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1
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Amini M, Frisch J, Jost P, Sarakpi T, Selejan SR, Becker E, Sellier A, Engel J, Böhm M, Hohl M, Noels H, Maack C, Schunk S, Roma LP, Niemeyer BA, Speer T, Alansary D. Purinergic receptor P2X7 regulates interleukin-1α mediated inflammation in chronic kidney disease in a reactive oxygen species-dependent manner. Kidney Int 2025; 107:457-475. [PMID: 39571908 DOI: 10.1016/j.kint.2024.10.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 10/11/2024] [Accepted: 10/17/2024] [Indexed: 01/12/2025]
Abstract
Onset, progression and cardiovascular outcome of chronic kidney disease (CKD) are influenced by the concomitant sterile inflammation. The pro-inflammatory cytokine family interleukin (IL)-1 is crucial in CKD with the key alarmin IL-1α playing an additional role as an adhesion molecule that facilitates immune cell tissue infiltration and consequently inflammation. Here, we investigate calcium ion and reactive oxygen species (ROS)-dependent regulation of different aspects of IL-1α-mediated inflammation. We show that human CKD monocytes exhibit altered purinergic calcium ion signatures. Monocyte IL-1α release was reduced when inhibiting P2X7, and to a lesser extent P2X4, two ATP-receptors that were found upregulated compared to monocytes from healthy people. In murine CKD models, deleting P2X7 (P2X7-/-) abolished IL-1α release but increased IL-1α surface presentation by bone marrow derived macrophages and impaired immune cell infiltration of the kidney without protecting kidney function. In contrast, immune cell infiltration into injured wild type and P2X7-/- hearts was comparable in a myocardial infarction model, independent of previous kidney injury. Both the chimeric mouse line harboring P2X7-/- immune cells in wild type recipient mice, and the inversely designed chimeric line showed less acute inflammation. However, only the chimera harboring P2X7-/- immune cells showed a striking resistance against injury-induced cardiac remodeling. Mechanistically, ROS measurements reveal P2X7-induced mitochondrial ROS as an essential factor for IL-1α release by monocytes. Our studies uncover a dual role of P2X7 in regulating IL-1α biogenesis with consequences for inflammation and inflammation-induced deleterious cardiac remodeling that may determine clinical outcomes in CKD therapies.
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MESH Headings
- Animals
- Receptors, Purinergic P2X7/genetics
- Receptors, Purinergic P2X7/metabolism
- Receptors, Purinergic P2X7/immunology
- Interleukin-1alpha/metabolism
- Interleukin-1alpha/immunology
- Renal Insufficiency, Chronic/immunology
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Reactive Oxygen Species/metabolism
- Humans
- Mice
- Mice, Knockout
- Monocytes/metabolism
- Monocytes/immunology
- Disease Models, Animal
- Inflammation/immunology
- Inflammation/metabolism
- Male
- Macrophages/immunology
- Macrophages/metabolism
- Kidney/immunology
- Kidney/pathology
- Kidney/metabolism
- Receptors, Purinergic P2X4/metabolism
- Mice, Inbred C57BL
- Purinergic P2X Receptor Antagonists/pharmacology
- Calcium/metabolism
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Affiliation(s)
- Maryam Amini
- Molecular Biophysics, Saarland University, Homburg, Germany
| | - Janina Frisch
- Institute of Biophysics, Saarland University, Homburg, Germany; Center of Human and Molecular Biology (ZHMB), Saarland University, Homburg, Germany; Center for Gender-Specific Biology and Medicine (CGBM), Saarland University, Homburg, Germany
| | - Priska Jost
- Molecular Biophysics, Saarland University, Homburg, Germany
| | - Tamim Sarakpi
- Department of Internal Medicine 4, Nephrology, Goethe University Frankfurt, Frankfurt, Germany; Goethe University Frankfurt, Else Kröner Fresenius Center for Nephrological Research, Frankfurt, Germany
| | - Simina-Ramona Selejan
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University, Homburg, Germany
| | - Ellen Becker
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, Homburg, Germany
| | - Alexander Sellier
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, Homburg, Germany
| | - Jutta Engel
- Institute of Biophysics, Saarland University, Homburg, Germany
| | - Michael Böhm
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University, Homburg, Germany
| | - Mathias Hohl
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University, Homburg, Germany
| | - Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital RWTH Aachen, Aachen, Germany
| | - Christoph Maack
- Medical Clinic 1, University Clinic Würzburg, Würzburg, Germany
| | - Stefan Schunk
- Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, Homburg, Germany
| | - Leticia Prates Roma
- Institute of Biophysics, Saarland University, Homburg, Germany; Center of Human and Molecular Biology (ZHMB), Saarland University, Homburg, Germany; Center for Gender-Specific Biology and Medicine (CGBM), Saarland University, Homburg, Germany
| | | | - Thimoteus Speer
- Department of Internal Medicine 4, Nephrology, Goethe University Frankfurt, Frankfurt, Germany; Goethe University Frankfurt, Else Kröner Fresenius Center for Nephrological Research, Frankfurt, Germany
| | - Dalia Alansary
- Molecular Biophysics, Saarland University, Homburg, Germany.
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2
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Ulrich H, Glaser T, Thomas AP. Purinergic signaling in liver disease: calcium signaling and induction of inflammation. Purinergic Signal 2025; 21:69-81. [PMID: 39320433 PMCID: PMC11958897 DOI: 10.1007/s11302-024-10044-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 08/15/2024] [Indexed: 09/26/2024] Open
Abstract
Purinergic signaling regulates many metabolic functions and is implicated in liver physiology and pathophysiology. Liver functionality is modulated by ionotropic P2X and metabotropic P2Y receptors, specifically P2Y1, P2Y2, and P2Y6 subtypes, which physiologically exert their influence through calcium signaling, a key second messenger controlling glucose and fat metabolism in hepatocytes. Purinergic receptors, acting through calcium signaling, play an important role in a range of liver diseases. Ionotropic P2X receptors, such as the P2X7 subtype, and certain metabotropic P2Y receptors can induce aberrant intracellular calcium transients that impact normal hepatocyte function and initiate the activation of other liver cell types, including Kupffer and stellate cells. These P2Y- and P2X-dependent intracellular calcium increases are particularly relevant in hepatic disease states, where stellate and Kupffer cells respond with innate immune reactions to challenges, such as excess fat accumulation, chronic alcohol abuse, or infections, and can eventually lead to liver fibrosis. This review explores the consequences of excessive extracellular ATP accumulation, triggering calcium influx through P2X4 and P2X7 receptors, inflammasome activation, and programmed cell death. In addition, P2Y2 receptors contribute to hepatic steatosis and insulin resistance, while inhibiting the expression of P2Y6 receptors can alleviate alcoholic liver steatosis. Adenosine receptors may also contribute to fibrosis through extracellular matrix production by fibroblasts. Thus, pharmacological modulation of P1 and P2 receptors and downstream calcium signaling may open novel therapeutic avenues.
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Affiliation(s)
- Henning Ulrich
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
| | - Talita Glaser
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
| | - Andrew P Thomas
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
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3
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Hirata Y, Yamada Y, Taguchi S, Kojima R, Masumoto H, Kimura S, Niijima T, Toyama T, Kise R, Sato E, Uchida Y, Ito J, Nakagawa K, Taguchi T, Inoue A, Saito Y, Noguchi T, Matsuzawa A. Conjugated fatty acids drive ferroptosis through chaperone-mediated autophagic degradation of GPX4 by targeting mitochondria. Cell Death Dis 2024; 15:884. [PMID: 39643606 PMCID: PMC11624192 DOI: 10.1038/s41419-024-07237-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: 02/07/2024] [Revised: 11/04/2024] [Accepted: 11/08/2024] [Indexed: 12/09/2024]
Abstract
Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
| | - Yuto Yamada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Soma Taguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Ryota Kojima
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Haruka Masumoto
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Shinnosuke Kimura
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takuya Niijima
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takashi Toyama
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Ryoji Kise
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yasunori Uchida
- Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Junya Ito
- Laboratory of Food Function Analysis, Graduate School of Agricultural Sciences, Tohoku University, Sendai, Japan
| | - Kiyotaka Nakagawa
- Laboratory of Food Function Analysis, Graduate School of Agricultural Sciences, Tohoku University, Sendai, Japan
| | - Tomohiko Taguchi
- Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Asuka Inoue
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
| | - Yoshiro Saito
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
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4
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Jang E, Kim C, Noh J, Yi H, Jo S, Park JS, Hwang W, Cha JY, Cho ML, Kim TH, Youn J. Bach2 repression of CD36 regulates lipid-metabolism-linked effector functions in follicular B cells. Cell Rep 2024; 43:114878. [PMID: 39412989 DOI: 10.1016/j.celrep.2024.114878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/24/2024] [Accepted: 09/30/2024] [Indexed: 10/18/2024] Open
Abstract
The transcription repressor Bach2 plays a crucial role in shaping humoral immunity, but its cell-autonomous function remains elusive. Here, we reveal the mechanism by which Bach2 regulates effector cell maturation in peripheral B cells. In response to Toll-like receptor (TLR) agonists, Bach2 deficiency promotes the differentiation of follicular, but not marginal zone, B cells into effector cells, producing interleukin (IL)-6 and antibodies. This phenomenon is associated with changes in lipid metabolism, such as increases in CD36 expression, lipid influx, and fatty acid oxidation. Consistent with this, Bach2-deficient B cells exhibit elevated levels of mitochondrial oxidative stress, lipid peroxidation, and p38 activation. Mechanistically, Bach2 acts as a repressor of Cd36, and inhibition of CD36 or fatty acid oxidation reduces the differentiation of naive B cells into IL-6- and antibody-secreting cells. These results indicate Bach2 as a key metabolic checkpoint regulator crucial for maintaining a functionally quiescent state of follicular B cells.
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Affiliation(s)
- Eunkyeong Jang
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul 04763, Korea.
| | - ChangYeon Kim
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Jeonghyun Noh
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Hansol Yi
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea
| | - Sungsin Jo
- Hanyang University Institute for Rheumatology Research (HYIRR), Hanyang University, Seoul 04763, Korea
| | - Jin-Sil Park
- Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
| | - Woochang Hwang
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Korea; Department of Pre-Medicine, College of Medicine, Hanyang University, Seoul 04763, Korea
| | - Ji-Young Cha
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21936, Korea
| | - Mi-La Cho
- Rheumatism Research Center, Catholic Institutes of Medical Science, The Catholic University of Korea, Seoul 06591, Korea
| | - Tae-Hwan Kim
- Hanyang University Institute for Rheumatology Research (HYIRR), Hanyang University, Seoul 04763, Korea
| | - Jeehee Youn
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul 04763, Korea; Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea.
