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Cao JT, Li HW, Chen JQ, Lv HL, Jiang YF. Hongjingtian alleviates arsenic-induced hepatocyte injury by inhibiting oxidative stress and endoplasmic reticulum stress. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2025:1-14. [PMID: 40285662 DOI: 10.1080/10286020.2025.2481290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 04/29/2025]
Abstract
This study explored Hongjingtian's (HJT) protective effects against arsenic-induced hepatotoxicity. NaAsO2 (8 μM, 24 h)-damaged hepatocytes treated with HJT (50/100 mg/L) showed restored cell viability via CCK-8/LDH assays. HJT reduced arsenic-induced ROS, improved mitochondrial membrane potential, elevated SOD/CAT activity, lowered MDA, and suppressed apoptosis by downregulating Caspase-3/Bax while upregulating Bcl-2. Additionally, HJT alleviated endoplasmic reticulum stress (ERS). Mechanistically, HJT attenuated arsenic-induced hepatocyte apoptosis by mitigating oxidative stress and ERS via ROS reduction.
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Affiliation(s)
- Jiang-Tao Cao
- School of Basic Medicine, Chengdu Medical College, Chengdu610500, China
| | - Hai-Wen Li
- School of Basic Medicine, Chengdu Medical College, Chengdu610500, China
| | - Jia-Qi Chen
- School of Basic Medicine, Chengdu Medical College, Chengdu610500, China
| | - Hai-Long Lv
- Section for HepatoPancreatoBiliary Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu610031, China
| | - Yu-Feng Jiang
- School of Basic Medicine, Chengdu Medical College, Chengdu610500, China
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Subramaniam NK, Mann KK. Mechanisms of Metal-Induced Hepatic Inflammation. Curr Environ Health Rep 2024; 11:547-556. [PMID: 39499483 DOI: 10.1007/s40572-024-00463-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2024] [Indexed: 11/07/2024]
Abstract
PURPOSE OF REVIEW Worldwide, there is an increasing prevalence of hepatic diseases. The most common diseases include alcoholic-associated liver disease (ALD), metabolic dysfunction-associated fatty liver disease/ metabolic dysfunction-associated steatohepatitis (MAFLD/MASH) and viral hepatitis. While there are many important mediators of these diseases, there is increasing recognition of the importance of the inflammatory immune response in hepatic disease pathogenesis. RECENT FINDINGS Hepatic inflammation triggers the onset and progression of liver diseases. Chronic and sustained inflammation can lead to fibrosis, then cirrhosis and eventually end-stage cancer, hepatocellular carcinoma. Importantly, growing evidence suggest that metal exposure plays a role in hepatic disease pathogenesis. While in recent years, studies have linked metal exposure and hepatic steatosis, studies emphasizing metal-induced hepatic inflammation are limited. Hepatic inflammation is an important hallmark of fatty liver disease. This review aims to summarize the mechanisms of arsenic (As), cadmium (Cd) and chromium (Cr)-induced hepatic inflammation as they contribute to hepatic toxicity and to identify data gaps for future investigation.
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Affiliation(s)
| | - Koren K Mann
- Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
- Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste Catherine Rd. Rm 202.1, Montréal, Québec, H3T 1E2, Canada.
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Shukla A, Rockey DC, Kamath PS, Kleiner DE, Singh A, Vaidya A, Koshy A, Goel A, Dökmeci AK, Meena B, Philips CA, Sharma CB, Payawal DA, Kim DJ, Lo GH, Han G, Qureshi H, Wanless IR, Jia J, Sollano JD, Al Mahtab M, Muthiah MD, Sonderup MW, Nahum MS, Merican MIB, Ormeci N, Kawada N, Reddy R, Dhiman RK, Gani R, Hameed SS, Harindranath S, Jafri W, Qi X, Chawla YK, Furuichi Y, Zheng MH, Sarin SK. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and management. Hepatol Int 2024; 18:1684-1711. [DOI: https:/doi.org/10.1007/s12072-024-10739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/28/2024] [Indexed: 04/13/2025]
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Shukla A, Rockey DC, Kamath PS, Kleiner DE, Singh A, Vaidya A, Koshy A, Goel A, Dökmeci AK, Meena B, Philips CA, Sharma CB, Payawal DA, Kim DJ, Lo GH, Han G, Qureshi H, Wanless IR, Jia J, Sollano JD, Al Mahtab M, Muthiah MD, Sonderup MW, Nahum MS, Merican MIB, Ormeci N, Kawada N, Reddy R, Dhiman RK, Gani R, Hameed SS, Harindranath S, Jafri W, Qi X, Chawla YK, Furuichi Y, Zheng MH, Sarin SK. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and management. Hepatol Int 2024; 18:1684-1711. [PMID: 39546143 DOI: 10.1007/s12072-024-10739-6] [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: 06/17/2024] [Accepted: 09/28/2024] [Indexed: 11/17/2024]
Abstract
Since the Asian Pacific Association for the Study of the Liver (APASL) published guidelines on non-cirrhotic portal fibrosis/idiopathic portal hypertension in 2007, there has been a surge in new information, especially with the introduction of the term porto-sinusoidal vascular disorder (PSVD). Non-cirrhotic intra-hepatic causes of portal hypertension include disorders with a clearly identifiable etiology, such as schistosomiasis, as well as disorders with an unclear etiology such as non-cirrhotic portal fibrosis (NCPF), also termed idiopathic portal hypertension (IPH). This entity is being increasingly recognized as being associated with systemic disease and drug therapy, especially cancer therapy. An international working group with extensive expertise in portal hypertension was assigned with formulating consensus guidelines to clarify the definition, diagnosis, histological features, natural history, and management of NCPF/IPH, especially in the context of PSVD. The guidelines were prepared based on evidence from existing published literature. Whenever there was paucity of evidence, expert opinion was included after detailed deliberation. The goal of this manuscript, therefore, is to enhance the current understanding and help create global consensus on the issues surrounding NCPF/IPH.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, MSC 623, Charleston, SC, 29425, USA
| | | | | | - Ankita Singh
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Arun Vaidya
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Abraham Koshy
- Department of Gastroenterology, VPS Lakeshore Hospital, Kochi, Kerala, India
| | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - A Kadir Dökmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Babulal Meena
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
| | - Chhagan Bihari Sharma
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Diana A Payawal
- Fatima University Medical Center Manila, Manila, Philippines
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - Gin-Ho Lo
- Department of Medical Research, E-Da Hospital, Kaohsiung, School of Medicine for International Students, I-Shou University, 1, Yi-Da Road, Kaohsiung, 824, Taiwan
| | - Guohong Han
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | | | - Ian R Wanless
- Department of Pathology, Dalhousie University, Halifax, Canada
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Beijing, Mainland, China
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark W Sonderup
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mendez Sanchez Nahum
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | | | - Necati Ormeci
- İstanbul Health and Technology University, Istanbul, Turkey
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Rajender Reddy
- Division of Gastroenterology and Hepatology, 2 Dulles, Liver Transplant Office, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - R K Dhiman
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Rino Gani
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Saeed S Hameed
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Sidharth Harindranath
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Wasim Jafri
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Nanjing, China
| | - Yogesh Kumar Chawla
- Department of Hepatology and Gastroenterology, Kalinga Institute of MedicalSciences, KIIT University, Bhubaneshwar, India
| | - Yoshihiro Furuichi
- Department of Clinical Laboratory and Endoscopy, Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, 325000, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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Qu M, He Q, Bao H, Ji X, Shen T, Barkat MQ, Wu X, Zeng LH. Multiple roles of arsenic compounds in phase separation and membraneless organelles formation determine their therapeutic efficacy in tumors. J Pharm Anal 2024; 14:100957. [PMID: 39253293 PMCID: PMC11381784 DOI: 10.1016/j.jpha.2024.02.011] [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: 11/12/2023] [Revised: 01/23/2024] [Accepted: 02/21/2024] [Indexed: 09/11/2024] Open
Abstract
Arsenic compounds are widely used for the therapeutic intervention of multiple diseases. Ancient pharmacologists discovered the medicinal utility of these highly toxic substances, and modern pharmacologists have further recognized the specific active ingredients in human diseases. In particular, Arsenic trioxide (ATO), as a main component, has therapeutic effects on various tumors (including leukemia, hepatocellular carcinoma, lung cancer, etc.). However, its toxicity limits its efficacy, and controlling the toxicity has been an important issue. Interestingly, recent evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation, which may determine their toxicity and therapeutic efficacy. Here, we summarize the arsenic compounds-regulating phase separation and membraneless organelles formation. We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds, highlighting potential mechanisms underlying the clinical application of arsenic compounds.
