all of the parameters). However, periductal fibrosis was improved significantly only in EG (p = 0.049), and mast cell infiltration was improved significantly only in IG (p = 0.038) in Dexmedetomidine groups. There was a significant decrease in the elevated caspase-3 and TUNEL levels after RAI administration in the Dexmedetomidine group in all lacrimal gland forms (p < 0.05 for all parameters). Dexmedetomidine attenuated NF-kb, TNF-α, and IL-6 levels significantly diminished total oxidant status and raised total antioxidant status levels (p < 0.05 for all parameters). CONCLUSIONS The results of this study demonstrated that following RAI, Dexmedetomidine diminished inflammation, tissue cytokine levels, and apoptosis and ameliorated impaired histopathologic patterns of the lacrimal glands.
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Affiliation(s)
- Evin Şingar
- Department of Ophthalmology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey.
| | - Aylin Akbulut
- Department of Nuclear Medicine, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
| | - Gökhan Koca
- Department of Nuclear Medicine, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
| | - Nuray Yazihan
- Department of Physiopathology, Ankara University, Ankara, Turkey
| | - Hasan İkbal Atilgan
- Department of Nuclear Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Nihat Yumuşak
- Veterinary Faculty, Department of Pathology, Harran University, Sanliurfa, Turkey
| | - Ayten Demir
- Faculty of Nursing, Ankara University, Ankara, Turkey
| | - Ayse Burcu
- Department of Ophthalmology, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
| | - Meliha Korkmaz
- Department of Nuclear Medicine, University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey
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Liu P, Zhao L, Zitvogel L, Kepp O, Kroemer G. The BCL2 inhibitor venetoclax mediates anticancer effects through dendritic cell activation. Cell Death Differ 2023; 30:2447-2451. [PMID: 37845384 PMCID: PMC10733328 DOI: 10.1038/s41418-023-01232-y] [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: 08/20/2023] [Revised: 09/26/2023] [Accepted: 10/03/2023] [Indexed: 10/18/2023] Open
Abstract
BCL2 is an apoptosis-inhibitory oncoprotein that also possesses apoptosis-unrelated activities. Pharmacological BCL2 inhibitors have been developed with the scope of driving BCL2-dependent cancer cells into apoptosis, and one BCL2 antagonist, venetoclax, has been clinically approved for the treatment of specific leukemias and lymphomas. Nonetheless, it appears that venetoclax, as well as genetic BCL2 inhibition, can mediate anticancer effects through an indirect action. Such an indirect effect relies on the enhancement of the immunostimulatory function of dendritic cells, hence increasing tumor immunosurveillance. Mechanistically, BCL2 inhibition involves improved antigen presentation by conventional type-1 dendritic cells (cDC1s) due to the activation of an interferon response, leading to a T cell-mediated anticancer immune response that can be further enhanced by PD-1 blockade. These findings support the emerging hypothesis that successful antineoplastic drugs generally mediate their effects indirectly, through the immune system, rather via merely cell-autonomous effects on malignant cells.
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Affiliation(s)
- Peng Liu
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France
| | - Liwei Zhao
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus, Villejuif, France
- Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR 1015, ClinicObiome, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France
- Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS) 1428, Villejuif, France
- Université Paris-Saclay, Gif-sur-Yvette, France
| | - Oliver Kepp
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Villejuif, France.
- Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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Hartley B, Bassiouni W, Schulz R, Julien O. The roles of intracellular proteolysis in cardiac ischemia-reperfusion injury. Basic Res Cardiol 2023; 118:38. [PMID: 37768438 DOI: 10.1007/s00395-023-01007-z] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023]
Abstract
Ischemic heart disease remains a leading cause of human mortality worldwide. One form of ischemic heart disease is ischemia-reperfusion injury caused by the reintroduction of blood supply to ischemic cardiac muscle. The short and long-term damage that occurs due to ischemia-reperfusion injury is partly due to the proteolysis of diverse protein substrates inside and outside of cardiomyocytes. Ischemia-reperfusion activates several diverse intracellular proteases, including, but not limited to, matrix metalloproteinases, calpains, cathepsins, and caspases. This review will focus on the biological roles, intracellular localization, proteolytic targets, and inhibitors of these proteases in cardiomyocytes following ischemia-reperfusion injury. Recognition of the intracellular function of each of these proteases includes defining their activation, proteolytic targets, and their inhibitors during myocardial ischemia-reperfusion injury. This review is a step toward a better understanding of protease activation and involvement in ischemic heart disease and developing new therapeutic strategies for its treatment.
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Affiliation(s)
- Bridgette Hartley
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Wesam Bassiouni
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Richard Schulz
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
- Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada.
| | - Olivier Julien
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
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González-Arzola K, Díaz-Quintana A. Mitochondrial Factors in the Cell Nucleus. Int J Mol Sci 2023; 24:13656. [PMID: 37686461 PMCID: PMC10563088 DOI: 10.3390/ijms241713656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
The origin of eukaryotic organisms involved the integration of mitochondria into the ancestor cell, with a massive gene transfer from the original proteobacterium to the host nucleus. Thus, mitochondrial performance relies on a mosaic of nuclear gene products from a variety of genomes. The concerted regulation of their synthesis is necessary for metabolic housekeeping and stress response. This governance involves crosstalk between mitochondrial, cytoplasmic, and nuclear factors. While anterograde and retrograde regulation preserve mitochondrial homeostasis, the mitochondria can modulate a wide set of nuclear genes in response to an extensive variety of conditions, whose response mechanisms often merge. In this review, we summarise how mitochondrial metabolites and proteins-encoded either in the nucleus or in the organelle-target the cell nucleus and exert different actions modulating gene expression and the chromatin state, or even causing DNA fragmentation in response to common stress conditions, such as hypoxia, oxidative stress, unfolded protein stress, and DNA damage.
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Affiliation(s)
- Katiuska González-Arzola
- Centro Andaluz de Biología Molecular y Medicina Regenerativa—CABIMER, Consejo Superior de Investigaciones Científicas—Universidad de Sevilla—Universidad Pablo de Olavide, 41092 Seville, Spain
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
| | - Antonio Díaz-Quintana
- Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, 41012 Seville, Spain
- Instituto de Investigaciones Químicas—cicCartuja, Universidad de Sevilla—C.S.I.C, 41092 Seville, Spain
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Frigo E, Tommasin L, Lippe G, Carraro M, Bernardi P. The Haves and Have-Nots: The Mitochondrial Permeability Transition Pore across Species. Cells 2023; 12:1409. [PMID: 37408243 PMCID: PMC10216546 DOI: 10.3390/cells12101409] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 07/07/2023] Open
Abstract
The demonstration that F1FO (F)-ATP synthase and adenine nucleotide translocase (ANT) can form Ca2+-activated, high-conductance channels in the inner membrane of mitochondria from a variety of eukaryotes led to renewed interest in the permeability transition (PT), a permeability increase mediated by the PT pore (PTP). The PT is a Ca2+-dependent permeability increase in the inner mitochondrial membrane whose function and underlying molecular mechanisms have challenged scientists for the last 70 years. Although most of our knowledge about the PTP comes from studies in mammals, recent data obtained in other species highlighted substantial differences that could be perhaps attributed to specific features of F-ATP synthase and/or ANT. Strikingly, the anoxia and salt-tolerant brine shrimp Artemia franciscana does not undergo a PT in spite of its ability to take up and store Ca2+ in mitochondria, and the anoxia-resistant Drosophila melanogaster displays a low-conductance, selective Ca2+-induced Ca2+ release channel rather than a PTP. In mammals, the PT provides a mechanism for the release of cytochrome c and other proapoptotic proteins and mediates various forms of cell death. In this review, we cover the features of the PT (or lack thereof) in mammals, yeast, Drosophila melanogaster, Artemia franciscana and Caenorhabditis elegans, and we discuss the presence of the intrinsic pathway of apoptosis and of other forms of cell death. We hope that this exercise may help elucidate the function(s) of the PT and its possible role in evolution and inspire further tests to define its molecular nature.
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Affiliation(s)
- Elena Frigo
- Department of Biomedical Sciences and CNR Neuroscience Institute, University of Padova, Via Ugo Bassi 58/B, I-35131 Padova, Italy; (E.F.); (L.T.); (M.C.)
| | - Ludovica Tommasin
- Department of Biomedical Sciences and CNR Neuroscience Institute, University of Padova, Via Ugo Bassi 58/B, I-35131 Padova, Italy; (E.F.); (L.T.); (M.C.)
| | - Giovanna Lippe
- Department of Medicine, University of Udine, Piazzale Kolbe 4, I-33100 Udine, Italy;
| | - Michela Carraro
- Department of Biomedical Sciences and CNR Neuroscience Institute, University of Padova, Via Ugo Bassi 58/B, I-35131 Padova, Italy; (E.F.); (L.T.); (M.C.)
| | - Paolo Bernardi
- Department of Biomedical Sciences and CNR Neuroscience Institute, University of Padova, Via Ugo Bassi 58/B, I-35131 Padova, Italy; (E.F.); (L.T.); (M.C.)