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5
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Pedrão LFAT, Medeiros POS, Leandro EC, Falquetto B. Parkinson's disease models and death signaling: what do we know until now? Front Neuroanat 2024; 18:1419108. [PMID: 39533977 PMCID: PMC11555652 DOI: 10.3389/fnana.2024.1419108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/04/2024] [Indexed: 11/16/2024] Open
Abstract
Parkinson's disease (PD) is the second neurodegenerative disorder most prevalent in the world, characterized by the loss of dopaminergic neurons in the Substantia Nigra (SN). It is well known for its motor and non-motor symptoms including bradykinesia, resting tremor, psychiatric, cardiorespiratory, and other dysfunctions. Pathological apoptosis contributes to a wide variety of diseases including PD. Various insults and/or cellular phenotypes have been shown to trigger distinct signaling events leading to cell death in neurons affected by PD. The intrinsic or mitochondrial pathway, inflammatory or oxidative stress-induced extrinsic pathways are the main events associated with apoptosis in PD-related neuronal loss. Although SN is the main brain area studied so far, other brain nuclei are also affected by the disease leading to non-classical motor symptoms as well as non-motor symptoms. Among these, the respiratory symptoms are often overlooked, yet they can cause discomfort and may contribute to patients shortened lifespan after disease diagnosis. While animal and in vitro models are frequently used to investigate the mechanisms involved in the pathogenesis of PD in both the SN and other brain regions, these models provide only a limited understanding of the disease's actual progression. This review offers a comprehensive overview of some of the most studied forms of cell death, including recent research on potential treatment targets for these pathways. It highlights key findings and milestones in the field, shedding light on the potential role of understanding cell death in the prevention and treatment of the PD. Therefore, unraveling the connection between these pathways and the notable pathological mechanisms observed during PD progression could enhance our comprehension of the disease's origin and provide valuable insights into potential molecular targets for the developing therapeutic interventions.
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Affiliation(s)
| | | | | | - Barbara Falquetto
- Department of Pharmacology, Instituto de Ciências Biomédica, Universidade de Sao Paulo, Sao Paulo, Brazil
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6
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Hirata Y, Nakata Y, Komatsu H, Kudoh Y, Takahashi M, Taguchi S, Noguchi T, Matsuzawa A. Roquin-2 promotes oxidative stress-induced cell death by ubiquitination-dependent degradation of TAK1. Free Radic Biol Med 2024; 221:31-39. [PMID: 38729452 DOI: 10.1016/j.freeradbiomed.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/01/2024] [Accepted: 05/04/2024] [Indexed: 05/12/2024]
Abstract
Reactive oxygen species (ROS) are highly reactive and their accumulation causes oxidative damage to cells. Cells maintain survival upon mild oxidative stress with anti-oxidative systems, such as the kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) system. On the other hand, upon severe oxidative stress, cells undergo regulated cell death, including apoptosis, for eliminating damaged cells. To execute efficient cell death, cells need to turn off the anti-oxidant systems, while triggering cell death. However, it remains unknown how cells orchestrate these two conflicting systems under excessive oxidative stress. Herein, we show that when cells are exposed to excessive oxidative damage, an E3 ubiquitin ligase Roquin-2 (also known as RC3H2) plays a key role in switching cell fate from survival to death by terminating activation of transforming growth factor-β-activated kinase 1 (TAK1), a positive regulator for Nrf2 activation. Roquin-2 interacted with TAK1 via four cysteine residues in TAK1 (C96, C302, C486, and C500) that are susceptible to oxidative stress and participate in oligomer formation via disulfide bonds, promoting K48-linked polyubiquitination and degradation of TAK1. Nrf2 was inactivated upon lethal oxidative stress in wild-type mouse embryonic fibroblast (MEF) cells, whereas it sustained activation and conferred resistance to Roquin-2 deficient cells, which was reversed by pharmacological or genetic inhibition of TAK1. These data demonstrate that in response to excessive ROS exposure, Roquin-2 promotes ubiquitination and degradation of TAK1 to suppress Nrf2 activation, and thereby contributes to an efficient cell death, providing insight into the pathogenesis of oxidative stress-related diseases, including cancer.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Yuya Nakata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Hiromu Komatsu
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Yuki Kudoh
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Miki Takahashi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Soma Taguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.
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7
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Kagi T, Inoue A, Noguchi T, Suzuki W, Takano S, Otani K, Naganuma R, Sekiguchi Y, Hirata Y, Shindo S, Hwang GW, Matsuzawa A. The NLRP3 Inflammasome Is a Major Cause of Acute Renal Failure Induced by Polypeptide Antibiotics. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1807-1818. [PMID: 38639584 DOI: 10.4049/jimmunol.2300193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 03/16/2024] [Indexed: 04/20/2024]
Abstract
Drug-induced acute renal failure (ARF) is a public health concern that hinders optimal drug therapy. However, pathological mechanisms of drug-induced ARF remain to be elucidated. Here, we show that a pathological process of drug-induced ARF is mediated by proinflammatory cross-talk between kidney tubular cells and macrophages. Both polymyxin B and colistin, polypeptide antibiotics, frequently cause ARF, stimulated the ERK and NF-κB pathways in kidney tubular cells, and thereby upregulated M-CSF and MCP-1, leading to infiltration of macrophages into the kidneys. Thereafter, the kidney-infiltrated macrophages were exposed to polypeptide antibiotics, which initiated activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Interestingly, blockade of the NLRP3 activation clearly ameliorated the pathology of ARF induced by polypeptide antibiotics, suggesting that a combination of the distinct cellular responses to polypeptide antibiotics in kidney tubular cells and macrophages plays a key role in the pathogenesis of colistin-induced ARF. Thus, our results provide a concrete example of how drugs initiate ARF, which may give insight into the underlying pathological process of drug-induced ARF.
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Affiliation(s)
- Tomohiro Kagi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Aya Inoue
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Wakana Suzuki
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Saya Takano
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Kohei Otani
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Rio Naganuma
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yuto Sekiguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Sawako Shindo
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
- Department of Environmental Toxicology, Meiji Pharmaceutical University, Tokyo, Japan
| | - Gi-Wook Hwang
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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8
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Zhang HL, Doblin S, Zhang ZW, Song ZJ, Dinesh B, Tabana Y, Saad DS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Wu S, Zhao R, Khaled B. Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model. World J Clin Oncol 2024; 15:208-242. [PMID: 38455130 PMCID: PMC10915939 DOI: 10.5306/wjco.v15.i2.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/10/2023] [Accepted: 01/12/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Sandai Doblin
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Babu Dinesh
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Dahham Sabbar Saad
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Department of Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Universiti Sains Malaysia, Advanced Medical and Dental Institute, Penang 13200, Malaysia
| | - Sen Wu
- Department of Biomedical Science, Universiti Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Barakat Khaled
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
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9
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Khorashad JS, Rizzo S, Tonks A. Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:5. [PMID: 38434766 PMCID: PMC10905166 DOI: 10.20517/cdr.2023.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/24/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024]
Abstract
Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field.
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Affiliation(s)
- Jamshid Sorouri Khorashad
- Department of Immunology and inflammation, Imperial College London, London, W12 0NN, UK
- Department of Molecular Pathology, Institute of Cancer Research, Sutton, SM2 5PT, UK
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Sian Rizzo
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Alex Tonks
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
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10
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Zheng M, Liu K, Li L, Feng C, Wu G. Traditional Chinese medicine inspired dual-drugs loaded inhalable nano-therapeutics alleviated idiopathic pulmonary fibrosis by targeting early inflammation and late fibrosis. J Nanobiotechnology 2024; 22:14. [PMID: 38166847 PMCID: PMC10763202 DOI: 10.1186/s12951-023-02251-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a highly debilitating and fatal chronic lung disease that is difficult to cure clinically. IPF is characterized by a gradual decline in lung function, which leads to respiratory failure and severely affects patient quality of life and survival. Oxidative stress and chronic inflammation are believed to be important pathological mechanisms underlying the onset and progression of IPF, and the vicious cycle of NOX4-derived ROS, NLRP3 inflammasome activation, and p38 MAPK in pulmonary fibrogenesis explains the ineffectiveness of single-target or single-drug interventions. In this study, we combined astragaloside IV (AS-IV) and ligustrazine (LIG) based on the fundamental theory of traditional Chinese medicine (TCM) of "tonifying qi and activating blood" and loaded these drugs onto nanoparticles (AS_LIG@PPGC NPs) that were inhalable and could penetrate the mucosal barrier. Our results suggested that inhalation of AS_LIG@PPGC NPs significantly improved bleomycin-induced lung injury and fibrosis by regulating the NOX4-ROS-p38 MAPK and NOX4-NLRP3 pathways to treat and prevent IPF. This study not only demonstrated the superiority, feasibility, and safety of inhalation therapy for IPF intervention but also confirmed that breaking the vicious cycle of ROS and the NLRP3 inflammasome is a promising strategy for the successful treatment of IPF. Moreover, this successful nanoplatform is a good example of the integration of TCM and modern medicine.
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Affiliation(s)
- Meiling Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100010, China
- Peking University People's Hospital, Beijing, 100032, China
| | - Kai Liu
- Division of Pulmonary and Critical Care Medicine, Kunming Children's Hospital, Kunming, 650000, China
| | - Lei Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, National Clinical Research Center for Obstetric & Gynecologic Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100032, China.
| | - Cuiling Feng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100010, China.
- Peking University People's Hospital, Beijing, 100032, China.
| | - Guanghao Wu
- School of Materials Science & Engineering, Beijing Institute of Technology, Beijing, 100081, China.