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Affiliation(s)
- Meiyu Qu
- Department of Pharmacy, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Qiangqiang He
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hangyang Bao
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xing Ji
- Department of Pharmacology, Hangzhou City University School of Medicine, Hangzhou, 310015, China
| | - Tingyu Shen
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Muhammad Qasim Barkat
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Ximei Wu
- Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Ling-Hui Zeng
- Department of Pharmacology, Hangzhou City University School of Medicine, Hangzhou, 310015, China
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Wang Q, Zhang A. Baicalein Alleviates Arsenic-induced Oxidative Stress through Activation of the Keap1/Nrf2 Signalling Pathway in Normal Human Liver Cells. Curr Mol Med 2024; 24:355-365. [PMID: 36959142 DOI: 10.2174/1566524023666230320163238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 01/25/2023] [Accepted: 01/31/2023] [Indexed: 03/25/2023]
Abstract
BACKGROUND Oxidative stress is a key mechanism underlying arsenicinduced liver injury, the Kelch-like epichlorohydrin-related protein 1 (Keap1)/nuclear factor E2 related factor 2 (Nrf2) pathway is the main regulatory pathway involved in antioxidant protein and phase II detoxification enzyme expression. The aim of the present study was to investigate the role and mechanism of baicalein in the alleviation of arsenic-induced oxidative stress in normal human liver cells. METHODS Normal human liver cells (MIHA cells) were treated with NaAsO2 (0, 5, 10, 20 μM) to observe the effect of different doses of NaAsO2 on MIHA cells. In addition, the cells were treated with DMSO (0.1%), NaAsO2 (20 μM), or a combination of NaAsO2 (20 μM) and Baicalein (25, 50 or 100 μM) for 24 h to observe the antagonistic effect of Baicalein on NaAsO2. Cell viability was determined using a Cell Counting Kit- 8 (CCK-8 kit). The intervention doses of baicalein in subsequent experiments were determined to be 25, 50 and 100μM. The intracellular content of reactive oxygen species (ROS) was assessed using a 2',7'-dichlorodihydrofluorescein diacetate (DCFHDA) probe kit. The malonaldehyde (MDA), Cu-Zn superoxide dismutase (Cu-Zn SOD) and glutathione peroxidase (GSH-Px) activities were determined by a test kit. The expression levels of key genes and proteins were determined by real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting. RESULTS Baicalein upregulated the protein expression levels of phosphorylated Nrf2 (p-Nrf2) and nuclear Nrf2, inhibited the downregulation of Nrf2 target genes induced by arsenic, and decreased the production of ROS and MDA. These results demonstrate that baicalein promotes Nrf2 nuclear translocation by upregulating p-Nrf2 and inhibiting the downregulation of Nrf2 target genes in arsenic-treated MIHA cells, thereby enhancing the antioxidant capacity of cells and reducing oxidative stress. CONCLUSION Baicalein alleviated arsenic-induced oxidative stress through activation of the Keap1/Nrf2 signalling pathway in normal human liver cells.
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Affiliation(s)
- Qi Wang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, P.R. China
| | - Aihua Zhang
- The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, P.R. China
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7
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Rance N. How single-cell transcriptomics provides insight on hepatic responses to TCDD. CURRENT OPINION IN TOXICOLOGY 2023; 36:100441. [PMID: 37981901 PMCID: PMC10653208 DOI: 10.1016/j.cotox.2023.100441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
The prototypical aryl hydrocarbon receptor (AHR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been a valuable model for investigating toxicant-associated fatty liver disease (TAFLD). TCDD induces dose-dependent hepatic lipid accumulation, followed by the development of inflammatory foci and eventual progression to fibrosis in mice. Previously, bulk approaches and in vitro examination of different cell types were relied upon to study the mechanisms underlying TCDD-induced liver pathologies. However, the advent of single-cell transcriptomic technologies, such as single-nuclei RNA sequencing (snRNAseq) and spatial transcriptomics (STx), has provided new insights into the responses of hepatic cell types to TCDD exposure. This review explores the application of these single-cell transcriptomic technologies and highlights their contributions towards unraveling the cell-specific mechanisms mediating the hepatic responses to TCDD.
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Affiliation(s)
- Nault Rance
- Institute for Integrative Toxicology, Michigan State University, Michigan, USA
- Department of Biochemistry & Molecular Biology, Michigan State University, Michigan, USA
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Lingas EC. Hematological Abnormalities in Cirrhosis: A Narrative Review. Cureus 2023; 15:e39239. [PMID: 37337504 PMCID: PMC10277171 DOI: 10.7759/cureus.39239] [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] [Accepted: 05/18/2023] [Indexed: 06/21/2023] Open
Abstract
Liver cirrhosis remains a major public health issue. Liver fibrosis leading to cirrhosis is the terminal stage of various chronic liver diseases. Inflammatory cytokines are involved in the pathogenesis. Patients with cirrhosis often have hematological abnormalities, such as anemia and thrombocytopenia, which have multifactorial etiologies. Anemia in cirrhosis could be related to bleeding leading to iron deficiency anemia or other nutritional anemia such as vitamin B12 and folate deficiency. The pathophysiology of thrombocytopenia in liver cirrhosis has been postulated to range from splenic sequestration to bone marrow suppression from toxic agents, such as alcohol. It often complicates management due to the risk of bleeding with severely low platelets. This review aimed to highlight pathogenesis of liver cirrhosis, hematological abnormalities in liver cirrhosis, and their clinical significance.
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Wang L, Zhang Y, Ren Y, Yang X, Ben H, Zhao F, Yang S, Wang L, Qing J. Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis. Eur J Pharmacol 2022; 932:175241. [PMID: 36058291 DOI: 10.1016/j.ejphar.2022.175241] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/18/2022]
Abstract
Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis.
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Affiliation(s)
- Lu Wang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yuwei Zhang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yafeng Ren
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610064, China
| | - Xue Yang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Haijing Ben
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, 100069, China
| | - Fulan Zhao
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Sijin Yang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China
| | - Li Wang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China.
| | - Jie Qing
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, China; MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
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Rajak S, Raza S, Tewari A, Sinha RA. Environmental Toxicants and NAFLD: A Neglected yet Significant Relationship. Dig Dis Sci 2022; 67:3497-3507. [PMID: 34383198 DOI: 10.1007/s10620-021-07203-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 07/27/2021] [Indexed: 01/09/2023]
Abstract
The liver is an organ of vital importance in the body; it is the center of metabolic activities and acts as the primary line of defense against toxic compounds. Exposure to environmental toxicants is an unavoidable fallout from rapid industrialization across the world and is even higher in developing countries. Technological development and industrialization have led to the release of toxicants such as pollutant toxic gases, chemical discharge, industrial effluents, pesticides and solvents, into the environment. In the last few years, a growing body of evidence has shed light on the potential impact of environmental toxicants on liver health, in particular, on non-alcoholic fatty liver disease (NAFLD) incidence and progression. NAFLD is a multifactorial disease linked to metabolic derangement including diabetes and other complications. Environmental toxicants including xenobiotics and pollutants may have a direct or indirect steatogenic/fibrogenic impact on the liver and should be considered as risk factors associated with NAFLD. This review discusses the contribution of environmental toxicants toward the increasing disease burden of NAFLD.
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Affiliation(s)
- Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rohit A Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
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11
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Whitlock B. Telomere Length and Arsenic: Improving Animal Models of Toxicity by Choosing Mice With Shorter Telomeres. Int J Toxicol 2021; 40:211-217. [PMID: 34008434 DOI: 10.1177/10915818211009844] [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: 11/15/2022]
Abstract
Arsenic is both a chemotherapeutic drug and an environmental toxicant that affects hundreds of millions of people each year. Arsenic exposure in drinking water has been called the worst poisoning in human history. How arsenic is handled in the body is frequently studied using rodent models to investigate how arsenic both causes and treats disease. These models, used in a variety of arsenic-related testing, from tumor formation to drug toxicity monitoring, have virtually always been developed from animals with telomeres that are unnaturally long, likely because of accidental artificial selective pressures. Mice that have been bred in captivity in laboratory conditions, often for over 100 years, are the standard in creating animal models for this research. Using these mice introduces challenges to any work that can be affected by the length of telomeres and the related capacities for tissue repair and cancer resistance. However, arsenic research is particularly susceptible to the misuse of such animal models due to the multiple and various interactions between arsenic and telomeres. Researchers in the field commonly find mouse models and humans behaving very differently upon exposure to acute and chronic arsenic, including drug therapies which seem safe in mice but are toxic in humans. Here, some complexities and apparent contradictions of the arsenic carcinogenicity and toxicity research are reconciled by an explanatory model that involves telomere length explained by the evolutionary pressures in laboratory mice. A low-risk hypothesis is proposed which has the power to determine whether researchers can easily develop more powerful and accurate mouse models by simply avoiding mouse lineages that are very old and have strangely long telomeres. Swapping in newer mouse lineages for the older, long-telomere mice may vastly improve our ability to research arsenic toxicity with virtually no increase in cost or difficulty of research.
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Affiliation(s)
- Brayden Whitlock
- University of Alberta Health Accelerator, Edmonton, Alberta, Canada.,Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
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12
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Cai J, Hu M, Chen Z, Ling Z. The roles and mechanisms of hypoxia in liver fibrosis. J Transl Med 2021; 19:186. [PMID: 33933107 PMCID: PMC8088569 DOI: 10.1186/s12967-021-02854-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis occurs in response to any etiology of chronic liver injury. Lack of appropriate clinical intervention will lead to liver cirrhosis or hepatocellular carcinoma (HCC), seriously affecting the quality of life of patients, but the current clinical treatments of liver fibrosis have not been developed yet. Recent studies have shown that hypoxia is a key factor promoting the progression of liver fibrosis. Hypoxia can cause liver fibrosis. Liver fibrosis can, in turn, profoundly further deepen the degree of hypoxia. Therefore, exploring the role of hypoxia in liver fibrosis will help to further understand the process of liver fibrosis, and provide the theoretical basis for its diagnosis and treatment, which is of great significance to avoid further deterioration of liver diseases and protect the life and health of patients. This review highlights the recent advances in cellular and molecular mechanisms of hypoxia in developments of liver fibrosis.
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Affiliation(s)
- Jingyao Cai
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Min Hu
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China.
| | - Zhiyang Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
| | - Zeng Ling
- Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
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13
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Deppermann C, Kratofil RM, Peiseler M, David BA, Zindel J, Castanheira FVES, van der Wal F, Carestia A, Jenne CN, Marth JD, Kubes P. Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets. J Exp Med 2020; 217:133651. [PMID: 31978220 PMCID: PMC7144524 DOI: 10.1084/jem.20190723] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 10/01/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022] Open
Abstract
Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver, we observed rapid accumulation of desialylated platelets predominantly on Kupffer cells, with only a few on endothelial cells and none on hepatocytes. Kupffer cell depletion prevented the removal of aged platelets from circulation. Ashwell-Morell receptor (AMR) deficiency alone had little effect on platelet uptake. Macrophage galactose lectin (MGL) together with AMR mediated clearance of desialylated or cold-stored platelets by Kupffer cells. Effective clearance is critical, as mice with an aged platelet population displayed a bleeding phenotype. Our data provide evidence that the MGL of Kupffer cells plays a significant role in the removal of desialylated platelets through a collaboration with the AMR, thereby maintaining a healthy and functional platelet compartment.