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9
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Xie L, Fang B, Zhang C. The role of ferroptosis in metabolic diseases. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119480. [PMID: 37127193 DOI: 10.1016/j.bbamcr.2023.119480] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 04/20/2023] [Accepted: 04/20/2023] [Indexed: 05/03/2023]
Abstract
The annual incidence of metabolic diseases such as diabetes, non-alcoholic fatty liver disease (NAFLD), osteoporosis, and atherosclerosis (AS) is increasing, resulting in a heavy burden on human health and the social economy. Ferroptosis is a novel form of programmed cell death driven by iron-dependent lipid peroxidation, which was discovered in recent years. Emerging evidence has suggested that ferroptosis contributes to the development of metabolic diseases. Here, we summarize the mechanisms and molecular signaling pathways involved in ferroptosis. Then we discuss the role of ferroptosis in metabolic diseases. Finally, we analyze the potential of targeting ferroptosis as a promising therapeutic approach for metabolic diseases.
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Affiliation(s)
- Ling Xie
- Department of Nephrology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430072, Hubei, China
| | - Bin Fang
- Department of Nephrology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430072, Hubei, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430072, Hubei, China.
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10
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Chen M, Wang L, Li M, Budai MM, Wang J. Mitochondrion-Mediated Cell Death through Erk1-Alox5 Independent of Caspase-9 Signaling. Cells 2022; 11:cells11193053. [PMID: 36231015 PMCID: PMC9564198 DOI: 10.3390/cells11193053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/22/2022] [Accepted: 09/25/2022] [Indexed: 02/02/2023] Open
Abstract
Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.
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Affiliation(s)
- Min Chen
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence: (M.C.); (J.W.)
| | - Lei Wang
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Min Li
- Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Marietta M. Budai
- Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Jin Wang
- Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
- Correspondence: (M.C.); (J.W.)
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11
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Wischhof L, Scifo E, Ehninger D, Bano D. AIFM1 beyond cell death: An overview of this OXPHOS-inducing factor in mitochondrial diseases. EBioMedicine 2022; 83:104231. [PMID: 35994922 PMCID: PMC9420475 DOI: 10.1016/j.ebiom.2022.104231] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/17/2022] Open
Abstract
Apoptosis-inducing factor (AIF) is a mitochondrial intermembrane space flavoprotein with diverse functions in cellular physiology. In this regard, a large number of studies have elucidated AIF's participation to chromatin condensation during cell death in development, cancer, cardiovascular and brain disorders. However, the discovery of rare AIFM1 mutations in patients has shifted the interest of biomedical researchers towards AIF's contribution to pathogenic mechanisms underlying inherited AIFM1-linked metabolic diseases. The functional characterization of AIF binding partners has rapidly advanced our understanding of AIF biology within the mitochondria and beyond its widely reported role in cell death. At the present time, it is reasonable to assume that AIF contributes to cell survival by promoting biogenesis and maintenance of the mitochondrial oxidative phosphorylation (OXPHOS) system. With this review, we aim to outline the current knowledge around the vital role of AIF by primarily focusing on currently reported human diseases that have been linked to AIFM1 deficiency.
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Affiliation(s)
- Lena Wischhof
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Enzo Scifo
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Dan Ehninger
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Daniele Bano
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
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12
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Qu Y, Sun Y, Yang Z, Ding C. Calcium Ions Signaling: Targets for Attack and Utilization by Viruses. Front Microbiol 2022; 13:889374. [PMID: 35859744 PMCID: PMC9289559 DOI: 10.3389/fmicb.2022.889374] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/15/2022] [Indexed: 12/25/2022] Open
Abstract
Calcium, as a second intracellular messenger, participate in various physiological and biochemical processes, including cell growth and proliferation, energy metabolism, information transfer, cell death, and immune response. Ca2+ channels or pumps in plasma and organelle membranes and Ca2+-related proteins maintain Ca2+ homeostasis by regulating Ca2+ inflow, outflow and buffering to avoid any adverse effects caused by Ca2+ overload or depletion. Thus, Ca2+ signaling also provides a target for virus invasion, replication, proliferation and release. After hijacking the host cell, viruses exploit Ca2+ signaling to regulate apoptosis and resist host immunity to establish persistent infection. In this review, we discuss cellular Ca2+ signaling and channels, interaction of calcium-associated proteins with viruses, and host cell fate, as well as the role of Ca2+ in cell death and antiviral response during viral infection.
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Affiliation(s)
- Yang Qu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, China
| | - Yingjie Sun
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, China
| | - Zengqi Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
- Zengqi Yang,
| | - Chan Ding
- Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- *Correspondence: Chan Ding,
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13
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Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death. Biomolecules 2022; 12:biom12020162. [PMID: 35204663 PMCID: PMC8961529 DOI: 10.3390/biom12020162] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023] Open
Abstract
The localization of Bcl-2 family members at the mitochondrial outer membrane (MOM) is a crucial step in the implementation of apoptosis. We review evidence showing the role of the components of the mitochondrial import machineries (translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM)) in the mitochondrial localization of Bcl-2 family members and how these machineries regulate the function of pro- and anti-apoptotic proteins in resting cells and in cells committed into apoptosis.
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14
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Liu L, Li J, Ke Y, Zeng X, Gao J, Ba X, Wang R. The key players of parthanatos: opportunities for targeting multiple levels in the therapy of parthanatos-based pathogenesis. Cell Mol Life Sci 2022; 79:60. [PMID: 35000037 PMCID: PMC11073082 DOI: 10.1007/s00018-021-04109-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 12/08/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022]
Abstract
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis.
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Affiliation(s)
- Libo Liu
- Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Provenice, Shandong Normal University, Jinan, 250014, Shandong, China
| | - Jiaxiang Li
- Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Provenice, Shandong Normal University, Jinan, 250014, Shandong, China
| | - Yueshuang Ke
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun, 130024, Jilin, China
| | - Xianlu Zeng
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun, 130024, Jilin, China
| | - Jinmin Gao
- Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Provenice, Shandong Normal University, Jinan, 250014, Shandong, China
| | - Xueqing Ba
- The Key Laboratory of Molecular Epigenetics of Education, School of Life Science, Northeast Normal University, Changchun, 130024, Jilin, China.
| | - Ruoxi Wang
- Institute of Biomedical Sciences, College of Life Sciences, Key Laboratory of Animal Resistance Biology of Shandong Provenice, Shandong Normal University, Jinan, 250014, Shandong, China.
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15
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Relevance of AIF/CypA Lethal Pathway in SH-SY5Y Cells Treated with Staurosporine. Int J Mol Sci 2021; 23:ijms23010265. [PMID: 35008690 PMCID: PMC8745523 DOI: 10.3390/ijms23010265] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/22/2021] [Accepted: 12/26/2021] [Indexed: 11/18/2022] Open
Abstract
The AIF/CypA complex exerts a lethal activity in several rodent models of acute brain injury. Upon formation, it translocates into the nucleus of cells receiving apoptotic stimuli, inducing chromatin condensation, DNA fragmentation, and cell death by a caspase-independent mechanism. Inhibition of this complex in a model of glutamate-induced cell death in HT-22 neuronal cells by an AIF peptide (AIF(370-394)) mimicking the binding site on CypA, restores cell survival and prevents brain injury in neonatal mice undergoing hypoxia-ischemia without apparent toxicity. Here, we explore the effects of the peptide on SH-SY5Y neuroblastoma cells stimulated with staurosporine (STS), a cellular model widely used to study Parkinson’s disease (PD). This will pave the way to understanding the role of the complex and the potential therapeutic efficacy of inhibitors in PD. We find that AIF(370-394) confers resistance to STS-induced apoptosis in SH-SY5Y cells similar to that observed with CypA silencing and that the peptide works on the AIF/CypA translocation pathway and not on caspases activation. These findings suggest that the AIF/CypA complex is a promising target for developing novel therapeutic strategies against PD.
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16
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Kameyanda Poonacha S, Harishkumar M, Radha M, Varadarajan R, Nalilu SK, Shetty SS, Shetty PK, Chandrashekharappa RB, Sreenivas MG, Bhandary Bavabeedu SK. Insight into OroxylinA-7- O-β-d-Glucuronide-Enriched Oroxylum indicum Bark Extract in Oral Cancer HSC-3 Cell Apoptotic Mechanism: Role of Mitochondrial Microenvironment. Molecules 2021; 26:7430. [PMID: 34946511 PMCID: PMC8704017 DOI: 10.3390/molecules26247430] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 02/08/2023] Open
Abstract
Oroxylum indicum, of the Bignoniaceae family, has various ethnomedical uses such as an astringent, anti-inflammatory, anti-bronchitis, anti-helminthic and anti-microbial, including anticancer properties. The druggability of OI stem bark extract was determined by its molecular docking interactions with PARP and Caspase-3, two proteins involved in cell survival and death. Note that 50 µg/mL of Oroxylum indicum extract (OIE) showed a significant (p < 0.05%) toxicity to HSC-3 cells. MTT aided cell viability and proliferation assay demonstrated that 50 µg/mL of OIE displayed significant (p < 0.5%) reduction in cell number at 4 h of incubation time. Cell elongation and spindle formation was noticed when HSC-3 cells were treated with 50 µg/mL of OIE. OIE initiated DNA breakage and apoptosis in HSC-3 cells, as evident from DNA ladder assay and calcein/EB staining. Apoptosis potential of OIE is confirmed by flow cytometer and triple-staining (live cell/apoptosis/necrosis) assay. Caspase-3/7 fluorescence quenching (LANCE) assay demonstrated that 50 µg/mL of OIE significantly enhanced the RFU of caspases-3/7, indicating that the apoptosis potential of OIE is probably through the activation of caspases. Immuno-cytochemistry of HSC-3 cells treated with 50 µg/mL of OIE showed a significant reduction in mitochondrial bodies as well as a reduction in RFU in 60 min of incubation time. Immunoblotting studies clearly showed that treatment of HSC-3 cells with OI extract caused caspase-3 activation and PARP deactivation, resulting in apoptotic cell death. Overall, our data indicate that OIE is an effective apoptotic agent for human squamous carcinoma cells and it could be a future cancer chemotherapeutic target.