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11
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Rahman SMT, Zhou W, Deiters A, Haugh JM. Dissection of MKK6 and p38 Signaling Using Light-Activated Protein Kinases. Chembiochem 2024; 25:e202300551. [PMID: 37856284 DOI: 10.1002/cbic.202300551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/18/2023] [Accepted: 10/18/2023] [Indexed: 10/21/2023]
Abstract
Stress-activated signaling pathways orchestrate cellular behaviors and fates. Studying the precise role(s) of stress-activated protein kinases is challenging, because stress conditions induce adaptation and impose selection pressure. To meet this challenge, we have applied an optogenetic system with a single plasmid to express light-activated p38α or its upstream activator, MKK6, in conjunction with live-cell fluorescence microscopy. In starved cells, decaging of constitutively active p38α or MKK6 by brief exposure to UV light elicits rapid p38-mediated signaling, release of cytochrome c from mitochondria, and apoptosis with different kinetics. In parallel, light activation of p38α also suppresses autophagosome formation, similarly to stimulation with growth factors that activate PI3K/Akt/mTORC1 signaling. Active MKK6 negatively regulates serum-induced ERK activity, which is p38-independent as previously reported. Here, we reproduce that result with the one plasmid system and show that although decaging active p38α does not reduce basal ERK activity in our cells, it can block growth factor-stimulated ERK signaling in serum-starved cells. These results clarify the roles of MKK6 and p38α in dynamic signaling programs, which act in concert to actuate apoptotic death while suppressing cell survival mechanisms.
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Affiliation(s)
- Shah Md Toufiqur Rahman
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, 911 Partners Way, Raleigh, NC, 27695, USA
| | - Wenyuan Zhou
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Alexander Deiters
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Jason M Haugh
- Department of Chemical and Biomolecular Engineering, North Carolina State University, Campus Box 7905, 911 Partners Way, Raleigh, NC, 27695, USA
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12
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Hirata Y, Kojima R, Ashida R, Nada Y, Kimura S, Sato E, Noguchi T, Matsuzawa A. Industrially produced trans-fatty acids are potent promoters of DNA damage-induced apoptosis. J Toxicol Sci 2024; 49:27-36. [PMID: 38191191 DOI: 10.2131/jts.49.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
trans-Fatty acids (TFAs) are unsaturated fatty acids harboring at least one carbon-carbon double bond in trans configuration, which are categorized into two groups according to their origin: industrial and ruminant TFAs, hereafter called iTFAs and rTFAs, respectively. Numerous epidemiological studies have shown a specific link of iTFAs to various diseases, such as cardiovascular and neurodegenerative diseases. However, there is little evidence for underlying mechanisms that can explain the specific toxicity of iTFAs, and how to mitigate their toxicity. Herein, we show that iTFAs, including elaidic acid (EA) and linoelaidic acid, but not rTFAs, facilitate apoptosis induced by doxorubicin (Dox), triggering DNA double-strand breaks. We previously established that EA promotes Dox-induced apoptosis by accelerating c-Jun N-terminal kinase (JNK) activation through mitochondrial reactive oxygen species (ROS) overproduction. Consistently, iTFAs specifically enhanced Dox-induced JNK activation. Furthermore, Dox-induced pro-apoptotic signaling by iTFAs was blocked in the presence of oleic acid (OA), the geometrical cis isomer of EA. These results demonstrate that iTFAs specifically exert their toxicity during DNA damage-induced apoptosis, which could be effectively suppressed by OA. Our study provides evidence for understanding the difference in toxic actions between TFA species, and for new strategies to prevent and combat TFA-related diseases.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Ryota Kojima
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Ryo Ashida
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Yuki Nada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Shinnosuke Kimura
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
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13
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Zhang HL, Sandai D, Zhang ZW, Song ZJ, Babu D, Tabana Y, Dahham SS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Zhao R, Barakat K, Harun MSR, Shapudin SNM, Lok B. Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy. World J Clin Oncol 2023; 14:549-569. [PMID: 38179405 PMCID: PMC10762532 DOI: 10.5306/wjco.v14.i12.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 12/22/2023] Open
Abstract
Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Doblin Sandai
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Dinesh Babu
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Sabbar Saad Dahham
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Khaled Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Mohammad Syamsul Reza Harun
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Siti Nurfatimah Mohd Shapudin
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Bronwyn Lok
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
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14
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Hirata Y, Kashiwabara N, Nada Y, Inoue A, Sato E, Noguchi T, Matsuzawa A. A comprehensive toxicological analysis of trans-fatty acids (TFAs) reveals a pro-apoptotic action specific to industrial TFAs counteracted by polyunsaturated FAs. Sci Rep 2023; 13:5883. [PMID: 37041254 PMCID: PMC10090069 DOI: 10.1038/s41598-023-32083-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 03/22/2023] [Indexed: 04/13/2023] Open
Abstract
trans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon-carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan
| | - Naoki Kashiwabara
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan
| | - Yuki Nada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan
| | - Aya Inoue
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.
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15
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von Mücke-Heim IA, Deussing JM. The P2X7 receptor in mood disorders: Emerging target in immunopsychiatry, from bench to bedside. Neuropharmacology 2023; 224:109366. [PMID: 36470368 DOI: 10.1016/j.neuropharm.2022.109366] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/09/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Psychiatric disorders are among the most burdensome disorders worldwide. Though therapies have evolved over the last decades, treatment resistance still affects many patients. Recently, neuroimmune systems have been identified as important factors of mood disorder biology. The underlying dysregulation in neuroimmune cross-talk is driven by genetic risk factors and accumulating adverse environmental influences like chronic psychosocial stress. These result in a cluster of proinflammatory cytokines and quantitative and functional changes of immune cell populations (e.g., microglia, monocytes, T cells), varying by disease entity and state. Among the emerging immune targets, purinergic signalling revolving around the membranous and ATP specific P2X7 receptor (P2X7R) has gained wider attention and clinical studies making use of antagonistic drugs are on-going. Still, no clinically meaningful applications have been identified so far. A major problem is the often overly simplified approach taken to translate findings from bench to bedside. Therefore, the present review focuses on purinergic signalling via P2X7R in the context of recent advances in immunopsychiatric mood disorder research. Our aim is to provide an overview of the current P2X7R-related findings, from bench to bedside. First, we summarize the characteristics of purinergic signalling and P2X7R, followed by a depiction of genetic and clinical data connecting P2X7R to mood disorders. We close with our perspective on current developments and discuss changes necessary to translate the evident potential of P2X7R signalling modulation into meaningful clinical application. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.
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Affiliation(s)
| | - Jan M Deussing
- Max Planck Institute for Psychiatry, Molecular Neurogenetics, Munich, Germany.
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16
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Alberto AVP, Ferreira NCDS, Bonavita AGC, Nihei OK, de Farias FP, Bisaggio RDC, de Albuquerque C, Savino W, Coutinho‐Silva R, Persechini PM, Alves LA. Physiologic roles of P2 receptors in leukocytes. J Leukoc Biol 2022; 112:983-1012. [PMID: 35837975 PMCID: PMC9796137 DOI: 10.1002/jlb.2ru0421-226rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/13/2022] [Indexed: 01/01/2023] Open
Abstract
Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system, purinergic receptors participate in innate immunity and in the modulation of the adaptive immune response. In particular, P2 receptors, which respond to extracellular nucleotides, are widely expressed on leukocytes, causing the release of cytokines and chemokines and the formation of inflammatory mediators, and inducing phagocytosis, degranulation, and cell death. The activity of these receptors is regulated by ectonucleotidases-expressed in these same cell types-which regulate the availability of nucleotides in the extracellular environment. In this article, we review the characteristics of the main purinergic receptor subtypes present in the immune system, focusing on the P2 family. In addition, we describe the physiologic roles of the P2 receptors already identified in leukocytes and how they can positively or negatively modulate the development of infectious diseases, inflammation, and pain.
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Affiliation(s)
- Anael Viana Pinto Alberto
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil
| | | | | | - Oscar Kenji Nihei
- Center of Education and LetterState University of the West of ParanáFoz do IguaçuPRBrazil
| | | | - Rodrigo da Cunha Bisaggio
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil,Federal Institute of Education, Science, and Technology of Rio de JaneiroRio de JaneiroRJBrazil
| | | | - Wilson Savino
- Laboratory on Thymus Research, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil,Brazilian National Institute of Science and Technology on NeuroimmunomodulationRio de Janeiro Research Network on NeuroinflammationRio de JaneiroRJBrazil
| | - Robson Coutinho‐Silva
- Laboratory of Immunophysiology, Carlos Chagas Filho Biophysics InstituteFederal University of Rio de JaneiroRio de JaneiroRJBrazil
| | - Pedro Muanis Persechini
- Laboratory of Immunobiophysics, Carlos Chagas Filho Biophysics InstituteFederal University of Rio de JaneiroRio de JaneiroRJBrazil
| | - Luiz Anastacio Alves
- Laboratory of Cellular Communication, Oswaldo Cruz InstituteOswaldo Cruz FoundationRio de JaneiroRJBrazil
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17
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The Distinct Roles of LKB1 and AMPK in p53-Dependent Apoptosis Induced by Cisplatin. Int J Mol Sci 2022; 23:ijms231710064. [PMID: 36077459 PMCID: PMC9456506 DOI: 10.3390/ijms231710064] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/27/2022] [Accepted: 08/31/2022] [Indexed: 11/17/2022] Open
Abstract
Liver kinase B1 (LKB1) is a serine/threonine protein kinase that acts as a key tumor suppressor protein by activating its downstream kinases, such as AMP-activated protein kinase (AMPK). However, the regulatory actions of LKB1 and AMPK on DNA damage response (DDR) remain to be explored. In this study, we investigated the function of LKB1 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that LKB1 stabilizes and activates p53 through the c-Jun N-terminal kinase (JNK) pathway, which promotes cisplatin-induced apoptosis in human fibrosarcoma cell line HT1080. On the other hand, we found that AMPKα1 and α2 double knockout (DKO) cells showed enhanced stabilization of p53 and increased susceptibility to apoptosis induced by cisplatin, suggesting that AMPK negatively regulates cisplatin-induced apoptosis. Moreover, the additional stabilization of p53 and subsequent apoptosis in AMPK DKO cells were clearly canceled by the treatment with the antioxidants, raising the possibility that AMPK suppresses the p53 activation mediated by oxidative stress. Thus, our findings unexpectedly demonstrate the reciprocal regulation of p53 by LKB1 and AMPK in DDR, which provides insights into the molecular mechanisms of DDR.