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Affiliation(s)
- Carsten Deppermann
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rachel M Kratofil
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Moritz Peiseler
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Bruna A David
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Joel Zindel
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Fernanda Vargas E Silva Castanheira
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Fardau van der Wal
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Agostina Carestia
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Craig N Jenne
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Jamey D Marth
- Center for Nanomedicine, SBP Medical Discovery Institute, and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.,Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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14
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Zhang Q, Niu X, Tian L, Liu J, Niu R, Quan J, Yu J, Lin W, Qian Z, Zeng P. CTRP13 attenuates the expression of LN and CAV-1 Induced by high glucose via CaMKKβ/AMPK pathway in rLSECs. Aging (Albany NY) 2020; 12:11485-11499. [PMID: 32554851 PMCID: PMC7343496 DOI: 10.18632/aging.103234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/30/2020] [Indexed: 12/16/2022]
Abstract
Objective: To investigate the effect and mechanism of CTRP13 on hepatic sinusoidal capillarization induced by high glucose in rat liver sinusoidal endothelial cells (rLSECs). Results: CTRP13 was reduced in high glucose-treated rLSECs. High glucose increased LN and CAV-1 expression and inhibited CaMKKβ and AMPK phosphorylation. CTRP13 overexpression protected rLSECs against high glucose-induced increase of LN and CAV-1 expression. Moreover, CTRP13 overexpression increased high glucose-induced inhibition of CaMKKβ and AMPK activation in CTRP13-overexpressing rLSECs. Inhibition of CaMKKβ and AMPK disturbed the protective effects of CTRP13 in high glucose-induced increase of LN and CAV-1. Hepatic steatosis was enhanced and basement membrane was thickened in liver of diabetic fatty liver rats. Conclusions: Our data identified the protective role of CTRP13 in hepatic sinusoidal capillarization induced by high glucose via activating CAMKKβ/AMPK pathway. CTRP13 may be a potential target for screening and treating diabetic fatty liver. Methods: Construct lentiviral CTRP13 overexpression vector and transfect rLSECs. Use STO-609 (a CaMKKβ inhibitor) or Compound C (an AMPK inhibitor) to treat rLSECs. CTRP13, CaMKKβ, AMPK, laminin (LN) and caveolin-1 (CAV-1) were detected by qRT-PCR and Western blotting. Establish rat model of diabetic fatty liver. Use immunohistochemistry, hematoxylin-eosin and silver staining to observe the histopathological features of liver.
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Affiliation(s)
- Qi Zhang
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China.,School of Life Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiang'e Niu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China.,School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Limin Tian
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Jing Liu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Ruilan Niu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Jinxing Quan
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Jing Yu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Wenyan Lin
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China
| | - Zibing Qian
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China.,School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Peiyun Zeng
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China.,Clinical Research Center for Metabolic Disease, Lanzhou 730000, Gansu Province, China.,School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
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15
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The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis. Cells 2019; 8:cells8121503. [PMID: 31771248 PMCID: PMC6952767 DOI: 10.3390/cells8121503] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023] Open
Abstract
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell–cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
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16
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Li W, Zhang J, Lv Y, Sheibani N. Quantitative proteomic study of arsenic treated mouse liver sinusoidal endothelial cells using a reverse super-SILAC method. Biochem Biophys Res Commun 2019; 514:475-481. [PMID: 31056257 DOI: 10.1016/j.bbrc.2019.04.172] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 04/25/2019] [Indexed: 02/09/2023]
Abstract
Liver sinusoidal endothelial cells are the border patrol in the liver. Their open transcellular fenestrations allow the transfer of small and dissolved substances from the blood into the liver parenchymal cells. Fenestrations are dynamic structures, and many drugs and diseases alter their size and number, thus making them an important target for modulation. There is an urgent need to understand how various diseases, toxic substances, and physiological conditions influence liver endothelial cell fenestrations, and how these changes affects liver function. This work represents a straightforward quantitative proteomics study of the in vivo arsenic-stressed liver sinusoidal endothelial cells using a reverse super-SILAC based method. The aim of this study was to identify proteins, which are up- or down-regulated in response to arsenic. This knowledge will aid in identification of potential targets and mechanisms of arsenic toxicity and novel ways to reverse these changes.
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Affiliation(s)
- Wenbo Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, 100850, China; National Engineering Research Center for Protein Drugs, Beijing, 100850, China
| | - Jiyang Zhang
- College of Mechatronic Engineering and Automatic Control, National University of Defense Technology, Changsha, 410073, China
| | - Yongzhuang Lv
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, 100850, China
| | - Nader Sheibani
- Departemnts of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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17
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Kus E, Kaczara P, Czyzynska-Cichon I, Szafranska K, Zapotoczny B, Kij A, Sowinska A, Kotlinowski J, Mateuszuk L, Czarnowska E, Szymonski M, Chlopicki S. LSEC Fenestrae Are Preserved Despite Pro-inflammatory Phenotype of Liver Sinusoidal Endothelial Cells in Mice on High Fat Diet. Front Physiol 2019; 10:6. [PMID: 30809151 PMCID: PMC6379824 DOI: 10.3389/fphys.2019.00006] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/07/2019] [Indexed: 01/06/2023] Open
Abstract
Healthy liver sinusoidal endothelial cells (LSECs) maintain liver homeostasis, while LSEC dysfunction was suggested to coincide with defenestration. Here, we have revisited the relationship between LSEC pro-inflammatory response, defenestration, and impairment of LSEC bioenergetics in non-alcoholic fatty liver disease (NAFLD) in mice. We characterized inflammatory response, morphology as well as bioenergetics of LSECs in early and late phases of high fat diet (HFD)-induced NAFLD. LSEC phenotype was evaluated at early (2-8 week) and late (15-20 week) stages of NAFLD progression induced by HFD in male C57Bl/6 mice. NAFLD progression was monitored by insulin resistance, liver steatosis and obesity. LSEC phenotype was determined in isolated, primary LSECs by immunocytochemistry, mRNA gene expression (qRT-PCR), secreted prostanoids (LC/MS/MS) and bioenergetics (Seahorse FX Analyzer). LSEC morphology was examined using SEM and AFM techniques. Early phase of NAFLD, characterized by significant liver steatosis and prominent insulin resistance, was related with LSEC pro-inflammatory phenotype as evidenced by elevated ICAM-1, E-selectin and PECAM-1 expression. Transiently impaired mitochondrial phosphorylation in LSECs was compensated by increased glycolysis. Late stage of NAFLD was featured by prominent activation of pro-inflammatory LSEC phenotype (ICAM-1, E-selectin, PECAM-1 expression, increased COX-2, IL-6, and NOX-2 mRNA expression), activation of pro-inflammatory prostaglandins release (PGE2 and PGF2α) and preserved LSEC bioenergetics. Neither in the early nor in the late phase of NAFLD, were LSEC fenestrae compromised. In the early and late phases of NAFLD, despite metabolic and pro-inflammatory burden linked to HFD, LSEC fenestrae and bioenergetics are functionally preserved. These results suggest prominent adaptive capacity of LSECs that might mitigate NAFLD progression.
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Affiliation(s)
- Edyta Kus
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Kraków, Poland
| | - Patrycja Kaczara
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Kraków, Poland
| | | | - Karolina Szafranska
- Jagiellonian University, Faculty of Physics, Astronomy, and Applied Computer Science, Centre for Nanometer-Scale Science and Advanced Materials, Kraków, Poland
| | - Bartlomiej Zapotoczny
- Jagiellonian University, Faculty of Physics, Astronomy, and Applied Computer Science, Centre for Nanometer-Scale Science and Advanced Materials, Kraków, Poland
| | - Agnieszka Kij
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Kraków, Poland
- Jagiellonian University Medical College, Chair and Department of Toxicology, Kraków, Poland
| | | | - Jerzy Kotlinowski
- Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology, Department of General Biochemistry, Kraków, Poland
| | - Lukasz Mateuszuk
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Kraków, Poland
| | | | - Marek Szymonski
- Jagiellonian University, Faculty of Physics, Astronomy, and Applied Computer Science, Centre for Nanometer-Scale Science and Advanced Materials, Kraków, Poland
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Kraków, Poland
- Jagiellonian University Medical College, Chair of Pharmacology, Kraków, Poland
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18
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Targeting Endothelial Erk1/2-Akt Axis as a Regeneration Strategy to Bypass Fibrosis during Chronic Liver Injury in Mice. Mol Ther 2018; 26:2779-2797. [PMID: 30266653 DOI: 10.1016/j.ymthe.2018.08.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 08/13/2018] [Accepted: 08/19/2018] [Indexed: 02/08/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) have great capacity for liver regeneration, and this capacity can easily switch to profibrotic phenotype, which is still poorly understood. In this study, we elucidated a potential target in LSECs for regenerative treatment that can bypass fibrosis during chronic liver injury. Proregenerative LSECs can be transformed to profibrotic phenotype after 4 weeks of carbon tetrachloride administration or 10 days of bile duct ligation. This phenotypic alternation of LSECs was mediated by extracellular regulated protein kinases 1 and 2 (Erk1/2)-Akt axis switch in LSECs during chronic liver injury; Erk1/2 was normally associated with maintenance of the LSEC proregenerative phenotype, inhibiting hepatic stellate cell (HSC) activation and promoting tissue repair by enhancing nitric oxide (NO)/reactive oxygen species (ROS) ratio and increasing expression of hepatic growth factor (HGF) and Wingless-type MMTV integration site family member 2 (Wnt2). Alternatively, Akt induced LSEC profibrotic phenotype, which mainly stimulated HSC activation and concomitant senescence by reducing NO/ROS ratio and decreasing HGF/Wnt2 expression. LSEC-targeted adenovirus or drug particle to promote Erk1/2 activity can alleviate liver fibrosis, accelerate fibrosis resolution, and enhance liver regeneration. This study demonstrated that the Erk1/2-Akt axis acted as a switch to regulate the proregenerative and profibrotic phenotypes of LSECs, and targeted therapy promoted liver regeneration while bypassing fibrosis, providing clues for a more effective treatment of liver diseases.