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Affiliation(s)
- Sharmila Kameyanda Poonacha
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
| | - Madhyastha Harishkumar
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
- Department of Cardio-Vascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 8891692, Japan;
| | - Madhyastha Radha
- Department of Cardio-Vascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 8891692, Japan;
| | - Remya Varadarajan
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
| | - Suchetha Kumari Nalilu
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
- Department of Biochemistry, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India
| | - Shilpa Sharathraj Shetty
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
| | - Praveen Kumar Shetty
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
- Department of Biochemistry, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India
| | | | - Mahendra Gowdru Sreenivas
- Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to Be) University, Mangaluru 575018, India; (R.B.C.); (M.G.S.)
| | - Satheesh Kumar Bhandary Bavabeedu
- Central Research Laboratory, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India; (S.K.P.); (R.V.); (S.K.N.); (S.S.S.); (P.K.S.)
- Department of Otorhinolarynology, K.S. Hegde Medical Academy, Nitte (Deemed to Be) University, Mangaluru 575018, India
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17
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Martínez-Morcillo FJ, Cantón-Sandoval J, Martínez-Navarro FJ, Cabas I, Martínez-Vicente I, Armistead J, Hatzold J, López-Muñoz A, Martínez-Menchón T, Corbalán-Vélez R, Lacal J, Hammerschmidt M, García-Borrón JC, García-Ayala A, Cayuela ML, Pérez-Oliva AB, García-Moreno D, Mulero V. NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death. PLoS Biol 2021; 19:e3001455. [PMID: 34748530 PMCID: PMC8601609 DOI: 10.1371/journal.pbio.3001455] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 11/18/2021] [Accepted: 10/22/2021] [Indexed: 01/26/2023] Open
Abstract
Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.
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Affiliation(s)
- Francisco J. Martínez-Morcillo
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - Joaquín Cantón-Sandoval
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - Francisco J. Martínez-Navarro
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - Isabel Cabas
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - Idoya Martínez-Vicente
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- Departamento de Bioquímica y Biología Molecular A e Inmmunología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain
| | - Joy Armistead
- Institute of Zoology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Julia Hatzold
- Institute of Zoology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Azucena López-Muñoz
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - Teresa Martínez-Menchón
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Raúl Corbalán-Vélez
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Jesús Lacal
- Departamento de Microbiología y Genética, Facultad de Biología, Universidad de Salamanca, Spain
| | - Matthias Hammerschmidt
- Institute of Zoology, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - José C. García-Borrón
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- Departamento de Bioquímica y Biología Molecular A e Inmmunología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain
| | - Alfonsa García-Ayala
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
| | - María L. Cayuela
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Ana B. Pérez-Oliva
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- * E-mail: (ABP-O); (DG-M); (VM)
| | - Diana García-Moreno
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- * E-mail: (ABP-O); (DG-M); (VM)
| | - Victoriano Mulero
- Departmento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria-Arrixaca, Murcia, Spain
- * E-mail: (ABP-O); (DG-M); (VM)
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18
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Bassiouni W, Seubert JM, Schulz R. Staurosporine-induced cleavage of apoptosis-inducing factor in human fibrosarcoma cells is independent of matrix metalloproteinase-2. Can J Physiol Pharmacol 2021; 100:184-191. [PMID: 34597523 DOI: 10.1139/cjpp-2021-0199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein which mediates staurosporine (STS)-induced cell death. AIF cleavage and translocation to the cytosol is thought to be calpain-1-dependent as calpain inhibitors reduced AIF proteolysis. However, many calpain inhibitors also inhibit matrix metalloproteinase-2 (MMP-2) activity, an intracellular and extracellular protease implicated in apoptosis. Here we investigated whether MMP-2 activity is affected in response to STS and if contributes to AIF cleavage. Human fibrosarcoma HT1080 cells were treated with STS (0.1 µM, 0.25-24 hr). A significant increase in cellular MMP-2 activity was seen by gelatin zymography after 6 hr STS treatment, prior to induction of cell necrosis. Western blot showed the time-dependent appearance of two forms of AIF (~60 and 45 kDa) in the cytosol which were significantly increased at 6 hr. Surprisingly, knocking down MMP-2 or inhibiting its activity with MMP-2 preferring inhibitors ARP-100 or ONO-4817, or inhibiting calpain activity with ALLM or PD150606, did not prevent the STS-induced increase in cytosolic AIF. These results show that although STS rapidly increases MMP-2 activity, the cytosolic release of AIF may be independent of the proteolytic activities of MMP-2 or calpain.
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Affiliation(s)
- Wesam Bassiouni
- University of Alberta Faculty of Medicine & Dentistry, 12357, Department of Pharmacology, Edmonton, Alberta, Canada;
| | - John M Seubert
- University of Alberta, Faculty of Pharmacy/Pharmaceutical Sciences, 3-142D Katz Group Centre for Pharmacy & Health Research, 11361 - 87 Ave., 2020M Katz Group Centre for Pharmacy and Health Research, Edmonton, Alberta, Canada, T6G 2E1;
| | - Richard Schulz
- University of Alberta, Pediatrics & Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, 462 HMRC, Edmonton, Alberta, Canada, T6G 2S2;
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19
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Rex DAB, Arun Kumar ST, Rai AB, Kotimoole CN, Modi PK, Prasad TSK. Novel Post-Translational Modifications and Molecular Substrates in Glioma Identified by Bioinformatics. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:463-473. [PMID: 34227895 DOI: 10.1089/omi.2021.0050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Glioma is the most common type of brain cancer that originates from the glial cells. It constitutes about one-third of all brain cancers. Recently, transcriptomics, proteomics, and multiomics approaches have been harnessed to discover potential biomarkers and therapeutic targets in glioma. Moreover, post-translational modifications (PTMs) of proteins play a major role in cell biology and function and offer new avenues of research in cancer. Using unbiased multi-PTM bioinformatics analyses of two proteomic datasets of glioma available in the public domain, we identified 866 proteins with common PTMs from both studies. Out of these 866 proteins, 19 proteins were identified with the common PTMs, with the same site modifications pertaining to glioma. Importantly, the identified PTMs belonged to proteins involved in integrin PI3K/Akt/mTOR, JAK/STAT, and Ras/Raf/MAPK pathways. These pathways are essential for cell proliferation in tumor cells and thus involved in glioma progression. Taken together, these findings call for validation in larger datasets in glioma and brain cancers and with an eye to future drug discovery and diagnostic innovation. Bioinformatics-guided discovery of novel PTMs from the publicly available proteomic data can offer new avenues for innovation in cancer research.
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Affiliation(s)
- Devasahayam Arokia Balaya Rex
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Sumaithangi Thattai Arun Kumar
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Akhila Balakrishna Rai
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Chinmaya Narayana Kotimoole
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
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20
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Eldohaji LM, Fayed B, Hamoda AM, Ershaid M, Abdin S, Alhamidi TB, Mohammad MG, Omar HA, Soliman SSM. Potential targeting of Hep3B liver cancer cells by lupeol isolated from Avicennia marina. Arch Pharm (Weinheim) 2021; 354:e2100120. [PMID: 34085721 DOI: 10.1002/ardp.202100120] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/29/2021] [Accepted: 05/14/2021] [Indexed: 11/08/2022]
Abstract
Medicinal plants are valuable sources of different active constituents that are known to have important pharmacological activities including anticancer effects. Lupeol, a pentacyclic triterpenoid, present in many medicinal plants, has a wide range of biological activities. Although the anticancer activity of lupeol was reported, the published data are inconsistent and the clear mechanism of action has never been assigned. The current study aims at investigating the anticancer specificity and mechanism of lupeol isolated from Avicennia marina, which grows in the desert of the United Arab Emirates. The compound was purified by chromatography and identified by spectroscopy. Compared with a negative control, lupeol caused significant (p < .001) growth inhibitory activity on MCF-7 and Hep3B parental and resistant cells by 45%, 46%, 72%, and 35%, respectively. The mechanism of action of lupeol was further explored by measuring its effect on key players in cancer development and progression, BCL-2 anti-apoptotic and BAX pro-apoptotic proteins. Lupeol significantly (p < .01) downregulated BCL-2 gene expression in parental and resistant Hep3B cells by 33 and 3.5 times, respectively, contributing to the induction of apoptosis in Hep3B cells, whereas it caused no effect on BAX. Furthermore, the immunoblotting analysis revealed that lupeol cleaved the executioner caspase-3 into its active form. Interestingly, lupeol showed no significant effect on the proliferation of monocytes, whereas it caused an increase in the sub-G1 population and a reduction in the apoptosis rates of monocytes at 48 and 72 h, indicative of no immuno-inflammatory responses. Collectively, lupeol can be considered as promising effective and safe anticancer agent, particularly against Hep3B cancer cells.