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18
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Anti-inflammatory effect of a triterpenoid from Balanophora laxiflora: results of bioactivity-guided isolation. Heliyon 2022; 8:e09070. [PMID: 35287327 PMCID: PMC8917289 DOI: 10.1016/j.heliyon.2022.e09070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/27/2021] [Accepted: 03/03/2022] [Indexed: 12/13/2022] Open
Abstract
Balanophora laxiflora, a medicinal plant traditionally used to treat fever, pain, and inflammation in Vietnam, has been reported to possess prominent anti-inflammatory activity. This study examined the active constituents and molecular mechanisms underlying these anti-inflammatory effects using bioactivity-guided isolation in combination with cell-based assays and animal models of inflammation. Among the isolated compounds, the triterpenoid (21α)-22-hydroxyhopan-3-one (1) showed the most potent inhibitory effect on COX-2 expression in LPS-stimulated Raw 264.7 macrophages. Furthermore, 1 suppressed the expression of the inflammatory mediators iNOS, IL-1β, INFβ, and TNFα in activated Raw 264.7 macrophages and alleviated the inflammatory response in carrageenan-induced paw oedema and a cotton pellet-induced granuloma model. Mechanistically, the anti-inflammatory effects of 1 were mediated via decreasing cellular reactive oxygen species (ROS) levels by inhibiting NADPH oxidases (NOXs) and free radical scavenging activities. By downregulating ROS signalling, 1 reduced the activation of MAPK signalling pathways, leading to decreased AP-1-dependent transcription of inflammatory mediators. These findings shed light on the chemical constituents that contribute to the anti-inflammatory actions of B. laxiflora and suggest that 1 is a promising candidate for treating inflammation-related diseases.
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19
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Fujie T, Ito K, Ozaki Y, Takahashi S, Yamamoto C, Kaji T. Induction of ZIP8, a ZIP transporter, via NF-κB signaling by the activation of IκBα and JNK signaling in cultured vascular endothelial cells exposed to cadmium. Toxicol Appl Pharmacol 2022; 434:115802. [PMID: 34822840 DOI: 10.1016/j.taap.2021.115802] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/11/2021] [Accepted: 11/14/2021] [Indexed: 12/22/2022]
Abstract
Cadmium is an environmental pollutant that adversely affects various organs in the human body and is a well-known risk factor for cardiovascular diseases. These disorders are caused by the dysfunction of the vascular endothelial cells that cover the luminal surface of blood vessels. The ZIP transporter ZIP8 is one of the primary importers of cadmium, and its expression appears to be important for the sensitivity of vascular endothelial cells to cadmium. In the present study, we investigated the influence of ZIP8 on cadmium-induced cytotoxicity in vascular endothelial cells, the induction of ZIP8 expression by cadmium, and its action mechanism in vascular endothelial cells. The study revealed that: (1) cadmium cytotoxicity in vascular endothelial cells was potentiated by the overexpression of ZIP8, and the intracellular accumulation of cadmium in the cells was increased; (2) cadmium highly induced the expression of ZIP8, but not other ZIPs; (3) lead and methylmercury moderately induced ZIP8 expression, but the other tested metals did not; (4) the induction of ZIP8 expression by cadmium was mediated by both NF-κB and JNK signaling, and the accumulation of NF-κB in the nucleus was regulated by JNK signaling. Particularly, it was found that cadmium activated NF-κB to transfer it into nuclei and activated JNK to stabilize NF-κB in nuclei, resulting in the induction of ZIP8 expression. This induction appears to be crucial for cadmium cytotoxicity in vascular endothelial cells.
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Affiliation(s)
- Tomoya Fujie
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan
| | - Keisuke Ito
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan
| | - Yusuke Ozaki
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan
| | - Suzuka Takahashi
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan
| | - Chika Yamamoto
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan
| | - Toshiyuki Kaji
- Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
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20
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The polypeptide antibiotic polymyxin B acts as a pro-inflammatory irritant by preferentially targeting macrophages. J Antibiot (Tokyo) 2022; 75:29-39. [PMID: 34824374 DOI: 10.1038/s41429-021-00490-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 10/05/2021] [Accepted: 10/27/2021] [Indexed: 11/09/2022]
Abstract
Polymyxin B (PMB) is an essential antibiotic active against multidrug-resistant bacteria, such as multidrug-resistant Pseudomonas aeruginosa (MDRP). However, the clinical use of PMB is limited, because PMB causes serious side effects, such as nephrotoxicity and neurotoxicity, probably due to its cytotoxic activity. However, cytotoxic mechanisms of PMB are poorly understood. In this study, we found that macrophages are particularly sensitive to PMB, when compared with other types of cells, including fibroblasts and proximal tubule (PT) cells. Of note, PMB-induced necrosis of macrophages allowed passive release of high mobility group box 1 (HMGB1). Moreover, upon exposure of PMB to macrophages, the innate immune system mediated by the NLR family pyrin domain containing 3 (NLRP3) inflammasome that promotes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) was stimulated. Interestingly, PMB-induced IL-1β release occurred in the absence of the pore-forming protein gasdermin D (GSDMD), which supports the idea that PMB causes plasma membrane rupture accompanying necrosis. Emerging evidence has suggested that both HMGB1 and IL-1β released from macrophages contribute to excessive inflammation that promote pathogenesis of various diseases, including nephrotoxicity and neurotoxicity. Therefore, these biochemical properties of PMB in macrophages may be associated with the induction of the adverse organ toxicity, which provides novel insights into the mechanisms of PMB-related side effects.
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21
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Ren W, Rubini P, Tang Y, Engel T, Illes P. Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases. Int J Mol Sci 2021; 23:ijms23010232. [PMID: 35008658 PMCID: PMC8745241 DOI: 10.3390/ijms23010232] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/21/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.
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Affiliation(s)
- Wenjing Ren
- International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, Chengdu 610075, China; (W.R.); (P.R.); (Y.T.)
- School of Acupunct3ure and Tuina, Chengdu University of TCM, Chengdu 610075, China
| | - Patrizia Rubini
- International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, Chengdu 610075, China; (W.R.); (P.R.); (Y.T.)
- School of Acupunct3ure and Tuina, Chengdu University of TCM, Chengdu 610075, China
| | - Yong Tang
- International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, Chengdu 610075, China; (W.R.); (P.R.); (Y.T.)
- School of Acupunct3ure and Tuina, Chengdu University of TCM, Chengdu 610075, China
| | - Tobias Engel
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland;
- FutureNeuro, SFI Research Centre for Chronic and Rare Neurological Diseases, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Peter Illes
- International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, Chengdu 610075, China; (W.R.); (P.R.); (Y.T.)
- School of Acupunct3ure and Tuina, Chengdu University of TCM, Chengdu 610075, China
- Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany
- Correspondence:
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22
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Savio LEB, Leite-Aguiar R, Alves VS, Coutinho-Silva R, Wyse ATS. Purinergic signaling in the modulation of redox biology. Redox Biol 2021; 47:102137. [PMID: 34563872 PMCID: PMC8479832 DOI: 10.1016/j.redox.2021.102137] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 01/07/2023] Open
Abstract
Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological and pathological circumstances activating purinergic type 2 receptors (P2 receptors): P2X ion channels and P2Y G protein-coupled receptors. The activation of these receptors triggers the production of reactive oxygen and nitrogen species and alters antioxidant defenses, modulating the redox biology of cells. The activation of P2 receptors is controlled by ecto-enzymes named ectonucleotidases, E-NTPDase1/CD39 and ecto-5'-nucleotidase/CD73) being the most relevant. The first enzyme hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP), and the second catalyzes the hydrolysis of AMP to adenosine. The activity of these enzymes is diminished by oxidative stress. Adenosine actives P1 G-coupled receptors that, in general, promote the maintenance of redox hemostasis by decreasing reactive oxygen species (ROS) production and increase antioxidant enzymes. Intracellular purine metabolism can also contribute to ROS generation via xanthine oxidase activity, which converts hypoxanthine into xanthine, and finally, uric acid. In this review, we describe the mechanisms of redox biology modulated by purinergic signaling and how this signaling may be affected by disturbances in the redox homeostasis of cells.
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Affiliation(s)
- Luiz Eduardo Baggio Savio
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Raíssa Leite-Aguiar
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vinícius Santos Alves
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Robson Coutinho-Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Angela T S Wyse
- Laboratório de Neuroproteção e Doenças Metabólicas, Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil
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23
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Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes. Nature 2021; 599:296-301. [PMID: 34707293 PMCID: PMC9186421 DOI: 10.1038/s41586-021-04019-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 09/13/2021] [Indexed: 12/13/2022]
Abstract
Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1)1,2. Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic β-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or β-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis.
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24
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An Open Question: Is Non-Ionizing Radiation a Tool for Controlling Apoptosis-Induced Proliferation? Int J Mol Sci 2021; 22:ijms222011159. [PMID: 34681819 PMCID: PMC8537877 DOI: 10.3390/ijms222011159] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022] Open
Abstract
Non-ionizing radiation is commonly used in the clinical setting, despite its known ability to trigger oxidative stress and apoptosis, which can lead to damage and cell death. Although induction of cell death is typically considered harmful, apoptosis can also be beneficial in the right context. For example, cell death can serve as the signal for new tissue growth, such as in apoptosis-induced proliferation. Recent data has shown that exposure to non-ionizing radiation (such as weak static magnetic fields, weak radiofrequency magnetic fields, and weak electromagnetic fields) is able to modulate proliferation, both in cell culture and in living organisms (for example during tissue regeneration). This occurs via in vivo changes in the levels of reactive oxygen species (ROS), which are canonical activators of apoptosis. This review will describe the literature that highlights the tantalizing possibility that non-ionizing radiation could be used to manipulate apoptosis-induced proliferation to either promote growth (for regenerative medicine) or inhibit it (for cancer therapies). However, as uncontrolled growth can lead to tumorigenesis, much more research into this exciting and developing area is needed in order to realize its promise.