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19
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Frediani JK, Naioti EA, Vos MB, Figueroa J, Marsit CJ, Welsh JA. Arsenic exposure and risk of nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults: an association modified by race/ethnicity, NHANES 2005-2014. Environ Health 2018; 17:6. [PMID: 29334960 PMCID: PMC5769436 DOI: 10.1186/s12940-017-0350-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 12/28/2017] [Indexed: 05/19/2023]
Abstract
BACKGROUND While associated with obesity, the cause of the rapid rise in prevalence of nonalcoholic fatty liver disease (NAFLD) in children, which is highest among Hispanics, is not well understood. Animal experiments have demonstrated that arsenic exposure contributes to liver injury. Our objective was to examine the association between arsenic exposure and NAFLD in humans and to determine if race/ethnicity modifies the association. METHODS Urinary inorganic arsenic concentrations among those ≥12 years in the National Health and Nutrition Examination Survey, 2005-2014 were used to assess the cross-sectional association with serum alanine aminotransferase (ALT) levels, a marker of liver dysfunction. We excluded high alcohol consumers (>4-5 drinks/day; n = 939), positive hepatitis B or C (n = 2330), those missing body mass index (n = 100) and pregnant women (n = 629) for a final sample of 8518. Arsenic was measured using liquid chromatography coupled with mass spectrometry and ALT was measured using standard methods. Sampling weights were used to obtain national estimates. Due to lack of normality, estimates were log transformed and are presented as geometric means. Logistic regression models controlling for age, sex, income, and weight category estimate adjusted odd ratios (aOR) of elevated ALT by quartile of arsenic and tested for effect modification by race/ethnicity and weight. Elevated ALT was defined as >25 IU/L and >22 IU/L for boys and girls ≤17 years, respectively and >30 IU/L and >19 IU/L for men and women, respectively. RESULTS Among all, aOR of elevated ALT were higher among those in the highest vs. lowest arsenic quartile (referent), 1.4 (95% confidence interval [CI]: 1.1, 1.7) with a borderline significant interaction (p = 0.07) by race/ethnicity but not weight (p = 0.4). In analysis stratified by race/ethnicity, aOR of elevated ALT among those in the 4th quartile were higher among Mexican Americans, 2.0 (CI: 1.3, 3.1) and non-Hispanic whites only, aOR 1.4 (CI: 1.1, 1.8) despite the fact that obesity prevalence was highest among non-Hispanic blacks. CONCLUSIONS Our findings demonstrate a positive association between urinary arsenic exposure and risk of NAFLD among U.S. adolescents and adults that is highest among Mexican Americans and among those obese, regardless of race/ethnicity.
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Affiliation(s)
| | - Eric A. Naioti
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA USA
| | - Miriam B. Vos
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA USA
| | - Janet Figueroa
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA USA
| | - Carmen J. Marsit
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA USA
| | - Jean A. Welsh
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA USA
- Wellness Department, Children’s Healthcare of Atlanta, Atlanta, GA USA
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20
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Proteomic Analysis Reveals Dab2 Mediated Receptor Endocytosis Promotes Liver Sinusoidal Endothelial Cell Dedifferentiation. Sci Rep 2017; 7:13456. [PMID: 29044176 PMCID: PMC5647404 DOI: 10.1038/s41598-017-13917-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/29/2017] [Indexed: 01/16/2023] Open
Abstract
Sinusoidal dedifferentiation is a complicated process induced by several factors, and exists in early stage of diverse liver diseases. The mechanism of sinusoidal dedifferentiation is poorly unknown. In this study, we established a NaAsO2-induced sinusoidal dedifferentiation mice model. Liver sinusoidal endothelial cells were isolated and isobaric tag for relative and absolute quantitation (iTRAQ) based proteomic approach was adopted to globally examine the effects of arsenic on liver sinusoidal endothelial cells (LSECs) during the progression of sinusoidal dedifferentiation. In all, 4205 proteins were identified and quantified by iTRAQ combined with LC-MS/MS analysis, of which 310 proteins were significantly changed in NaAsO2 group, compared with the normal control. Validation by western blot showed increased level of clathrin-associated sorting protein Disabled 2 (Dab2) in NaAsO2 group, indicating that it may regulate receptor endocytosis, which served as a mechanism to augment intracellular VEGF signaling. Moreover, we found that knockdown of Dab2 reduced the uptake of VEGF in LSECs, furthermore blocking VEGF-mediated LSEC dedifferentiation and angiogenesis.
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21
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Negro Silva LF, Lemaire M, Lemarié CA, Plourde D, Bolt AM, Chiavatti C, Bohle DS, Slavkovich V, Graziano JH, Lehoux S, Mann KK. Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the Mouse Model and the Role of As3mt-Mediated Methylation. ENVIRONMENTAL HEALTH PERSPECTIVES 2017; 125:077001. [PMID: 28728140 PMCID: PMC5744679 DOI: 10.1289/ehp806] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 12/21/2016] [Accepted: 12/21/2016] [Indexed: 05/03/2023]
Abstract
BACKGROUND Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined. OBJECTIVES Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis. METHODS We utilized the apoE−/− mouse model to compare atherosclerotic plaque size and composition after inorganic arsenic, methylated arsenical, or arsenobetaine exposure in drinking water. We also generated apoE−/−/As3mt−/− double knockout mice to test whether As3MT-mediated biotransformation was required for the proatherogenic effects of inorganic arsenite. Furthermore, As3MT expression and function were assessed in in vitro cultures of plaque-resident cells. Finally, bone marrow transplantation studies were performed to define the contribution of As3MT-mediated methylation in different cell types to the development of atherosclerosis after inorganic arsenic exposure. RESULTS We found that methylated arsenicals, but not arsenobetaine, are proatherogenic and that As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis. Importantly, As3MT was expressed and functional in multiple plaque-resident cell types, and transplant studies indicated that As3MT is required in extrahepatic tissues to promote atherosclerosis. CONCLUSION Taken together, our findings indicate that As3MT acts to promote cardiovascular toxicity of arsenic and suggest that human AS3MT SNPs that correlate with enzyme function could predict those most at risk to develop atherosclerosis among the millions that are exposed to arsenic. https://doi.org/10.1289/EHP806.
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Affiliation(s)
| | - Maryse Lemaire
- Lady Davis Institute for Medical Research
- Department of Oncology
| | | | | | - Alicia M Bolt
- Lady Davis Institute for Medical Research
- Department of Oncology
| | | | - D Scott Bohle
- Department of Chemistry, McGill University, Montréal, Québec, Canada
| | - Vesna Slavkovich
- Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Joseph H Graziano
- Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Stéphanie Lehoux
- Lady Davis Institute for Medical Research
- Division of Experimental Medicine
- Department of Medicine, and
| | - Koren K Mann
- Lady Davis Institute for Medical Research
- Division of Experimental Medicine
- Department of Oncology
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22
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Yang MH, Chang KJ, Zheng JC, Huang H, Sun GY, Zhao XW, Li B, Xiu QY. Anti-angiogenic effect of arsenic trioxide in lung cancer via inhibition of endothelial cell migration, proliferation and tube formation. Oncol Lett 2017; 14:3103-3109. [PMID: 28928847 DOI: 10.3892/ol.2017.6518] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 03/10/2017] [Indexed: 12/20/2022] Open
Abstract
Arsenic trioxide (As2O3) exhibits a remarkable effect on leukemia treatment; however, its effect on solid tumors remains poorly explored. The present study demonstrated the inhibitory effect of As2O3 on lung cancer and explored its possible mechanism. It was observed that As2O3 significantly inhibited the growth of lung cancer xenografts and tumor angiogenesis in vivo. The inhibitory effect of As2O3 on cell proliferation in vitro was more remarkable in vascular endothelial cells than in lung cancer cells. It was also observed that As2O3 inhibited the migration of vascular endothelial cells and disrupted vascular tube formation on Matrigel assays. In addition, a series of key signaling factors involved in multiple stages of angiogenesis, including matrix metalloproteinase (MMP)-2, MMP-9, platelet-derived growth factor (PDGF)-BB/PDGF receptor-β, vascular endothelial growth factor (VEGF)-A/VEGF receptor-2, basic fibroblast growth factor (FGF)/FGF receptor-1 and delta like canonical Notch ligand 4/Notch-1, were regulated by As2O3. These findings suggested that anti-angiogenesis may be an underlying mechanism of As2O3 anticancer activity in lung cancer.