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Affiliation(s)
- Leen M Eldohaji
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Bahgat Fayed
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,Chemistry of Natural and Microbial Product Department, National Research Centre, Cairo, Egypt
| | - Alshaimaa M Hamoda
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Medicine, University of Sharjah, Sharjah, UAE.,Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Mai Ershaid
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Shifaa Abdin
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Tasneem B Alhamidi
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE
| | - Mohammad G Mohammad
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, UAE
| | - Hany A Omar
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Pharmacy, University of Sharjah, Sharjah, UAE
| | - Sameh S M Soliman
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, UAE.,College of Pharmacy, University of Sharjah, Sharjah, UAE
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21
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Diao L, Tang N, Zhang C, Cheng J, Zhang Z, Wang S, Wu C, Zhang L, Tao L, Li Z, Zhang Y. Avermectin induced DNA damage to the apoptosis and autophagy in human lung epithelial A549 cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 215:112129. [PMID: 33740486 DOI: 10.1016/j.ecoenv.2021.112129] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 06/12/2023]
Abstract
Avermectin (AVM), as a biological insecticide, is widely used in agriculture and forestry production globally. However, inhalation of AVM may pose a risk, and the lung is the direct target, but the cytotoxicity of AVM on human lung cells is still unclear. Here, we attempted to elucidate the cytotoxic effect and molecular mechanism of AVM on human lung A549 cells. The results indicated that AVM inhibits cell proliferation, and enhances programmed cell death (apoptosis and autophagy). In addition, we found the AVM-treated cells showed an obvious drop in mitochondrial membrane potential and LC3-I/II, increased ROS production, DNA double-strand breaks, caspase-3/9 activated, PARP cleaved, cytochrome c and Bax/Bcl-2 content rise. The results showed that AVM induced mitochondria-related apoptosis and autophagy in lung A549 cells. These results indicate that AVM can pose a potential threat to human health by inducing DNA damage and programmed cell death.
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Affiliation(s)
- Lin Diao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Ning Tang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Cheng Zhang
- Department of Pathology, UT southwestern Medical Center, Dallas, TX 75390, United States
| | - Jiagao Cheng
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhenhai Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Siyu Wang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Can Wu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Lutong Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Liming Tao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhong Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yang Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
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22
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Mitochondrial K + Transport: Modulation and Functional Consequences. Molecules 2021; 26:molecules26102935. [PMID: 34069217 PMCID: PMC8156104 DOI: 10.3390/molecules26102935] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 01/28/2023] Open
Abstract
The existence of a K+ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known to participate in K+ cycling is the ATP-sensitive K+ channel, MitoKATP. This channel was vastly studied for promoting protection against ischemia reperfusion when pharmacologically activated, although its molecular identity remained unknown for decades. The recent molecular characterization of MitoKATP has opened new possibilities for modulation of this channel as a mechanism to control cellular processes. Here, we discuss different strategies to control MitoKATP activity and consider how these could be used as tools to regulate metabolism and cellular events.
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23
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de Oliveira MF, Medeiros RCA, Mietto BS, Calvo TL, Mendonça APM, Rosa TLSA, da Silva DS, do Carmo de Vasconcelos KG, Pereira AMR, de Macedo CS, Pereira GMB, de Berrêdo Pinho Moreira M, Pessolani MCV, Moraes MO, Lara FA. Reduction of host cell mitochondrial activity as Mycobacterium leprae's strategy to evade host innate immunity. Immunol Rev 2021; 301:193-208. [PMID: 33913182 PMCID: PMC10084840 DOI: 10.1111/imr.12962] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/20/2022]
Abstract
Leprosy is a much-feared incapacitating infectious disease caused by Mycobacterium leprae or M lepromatosis, annually affecting roughly 200,000 people worldwide. During host-pathogen interaction, M leprae subverts the immune response, leading to development of disease. Throughout the last few decades, the impact of energy metabolism on the control of intracellular pathogens and leukocytic differentiation has become more evident. Mitochondria play a key role in regulating newly-discovered immune signaling pathways by controlling redox metabolism and the flow of energy besides activating inflammasome, xenophagy, and apoptosis. Likewise, this organelle, whose origin is probably an alphaproteobacterium, directly controls the intracellular pathogens attempting to invade its niche, a feature conquered at the expense of billions of years of coevolution. In the present review, we discuss the role of reduced host cell mitochondrial activity during M leprae infection and the consequential fates of M leprae and host innate immunity. Conceivably, inhibition of mitochondrial energy metabolism emerges as an overlooked and novel mechanism developed by M leprae to evade xenophagy and the host immune response.
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Affiliation(s)
- Marcus Fernandes de Oliveira
- Laboratório de Bioquímica de Resposta ao Estresse, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | - Bruno Siqueira Mietto
- Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Minas Gerais, Brazil
| | - Thyago Leal Calvo
- Laboratório de Hanseníase, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Ana Paula Miranda Mendonça
- Laboratório de Bioquímica de Resposta ao Estresse, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | | | | | | | - Cristiana Santos de Macedo
- Laboratório de Microbiologia Celular, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
- Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | | | | | | | | | - Flavio Alves Lara
- Laboratório de Microbiologia Celular, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
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24
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Bernardi P. Looking Back to the Future of Mitochondrial Research. Front Physiol 2021; 12:682467. [PMID: 33995132 PMCID: PMC8119648 DOI: 10.3389/fphys.2021.682467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/12/2021] [Indexed: 12/03/2022] Open
Affiliation(s)
- Paolo Bernardi
- Department of Biomedical Sciences, University of Padova, Padova, Italy
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25
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Rodriguez J, Li T, Xu Y, Sun Y, Zhu C. Role of apoptosis-inducing factor in perinatal hypoxic-ischemic brain injury. Neural Regen Res 2021; 16:205-213. [PMID: 32859765 PMCID: PMC7896227 DOI: 10.4103/1673-5374.290875] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Perinatal complications, such as asphyxia, can cause brain injuries that are often associated with subsequent neurological deficits, such as cerebral palsy or mental retardation. The mechanisms of perinatal brain injury are not fully understood, but mitochondria play a prominent role not only due to their central function in metabolism but also because many proteins with apoptosis-related functions are located in the mitochondrion. Among these proteins, apoptosis-inducing factor has already been shown to be an important factor involved in neuronal cell death upon hypoxia-ischemia, but a better understanding of the mechanisms behind these processes is required for the development of more effective treatments during the early stages of perinatal brain injury. In this review, we focus on the molecular mechanisms of hypoxic-ischemic encephalopathy, specifically on the importance of apoptosis-inducing factor. The relevance of apoptosis-inducing factor is based not only because it participates in the caspase-independent apoptotic pathway but also because it plays a crucial role in mitochondrial energetic functionality, especially with regard to the maintenance of electron transport during oxidative phosphorylation and in oxidative stress, acting as a free radical scavenger. We also discuss all the different apoptosis-inducing factor isoforms discovered, focusing especially on apoptosis-inducing factor 2, which is only expressed in the brain and the functions of which are starting now to be clarified. Finally, we summarized the interaction of apoptosis-inducing factor with several proteins that are crucial for both apoptosis-inducing factor functions (pro-survival and pro-apoptotic) and that are highly important in order to develop promising therapeutic targets for improving outcomes after perinatal brain injury.
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Affiliation(s)
- Juan Rodriguez
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tao Li
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yiran Xu
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yanyan Sun
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Anatomy, School of Basic Medical Science, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Changlian Zhu
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
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26
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Yokoyama S, Ohno Y, Egawa T, Ohashi K, Ito R, Ortuste Quiroga HP, Yamashita T, Goto K. MBNL1-Associated Mitochondrial Dysfunction and Apoptosis in C2C12 Myotubes and Mouse Skeletal Muscle. Int J Mol Sci 2020; 21:ijms21176376. [PMID: 32887414 PMCID: PMC7503908 DOI: 10.3390/ijms21176376] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/27/2020] [Accepted: 08/31/2020] [Indexed: 01/06/2023] Open
Abstract
We explored the interrelationship between a tissue-specific alternative splicing factor muscleblind-like 1 (MBNL1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) in C2C12 myotubes and mouse skeletal muscle to investigate a possible physiological role of MBNL1 in mitochondrial-associated apoptosis of skeletal muscle. Expression level of PGC-1α and mitochondrial membrane potential evaluated by the fluorescence ratio of JC-1 aggregate to monomer in C2C12 myotubes were suppressed by knockdown of MBNL1. Conversely, the ratio of Bax to Bcl-2 as well as the apoptotic index in C2C12 myotubes was increased by MBNL1 knockdown. In plantaris muscle, on the other hand, not only the minimum muscle fiber diameter but also the expression level of MBNL1 and PGC-1α in of 100-week-old mice were significantly lower than that of 10-week-old mice. Furthermore, the ratio of Bax to Bcl-2 in mouse plantaris muscle was increased by aging. These results suggest that MBNL1 may play a key role in aging-associated muscle atrophy accompanied with mitochondrial dysfunction and apoptosis via mediating PGC-1α expression in skeletal muscle.