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25
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Hirata Y. trans-Fatty Acids as an Enhancer of Inflammation and Cell Death: Molecular Basis for Their Pathological Actions. Biol Pharm Bull 2021; 44:1349-1356. [PMID: 34602541 DOI: 10.1248/bpb.b21-00449] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
trans-Fatty acids (TFAs) are food-derived fatty acids that possess one or more trans double bonds between carbon atoms. Compelling epidemiological and clinical evidence has demonstrated the association of TFA consumption with various diseases, such as cardiovascular diseases, and neurodegenerative diseases. However, the underlying etiology is poorly understood since the mechanisms of action of TFAs remain to be clarified. Previous studies have shown that single treatment with TFAs induce inflammation and cell death, but to a much lesser extent than saturated fatty acids (SFAs) that are well established as a risk factor for diseases linked with inflammation and cell death, which cannot explain the particularly higher association of TFAs with atherosclerosis than SFAs. In our series of studies, we have established the role of TFAs as an enhancer of inflammation and cell death. We found that pretreatment with TFAs strongly promoted apoptosis induced by either extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from damaged cells, or DNA damaging-agents, including doxorubicin and cisplatin, thorough enhancing activation of the stress-responsive mitogen-activated protein (MAP) kinase p38/c-jun N-terminal kinase (JNK) pathways; pretreatment with SFAs or cis isomers of TFAs had only minor or no effect, suggesting the uniqueness of the pro-apoptotic role of TFAs among fatty acids. Our findings will provide an insight into understanding of the pathogenesis mechanisms, and open up a new avenue for developing prevention strategies and therapies for TFA-related diseases.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
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26
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Taylor JP, Tse HM. The role of NADPH oxidases in infectious and inflammatory diseases. Redox Biol 2021; 48:102159. [PMID: 34627721 PMCID: PMC8487856 DOI: 10.1016/j.redox.2021.102159] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/30/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are enzymes that generate superoxide or hydrogen peroxide from molecular oxygen utilizing NADPH as an electron donor. There are seven enzymes in the NOX family: NOX1-5 and dual oxidase (DUOX) 1-2. NOX enzymes in humans play important roles in diverse biological functions and vary in expression from tissue to tissue. Importantly, NOX2 is involved in regulating many aspects of innate and adaptive immunity, including regulation of type I interferons, the inflammasome, phagocytosis, antigen processing and presentation, and cell signaling. DUOX1 and DUOX2 play important roles in innate immune defenses at epithelial barriers. This review discusses the role of NOX enzymes in normal physiological processes as well as in disease. NOX enzymes are important in autoimmune diseases like type 1 diabetes and have also been implicated in acute lung injury caused by infection with SARS-CoV-2. Targeting NOX enzymes directly or through scavenging free radicals may be useful therapies for autoimmunity and acute lung injury where oxidative stress contributes to pathology.
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Affiliation(s)
- Jared P Taylor
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hubert M Tse
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA.
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27
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Li Y, Li J, Yuan Q, Bian X, Long F, Duan R, Gao F, Gao S, Wei S, Wang A, Liu A, Li X, Sun W, Liu Q. Deficiency in WDFY4 reduces the number of CD8 + T cells via reactive oxygen species-induced apoptosis. Mol Immunol 2021; 139:131-138. [PMID: 34482201 DOI: 10.1016/j.molimm.2021.08.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 08/18/2021] [Accepted: 08/28/2021] [Indexed: 12/16/2022]
Abstract
WDFY4 (WD repeat and FYVE domain-containing 4) is a susceptibility gene involved in several autoimmune diseases and plays an important role in the immune system. However, it is not clear how WDFY4 affects T cells. We have generated a Wdfy4-knockout mouse and found that selective deficiency of Wdfy4 in T cells led to a reduction in the number of CD8+ T cells in the periphery, thus promoting tumor growth when mice were challenged with a transplantable tumor. Moreover, conditional ablation of Wdfy4 in T cells enhanced the apoptosis of CD8+ T cells and increased the intracellular levels of reactive oxygen species accompanied by the upregulation of Nox2. Mechanistically, the decrease in the CD8+ T-cell numbers in Wdfy4-knockout mice was associated with activation of the p53 pathway and inhibition of the extracellular signal-regulated kinase pathway. In addition, WDFY4 participated in cell proliferation. In conclusion, our results elucidate the biological role of WDFY4 in apoptosis and establish a link between WDFY4 and T cells.
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Affiliation(s)
- Yan Li
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jiangxia Li
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Qianqian Yuan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xianli Bian
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Feng Long
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Ruonan Duan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Fei Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shang Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shijun Wei
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Anran Wang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Ai Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xi Li
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Wenjie Sun
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Qiji Liu
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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28
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Xu G, Liu S, Huang M, Jiang X, Yang M. Cadmium induces apoptosis of human granulosa cell line KGN via mitochondrial dysfunction-mediated pathways. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 220:112341. [PMID: 34020281 DOI: 10.1016/j.ecoenv.2021.112341] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/07/2021] [Accepted: 05/01/2021] [Indexed: 05/20/2023]
Abstract
Cadmium (Cd) is an important industrial and environmental pollutant, which is closely correlated with female infertility. Although Cd-induced developmental disorders of human ovarian follicles have been widely reported, the underlying mechanisms remain not fully elucidated. In this study, we explored the mechanism underlying Cd-triggered apoptosis in granulosa cells. Following the treatment with various levels of Cd (0, 0.625, 1.25, 2.5 and 5 μM), we found that Cd triggered the death of KGN cells (a human granulosa-like tumor cell line) in a dose- as well as time-dependent manner. The levels of expressions of Bax and Bak were significantly increased, whereas the expression levels of Mcl-1 and Bcl-2 were considerably decreased after being treated with high levels of Cd. We showed that Cd exposure remarkably triggered mitochondrial dysfunction, including increased intracellular ROS and free Ca2+ levels, and decreased ATP generation and mitochondrial membrane potential. Furthermore, we found that mitochondrial dysfunction, especially excessive ROS production and intracellular Ca2+ overload, serve a vital role in Cd-triggered apoptosis of KGN cells. After using inhibitors to block the corresponding signaling cascades, Cd-mediated apoptosis was markedly repressed by ASK1 and p38 inhibitors in contrast with the control group. This suggests the activation of downstream pathways triggered by mitochondrial dysfunction participates in granulosa cell death and may cause female reproductive toxicity after Cd exposure.
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Affiliation(s)
- Guofeng Xu
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Shuang Liu
- Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Mingquan Huang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Sichuan Treatment Center for Gynaecologic and Breast Diseases (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xue Jiang
- Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Meng Yang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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29
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Hirata Y, Nada Y, Yamada Y, Toyama T, Fukunaga K, Hwang GW, Noguchi T, Matsuzawa A. Elaidic Acid Potentiates Extracellular ATP-Induced Apoptosis via the P2X 7-ROS-ASK1-p38 Axis in Microglial Cell Lines. Biol Pharm Bull 2021; 43:1562-1569. [PMID: 32999166 DOI: 10.1248/bpb.b20-00409] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
trans-Fatty acids (TFAs) are unsaturated fatty acids with at least one carbon-carbon double bond in trans configuration. TFA consumption has been epidemiologically associated with neurodegenerative diseases (NDs) including Alzheimer's disease. However, the underlying mechanisms of TFA-related NDs remain unknown. Here, we show a novel microglial signaling pathway that induces inflammation and cell death, which is dramatically enhanced by elaidic acid (EA), the most abundant TFA derived from food. We found that extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from injured cells, induced activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway, which is one of the major stress-responsive mitogen-activated protein (MAP) kinase signaling pathways, and subsequent caspase-3 cleavage and DNA ladder formation (hallmarks of apoptosis) in mouse microglial cell lines including BV2 and MG6 cells. Furthermore, we found that in these microglial cell lines, EA, but not its cis isomer oleic acid, facilitated extracellular ATP-induced ASK1/p38 activation and apoptosis, which was suppressed by pharmacological inhibition of either p38, reactive oxygen species (ROS) generation, P2X purinoceptor 7 (P2X7), or Ca2+/calmodulin-dependent kinase II (CaMKII). These results demonstrate that in microglial cells, extracellular ATP induces activation of the ASK1-p38 MAP kinase pathway and ultimately apoptosis downstream of P2X7 receptor and ROS generation, and that EA promotes ATP-induced apoptosis through CaMKII-dependent hyperactivation of the ASK1-p38 pathway, in the same manner as in macrophages. Our study may provide an insight into the pathogenesis of NDs associated with TFAs.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Yuki Nada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Yuto Yamada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Takashi Toyama
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Kohji Fukunaga
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Gi-Wook Hwang
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
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30
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Hirata Y, Takahashi M, Yamada Y, Matsui R, Inoue A, Ashida R, Noguchi T, Matsuzawa A. trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway. Sci Rep 2021; 11:10350. [PMID: 33990641 PMCID: PMC8121903 DOI: 10.1038/s41598-021-89506-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 04/27/2021] [Indexed: 12/31/2022] Open
Abstract
trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Miki Takahashi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Yuto Yamada
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Ryosuke Matsui
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Aya Inoue
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Ryo Ashida
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
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31
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Toyama T, Hoshi T, Noguchi T, Saito Y, Matsuzawa A, Naganuma A, Hwang GW. Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia. Sci Rep 2021; 11:9832. [PMID: 33972601 PMCID: PMC8110582 DOI: 10.1038/s41598-021-89210-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/15/2021] [Indexed: 02/08/2023] Open
Abstract
We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.
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Affiliation(s)
- Takashi Toyama
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Takayuki Hoshi
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan
| | - Takuya Noguchi
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan
| | - Yoshiro Saito
- Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan
| | - Akira Naganuma
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan
| | - Gi-Wook Hwang
- Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aoba-ku, Aramaki, Sendai, Miyagi, 980-8578, Japan.
- Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.
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Matsuzawa A. [Molecular Mechanisms Underlying Toxic Actions of trans-Fatty Acids and Prevention of Related Diseases]. YAKUGAKU ZASSHI 2021; 141:675-679. [PMID: 33952751 DOI: 10.1248/yakushi.20-00243-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
trans-Fatty acids (TFAs), including elaidic acid and linoelaidic acid, are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. TFAs are not synthesized in the human body, but are taken into the body from various foods, which are mainly produced during industrial food manufacturing. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, such as atherosclerosis, cardiovascular diseases, allergic diseases, and dementia. However, the underlying pathogenic mechanisms of TFA-related disorders and the specific molecular targets evoking TFA toxicity are largely unknown. To elucidate the molecular mechanisms by which TFAs cause the cytotoxicity, we focused on cell death and inflammation, which are the main and common pathogenesis of the TFA-related diseases, and analyzed the effects of TFAs on cellular responses to various stimulations inducing cell death and inflammation. This review provides recent progress in our studies on the molecular mechanisms causing toxic actions of TFAs, which lead to diverse TFA-related disorders.