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Affiliation(s)
- Meng-Hang Yang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Ke-Jie Chang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jin-Cheng Zheng
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Hai Huang
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Guang-Yuan Sun
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Xue-Wei Zhao
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Bing Li
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Qing-Yu Xiu
- Department of Respiratory Medicine, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
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Khairul I, Wang QQ, Jiang YH, Wang C, Naranmandura H. Metabolism, toxicity and anticancer activities of arsenic compounds. Oncotarget 2017; 8:23905-23926. [PMID: 28108741 PMCID: PMC5410354 DOI: 10.18632/oncotarget.14733] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 01/11/2017] [Indexed: 01/17/2023] Open
Abstract
A variety of studies indicated that inorganic arsenic and its methylated metabolites have paradoxical effects, namely, carcinogenic and anticancer effects. Epidemiological studies have shown that long term exposure to arsenic can increase the risk of cancers of lung, skin or bladder in man, which is probably associated with the arsenic metabolism. In fact, the enzymatic conversion of inorganic arsenic by Arsenic (+3 oxidation state) methyltransferase (AS3MT) to mono- and dimethylated arsenic species has long been considered as a major route for detoxification. However, several studies have also indicated that biomethylation of inorganic arsenic, particularly the production of trivalent methylated metabolites, is a process that activates arsenic as a toxin and a carcinogen. On the other hand, arsenic trioxide (As2O3) has recently been recognized as one of the most effective drugs for the treatment of APL. However, elaboration of the cytotoxic mechanisms of arsenic and its methylated metabolites in eradicating cancer is sorely lacking. To provide a deeper understanding of the toxicity and carcinogenicity along with them use of arsenic in chemotherapy, caution is required considering the poor understanding of its various mechanisms of exerting toxicity. Thereby, in this review, we have focused on arsenic metabolic pathway, the roles of the methylated arsenic metabolites in toxicity and in the therapeutic efficacy for the treatments of solid tumors, APL and/or non-APL malignancies.
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Affiliation(s)
- Islam Khairul
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
| | - Qian Qian Wang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yu Han Jiang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- Ocean College, Zhejiang University, Hangzhou, China
| | - Chao Wang
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
| | - Hua Naranmandura
- Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Ocean College, Zhejiang University, Hangzhou, China
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Zhao ZM, Liu HL, Sun X, Guo T, Shen L, Tao YY, Liu CH. Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway. Exp Biol Med (Maywood) 2017; 242:974-985. [PMID: 28440736 DOI: 10.1177/1535370217701005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Levistilide A (C24H28O4, molecular weight = 380.48) derived from Angelica sinensis (Danggui) has been reported to inhibit hepatic stellate cell proliferation. This study investigated the effects of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. LX-2 cells were activated by TGF-β1, and the human hepatic sinusoidal endothelial cells (HHSECs) were induced by endothelial cell growth supplement. Cell viability was detected using a methylthiazoldiphenyl-tetrazolium bromide assay; F-actin was visualized through the fluorescence probe method; cell proliferation was examined using the EdU kit; antiangiogenesis activity was assessed using the tube formation assay and transgenic zebrafish model. To verify the results in vivo, rats were subcutaneously injected with CCl4 twice a week for six weeks to duplicate the liver fibrosis model and then treated with 10 mL/kg of normal saline, 4 mg/kg of sorafenib, and 3 and 6 mg/kg of levistilide A for three weeks from the fourth week. Collagen deposition was detected through Sirius Red staining; liver microvasculature was examined through vWF labeling and X-ray 2D imaging; sinusoidal fenestrations were observed through scanning electron microscopy; collagen I, α-SMA, CD31, vascular endothelial growth factor (VEGF), and VEGF-R2 were detected through Western blotting. Our results indicated that levistilide A attenuated LX-2 cell activation and HHSEC proliferation. The ability of HHSECs to form tubelike structures in Matrigel was inhibited, and the number of functional vessels in transgenic zebrafish decreased. In in vivo experiments, levistilide A reduced collagen deposition and the number of new microvessels; ameliorated sinusoid capillarization; and downregulated the expression of CD31, VEGF, and VEGF-R2. These findings suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the VEGF signaling pathway. Impact statement Levistilide A has been reported to inhibit hepatic stellate cell (HSC) proliferation. In this study, we further investigated the mechanisms of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. The cell models of HSC and liver sinusoidal endothelial cell and CCl4 induced liver fibrosis model were used. These results suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the vascular endothelial growth factor signaling pathway. The effect of levistilide A on liver fibrosis was confirmed, and its detailed mechanism was also discussed. These findings suggest that levistilide A may be a great potential drug for treating liver fibrosis through antiangiogenesis, and this effect will be verified in other fibrotic animal model studies or by clinical trials.
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Affiliation(s)
- Zhi-Min Zhao
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,2 Shanghai Key Lab of Liver Diseases of TCM, Shanghai 201203, China
| | - Hong-Liang Liu
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xin Sun
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Guo
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Shen
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Yan Tao
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng-Hai Liu
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,2 Shanghai Key Lab of Liver Diseases of TCM, Shanghai 201203, China.,3 E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, Shanghai 201203, China
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Vimalraj S, Sumantran VN, Chatterjee S. MicroRNAs: Impaired vasculogenesis in metal induced teratogenicity. Reprod Toxicol 2017; 70:30-48. [PMID: 28249814 DOI: 10.1016/j.reprotox.2017.02.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 02/14/2017] [Accepted: 02/21/2017] [Indexed: 02/07/2023]
Abstract
Certain metals have been known for their toxic effects on embryos and fetal development. The vasculature in early pregnancy is extremely dynamic and plays an important role in organogenesis. Nascent blood vessels in early embryonic life are considered to be a primary and delicate target for many teratogens since the nascent blood islands follow a tightly controlled program to form vascular plexus around and inside the embryo for resourcing optimal ingredients for its development. The state of the distribution of toxic metals, their transport mechanisms and the molecular events by which they notch extra-embryonic and embryonic vasculatures are illustrated. In addition, pharmacological aspects of toxic metal induced teratogenicity have also been portrayed. The work reviewed state of the current knowledge of specific role of microRNAs (miRNAs) that are differentially expressed in response to toxic metals, and how they interfere with the vasculogenesis that manifests into embryonic anomalies.
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Affiliation(s)
- Selvaraj Vimalraj
- Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai, India.
| | | | - Suvro Chatterjee
- Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai, India; Department of Biotechnology, Anna University, Chennai, India.
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26
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Three-dimensional visualization of arsenic stimulated mouse liver sinusoidal by FIB-SEM approach. Protein Cell 2016; 7:227-32. [PMID: 26856874 PMCID: PMC4791422 DOI: 10.1007/s13238-016-0246-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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27
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Hsu LI, Wang YH, Hsieh FI, Yang TY, Wen-Juei Jeng R, Liu CT, Chen CL, Hsu KH, Chiou HY, Wu MM, Chen CJ. Effects of Arsenic in Drinking Water on Risk of Hepatitis or Cirrhosis in Persons With and Without Chronic Viral Hepatitis. Clin Gastroenterol Hepatol 2016; 14:1347-1355.e4. [PMID: 27060428 DOI: 10.1016/j.cgh.2016.03.043] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 03/26/2016] [Accepted: 03/28/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Arsenic in drinking water is associated with hepatomegaly and death from liver cancer. However, confounding factors related to liver diseases have not been carefully studied. We examined associations between exposure of arsenic in drinking water and risk of hepatitis and cirrhosis, and the interaction with chronic viral hepatitis, in people living in the Lanyang Basin of northeastern Taiwan, where well water has an arsenic content that ranges from undetectable to 3590 μg/L. METHODS We tested blood samples from 4387 people who lived in arseniasis-endemic areas in northeastern Taiwan from 1991 through 1994 for hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), and antibodies against hepatitis C virus (anti-HCV). We measured arsenic concentrations in well water and collected information on residents' histories of major chronic diseases. Reports of chronic hepatitis or cirrhosis were ascertained using the Taiwan National Health Insurance database. Reports of liver cancer were ascertained using the Taiwan National Cancer Registry. RESULTS Prevalence odds ratios in the overall study population for chronic hepatitis or cirrhosis for well water arsenic concentrations of ≤10 μg/L were 1.00 (reference), 0.93 for 10.1-49.9 μg/L (95% confidence interval [CI], 0.57-1.52), 1.24 for 50.0-99.9 μg/L (95% CI, 0.68-2.23), 0.98 for 100.0-299.9 (95% CI, 0.52-1.85), and 1.86 for ≥300.0 μg/L (95% CI, 1.08-3.20). Increasing levels of arsenic in drinking water were associated with increasing prevalence of chronic hepatitis or cirrhosis in residents who were seronegative for HBsAg and seronegative for anti-HCV, but not for seropositive for either HBsAg or anti-HCV. In individuals who were seropositive for HBsAg or anti-HCV, we observed an inverse association between hepatitis or cirrhosis and consumption of water with levels of arsenic ≥100.0 μg/L. Among participants who were seropositive for HBsAg or anti-HCV, consumption of water with levels of arsenic ≥100.0 μg/L was associated with a reduced risk of liver cancer (multivariate-adjusted hazard ratio, 0.29; 95% CI, 0.09-0.95; P < .05). A higher proportion of individuals exposed to cumulative arsenic level >14,000 μg/L ×year were carriers of inactive hepatitis B virus (DNA <10,000 copies/mL) and were positive for HBsAg (60%) than individuals exposed to water below this arsenic level (35%). CONCLUSIONS Concentrations of arsenic concentration in drinking water ≥300.0 μg/L significantly increase risk of hepatitis or cirrhosis in people without chronic viral hepatitis. However, in people with chronic viral hepatitis, levels of arsenic ≥100.0 μg/L in drinking water significantly reduce the risk of chronic hepatitis or cirrhosis.
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Affiliation(s)
- Ling-I Hsu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Department of Health Care Management, Chang-Gung University, Taoyuan City, Taiwan
| | - Yuan-Hung Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Fang-I Hsieh
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Tse-Yen Yang
- Molecular and Genomic Epidemiology Center, China Medical University Hospital, Taichung, Taiwan
| | - Rachel Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Division of Hepatology Chang Gung Medical Foundation, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | | | - Chi-Ling Chen
- Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuang-Hung Hsu
- Laboratory for Epidemiology, Department of Health Care Management, and Health Aging Research Center, Chang Gung University, Taoyuan City, Taiwan; Department of Urology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hung-Yi Chiou
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Meei-Maan Wu
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan.