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Affiliation(s)
- Shingo Yokoyama
- Laboratory of Physiology, School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (S.Y.); (K.O.)
| | - Yoshitaka Ohno
- Faculty of Rehabilitation and Care, Seijoh University, Tokai 476-8588, Japan;
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
| | - Tatsuro Egawa
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8511, Japan
| | - Kazuya Ohashi
- Laboratory of Physiology, School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (S.Y.); (K.O.)
| | - Rika Ito
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
| | - Huascar Pedro Ortuste Quiroga
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
| | - Tomohiro Yamashita
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
| | - Katsumasa Goto
- Laboratory of Physiology, School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (S.Y.); (K.O.)
- Department of Physiology, Graduate School of Health Science, Toyohashi SOZO University, Toyohashi 440-8511, Japan; (T.E.); (R.I.); (H.P.O.Q.); (T.Y.)
- Correspondence:
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27
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Monti A, Sturlese M, Caporale A, Roger JDA, Mascanzoni F, Ruvo M, Doti N. Design, synthesis, structural analysis and biochemical studies of stapled AIF(370-394) analogues as ligand of CypA. Biochim Biophys Acta Gen Subj 2020; 1864:129717. [PMID: 32861757 DOI: 10.1016/j.bbagen.2020.129717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/28/2020] [Accepted: 08/19/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The neuronal apoptotic process requires the nuclear translocation of Apoptosis Inducing Factor (AIF) in complex with Cyclophilin A (CypA) with consequent chromatin condensation and DNA degradation events. Targeting CypA by delivering an AIF-blocking peptide (AIF(370-394)) provides a significant neuroprotection, demonstrating the biological relevance of the AIF/CypA complex. To date pharmaceutical compounds targeting this complex are missing. METHODS We designed and synthesized a set of mono and bicyclic AIF(370-394) analogs containing both disulfide and 1,2,3-triazole bridges, in the attempt to both stabilize the peptide conformation and improve its binding affinity to CypA. Peptide structures in solution and in complex with CypA have been studied by circular dichroism (CD), Nuclear Magnetic Resonance (NMR) and molecular modeling. The ability of stapled peptides to interact with CypA was evaluated by using Epic Corning label free technique and Isothermal Titration Calorimetry experiments. RESULTS We identified a stapled peptide analogue of AIF(370-394) with a ten-fold improved affinity for CypA. Molecular modeling studies reveal that the new peptide acquires β-turn/β-fold structures and shares with the parent molecule the same binding region on CypA. CONCLUSIONS Data obtained provide invaluable assistance in designing new ligand of CypA for therapeutic approaches in neurodegenerative diseases. GENERAL SIGNIFICANCE Due to the crucial role of AIF/CypA complex formation in neurodegeneration, identification of selective inhibitors is of high importance for targeted therapies. We describe new bicyclic peptide inhibitors with improved affinity for CypA, investigating the kinetic, thermodynamic and structural effects of conformational constraints on the protein-ligand interaction, and their utility for drug design.
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Affiliation(s)
- Alessandra Monti
- Istituto di Biostrutture e Bioimmagini-CNR; Via Mezzocannone, 16, 80134 Napoli, Italy; DISTABIF, Università degli Studi della Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, CE, Italy
| | - Mattia Sturlese
- Molecular Modeling Section, Dipartimento di Scienze del Farmaco, Università di Padova, via F. Marzolo 5, 35131 Padova, Italy
| | - Andrea Caporale
- Istituto di Biostrutture e Bioimmagini-CNR; Via Mezzocannone, 16, 80134 Napoli, Italy
| | - Jessica De Almeida Roger
- Molecular Modeling Section, Dipartimento di Scienze del Farmaco, Università di Padova, via F. Marzolo 5, 35131 Padova, Italy
| | - Fabiola Mascanzoni
- Istituto di Biostrutture e Bioimmagini-CNR; Via Mezzocannone, 16, 80134 Napoli, Italy
| | - Menotti Ruvo
- Istituto di Biostrutture e Bioimmagini-CNR; Via Mezzocannone, 16, 80134 Napoli, Italy
| | - Nunzianna Doti
- Istituto di Biostrutture e Bioimmagini-CNR; Via Mezzocannone, 16, 80134 Napoli, Italy.
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28
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Herrmann JM, Riemer J. Apoptosis inducing factor and mitochondrial NADH dehydrogenases: redox-controlled gear boxes to switch between mitochondrial biogenesis and cell death. Biol Chem 2020; 402:289-297. [PMID: 32769219 DOI: 10.1515/hsz-2020-0254] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 08/03/2020] [Indexed: 02/07/2023]
Abstract
The mitochondrial complex I serves as entry point for NADH into the electron transport chain. In animals, fungi and plants, additional NADH dehydrogenases carry out the same electron transfer reaction, however they do not pump protons. The apoptosis inducing factor (AIF, AIFM1 in humans) is a famous member of this group as it was the first pro-apoptotic protein identified that can induce caspase-independent cell death. Recent studies on AIFM1 and the NADH dehydrogenase Nde1 of baker's yeast revealed two independent and experimentally separable activities of this class of enzymes: On the one hand, these proteins promote the functionality of mitochondrial respiration in different ways: They channel electrons into the respiratory chain and, at least in animals, promote the import of Mia40 (named MIA40 or CHCHD4 in humans) and the assembly of complex I. On the other hand, they can give rise to pro-apoptotic fragments that are released from the mitochondria to trigger cell death. Here we propose that AIFM1 and Nde1 serve as conserved redox switches which measure metabolic conditions on the mitochondrial surface and translate it into a binary life/death decision. This function is conserved among eukaryotic cells and apparently used to purge metabolically compromised cells from populations.
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Affiliation(s)
- Johannes M Herrmann
- Department of Cell Biology, University of Kaiserslautern, Erwin-Schrödinger-Strasse 13, D-67663Kaiserslautern, Germany
| | - Jan Riemer
- Department of Biochemistry, University of Cologne, Zülpicher Str. 47A, D-50674Cologne, Germany
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29
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Lo SM, Martinez PA, Marques EF, Miyamoto S, Valdameri G, Moure VR, Zanata SM, Nakao LS. Oxidation of apoptosis-inducing factor (AIF) to disulfide-linked conjugates. Arch Biochem Biophys 2020; 692:108515. [PMID: 32791141 DOI: 10.1016/j.abb.2020.108515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 07/01/2020] [Accepted: 07/24/2020] [Indexed: 01/09/2023]
Abstract
Apoptosis-inducing factor (AIF) is a flavoprotein and essential partner of the CHCHD4 redox protein during the mitochondrial intermembrane space import machinery. Mammalian AIF has three cysteine residues, which have received little attention. Previous reports have evidenced a redox interaction between AIF and thioredoxin 1 (Trx1), particularly after oxidant conditions. Therefore, we asked whether the cysteine residues of the human AIF could be oxidized. Our data showed that endogenous AIF could be oxidized to disulfide-linked conjugates (DLC). Overexpressed WT AIF in HEK293T cells, as well as recombinant WT AIF, formed DLC. Expression of C256S, C317S or C441S AIF mutants severely inhibited DLC formation in cells exposed to oxidants. In vitro, DLC formation was completely precluded with C256S and C441S AIF mutants and partially inhibited with the C317S mutant. DLC was shown to enhance cellular susceptibility to apoptosis induced by staurosporine, likely by preventing AIF to maintain mitochondrial oxidative phosphorylation. Cells with decreased expression of Trx1 produced more AIF DLC than those with normal Trx1 levels, and in vitro, Trx1 was able to decrease the amount of AIF DLC. Finally, confocal analysis, as well as immunoblotting of mitochondrial fraction, indicated that a fraction of Trx1 is present in mitochondria. Overall, these data provide evidence that all three cysteine residues of AIF can be oxidized to DLC, which can be disrupted by mitochondrial Trx1.
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Affiliation(s)
- Sze M Lo
- Department of Basic Pathology, Universidade Federal do Paraná, Centro Politécnico, 81531-980, Curitiba, Paraná, Brazil
| | - Pierina A Martinez
- Department of Basic Pathology, Universidade Federal do Paraná, Centro Politécnico, 81531-980, Curitiba, Paraná, Brazil
| | - Emerson F Marques
- Department of Biochemistry, Instituto de Química, Universidade de São Paulo, 05508-000, São Paulo, Brazil
| | - Sayuri Miyamoto
- Department of Biochemistry, Instituto de Química, Universidade de São Paulo, 05508-000, São Paulo, Brazil
| | - Glaucio Valdameri
- Laboratory of Cancer Drug Resistance, Pharmaceutical Sciences Graduate Program, Universidade Federal do Paraná, 80210-170, Curitiba, Paraná, Brazil
| | - Vivian R Moure
- Laboratory of Cancer Drug Resistance, Pharmaceutical Sciences Graduate Program, Universidade Federal do Paraná, 80210-170, Curitiba, Paraná, Brazil
| | - Silvio M Zanata
- Department of Basic Pathology, Universidade Federal do Paraná, Centro Politécnico, 81531-980, Curitiba, Paraná, Brazil
| | - Lia S Nakao
- Department of Basic Pathology, Universidade Federal do Paraná, Centro Politécnico, 81531-980, Curitiba, Paraná, Brazil.