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Affiliation(s)
- Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
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Zhang T, Tsutsuki H, Islam W, Ono K, Takeda K, Akaike T, Sawa T. ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation. Redox Biol 2021; 41:101930. [PMID: 33740502 PMCID: PMC7995658 DOI: 10.1016/j.redox.2021.101930] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/29/2021] [Accepted: 03/01/2021] [Indexed: 12/20/2022] Open
Abstract
The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders.
ATP stimulates rapid glutathione (GSH) efflux via the P2X7 receptor. GSH efflux is an upstream event for NLRP3 inflammasome complex assembly. Exogenous GSH weakens ATP-caused GSH efflux and NLRP3 inflammasome activation. GSH or GSSG suppressed interleukin-1β production in an inflammatory mouse model.
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Affiliation(s)
- Tianli Zhang
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Hiroyasu Tsutsuki
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Waliul Islam
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Katsuhiko Ono
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Kohsuke Takeda
- Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan
| | - Takaaki Akaike
- Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Tomohiro Sawa
- Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
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Huang M, Li X, Jia S, Liu S, Fu L, Jiang X, Yang M. Bisphenol AF induces apoptosis via estrogen receptor beta (ERβ) and ROS-ASK1-JNK MAPK pathway in human granulosa cell line KGN. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 270:116051. [PMID: 33189448 DOI: 10.1016/j.envpol.2020.116051] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/14/2020] [Accepted: 11/06/2020] [Indexed: 06/11/2023]
Abstract
Bisphenol AF (BPAF) is an emerging environmental pollutant. Although BPAF is widely spread in the environment and human surroundings, its interference with ovarian function has not been fully elucidated. The aim of this study was to identify the mechanism underlying the effect of BPAF on the apoptosis of KGN cells, which maintain the physiological characteristics of ovarian granulosa cells. Our results indicated that BPAF induces KGN cell apoptosis in a concentration- and time-dependent manner. Meanwhile, BPAF exposure significantly promoted the expression of pro-apoptotic proteins, including Bax, Bid and Bak, while the expression of anti-apoptotic proteins, such as Bcl-2, Bcl-xL and Mcl-1, decreased significantly. We further detected a significant increase in intracellular ROS levels in response to high concentrations of BPAF exposure. After blocking the corresponding pathway, it was found that ROS mediates ASK1 and JNK activation. Furthermore, the role of Ca2+ overload and estrogen receptor β (ERβ) in BPAF-induced KGN cell apoptosis was also confirmed by using inhibitors. These results suggest that BPAF has potential reproductive toxicity for females, and ROS-ASK1-JNK axis may play a key role in BPAF-induced ovarian dysfunction. In addition, Ca2+ overload and ERβ pathway activation may also be an important mechanism of reproductive toxicity of BPAF.
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Affiliation(s)
- Mingquan Huang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China; Sichuan Treatment Center for Gynaecologic and Breast Diseases (Breast Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xingjie Li
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Shengjun Jia
- Animal Disease Prevention and Control Center of Zhongshan District, Liupanshui, 553000, China
| | - Shuang Liu
- Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Li Fu
- Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Xue Jiang
- Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Meng Yang
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China; Department of Reproductive Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
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Udagawa T, Seki M, Okuyama T, Adachi S, Natsume T, Noguchi T, Matsuzawa A, Inada T. Failure to Degrade CAT-Tailed Proteins Disrupts Neuronal Morphogenesis and Cell Survival. Cell Rep 2021; 34:108599. [PMID: 33406423 DOI: 10.1016/j.celrep.2020.108599] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 07/24/2020] [Accepted: 12/14/2020] [Indexed: 12/25/2022] Open
Abstract
Ribosome-associated quality control (RQC) relieves stalled ribosomes and eliminates potentially toxic nascent polypeptide chains (NCs) that can cause neurodegeneration. During RQC, RQC2 modifies NCs with a C-terminal alanine and threonine (CAT) tail. CAT tailing promotes ubiquitination of NCs for proteasomal degradation, while RQC failure in budding yeast disrupts proteostasis via CAT-tailed NC aggregation. However, the CAT tail and its cytotoxicity in mammals have remained largely uncharacterized. We demonstrate that NEMF, a mammalian RQC2 homolog, modifies translation products of nonstop mRNAs, major erroneous mRNAs in mammals, with a C-terminal tail mainly composed of alanine with several other amino acids. Overproduction of nonstop mRNAs induces NC aggregation and caspase-3-dependent apoptosis and impairs neuronal morphogenesis, which are ameliorated by NEMF depletion. Moreover, we found that homopolymeric alanine tailing at least partially accounts for CAT-tail cytotoxicity. These findings explain the cytotoxicity of CAT-tailed NCs and demonstrate physiological significance of RQC on proper neuronal morphogenesis and cell survival.
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Affiliation(s)
- Tsuyoshi Udagawa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
| | - Moeka Seki
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Taku Okuyama
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Shungo Adachi
- Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
| | - Tohru Natsume
- Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
| | - Takuya Noguchi
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Atsushi Matsuzawa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Toshifumi Inada
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
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36
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Suzuki M, Asai Y, Kagi T, Noguchi T, Yamada M, Hirata Y, Matsuzawa A. TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms. Int J Mol Sci 2020; 21:ijms21249497. [PMID: 33327477 PMCID: PMC7764951 DOI: 10.3390/ijms21249497] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 12/20/2022] Open
Abstract
It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by H2O2. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.
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Affiliation(s)
| | | | | | - Takuya Noguchi
- Correspondence: (T.N.); (A.M.); Tel.: +81-22-795-6828 (T.N.); +81-22-795-6827 (A.M.); Fax: +81-22-795-6826 (T.N. & A.M.)
| | | | | | - Atsushi Matsuzawa
- Correspondence: (T.N.); (A.M.); Tel.: +81-22-795-6828 (T.N.); +81-22-795-6827 (A.M.); Fax: +81-22-795-6826 (T.N. & A.M.)
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Huang X, Tao Y, Gao J, Zhou X, Tang S, Deng C, Lai Z, Lin X, Wang Q, Li T. UBC9 coordinates inflammation affecting development of bladder cancer. Sci Rep 2020; 10:20670. [PMID: 33244139 PMCID: PMC7691338 DOI: 10.1038/s41598-020-77623-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2020] [Indexed: 01/18/2023] Open
Abstract
Dysregulation of SUMO modification is linked to carcinogenesis. UBC9 is the sole conjugating enzyme in sumoylation and plays a pivotal role in maintaining homeostasis and restraining stress reactions. However, the clinical significance and function of UBC9 in bladder cancer remain unclear. In this study, immunohistochemistry was used to determine the expression of UBC9. UBC9 knock-down and SUMO inhibition were conducted followed by proliferation, migration, and cell cycle assays. RNA sequencing and bioinformatic analysis were used to identify potential mechanisms of UBC9. Cytokine membrane antibody array was used to detect the expression of cytokine. The mass cytometry TOF (CyTOF) was used to explore the association between bladder cancer stem cell-like population and UBC9 expression. Our results showed that UBC9 played a dual role in bladder cancer. UBC9 was up-regulated in bladder cancer, but was negatively correlated with TNM stage and grade. Knocking-down of UBC9 resulted in dramatic activation of inflammatory gene expression, which might cause inhibition of cell proliferation and inducing cell apoptosis. IL6 was the hub gene in UBC9 regulatory network. Markedly up-regulated IL6 after knocking-down of UBC9 activated the expression of CD44, which was a prominent marker of cancer stem cells. Thus, our results revealed an important and previously undescribed role for UBC9 in modulation of inflammatory signaling of bladder cancer. UBC9 in bladder cancer cells is required to maintain high sumoylation levels and alleviate stress-related inflammation threats to cell survival. Lacking UBC9 contributes to inflammation activation, epithelial-mesenchymal transition and stem cell-like population formation, leading to cancer progression.
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Affiliation(s)
- Xiaoliang Huang
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yuting Tao
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Jiamin Gao
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xianguo Zhou
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Shaomei Tang
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Caiwang Deng
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Zhiyong Lai
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Xinggu Lin
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Qiuyan Wang
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China. .,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China. .,Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.
| | - Tianyu Li
- Department of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China. .,Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China. .,Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi, Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, China.
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He Q, Wang Y, Yang H, Wang J, Zhang J, Liu D. Apelin‑36 protects against lipopolysaccharide‑induced acute lung injury by inhibiting the ASK1/MAPK signaling pathway. Mol Med Rep 2020; 23:6. [PMID: 33179090 PMCID: PMC7673347 DOI: 10.3892/mmr.2020.11644] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/30/2020] [Indexed: 11/20/2022] Open
Abstract
Apelin-36 is able to mediate a range of effects on various diseases, and is upregulated in lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, to the best of our knowledge, whether apelin-36 is able to regulate LPS-induced ALI has yet to be investigated. The present study aimed to investigate the role of apelin-36 in LPS-induced ALI, and the putative underlying mechanisms. Rats were assigned to one of four treatment groups: The Control group, apelin-36 group, LPS group and LPS + apelin-36 group. At 4 h after intratracheal instillation of LPS (5 mg/kg), rats were intraperitoneally treated with 10 nmol/kg apelin-36. Subsequently, pathological manifestations and the extent of inflammation and apoptosis of the lung tissues were assessed. Untransfected and apoptosis signal-regulating kinase 1 (ASK1)-overexpressing Beas-2B cells were treated with LPS in the absence or presence of apelin-36, and subsequently the levels of inflammation and apoptosis were assessed. The results obtained showed that the level of apelin-36 was increased in the bronchoalveolar lavage fluid (BALF) of LPS-treated rats. Co-treatment with apelin-36 alleviated LPS-induced lung injury and pulmonary edema, reduced the levels of pro-inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1 and tumor necrosis factor-α, in BALF, and inhibited apoptosis in the lung tissues. The presence of apelin-36 also blocked the activation of LPS-induced ASK1, p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase in lung tissues. In vitro studies performed with Beas-2B cells showed that the addition of apelin-36 led to an increase in the cell viability of LPS-induced Beas-2B cells in a concentration-dependent manner. Additionally, co-treatment with 1 µM apelin-36 prevented LPS-induced inflammation and apoptosis. However, overexpression of ASK1 significantly reversed the inhibitory effects of apelin-36 on LPS-induced inflammation and apoptosis. Taken together, the results of the present study demonstrated that apelin-36 was able to protect against LPS-induced lung injury both in vivo and in vitro, and these actions may be dependent on inhibition of the ASK1/mitogen-activated protein kinase signaling pathway.