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28
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Liu P. Inhibition of pathological angiogenesis of Chinese medicine against liver fibrosis. Chin J Integr Med 2016; 22:569-572. [PMID: 27107572 DOI: 10.1007/s11655-016-2468-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Indexed: 12/18/2022]
Abstract
Pathological angiogenesis of liver which includes liver sinusoidal capillarization due to lose of fenestraes of liver sinusoidal endothelial cells (LSECs) and formation of new vascular, is a crucial mechanism responsible for origination and development of liver fifibrosis and closely involves in the development of cirrhosis and hepatic cancer. Anti-neovascularization medicine such as sorafenib can decrease portosystemic shunts, improve splanchnic hyperdynamic circulation, lower portal hypertension, while it can not be applied in clinic due to its serious toxic and side reactions. Chinese herbal formula can effectively inhibit pathological angiogenesis of liver, improve microcirculation of liver, and decrease the probability of gastrointestinal hemorrhage in cirrhotic patients. Different Chinese herbal formula are of different characteristics on inhibiting pathological angiogenesis in liver fifibrosis, which partly explains synergistic effect of different compatibility of Chinese materia medica and opens up good vista for Chinese medicine against liver fifibrosis through inhibiting angiogenesis.
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Affiliation(s)
- Ping Liu
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201023, China.
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Lee HS, Shin HS, Choi J, Bae SJ, Wee HJ, Son T, Seo JH, Park JH, Kim SW, Kim KW. AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages. Int J Oncol 2016; 49:1407-14. [DOI: 10.3892/ijo.2016.3627] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 05/04/2016] [Indexed: 11/05/2022] Open
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30
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Feng RB. Relationship between chronic liver disease and liver hypoxia. Shijie Huaren Xiaohua Zazhi 2016; 24:2184-2190. [DOI: 10.11569/wcjd.v24.i14.2184] [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] [Indexed: 02/06/2023] Open
Abstract
The liver is an organ that metabolizes various substances very vigorously. During hepatic metabolism a large amount of oxygen needs to be provided for the liver, so the liver is vulnerable to hypoxia. Many chronic liver diseases are accompanied by liver cell hypoxia. In turn, liver cell hypoxia not only worsens liver tissue damage on the basis of primary liver lesion and inhibits hepatocellular regeneration but also accelerates liver fibrosis, cirrhosis, and even primary liver carcinoma. With chronic liver diseases exacerbating, liver hypoxia becomes more and more serious, and vice versa. This is an important mechanism by which chronic liver diseases gradually get worse and worse. As the most important hypoxia signal transduction factor in vivo, hypoxia inducible factor-1α (HIF-1α) plays an indispensable key role in the process of adaptive responses of the liver to hypoxia stimulus. Some progress in therapy for chronic liver diseases has been being made as the relationship between chronic liver diseases and liver hypoxia has been revealed and understood more deeply, especially by regulating and controlling HIF-1α and its downstream target to treat liver fibrosis. In addition, it has been found that some medicines have positive therapeutic effects on patients with chronic liver diseases through improving liver microcirculation and ameliorating liver hypoxia. However, the very complicated mechanism of interaction between chronic liver diseases and liver hypoxia, which involves a number of complex signal pathways, has not been completely elucidated, and therefore more basic and clinical studies need to be carried out for the clarification of their interaction.
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Goel A, Christudoss P, George R, Ramakrishna B, Amirtharaj GJ, Keshava SN, Ramachandran A, Balasubramanian KA, Mackie I, Fleming JJ, Elias E, Eapen CE. Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension. Indian J Gastroenterol 2016; 35:207-15. [PMID: 27225799 DOI: 10.1007/s12664-016-0660-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 04/28/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality. METHODS Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty-four percent to 96 % of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry. RESULTS Nail arsenic levels were raised in five (10 %) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11 %) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5 μg/L). CONCLUSIONS Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'.
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Affiliation(s)
- Ashish Goel
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India
| | - Pamela Christudoss
- Department of Clinical Biochemistry, Christian Medical College, Vellore, 632 004, India
| | - Renu George
- Department of Dermatology, Christian Medical College, Vellore, 632 004, India
| | | | | | | | - Anup Ramachandran
- Wellcome Trust Research Laboratory, Christian Medical College, Vellore, 632 004, India
| | - K A Balasubramanian
- Wellcome Trust Research Laboratory, Christian Medical College, Vellore, 632 004, India
| | - Ian Mackie
- Haemostasis Research Unit, Haematology Department, University College London, London, UK
| | - Jude J Fleming
- Department of Clinical Biochemistry, Christian Medical College, Vellore, 632 004, India
| | - Elwyn Elias
- Department of Hepatology, Christian Medical College, Vellore, 632 004, India.,University Hospital Birmingham, Birmingham, UK
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Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism. Toxicol Appl Pharmacol 2015; 289:397-408. [PMID: 26529668 DOI: 10.1016/j.taap.2015.10.020] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 10/15/2015] [Accepted: 10/28/2015] [Indexed: 02/07/2023]
Abstract
Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes.
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Massey VL, Stocke KS, Schmidt RH, Tan M, Ajami N, Neal RE, Petrosino JF, Barve S, Arteel GE. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction. Toxicol Appl Pharmacol 2015; 284:304-14. [PMID: 25759243 PMCID: PMC4515777 DOI: 10.1016/j.taap.2015.02.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Revised: 02/25/2015] [Accepted: 02/26/2015] [Indexed: 12/11/2022]
Abstract
Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9ppm as sodium arsenite) for 10weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects.
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Affiliation(s)
- Veronica L Massey
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Kendall S Stocke
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Robin H Schmidt
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Min Tan
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Nadim Ajami
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Rachel E Neal
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Joseph F Petrosino
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA; Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX, USA
| | - Shirish Barve
- Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, USA
| | - Gavin E Arteel
- Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
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Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, Ganzer L, Fiocchi A, Vacca M, Aiolfi R, Sammicheli S, Mainetti M, Cataudella T, Raimondi A, Gonzalez-Aseguinolaza G, Protzer U, Ruggeri ZM, Chisari FV, Isogawa M, Sitia G, Iannacone M. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 2015; 161:486-500. [PMID: 25892224 PMCID: PMC11630812 DOI: 10.1016/j.cell.2015.03.005] [Citation(s) in RCA: 238] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 12/18/2014] [Accepted: 02/24/2015] [Indexed: 02/06/2023]
Abstract
Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae. Hepatocellular antigen recognition triggers effector functions in a diapedesis-independent manner and is inhibited by the processes of sinusoidal defenestration and capillarization that characterize liver fibrosis. These findings reveal the dynamic behavior whereby CD8 TE control hepatotropic pathogens and suggest how liver fibrosis might reduce CD8 TE immune surveillance toward infected or transformed hepatocytes.
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Affiliation(s)
- Luca G Guidotti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
| | - Donato Inverso
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Laura Sironi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Physics, University of Milano Bicocca, 20126 Milan, Italy
| | - Pietro Di Lucia
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Jessica Fioravanti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Lucia Ganzer
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Physics, University of Milano Bicocca, 20126 Milan, Italy
| | - Amleto Fiocchi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Maurizio Vacca
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Roberto Aiolfi
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Stefano Sammicheli
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marta Mainetti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Tiziana Cataudella
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Andrea Raimondi
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Ulrike Protzer
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Zaverio M Ruggeri
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Francis V Chisari
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Masanori Isogawa
- Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Giovanni Sitia
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
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Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment. Toxicology 2015; 331:78-99. [PMID: 25771173 DOI: 10.1016/j.tox.2015.02.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 02/09/2015] [Accepted: 02/27/2015] [Indexed: 11/20/2022]
Abstract
The possibility of an association between inorganic arsenic (iAs) exposure and cardiovascular outcomes has received increasing attention in the literature over the past decade. The United States Environmental Protection Agency (US EPA) is currently revising its Integrated Risk Assessment System (IRIS) review of iAs, and one of the non-cancer endpoints of interest is cardiovascular disease (CVD). Despite the increased interest in this area, substantial gaps remain in the available information, particularly regarding the mechanism of action (MOA) by which iAs could cause or exacerbate CVD. Few studies specifically address the plausibility of an association between iAs and CVD at the low exposure levels which are typical in the United States (i.e., below 100 μg As/L in drinking water). We have conducted a review and evaluation of the animal, mechanistic, and human data relevant to the potential MOAs of iAs and CVD. Specifically, we evaluated the most common proposed MOAs, which include disturbance of endothelial function and hepatic dysfunction. Our analysis of the available evidence indicates that there is not a well-established MOA for iAs in the development or progression of CVD. Few human studies of the potential MOAs have addressed plausibility at low doses and the applicability of extrapolation from animal studies to humans is questionable. However, the available evidence indicates that regardless of the specific MOA, the effects of iAs on physiological processes at the cellular level appear to operate via a threshold mechanism. This finding is consistent with the lack of association of CVD with iAs exposure in humans at levels below 100 μg/L, particularly when considering important exposure and risk modifiers such as nutrition and genetics. Based on this analysis, we conclude that there are no data supporting a linear dose-response relationship between iAs and CVD, indicating this relationship has a threshold.