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30
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Liu Z, Du Z, Li K, Han Y, Ren G, Yang Z. TRPC6-Mediated Ca 2+ Entry Essential for the Regulation of Nano-ZnO Induced Autophagy in SH-SY5Y Cells. Neurochem Res 2020; 45:1602-1613. [PMID: 32274628 DOI: 10.1007/s11064-020-03025-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 04/02/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023]
Abstract
Recently, possible applications of zinc oxide nanoparticles (nano-ZnO) have been extensively studied owing to their ease of synthesis. However, the effect of nano-ZnO on the nervous system remains unclear. This study investigates the action of nano-ZnO on SH-SY5Y neuroblastoma cells. We found that nano-ZnO (0-50 µg/mL) induced a significant decrease in cell survival rate in a dose-dependent manner, and increased LC3 puncta formation. However, the apoptosis was not affected by nano-ZnO, because the protein levels of cytochrome c, caspase-3, Bcl-xL, and BAX were not varied by the nano-ZnO treatment. Nano-ZnO increased Ca2+ entry and the expression of TRPC6.The results suggested that nano-ZnO increased [Ca2+] through the TRPC-dependent Ca2+ influx, since Ca2+ influx can be prevented by the TRPC inhibitor. Furthermore, cells on nano-ZnO-treatment groups displayed loss of F-actin in a dose dependent manner, which also could be prevented by TRPC inhibitor. Herein, we demonstrated that the nano-ZnO activated TRPC6 channel, thereby increasing the Ca2+ flux and resulting in increased autophagy. Nano-ZnO could have possible anticancer effects in neuroblastoma by inhibiting the proliferation of tumor cells. However, we should also pay attention toward the biosecurity of nano materials.
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Affiliation(s)
- Zhaowei Liu
- College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, No.94, Weijin Road, Nankai District, Tianjin, 300071, China.
| | - Zhanqiang Du
- College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, No.94, Weijin Road, Nankai District, Tianjin, 300071, China
| | - Kai Li
- College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, No.94, Weijin Road, Nankai District, Tianjin, 300071, China
| | - Yangguang Han
- School of precision instrument and optoelectronic engineering, Tianjin University, Tianjin, 300072, China
| | - Guogang Ren
- Science and Technology Research Institute, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK
| | - Zhuo Yang
- College of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, No.94, Weijin Road, Nankai District, Tianjin, 300071, China.
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31
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Jiao R, Xu F, Huang X, Li H, Liu W, Cao H, Zang L, Li Z, Hua H, Li D. Antiproliferative chromone derivatives induce K562 cell death through endogenous and exogenous pathways. J Enzyme Inhib Med Chem 2020; 35:759-772. [PMID: 32183548 PMCID: PMC7144234 DOI: 10.1080/14756366.2020.1740696] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.
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Affiliation(s)
- Runwei Jiao
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Fanxing Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Xiaofang Huang
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Haonan Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Weiwei Liu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Hao Cao
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Linghe Zang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Zhanlin Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, P. R. China
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Henry MN, MacDonald MA, Orellana CA, Gray PP, Gillard M, Baker K, Nielsen LK, Marcellin E, Mahler S, Martínez VS. Attenuating apoptosis in Chinese hamster ovary cells for improved biopharmaceutical production. Biotechnol Bioeng 2020; 117:1187-1203. [DOI: 10.1002/bit.27269] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/25/2019] [Accepted: 01/04/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Matthew N. Henry
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
| | - Michael A. MacDonald
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
| | - Camila A. Orellana
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
| | - Peter P. Gray
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
| | - Marianne Gillard
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
| | - Kym Baker
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
- Patheon Biologics—A Part of Thermo Fisher Scientific Brisbane Queensland Australia
| | - Lars K. Nielsen
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
- Metabolomics Australia The University of Queensland Brisbane Queensland Australia
- The Novo Nordisk Foundation Center for Biosustainability Technical University of Denmark Kgs. Lyngby Denmark
| | - Esteban Marcellin
- Australian Institute for Bioengineering and Nanotechnology (AIBN) The University of Queensland Brisbane Queensland Australia
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
- Metabolomics Australia The University of Queensland Brisbane Queensland Australia
| | - Stephen Mahler
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
| | - Verónica S. Martínez
- ARC Training Centre for Biopharmaceutical Innovation (CBI) Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland Brisbane Queensland Australia
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Kowaltowski AJ, Oliveira MF. Mitochondria: New developments in pathophysiology. Mol Aspects Med 2019; 71:100841. [PMID: 31899000 DOI: 10.1016/j.mam.2019.100841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 12/27/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Alicia J Kowaltowski
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, SP, Brazil.
| | - Marcus F Oliveira
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, RJ, Brazil.
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Insights into mechanisms of pranoprofen-induced apoptosis and necroptosis in human corneal stromal cells. Toxicol Lett 2019; 320:9-18. [PMID: 31765691 DOI: 10.1016/j.toxlet.2019.11.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 11/15/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022]
Abstract
Pranoprofen (PPF) is a wildly used anti-inflammatory ophthalmic drug. It was reported that PPF could decrease early epithelialization of scrape wounds in rabbit cornea and could reduce cell activities of cultured human corneal endothelial cells. However, effects of PPF on corneal stromal cells playing important roles in corneal wound healing remain unknown. In this study,in vitro model of cultured human corneal stomal (HCS) cells and in vivo model of rabbit corneas were used to investigate the effects and underlying mechanisms of PPF. Our findings showed that high concentrations of PPF treatment (0.1 % to 0.0125 %) caused limited chromatin condensation and quickly decreased cell viability that was proved to initiate necroptosis in HCS cells through activating receptor interacting protein kinase (RIPK) and mixed lineage kinase domain-like (MLKL). While low concentrations of PPF treatment (0.00625 %) induced DNA fragmentation, apoptotic body formation, ROS generation, activation of caspases and increase in cytoplasmic content of Bad, Bax and cytoplasmic cytochrome c that suggested apoptosis happened through ROS-mediated caspase-dependent and caspase-independent pathways. Studies of rabbit corneas treated with 0.1 % PPF (the clinical concentration) showed that PPF could induce apoptosis of rabbit corneal stromal cells. This work would be helpful for better understanding cytotoxic effects PPF on human corneal cells.
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Chaanine AH. Morphological Stages of Mitochondrial Vacuolar Degeneration in Phenylephrine-Stressed Cardiac Myocytes and in Animal Models and Human Heart Failure. ACTA ACUST UNITED AC 2019; 55:medicina55060239. [PMID: 31163678 PMCID: PMC6630802 DOI: 10.3390/medicina55060239] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/04/2019] [Accepted: 05/31/2019] [Indexed: 01/13/2023]
Abstract
Background and objectives: Derangements in mitochondrial integrity and function constitute an important pathophysiological feature in the pathogenesis of heart failure (HF) and play an important role in myocardial remodeling and systolic dysfunction. In systolic HF, we and others have shown an imbalance in mitochondrial dynamics toward mitochondrial fission and fragmentation with evidence of mitophagy, mitochondrial vacuolar degeneration, and impairment in mitochondrial oxidative capacity. The morphological stages of mitochondrial vacuolar degeneration have not been defined. We sought to elucidate the progressive stages of mitochondrial vacuolar degeneration, which would serve as a measure to define, morphologically, the severity of mitochondrial damage. Materials and Methods: Transmission electron microscopy was used to study mitochondrial morphology and pathology in phenylephrine-stressed cardiac myocytes in vitro and in left ventricular myocardium from a rat model of pressure overload induced systolic dysfunction and from patients with systolic HF. Results: In phenylephrine-stressed cardiomyocytes for two hours, alterations in mitochondrial cristae morphology (Stage A) and loss and dissolution of mitochondrial cristae in one (Stage B) or multiple (early Stage B→C) mitochondrion area(s) were evident in the earliest stages of mitochondrial vacuolar degeneration. Mitochondrial swelling and progressive dissolution of mitochondrial cristae (advanced Stage B→C), followed by complete loss and dissolution of mitochondrial cristae and permeabilization and destruction of inner mitochondrial membrane (Stage C) then outer mitochondrial membrane rupture (Stage D) constituted advanced stages of mitochondrial vacuolar degeneration. Similar morphological changes in mitochondrial vacuolar degeneration were seen in vivo in animal models and in patients with systolic HF; where about 60-70% of the mitochondria are mainly observed in stages B→C and fewer in stages C and D. Conclusion: Mitochondrial vacuolar degeneration is a prominent mitochondrial morphological feature seen in HF. Defining the progressive stages of mitochondrial vacuolar degeneration would serve as a measure to assess morphologically the severity of mitochondrial damage.
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Affiliation(s)
- Antoine H Chaanine
- Division of cardiovascular diseases, Mayo Clinic, Rochester, MN 55902, USA.
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36
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Bloemberg D, Quadrilatero J. Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle. Am J Physiol Cell Physiol 2019; 317:C111-C130. [PMID: 31017800 DOI: 10.1152/ajpcell.00261.2018] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Apoptosis and autophagy are processes resulting from the integration of cellular stress and death signals. Their individual importance is highlighted by the lethality of various mouse models missing apoptosis or autophagy-related genes. In addition to their independent roles, significant overlap exists with respect to the signals that stimulate these processes as well as their effector consequences. While these cellular systems exemplify the programming redundancies that underlie many fundamental biological mechanisms, their intertwined relationship means that dysfunction can promote pathology. Although both autophagic and apoptotic signaling are active in skeletal muscle during various diseases and atrophy, their specific roles here are somewhat unique. Given our growing understanding of how specific changes at the cellular level impact whole-organism physiology, there is an equally growing interest in pharmacological manipulation of apoptosis and/or autophagy for altering human physiology and health.