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Affiliation(s)
- Qiong He
- Department of Critical Care Medicine, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
| | - Yuqiao Wang
- Department of Critical Care Medicine, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
| | - Hua Yang
- Department of Critical Care Medicine, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
| | - Jianmin Wang
- Department of Critical Care Medicine, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
| | - Jia Zhang
- Department of Critical Care Medicine, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
| | - Danni Liu
- Department of Cardiology, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China
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39
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Hattori K, Wakatsuki H, Sakauchi C, Furutani S, Sugawara S, Hatta T, Natsume T, Ichijo H. β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes. PLoS One 2020; 15:e0232645. [PMID: 33108364 PMCID: PMC7591029 DOI: 10.1371/journal.pone.0232645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 09/03/2020] [Indexed: 12/31/2022] Open
Abstract
Boosting energy expenditure by harnessing the activity of brown adipocytes is a promising strategy for combatting the global epidemic of obesity. Many studies have revealed that the β3-adrenergic receptor agonist is a potent activator of brown adipocytes, even in humans, and PKA and p38 MAPK have been demonstrated for regulating the transcription of a wide range of critical genes such as Ucp1. We previously revealed that the PKA-ASK1-p38 axis is activated in immature brown adipocytes and contributes to functional maturation. However, the downstream mechanisms of PKA that initiate the p38 MAPK cascade are still mostly unknown in mature brown adipocytes. Here, we identified the ASK family as a crucial signaling molecule bridging PKA and MAPK in mature brown adipocytes. Mechanistically, the phosphorylation of ASK1 at threonine 99 and serine 993 is critical in PKA-dependent ASK1 activation. Additionally, PKA also activates ASK2, which contributes to MAPK regulation. These lines of evidence provide new details for tailoring a βAR-dependent brown adipocyte activation strategy.
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Affiliation(s)
- Kazuki Hattori
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- * E-mail: (KH); (HI)
| | - Hiroaki Wakatsuki
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Chihiro Sakauchi
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Shotaro Furutani
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Sho Sugawara
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Tomohisa Hatta
- Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Tohru Natsume
- Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Hidenori Ichijo
- The Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- * E-mail: (KH); (HI)
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Marcar L, Bardhan K, Gheorghiu L, Dinkelborg P, Pfäffle H, Liu Q, Wang M, Piotrowska Z, Sequist LV, Borgmann K, Settleman JE, Engelman JA, Hata AN, Willers H. Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity. Cell Rep 2020; 27:3422-3432.e4. [PMID: 31216465 PMCID: PMC6624074 DOI: 10.1016/j.celrep.2019.05.058] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 02/25/2019] [Accepted: 05/16/2019] [Indexed: 12/21/2022] Open
Abstract
Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells.
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Affiliation(s)
- Lynnette Marcar
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Kankana Bardhan
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Liliana Gheorghiu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Patrick Dinkelborg
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Eppendorf, Hamburg 20251, Germany
| | - Heike Pfäffle
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Qi Liu
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Meng Wang
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zofia Piotrowska
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lecia V Sequist
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Kerstin Borgmann
- Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Eppendorf, Hamburg 20251, Germany
| | - Jeffrey E Settleman
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Jeffrey A Engelman
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
| | - Aaron N Hata
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Henning Willers
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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Mészáros Á, Molnár K, Nógrádi B, Hernádi Z, Nyúl-Tóth Á, Wilhelm I, Krizbai IA. Neurovascular Inflammaging in Health and Disease. Cells 2020; 9:cells9071614. [PMID: 32635451 PMCID: PMC7407516 DOI: 10.3390/cells9071614] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022] Open
Abstract
Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.
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Affiliation(s)
- Ádám Mészáros
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Doctoral School of Biology, University of Szeged, 6726 Szeged, Hungary
| | - Kinga Molnár
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Theoretical Medicine Doctoral School, University of Szeged, 6720 Szeged, Hungary
| | - Bernát Nógrádi
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Foundation for the Future of Biomedical Sciences in Szeged, Szeged Scientists Academy, 6720 Szeged, Hungary
| | - Zsófia Hernádi
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Foundation for the Future of Biomedical Sciences in Szeged, Szeged Scientists Academy, 6720 Szeged, Hungary
| | - Ádám Nyúl-Tóth
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Imola Wilhelm
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania
| | - István A. Krizbai
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania
- Correspondence: ; Tel.: +36-62-599-794
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Lara R, Adinolfi E, Harwood CA, Philpott M, Barden JA, Di Virgilio F, McNulty S. P2X7 in Cancer: From Molecular Mechanisms to Therapeutics. Front Pharmacol 2020; 11:793. [PMID: 32581786 PMCID: PMC7287489 DOI: 10.3389/fphar.2020.00793] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/13/2020] [Indexed: 12/18/2022] Open
Abstract
P2X7 is a transmembrane receptor expressed in multiple cell types including neurons, dendritic cells, macrophages, monocytes, B and T cells where it can drive a wide range of physiological responses from pain transduction to immune response. Upon activation by its main ligand, extracellular ATP, P2X7 can form a nonselective channel for cations to enter the cell. Prolonged activation of P2X7, via high levels of extracellular ATP over an extended time period can lead to the formation of a macropore, leading to depolarization of the plasma membrane and ultimately to cell death. Thus, dependent on its activation state, P2X7 can either drive cell survival and proliferation, or induce cell death. In cancer, P2X7 has been shown to have a broad range of functions, including playing key roles in the development and spread of tumor cells. It is therefore unsurprising that P2X7 has been reported to be upregulated in several malignancies. Critically, ATP is present at high extracellular concentrations in the tumor microenvironment (TME) compared to levels observed in normal tissues. These high levels of ATP should present a survival challenge for cancer cells, potentially leading to constitutive receptor activation, prolonged macropore formation and ultimately to cell death. Therefore, to deliver the proven advantages for P2X7 in driving tumor survival and metastatic potential, the P2X7 macropore must be tightly controlled while retaining other functions. Studies have shown that commonly expressed P2X7 splice variants, distinct SNPs and post-translational receptor modifications can impair the capacity of P2X7 to open the macropore. These receptor modifications and potentially others may ultimately protect cancer cells from the negative consequences associated with constitutive activation of P2X7. Significantly, the effects of both P2X7 agonists and antagonists in preclinical tumor models of cancer demonstrate the potential for agents modifying P2X7 function, to provide innovative cancer therapies. This review summarizes recent advances in understanding of the structure and functions of P2X7 and how these impact P2X7 roles in cancer progression. We also review potential therapeutic approaches directed against P2X7.
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Affiliation(s)
- Romain Lara
- Biosceptre (UK) Limited, Cambridge, United Kingdom
| | - Elena Adinolfi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Catherine A Harwood
- Centre for Cell Biology and Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Mike Philpott
- Centre for Cutaneous Research, Blizard Institute, Bart's & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
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Wilkaniec A, Cieślik M, Murawska E, Babiec L, Gąssowska-Dobrowolska M, Pałasz E, Jęśko H, Adamczyk A. P2X7 Receptor is Involved in Mitochondrial Dysfunction Induced by Extracellular Alpha Synuclein in Neuroblastoma SH-SY5Y Cells. Int J Mol Sci 2020; 21:ijms21113959. [PMID: 32486485 PMCID: PMC7312811 DOI: 10.3390/ijms21113959] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 12/12/2022] Open
Abstract
The purinergic P2X7 receptor (P2X7R) belongs to a family of trimeric ion channels that are gated by extracellular adenosine 5′-triphosphate (ATP). Several studies have pointed to a role of P2X7R-dependent signalling in Parkinson's disease (PD)-related neurodegeneration. The pathology of (PD) is characterized by the formation of insoluble alpha-synuclein (α-Syn) aggregates—Lewy bodies, but the mechanisms underlying α-Syn-induced dopaminergic cell death are still partially unclear. Our previous studies indicate that extracellular α-Syn directly interact with neuronal P2X7R and induces intracellular free calcium mobilization in neuronal cells. The main objective of this study was to examine the involvement of P2X7R receptor in α-Syn-induced mitochondrial dysfunction and cell death. We found that P2X7R stimulation is responsible for α-Syn-induced oxidative stress and activation of the molecular pathways of programmed cell death. Exogenous α-Syn treatment led to P2X7R-dependent decrease in mitochondrial membrane potential as well as elevation of mitochondrial ROS production resulting in breakdown of cellular energy production. Moreover, P2X7R-dependent deregulation of AMP-activated protein kinase as well as decrease in parkin protein level could be responsible for α-Syn-induced mitophagy impairment and accumulation of dysfunctional mitochondria. P2X7R might be putative pharmacological targets in molecular mechanism of extracellular α-Syn toxicity.
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Affiliation(s)
- Anna Wilkaniec
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
- Correspondence: ; Tel.: +48-22-608-66-00; Fax: +48-22-608-64-13
| | - Magdalena Cieślik
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
| | - Emilia Murawska
- Department of Applied Microbiology, Institute of Microbiology, Warsaw University, Miecznikowa 1 Street, 02-096 Warsaw, Poland;
| | - Lidia Babiec
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
| | - Magdalena Gąssowska-Dobrowolska
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
| | - Ewelina Pałasz
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
| | - Henryk Jęśko
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
| | - Agata Adamczyk
- Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland; (M.C.); (L.B.); (M.G.-D.); (E.P.); (H.J.); (A.A.)
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Brys R, Gibson K, Poljak T, Van Der Plas S, Amantini D. Discovery and development of ASK1 inhibitors. PROGRESS IN MEDICINAL CHEMISTRY 2020; 59:101-179. [PMID: 32362327 DOI: 10.1016/bs.pmch.2020.02.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aberrant activation of mitogen-activated protein kinases (MAPKs) like c-Jun N-terminal kinase (JNK) and p38 is an event involved in the pathophysiology of numerous human diseases. The apoptosis signal-regulating kinase 1 (ASK1) is an upstream target that gets activated only under pathological conditions and as such is a promising target for therapeutic intervention. In the first part of this review the molecular mechanisms leading to ASK1 activation and regulation will be described as well as the evidences supporting a pathogenic role for ASK1 in human disease. In the second part, an update on drug discovery efforts towards the discovery and development of ASK1-targeting therapies will be provided.