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36
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Duranova H, Martiniakova M, Omelka R, Grosskopf B, Bobonova I, Toman R. Changes in compact bone microstructure of rats subchronically exposed to cadmium. Acta Vet Scand 2014; 56:64. [PMID: 25279860 PMCID: PMC4189194 DOI: 10.1186/s13028-014-0064-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Accepted: 09/08/2014] [Indexed: 01/19/2023] Open
Abstract
Background Chronic exposure to cadmium (Cd), even at low concentrations, has an adverse impact on the skeletal system. Histologically, primary and secondary osteons as basic structural elements of compact bone can also be affected by several toxicants leading to changes in bone vascularization and mechanical properties of the bone. The current study was designed to investigate the effect of subchronic peroral exposure to Cd on femoral bone structure including histomorphometry of the osteons in adult male rats. In our study, 20 one-month-old male Wistar rats were randomly divided into two experimental groups. In the first group, young males received a drinking water containing 30 mg of CdCl2/L, for 90 days. Ten one-month-old males without Cd intoxication served as a control group. After 90 days of daily peroral exposure, body weight, femoral weight, femoral length, cortical bone thickness and histological structure of the femora were analysed. Results We found that subchronic peroral application of Cd had no significant effect on body weight, femoral length and cortical bone thickness in adult rats. On the other hand, femoral weight was significantly increased (P < 0.05) in Cd-intoxicated rats. These rats also displayed different microstructure in the middle part of the compact bone where vascular canals expanded into central area of substantia compacta and supplied primary and secondary osteons. Additionally, a few resorption lacunae which are connected with an early stage of osteoporosis were identified in these individuals. Histomorphometrical evaluations showed that all variables (area, perimeter, maximum and minimum diameter) of the primary osteons’ vascular canals, Haversian canals and secondary osteons were significantly decreased (P < 0.05) in the Cd group rats. This fact points to alterations in bone vascularization. Conclusions Subchronic peroral exposure to Cd significantly influences femoral weight and histological structure of compact bone in adult male rats. It induces an early stage of osteoporosis and causes reduced bone vascularization. Histomorphometrical changes of primary and secondary osteons allow for the conclusion that the bone mechanical properties could be weakened in the Cd group rats. The current study significantly expands the knowledge on damaging action of Cd on the bone.
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Nakadate K, Motojima K, Tanaka-Nakadate S. Dilatation of Sinusoidal Capillary and Swelling of Sinusoidal Fenestration in Obesity: An Ultrastructural Study. Ultrastruct Pathol 2014; 39:30-7. [DOI: 10.3109/01913123.2014.947010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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38
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Fabrisia A, Elke B, Donna S, Ricardo F, Bret G, Bridget D, Giovanna D, Alexandra R, Amin C, Yesica G, Aaron B. Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics. Free Radic Biol Med 2014; 74:64-73. [PMID: 24960579 PMCID: PMC4159748 DOI: 10.1016/j.freeradbiomed.2014.06.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 05/20/2014] [Accepted: 06/17/2014] [Indexed: 02/07/2023]
Abstract
Over 4 million individuals in the United States, and over 140 million individuals worldwide, are exposed daily to arsenic-contaminated drinking water. Human exposures can range from below the current limit of 10 μg/L to over 1mg/L, with 100 μg/L promoting disease in a large portion of those exposed. Although increased attention has recently been paid to myopathy following arsenic exposure, the pathogenic mechanisms underlying clinical symptoms remain poorly understood. This study tested the hypothesis that arsenic induces lasting muscle mitochondrial dysfunction and impairs metabolism. Compared to nonexposed controls, mice exposed to drinking water containing 100 μg/L arsenite for 5 weeks demonstrated impaired muscle function, mitochondrial myopathy, and altered oxygen consumption that were concomitant with increased mitochondrial fusion gene transcription. There were no differences in the levels of inorganic arsenic or its monomethyl and dimethyl metabolites between controls and exposed muscles, confirming that arsenic does not accumulate in muscle. Nevertheless, muscle progenitor cells isolated from exposed mice recapitulated the aberrant myofiber phenotype and were more resistant to oxidative stress, generated more reactive oxygen species, and displayed autophagic mitochondrial morphology, compared to cells isolated from nonexposed mice. These pathological changes from a possible maladaptive oxidative stress response provide insight into declines in muscle functioning caused by exposure to this common environmental contaminant.
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Affiliation(s)
- Ambrosio Fabrisia
- Department of Physical Medicine & Rehabilitation,
University of Pittsburgh, Pittsburgh, PA 15219
| | - Brown Elke
- Department of Physical Medicine & Rehabilitation,
University of Pittsburgh, Pittsburgh, PA 15219,
| | - Stolz Donna
- Department of Cell Biology, University of Pittsburgh, Pittsburgh,
PA 15213,
| | - Ferrari Ricardo
- Department of Physical Medicine & Rehabilitation,
University of Pittsburgh, Pittsburgh, PA,
| | - Goodpaster Bret
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
15213,
| | - Deasy Bridget
- Department of Orthopaedic Surgery, University of Pittsburgh,
Pittsburgh, PA 15213,
| | - Distefano Giovanna
- Department of Physical Therapy, University of Pittsburgh,
Pittsburgh, PA, 15213,
| | - Roperti Alexandra
- Department of Bioengineering, University of Pittsburgh, Pittsburgh,
PA, 15213,
| | - Cheikhi Amin
- Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA, 15219,
| | - Garciafigueroa Yesica
- Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA, 15219,
| | - Barchowsky Aaron
- Department of Environmental and Occupational Health, University of
Pittsburgh, Pittsburgh, PA, 15219,
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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40
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Wahlang B, Beier JI, Clair HB, Bellis-Jones HJ, Falkner KC, McClain CJ, Cave MC. Toxicant-associated steatohepatitis. Toxicol Pathol 2013; 41:343-60. [PMID: 23262638 PMCID: PMC5114851 DOI: 10.1177/0192623312468517] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatotoxicity is the most common organ injury due to occupational and environmental exposures to industrial chemicals. A wide range of liver pathologies ranging from necrosis to cancer have been observed following chemical exposures both in humans and in animal models. Toxicant-associated fatty liver disease (TAFLD) is a recently named form of liver injury pathologically similar to alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Toxicant-associated steatohepatitis (TASH) is a more severe form of TAFLD characterized by hepatic steatosis, inflammatory infiltrate, and in some cases, fibrosis. While subjects with TASH have exposures to industrial chemicals, such as vinyl chloride, they do not have traditional risk factors for fatty liver such as significant alcohol consumption or obesity. Conventional biomarkers of hepatotoxicity including serum alanine aminotransferase activity may be normal in TASH, making screening problematic. This article examines selected chemical exposures associated with TAFLD in human subjects or animal models and concisely reviews the closely related NAFLD and ALD.
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Affiliation(s)
- Banrida Wahlang
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Juliane I. Beier
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather B. Clair
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Heather J. Bellis-Jones
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - K. Cameron Falkner
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Craig J. McClain
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
| | - Matt C. Cave
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Louisville VAMC, Louisville, Kentucky, USA
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Bhattacharya A, Dhar P, Mehra RD. Preliminary morphological and biochemical changes in rat liver following postnatal exposure to sodium arsenite. Anat Cell Biol 2012; 45:229-40. [PMID: 23301191 PMCID: PMC3531587 DOI: 10.5115/acb.2012.45.4.229] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 09/15/2012] [Accepted: 10/25/2012] [Indexed: 12/13/2022] Open
Abstract
The effects of sodium arsenite exposure on the hepatic maturation period of cellular and functional reorganization in developing rat livers were evaluated. Animals received intraperitoneal injections of sodium arsenite (1.5 mg/kg body weight) or distilled water on days 9 to 28 after birth. On day 29, the animals were sacrificed either by cervical dislocation or by perfusion fixation. The perfusion fixed liver tissue was processed for paraffin embedding, sectioning and hematoxylin and eosin staining. The fresh liver tissue was processed for cryo-sectioning followed by Sudan Black B staining and for biochemical estimation of reduced glutathione. Microscopic observation revealed comparable preserved hepatic lobular patterns and distributions of uninucleate and binucleate hepatocytes in the control and the experimental groups. The mean nuclear area and diameter of the hepatocytes was increased in the experimental group. Lipid droplet distribution pattern in Sudan Black B stained sections revealed higher staining intensity towards the centrilobular area in both groups. Semiquantitative estimation of staining intensity showed lower mean gray values in zone 3 than in zones 2 and 1 (suggestive of the setting in of the adult pattern) in both groups. The reduced glutathione levels in the liver tissue and the altered nuclear size of the hepatocytes in the experimental group suggested the impairment of morphological and biochemical processes induced by arsenic exposure during the postnatal period.
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Affiliation(s)
- Arnab Bhattacharya
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
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Das N, Paul S, Chatterjee D, Banerjee N, Majumder NS, Sarma N, Sau TJ, Basu S, Banerjee S, Majumder P, Bandyopadhyay AK, States JC, Giri AK. Arsenic exposure through drinking water increases the risk of liver and cardiovascular diseases in the population of West Bengal, India. BMC Public Health 2012; 12:639. [PMID: 22883023 PMCID: PMC3441389 DOI: 10.1186/1471-2458-12-639] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 07/24/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Arsenic is a natural drinking water contaminant affecting 26 million people in West Bengal, India. Chronic arsenic exposure causes cancer, cardiovascular disease, liver disease, neuropathies and ocular diseases. The aims of the present study were to assess bioindicators of hepatocellular injury as indicated by the levels of liver enzymes, to determine the auto immune status, as indicated by the amounts of anti-nuclear antibodies (ANA) and anti-dsDNA antibodies in their serum, and to predict cardiovascular risk in the arsenic exposed population. METHODS Effect of chronic arsenic exposure on liver was determined by liver function tests. Autoimmune status was measured by measuring ANA and anti-dsDNA in serum. Inflammatory cytokines associated with increased cardiovascular disease risk, IL6, IL8 and MCP-1 were determined. RESULTS Our results indicated that serum levels of bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase and ANA were increased in the arsenic exposed population. Serum levels of IL6 and IL8 also increased in the arsenic exposed group. CONCLUSIONS Chronic arsenic exposure causes liver injury, increases the serum levels of autoimmune markers and imparts increased cardiovascular risk.
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Affiliation(s)
- Nandana Das
- Molecular and Human Genetics Division, CSIR- Indian Institute of Chemical Biology, 4, Raja S, C, Mullick Road, Kolkata, 700 032, India.
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States JC, Singh AV, Knudsen TB, Rouchka EC, Ngalame NO, Arteel GE, Piao Y, Ko MSH. Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis. PLoS One 2012; 7:e38713. [PMID: 22719926 PMCID: PMC3376138 DOI: 10.1371/journal.pone.0038713] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 05/11/2012] [Indexed: 01/07/2023] Open
Abstract
The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE−/−) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE−/− mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.