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Affiliation(s)
- Darin Bloemberg
- Department of Kinesiology, University of Waterloo , Waterloo, Ontario , Canada
| | - Joe Quadrilatero
- Department of Kinesiology, University of Waterloo , Waterloo, Ontario , Canada
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Zhu J, Xu J, Jiang LL, Huang JQ, Yan JY, Chen YW, Yang Q. Improved antitumor activity of cisplatin combined with Ganoderma lucidum polysaccharides in U14 cervical carcinoma-bearing mice. Kaohsiung J Med Sci 2019; 35:222-229. [PMID: 30958641 DOI: 10.1002/kjm2.12020] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 01/20/2019] [Indexed: 02/01/2023] Open
Abstract
Research on anticervical cancer is urgently required to enhance clinical outcomes. As a main anticancer drug for cervical carcinoma, cisplatin (CIS) has been used for a lot of years in clinical therapy. However, serious adverse effects including nephrotoxicity and neurotoxicity limit its long-term treatment. Our main goal of this study is to investigate the improvement of Ganoderma lucidum polysaccharides (GPS) on CIS-induced antitumor effect of in U14 cervical carcinoma-bearing mice. The results showed that GPS + CIS could not only inhibit the growth of the tumor but also improve the spleen and thymus indexes. Moreover, little toxicological effects were observed on hepatic function and renal function in GPS + CIS treated mice bearing U14 tumor cells. Further analysis of the tumor inhibition mechanism indicated that the number of apoptotic tumor cells increased significantly, the expression of Bax increased and the expression of Bcl-2 decreased dramatically in cervical cancer sections after oral administration of GPS + CIS for 14 days. This GPS/CIS combined therapy represents intriguing therapeutic strategy for U14 cervical carcinoma providing not only superior efficacy but also a higher safety level.
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Affiliation(s)
- Jun Zhu
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Jia Xu
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Ling-Ling Jiang
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Jin-Qun Huang
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Jin-Yu Yan
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Yi-Wan Chen
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
| | - Qian Yang
- Department of Gynaecology and Obstetrics, First People's Hospital of Wenling, Wenling, China
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38
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A Disturbance in the Force: Cellular Stress Sensing by the Mitochondrial Network. Antioxidants (Basel) 2018; 7:antiox7100126. [PMID: 30249006 PMCID: PMC6211095 DOI: 10.3390/antiox7100126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/13/2018] [Accepted: 09/17/2018] [Indexed: 12/15/2022] Open
Abstract
As a highly dynamic organellar network, mitochondria are maintained as an organellar network by delicately balancing fission and fusion pathways. This homeostatic balance of organellar dynamics is increasingly revealed to play an integral role in sensing cellular stress stimuli. Mitochondrial fission/fusion balance is highly sensitive to perturbations such as loss of bioenergetic function, oxidative stress, and other stimuli, with mechanistic contribution to subsequent cell-wide cascades including inflammation, autophagy, and apoptosis. The overlapping activity with m-AAA protease 1 (OMA1) metallopeptidase, a stress-sensitive modulator of mitochondrial fusion, and dynamin-related protein 1 (DRP1), a regulator of mitochondrial fission, are key factors that shape mitochondrial dynamics in response to various stimuli. As such, OMA1 and DRP1 are critical factors that mediate mitochondrial roles in cellular stress-response signaling. Here, we explore the current understanding and emerging questions in the role of mitochondrial dynamics in sensing cellular stress as a dynamic, responsive organellar network.
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39
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Lee YJ, Lee C. Porcine deltacoronavirus induces caspase-dependent apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway. Virus Res 2018; 253:112-123. [PMID: 29940190 PMCID: PMC7114866 DOI: 10.1016/j.virusres.2018.06.008] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/09/2018] [Accepted: 06/20/2018] [Indexed: 01/23/2023]
Abstract
Porcine deltacoronavirus (PDCoV), a newly discovered enteric coronavirus, is a causative agent of severe clinical diarrhea and intestinal pathological damage in piglets. As a first step toward understanding the effect of PDCoV on host cells, we elucidated mechanisms underlying the process of apoptotic cell death after PDCoV infection. The use of a pan-caspase inhibitor resulted in the inhibition of PDCoV-induced apoptosis and reduction of PDCoV replication, suggestive of the association of a caspase-dependent pathway. Furthermore, PDCoV infection necessitated the activation of the initiator caspase-9 responsible for the intrinsic mitochondrial apoptosis pathway. Experimental data indicated that PDCoV infection led to Bax-mediated mitochondrial outer membrane permeabilization (MOMP), resulting in specific relocation of the mitochondrial cytochrome c (cyt c) into the cytoplasm. Treatment with cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP) opening, significantly suppressed PDCoV-triggered apoptosis and viral replication. Moreover, cyt c release was completely abrogated in PDCoV-infected cells in the presence of CsA, suggesting the critical role of MPTP in intrinsic apoptosis in response to PDCoV infection. Altogether, our results indicate that PDCoV infection stimulates MOMP either via Bax recruitment or MPTP opening to permit the release of apoptogenic cyt c into the cytoplasm, thereby leading to execution of the caspase-dependent intrinsic apoptosis pathway to facilitate viral replication in vitro.
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Affiliation(s)
- Yoo Jin Lee
- Animal Virology Laboratory, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Changhee Lee
- Animal Virology Laboratory, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea.
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40
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Lewerenz J, Ates G, Methner A, Conrad M, Maher P. Oxytosis/Ferroptosis-(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System. Front Neurosci 2018; 12:214. [PMID: 29731704 PMCID: PMC5920049 DOI: 10.3389/fnins.2018.00214] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 03/19/2018] [Indexed: 12/12/2022] Open
Abstract
Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron. Since then there has been a great deal of discussion in the literature about whether these are two distinct pathways or cell type- and insult-dependent variations on the same pathway. In this review, we compare and contrast in detail the commonalities and distinctions between the two pathways concluding that the molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical. Thus, we suggest that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway. In addition, we describe the potential physiological relevance of oxytosis/ferroptosis in multiple neurological diseases.
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Affiliation(s)
- Jan Lewerenz
- Department of Neurology, Ulm University, Ulm, Germany
| | - Gamze Ates
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, United States
| | - Axel Methner
- Department of Neurology, University Medical Center and Focus Program Translational Neuroscience of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Marcus Conrad
- Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Pamela Maher
- Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, United States
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41
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Jadaun P, Yadav D, Bisen PS. Spirulina platensis prevents high glucose-induced oxidative stress mitochondrial damage mediated apoptosis in cardiomyoblasts. Cytotechnology 2018; 70:523-536. [PMID: 28702859 PMCID: PMC5851949 DOI: 10.1007/s10616-017-0121-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 07/05/2017] [Indexed: 12/26/2022] Open
Abstract
The current study was undertaken to study the effect of Spirulina platensis (Spirulina) extract on enhanced oxidative stress during high glucose induced cell death in H9c2 cells. H9c2 cultured under high glucose (33 mM) conditions resulted in a noteworthy increase in oxidative stress (free radical species) accompanied by loss of mitochondrial membrane potential, release of cytochrome c, increase in caspase activity and pro-apoptotic protein (Bax). Spirulina extract (1 μg/mL), considerably inhibited increased ROS and RNS levels, reduction in cytochrome c release, raise in mitochondrial membrane potential, decreased the over expression of proapoptotic protein Bax and suppressed the Bax/Bcl2 ratio with induced apoptosis without affecting cell viability. Overall results suggest that Spirulina extract plays preventing role against enhanced oxidative stress during high glucose induced apoptosis in cardiomyoblasts as well as related dysfunction in H9c2 cells.
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Affiliation(s)
- Pratiksha Jadaun
- School of Studies in Biotechnology, Jiwaji University, Gwalior, 474011 MP India
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, Kangwon-Do 712-749 Korea
| | - Prakash Singh Bisen
- School of Studies in Biotechnology, Jiwaji University, Gwalior, 474011 India
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42
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Li C, Wang K, Guo L, Sun H, Huang H, Lin X, Li Q. Inhibition of miR-34a-5p alleviates hypoxia-reoxygenation injury by enhancing autophagy in steatotic hepatocytes. Biol Open 2018; 7:7/3/bio033290. [PMID: 29581146 PMCID: PMC5898271 DOI: 10.1242/bio.033290] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hypoxia-reoxygenation (H/R) injury in steatotic hepatocytes has been implicated in liver dysfunction after liver transplantation. MicroRNAs (miRs) play important roles in regulating several cell biology mechanisms related to H/R injury. However, the role of miRs in regulating H/R injury in steatotic hepatocytes is still unclear. We established an in vitro model for studying H/R injury in steatotic hepatocytes and identified miR-34a-5p as a miR that was substantially upregulated in steatotic hepatocytes under H/R challenge. MiR-34a-5p expression was modified by transfecting miR-34a-5p mimic and inhibitor into H/R-challenged steatotic hepatocytes. We found that inhibition of miR-34a-5p alleviated H/R-induced apoptosis and promoted post-H/R proliferation in steatotic hepatocytes. Whereas, overexpression of miR-34a-5p augmented H/R-induced apoptosis and prohibited post-H/R proliferation. By examining autophagy, our data demonstrated that miR-34a-5p suppressed autophagy in H/R-challenged steatotic hepatocytes, induction of autophagy partially rescued the exaggeration of H/R injury induced by miR-34a-5p mimic, while inhibition of autophagy impaired the protection of the miR-34a-5p inhibitor against H/R injury. In conclusion, miR-34a-5p is crucial in exaggerating H/R injury, likely by suppressing autophagy in steatotic hepatocytes. Inhibition of miR-34a may be a promising strategy to protect steatotic hepatocytes against H/R-injury.