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Affiliation(s)
| | - Karl Gibson
- Sandexis Medicinal Chemistry Ltd, Innovation House Discovery ParkSandwich, Kent, United Kingdom
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Hirata Y. [Reactive Oxygen Species (ROS) Signaling: Regulatory Mechanisms and Pathophysiological Roles]. YAKUGAKU ZASSHI 2020; 139:1235-1241. [PMID: 31582606 DOI: 10.1248/yakushi.19-00141] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Reactive oxygen species (ROS) are highly reactive molecules generated during mitochondrial respiration and under various environmental stresses, and cause damage to DNA, proteins, and lipids, which is linked to a wide variety of pathologies. However, recent studies have revealed the physiological importance of ROS as signaling molecules, which play crucial roles in the maintenance of cellular functions and homeostasis. According to the extent and duration of ROS generation, ROS-mediated oxidation-reduction (redox) signaling (ROS signaling) is tightly regulated by various molecules and post-translational modifications (PTMs), for inducing appropriate cellular responses. Dysregulation of ROS signaling causes cellular malfunctions, which are also linked to various diseases, such as cancer, neurodegeneration and inflammatory diseases. In this review, we focus on a ROS-responsive protein kinase apoptosis signal-regulating kinase 1 (ASK1) that belongs to the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, and activates the c-jun N-terminal kinase (JNK) and p38 MAP kinase pathways, which consequently induces various cellular responses, including apoptosis and inflammation. Here, we introduce a novel regulatory mechanism and the pathophysiological significance of ASK1 activation. We found that an E3 ubiquitin ligase TRIM48 orchestrates fine-tuning of ROS-induced ASK1 activation mediated by multiple types of PTMs, including ubiquitination, methylation, and phosphorylation. We also found that trans-fatty acids (TFAs) enhance ROS-dependent ASK1 activation induced by extracellular ATP, a damage-associated molecular pattern (DAMP), and thereby promotes apoptosis, which possibly contributes to the pathogenesis of TFA-related diseases including atherosclerosis. Thus, this review provides recent advances in the study of ROS signaling, especially ROS-ASK1 signaling pathway.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
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46
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Munoz FM, Patel PA, Gao X, Mei Y, Xia J, Gilels S, Hu H. Reactive oxygen species play a role in P2X7 receptor-mediated IL-6 production in spinal astrocytes. Purinergic Signal 2020; 16:97-107. [PMID: 32146607 DOI: 10.1007/s11302-020-09691-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 02/11/2020] [Indexed: 01/29/2023] Open
Abstract
Astrocytes mediate a remarkable variety of cellular functions, including gliotransmitter release. Under pathological conditions, high concentrations of the purinergic receptor agonist adenosine triphosphate (ATP) are released into the extracellular space leading to the activation of the purinergic P2X7 receptor, which in turn can initiate signaling cascades. It is well-established that reactive oxygen species (ROS) increase in macrophages and microglia following P2X7 receptor activation. However, direct evidence that activation of P2X7 receptor leads to ROS production in astrocytes is lacking to date. While it is known that P2X7R activation induces cytokine production, the mechanism involved in this process is unclear. In the present study, we demonstrated that P2X7 receptor activation induced ROS production in spinal astrocytes in a concentration-dependent manner. We also found that P2X7R-mediated ROS production is at least partially through NADPH oxidase. In addition, our ELISA data show that P2X7R-induced IL-6 release was dependent on NADPH oxidase-mediated production of ROS. Collectively, these results reveal that activation of the P2X7 receptor on spinal astrocytes increases ROS production through NADPH oxidase, subsequently leading to IL-6 release. Our results reveal a role of ROS in the P2X7 signaling pathway in mouse spinal cord astrocytes and may indicate a potential mechanism for the astrocytic P2X7 receptor in chronic pain.
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Affiliation(s)
- Frances M Munoz
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Priya A Patel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Xinghua Gao
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China
| | - Yixiao Mei
- Department of Anesthesiology, Rutgers New Jersey Medical School, 185 S. Orange Ave., Newark, NJ, 07103, USA
| | - Jingsheng Xia
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Sofia Gilels
- Department of Anesthesiology, Rutgers New Jersey Medical School, 185 S. Orange Ave., Newark, NJ, 07103, USA
| | - Huijuan Hu
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA. .,Department of Anesthesiology, Rutgers New Jersey Medical School, 185 S. Orange Ave., Newark, NJ, 07103, USA.
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trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop. Sci Rep 2020; 10:2743. [PMID: 32066809 PMCID: PMC7026443 DOI: 10.1038/s41598-020-59636-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
trans-Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.
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Zhang X, Liu Z, Li C, Zhang Y, Wang L, Wei J, Qin Q. Characterization of orange-spotted grouper (Epinephelus coioides) ASC and caspase-1 involved in extracellular ATP-mediated immune signaling in fish. FISH & SHELLFISH IMMUNOLOGY 2020; 97:58-71. [PMID: 31837409 DOI: 10.1016/j.fsi.2019.12.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/02/2019] [Accepted: 12/08/2019] [Indexed: 06/10/2023]
Abstract
Apoptosis-associated speck-like protein containing a CARD domain (ASC) is a critical adaptor molecule in multiple inflammasome protein complexes that mediate inflammation and host defense. Caspase-1 is a member of inflammatory caspases that play important roles in the innate immune system. However, few studies have been performed in lower vertebrates such as teleosts and implications of extracellular ATP-mediated immune signalling in fish. Here we identified and characterized novel ASC and caspase-1 genes (namely EcASC and EcCaspase-1) from the orange-spotted grouper (Epinephelus coioides). EcASC and EcCaspase-1 encode 204- and 388-aa proteins which shared 55.34% and 72.89% identity with those in Siniperca chuatsi and Perca flavescens, respectively. EcASC contained a PYRIN domain (aa 5-82) and CARD domain (aa 107-201). EcCaspase1 contained a CARD domain (aa 1-88) and a CASc domain (aa 127-376). Both EcASC and EcCaspase-1 were distributed in all tissues tested in the healthy grouper. The expression of EcASC and EcCaspase-1 was significantly upregulated in response to ATP infection. Subcellular localization analysis showed that EcCaspase-1 exhibited a clear distribution in both cytoplasm and nucleus. In contrast, EcASC was observed in the cytoplasm as speck-like structures, which are called "pyroptosomes". EcCaspase-1 co-localized with the spot-like protein (EcASC). Overexpression of EcASC and EcCaspase-1 inhibited NF-κB activation and promoted P53 activation in grouper spleen (GS) cells. Extracellular ATP was an effective signaling molecule that activates the innate immune response, rapidly upregulating the expression of EcASC and EcCaspase1, and enhancing their promotion of proinflammatory cytokine expression in GS cells. Both EcASC and EcCaspase-1 promoted ATP-induced apoptosis. Our results suggested that the interactions of inflammatory EcCaspase-1 with EcASC proteins were associated with extracellular ATP-mediated immune signaling in fish.
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Affiliation(s)
- Xin Zhang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Zetian Liu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Chen Li
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Ya Zhang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Liqun Wang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China
| | - Jingguang Wei
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China.
| | - Qiwei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, China.
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Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. ADVANCES IN ANATOMY EMBRYOLOGY AND CELL BIOLOGY 2019; 228:63-86. [PMID: 29288386 DOI: 10.1007/978-3-319-68483-3_4] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Apoptosis plays an essential role in homeostasis and pathogenesis of a variety of human diseases. Endothelial cells are exposed to various environmental and internal stress and endothelial apoptosis is a pathophysiological consequence of these stimuli. Pulmonary endothelial cell apoptosis initiates or contributes to progression of a number of lung diseases. This chapter will focus on the current understanding of the role of pulmonary endothelial cell apoptosis in the development of emphysema and acute lung injury (ALI) and the factors controlling pulmonary endothelial life and death.
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50
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da Silva CS, Calió ML, Mosini AC, Pires JM, Rêgo DDSB, Mello LE, Leslie ATFS. LPS-Induced Systemic Neonatal Inflammation: Blockage of P2X7R by BBG Decreases Mortality on Rat Pups and Oxidative Stress in Hippocampus of Adult Rats. Front Behav Neurosci 2019; 13:240. [PMID: 31798427 PMCID: PMC6878118 DOI: 10.3389/fnbeh.2019.00240] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022] Open
Abstract
Neonatal lipopolysaccharide (LPS) exposure-induced brain inflammation has been associated to neuronal injury and facilitates the development of models of neurological disorders in adult rats. The P2X7 receptor (P2X7R) plays a fundamental role in the onset and maintenance of the inflammatory cascade. Brilliant blue G (BBG), a P2X7R antagonist, has been shown to effectively promote neuroinflammatory protection. Here, we have investigated the long-term effects of the neonatal systemic inflammation on hippocampal oxidative stress, anxiety behavior and pain sensitivity in adulthood. We hypothesized that P2X7R blockade is able to modulate the effects of inflammation on these variables. Male and female rat pups received LPS and/or BBG solution intraperitoneally on the 1st, 3rd, 5th and 7th postnatal days. The survival rate and body weight were evaluated during the experimental procedures. The animals were submitted to behavioral tests for anxiety (elevated plus maze, EPM) and nociception (hot-plate and tail-flick) and the oxidative stress was measured by superoxide production in the dentate gyrus of the hippocampus using dihydroethidium (DHE) probe. BBG increased the survival rate in LPS-treated rats. No significant differences were found regarding anxiety behavior and pain sensitivity between the experimental groups. Systemic neonatal inflammation leads to a higher production of superoxide anion in the dentate gyrus of the hippocampus in adulthood and BBG inhibited that effect. Our data suggest that blocking the activation of the P2X7R during neonatal systemic inflammation may have a potential neuroprotective effect in adulthood.
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Affiliation(s)
| | - Michele Longoni Calió
- Departamento de Bioquímica, Universidade Federal de São Paulo-UNIFESP, São Paulo, Brazil
| | - Amanda Cristina Mosini
- Departamento de Fisiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo, Brazil
| | - Jaime Moreira Pires
- Departamento de Fisiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo, Brazil
| | | | - Luiz E Mello
- Departamento de Fisiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo, Brazil.,D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil
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