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Affiliation(s)
- J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America.
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Hang TC, Lauffenburger DA, Griffith LG, Stolz DB. Lipids promote survival, proliferation, and maintenance of differentiation of rat liver sinusoidal endothelial cells in vitro. Am J Physiol Gastrointest Liver Physiol 2012; 302:G375-88. [PMID: 22075778 PMCID: PMC3287397 DOI: 10.1152/ajpgi.00288.2011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary rat liver sinusoidal endothelial cells (LSEC) are difficult to maintain in a differentiated state in culture for scientific studies or technological applications. Relatively little is known about molecular regulatory processes that affect LSEC differentiation because of this inability to maintain cellular viability and proper phenotypic characteristics for extended times in vitro, given that LSEC typically undergo death and detachment around 48-72 h even when treated with VEGF. We demonstrate that particular lipid supplements added to serum-free, VEGF-containing medium increase primary rat liver LSEC viability and maintain differentiation. Addition of a defined lipid combination, or even oleic acid (OA) alone, promotes LSEC survival beyond 72 h and proliferation to confluency. Moreover, assessment of LSEC cultures for endocytic function, CD32b surface expression, and exhibition of fenestrae showed that these differentiation characteristics were maintained when lipids were included in the medium. With respect to the underlying regulatory pathways, we found lipid supplement-enhanced phosphatidylinositol 3-kinase and MAPK signaling to be critical for ensuring LSEC function in a temporally dependent manner. Inhibition of Akt activity before 72 h prevents growth of SEC, whereas MEK inhibition past 72 h prevents survival and proliferation. Our findings indicate that OA and lipids modulate Akt/PKB signaling early in culture to mediate survival, followed by a switch to a dependence on ERK signaling pathways to maintain viability and induce proliferation after 72 h. We conclude that free fatty acids can support maintenance of liver LSEC cultures in vitro; key regulatory pathways involved include early Akt signaling followed by ERK signaling.
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Affiliation(s)
- Ta-Chun Hang
- 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; and
| | - Douglas A. Lauffenburger
- 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; and
| | - Linda G. Griffith
- 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; and
| | - Donna B. Stolz
- 2Department of Cell Biology & Physiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X. MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol 2012; 227:772-83. [PMID: 21503876 DOI: 10.1002/jcp.22789] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Environmental exposure to inorganic arsenic compounds has been reported to have serious health effects on humans. Recent studies reported that arsenic targets endothelial cells lining blood vessels, and endothelial cell activation or dysfunction, may underlie the pathogenesis of arsenic-induced diseases and developmental toxicity. It has been reported that microRNAs (miRNAs) may act as an angiogenic switch by regulating related genes. The present study was designed to test the hypothesis that arsenite-regulated miRNAs play pivotal roles in arsenic-induced toxicity. Fertilized eggs were injected via the yolk sac with 100 nM sodium arsenite at Hamburger-Hamilton (HH) stages 6, 9, and 12, and harvested at HH stage 18. To identify the individual miRNAs and mRNAs that may regulate the genetic network, the expression profiles of chick embryos were analyzed by microarray analysis. Microarray analyses revealed that the expression of a set of miRNAs changed after arsenite administration, especially miRNA-9, 181b, 124, 10b, and 125b, which exhibited a massive decrease in expression. Integrative analyses of the microarray data revealed that several miRNAs, including miR-9 and miR-181b, might target several key genes involved in arsenic-induced developmental toxicity. A luciferase reporter assay confirmed neuropilin-1 (Nrp1) as a target of mir-9 and mir-181b. Data from the transwell migration assay and the tube-formation assay indicated that miR-9 and mir-181b inhibited the arsenic-induced EA.hy926 cell migration and tube formation by targeting NRP1. Our study demonstrates that the environmental toxin, sodium arsenite, induced angiogenesis by altering the expression of miRNAs and their cognate mRNA targets.
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Affiliation(s)
- Yi Cui
- Department of Genetics, Graduate School of Peking Union Medical College, Beijing, China
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46
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Dávila-Esqueda ME, Jiménez-Capdeville ME, Delgado JM, De la Cruz E, Aradillas-García C, Jiménez-Suárez V, Escobedo RF, Llerenas JR. Effects of arsenic exposure during the pre- and postnatal development on the puberty of female offspring. ACTA ACUST UNITED AC 2012; 64:25-30. [DOI: 10.1016/j.etp.2010.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 04/20/2010] [Accepted: 06/02/2010] [Indexed: 10/19/2022]
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States JC, Barchowsky A, Cartwright IL, Reichard JF, Futscher BW, Lantz RC. Arsenic toxicology: translating between experimental models and human pathology. ENVIRONMENTAL HEALTH PERSPECTIVES 2011; 119:1356-63. [PMID: 21684831 PMCID: PMC3230447 DOI: 10.1289/ehp.1103441] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 06/17/2011] [Indexed: 05/21/2023]
Abstract
BACKGROUND Chronic arsenic exposure is a worldwide health problem. How arsenic exposure promotes a variety of diseases is poorly understood, and specific relationships between experimental and human exposures are not established. We propose phenotypic anchoring as a means to unify experimental observations and disease outcomes. OBJECTIVES We examined the use of phenotypic anchors to translate experimental data to human pathology and investigated research needs for which phenotypic anchors need to be developed. METHODS During a workshop, we discussed experimental systems investigating arsenic dose/exposure and phenotypic expression relationships and human disease responses to chronic arsenic exposure and identified knowledge gaps. In a literature review, we identified areas where data exist to support phenotypic anchoring of experimental results to pathologies from specific human exposures. DISCUSSION Disease outcome is likely dependent on cell-type-specific responses and interaction with individual genetics, other toxicants, and infectious agents. Potential phenotypic anchors include target tissue dosimetry, gene expression and epigenetic profiles, and tissue biomarkers. CONCLUSIONS Translation to human populations requires more extensive profiling of human samples along with high-quality dosimetry. Anchoring results by gene expression and epigenetic profiling has great promise for data unification. Genetic predisposition of individuals affects disease outcome. Interactions with infectious agents, particularly viruses, may explain some species-specific differences between human pathologies and experimental animal pathologies. Invertebrate systems amenable to genetic manipulation offer potential for elaborating impacts of specific biochemical pathways. Anchoring experimental results to specific human exposures will accelerate understanding of mechanisms of arsenic-induced human disease.
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Affiliation(s)
- J Christopher States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.
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48
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Ghouleh IA, Khoo NK, Knaus UG, Griendling KK, Touyz RM, Thannickal VJ, Barchowsky A, Nauseef WM, Kelley EE, Bauer PM, Darley-Usmar V, Shiva S, Cifuentes-Pagano E, Freeman BA, Gladwin MT, Pagano PJ. Oxidases and peroxidases in cardiovascular and lung disease: new concepts in reactive oxygen species signaling. Free Radic Biol Med 2011; 51:1271-88. [PMID: 21722728 PMCID: PMC3205968 DOI: 10.1016/j.freeradbiomed.2011.06.011] [Citation(s) in RCA: 192] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 06/06/2011] [Accepted: 06/07/2011] [Indexed: 12/17/2022]
Abstract
Reactive oxygen species (ROS) are involved in numerous physiological and pathophysiological responses. Increasing evidence implicates ROS as signaling molecules involved in the propagation of cellular pathways. The NADPH oxidase (Nox) family of enzymes is a major source of ROS in the cell and has been related to the progression of many diseases and even environmental toxicity. The complexity of this family's effects on cellular processes stems from the fact that there are seven members, each with unique tissue distribution, cellular localization, and expression. Nox proteins also differ in activation mechanisms and the major ROS detected as their product. To add to this complexity, mounting evidence suggests that other cellular oxidases or their products may be involved in Nox regulation. The overall redox and metabolic status of the cell, specifically the mitochondria, also has implications on ROS signaling. Signaling of such molecules as electrophilic fatty acids has an impact on many redox-sensitive pathologies and thus, as anti-inflammatory molecules, contributes to the complexity of ROS regulation. This review is based on the proceedings of a recent international Oxidase Signaling Symposium at the University of Pittsburgh's Vascular Medicine Institute and Department of Pharmacology and Chemical Biology and encompasses further interaction and discussion among the presenters.
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Affiliation(s)
- Imad Al Ghouleh
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
| | - Nicholas K.H. Khoo
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
| | - Ulla G. Knaus
- Conway Institute, University College Dublin, Dublin, Ireland
| | - Kathy K. Griendling
- Department of Medicine, Division of Cardiology, Emory University, Atlanta, GA
| | - Rhian M. Touyz
- Ottawa Hospital Research Institute, Univ of Ottawa, Ottawa, Ontario, Canada
| | - Victor J. Thannickal
- Pulmonary, Allergy & Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Aaron Barchowsky
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA
| | - William M. Nauseef
- Inflammation Program, Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- Department of Microbiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- Veterans Administration Medical Center, Iowa City, IA
| | - Eric E. Kelley
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
- Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA
| | - Phillip M. Bauer
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Victor Darley-Usmar
- Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL
| | - Sruti Shiva
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
| | - Eugenia Cifuentes-Pagano
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
| | - Bruce A. Freeman
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
| | - Mark T. Gladwin
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
- Department of Pulmonary, Allergy & Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Patrick J. Pagano
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
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Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. Toxicol Appl Pharmacol 2011; 257:356-64. [PMID: 21983427 DOI: 10.1016/j.taap.2011.09.019] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 09/09/2011] [Accepted: 09/21/2011] [Indexed: 12/13/2022]
Abstract
Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations.
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Tian XF, Xia XB, Xu HZ, Xiong SQ, Jiang J. Caveolin-1 expression regulates blood-retinal barrier permeability and retinal neovascularization in oxygen-induced retinopathy. Clin Exp Ophthalmol 2011; 40:e58-66. [DOI: 10.1111/j.1442-9071.2011.02656.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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