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Affiliation(s)
- Chuanjiang Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China .,Department of Surgery, Linzhi Municipal People's Hospital, Linzhi, Tibet 860100, China
| | - Kai Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Linghong Guo
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Hang Sun
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Hai Huang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - XinXin Lin
- The First Clinical College, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Qingping Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
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Bano D, Prehn JHM. Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer. EBioMedicine 2018; 30:29-37. [PMID: 29605508 PMCID: PMC5952348 DOI: 10.1016/j.ebiom.2018.03.016] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 03/05/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022] Open
Abstract
Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms of onset, organ involvement and symptoms. Finally, we summarize how the study of AIFM1-linked pathologies may help to further expand our understanding of rare inherited forms of mitochondrial diseases.
AIF is a mitochondrial NADH-dependent oxidoreductase. Nuclear translocation of AIF occurs during cell death and has been associated with human disorders. Under physiological settings, AIF participates to the biogenesis of the respiratory complexes. AIFM1 mutations have been identified in patients with impaired mitochondrial bioenergetics. Inherited AIFM1 mutations lead to a variety of clinical manifestations, including severe childhood-onset mitochondrial diseases.
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Affiliation(s)
- Daniele Bano
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin 2, Ireland
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The sirtuin 1/2 inhibitor tenovin-1 induces a nonlinear apoptosis-inducing factor-dependent cell death in a p53 null Ewing’s sarcoma cell line. Invest New Drugs 2017; 36:396-406. [DOI: 10.1007/s10637-017-0541-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/10/2017] [Indexed: 01/30/2023]
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45
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Shanmugapriya, Chen Y, Kanwar JR, Sasidharan S. Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells. Nutr Cancer 2017; 69:1308-1324. [PMID: 29068745 DOI: 10.1080/01635581.2017.1367944] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
This study was conducted to investigate the anticancer effects and mechanism of Calophyllum inophyllum fruit extract against MCF-7 cells. C. inophyllum fruit extract was found to have markedly cytotoxic effect against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 23.59 µg/mL. Flow cytometry analysis revealed that C. inophyllum fruit extract mediated cell cycle at G0/G1 and G2/M phases, and MCF-7 cells entered the early phase of apoptosis. The expression of anti-apoptotic proteins Bcl-2 was decreased whereas the expression of the pro-apoptotic protein Bax, cytochrome C and p53 were increased after treatment. C. inophyllum fruit extract led to apoptosis in MCF-7 cells via the mitochondrial pathway in a dose dependent manner. This is evidenced by the elevation of intracellular ROS, the loss of mitochondria membrane potential (Δψm), and activation of caspase-3. Meanwhile, dose-dependent genomic DNA fragmentation was observed after C. inophyllum fruits extract treatment by comet assay. This study shows that C. inophyllum fruits extract-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3. C. inophyllum fruit extract could be an excellent source of chemopreventive agent in the treatment of breast cancer and has potential to be explored as green anticancer agent.
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Affiliation(s)
- Shanmugapriya
- a Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia , Pulau Pinang , Malaysia
| | - Yeng Chen
- b Department of Oral & Craniofacial Sciences, and Oral Cancer Research and Coordinating Center (OCRCC) , Faculty of Dentistry, University of Malaya , Kuala Lumpur , Malaysia
| | - Jagat R Kanwar
- c Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (LIMBR), School of Medicine (SoM), Faculty of Health, Deakin University , Waurn Ponds , VIC , Australia
| | - Sreenivasan Sasidharan
- a Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia , Pulau Pinang , Malaysia
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Zhang Y, Chang Y, Cao H, Xu W, Li Z, Tao L. Potential threat of Chlorpyrifos to human liver cells via the caspase-dependent mitochondrial pathways. FOOD AGR IMMUNOL 2017. [DOI: 10.1080/09540105.2017.1373271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Yang Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
| | - Yuansen Chang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
| | - Haijing Cao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
| | - Wenping Xu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
| | - Zhong Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
| | - Liming Tao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China
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TMEM16A exacerbates renal injury by activating P38/JNK signaling pathway to promote podocyte apoptosis in diabetic nephropathy mice. Biochem Biophys Res Commun 2017; 487:201-208. [PMID: 28392397 DOI: 10.1016/j.bbrc.2017.04.021] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 04/05/2017] [Indexed: 11/20/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common microvascular complication of diabetes mellitus (DM) as well as the main reason resulting in chronic renal failure. Transmembrane protein 16A (TMEM16A) plays an important role in multiple physiological actions. Here we found that it was up-regulated in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) amplification, Western blot detection, Periodic Acid Schiff (PAS) staining and immunohistochemical analysis confirmed that TMEM16A deficiency alleviated renal injury in diabetic mice and TMEM16A knockout diabetic mice were protected from the HFD-induced reduction in Nephrin expression. To understand further the molecular mechanism of its function, podocytes treated with high glucose (HG, 30 mmol/L glucose) in vitro was chosen as a model to study its signal transduction pathway. Nephrin expression level in siRNA-TMEM16A group was significantly higher than that of the HG group (also called Model group). Flow cytometric analysis revealed that podocyte apoptosis in siRNA-TMEM16A group was significantly lower than that of the Model group. RT-PCR and Western blot exhibited that apoptosis-related genes including apoptosis-inducing factor (AIF) and cystinylaspartate specific protease-3/-9 (caspase-3/-9) were dramatically down regulated in siRNA-TMEM16A group, compared with Model group. Phosphorylation levels of P38 and JNK in siRNA-TMEM16A group were lower than that of the Model group. Thus, TMEM16A is one of the critical components of a signal transduction pathway that links renal injury to podocyte apoptosis in DN.
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D'Orsi B, Mateyka J, Prehn JHM. Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok. Neurochem Int 2017; 109:162-170. [PMID: 28315370 DOI: 10.1016/j.neuint.2017.03.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/07/2017] [Accepted: 03/09/2017] [Indexed: 01/14/2023]
Abstract
Neuronal cell death is often triggered by events that involve intracellular increases in Ca2+. Under resting conditions, the intracellular Ca2+ concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca2+ overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca2+-dependent cell death. Excessive Ca2+ entry though glutamate receptors (excitotoxicity) has been implicated in several neurologic and chronic neurodegenerative diseases, including ischemic stroke, epilepsy, and Alzheimer's disease. Recent evidence has revealed that excitotoxic cell death is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins. Bcl-2 proteins, comprising of both pro-apoptotic and anti-apoptotic members, have been shown to not only mediate the intrinsic apoptosis pathway by controlling mitochondrial outer membrane (MOM) integrity, but to also control neuronal Ca2+ homeostasis and energetics. In this review, the role of Bcl-2 family proteins in the regulation of apoptosis, their expression in the central nervous system and how they control Ca2+-dependent neuronal injury are summarized. We review the current knowledge on Bcl-2 family proteins in the regulation of mitochondrial function and bioenergetics, including the fusion and fission machinery, and their role in Ca2+ homeostasis regulation at the mitochondria and ER. Specifically, we discuss how the 'pro-apoptotic' Bcl-2 family proteins, Bax and Bok, physiologically expressed in the nervous system, regulate such 'non-apoptotic/daytime' functions.
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Affiliation(s)
- Beatrice D'Orsi
- Department of Physiology & Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Julia Mateyka
- Department of Physiology & Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
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Mohammadi-Bardbori A, Bastan F, Akbarizadeh AR. The highly bioactive molecule and signal substance 6-formylindolo[3,2-b]carbazole (FICZ) plays bi-functional roles in cell growth and apoptosis in vitro. Arch Toxicol 2017; 91:3365-3372. [DOI: 10.1007/s00204-017-1950-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 02/23/2017] [Indexed: 01/12/2023]
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Molecular Biology Digest of Cell Mitophagy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 332:233-258. [PMID: 28526134 DOI: 10.1016/bs.ircmb.2016.12.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The homeostasis of eukaryotic cells relies on efficient mitochondrial function. The control of mitochondrial quality is framed by the combination of distinct but interdependent mechanisms spanning biogenesis, regulation of dynamic network, and finely tuned degradation either through ubiquitin-proteasome system or autophagy (mitophagy). There is continuous evolution on the pathways orchestrating the mitochondrial response to stress signals and the organelle adaptation to quality control during acute and subtle dysfunctions. Notably, it remains indeed ill-defined whether active mitophagy leads to cell survival or death by defective mitochondrial degradation. Above all, uncharted is whether and how pharmacologically tackle these mechanisms may lead to conceive novel therapeutic strategies for treating conditions associated with the defective mitochondria. Here, we attempt to provide a chronological and comprehensive overview of the determining discoveries, which have led to the current knowledge of mitophagy.
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