|
1
|
Guan J, Wu F, Wu S, Ren Y, Wang J, Zhu H. FTY720 alleviates D-GalN/LPS-induced acute liver failure by regulating the JNK/MAPK pathway. Int Immunopharmacol 2025; 157:114726. [PMID: 40311319 DOI: 10.1016/j.intimp.2025.114726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 04/20/2025] [Accepted: 04/22/2025] [Indexed: 05/03/2025]
Abstract
Acute liver failure (ALF) poses a considerable health and economic burden worldwide and has limited treatment options. Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive phospholipid that participates in various cellular processes by through S1P receptors (S1PRs). Previous studies have showed that the hepatic S1P levels were increased. Notably, deletion or inhibition of sphingosine kinase 1 (SphK1), the key enzyme responsible for S1P biosynthesis, could alleviate D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF in mice. However, the role of the S1P receptor modulator FTY720 in ALF remains unclear. In this study, we investigated the effects of FTY720 on D-GalN/LPS-induced ALF model. Our results demonstrated that FTY720 pretreatment significantly alleviated liver injury, decreased the serum levels of alanine aminotransferase and aspartate aminotransferase, and mitigated histopathological damage in ALF model mice. Mechanistically, FTY720 could inhibit the inflammatory response and reduced apoptosis. The protective effect of FTY720 was mediated by c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signalling. A pharmacological JNK activator (anisomycin) partially counteracted these protective effects. FTY720, targeting S1PRs, is expected to be an effective therapeutic strategy for ALF.
Collapse
Affiliation(s)
- Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shanshan Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yanli Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Haihong Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| |
Collapse
|
|
2
|
Song H, Wei L, Zhong M, Chen X, Xie C, Chen X, Wang X, Huang B, Liu Y, Zhang M, Qi Y, Wang X. Ambient ultraviolet B radiation induced valve behavioral acclimation of Pacific oyster which resulted from the different response strategies of smooth and striated adductor muscles. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 228:113035. [PMID: 34863076 DOI: 10.1016/j.ecoenv.2021.113035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/18/2021] [Accepted: 11/25/2021] [Indexed: 06/13/2023]
Abstract
Light not only conveys image-forming vision but also has an impact on various physiological functions. In particular, ultraviolet B (UVB) radiation has the closest relationship with living organisms. For Pacific oysters (Crassostrea gigas), alteration of valve behavior is one of the most important ways responding to ambient UVB. In the present study, the response of adult C. gigas to sunlight (especially UVB) was evaluated by monitoring valve activity and further elucidated at the physiological and metabolomic levels. After exposure, the valve activity of C. gigas demonstrated flexible acclimation to the ambient conditions. The potential adjustment of osmoregulation and oxidative stress might be related to ambient UVB radiation. Mycosporine-like amino acids might contribute to the protection of C. gigas against UVB, while precursors of β-alanine and degradation products of 5-hydroxytryptamine might adjust the contraction of the adductor muscles. The different responses of the adductor muscles (smooth and striated) were manifested in signal transduction and metabolisms of energy and nucleotide. This study not only indicated the correlation between the valve behavioral changes in oysters and light radiation, especially UVB, but illustrated the acclimation strategies of oysters to ambient light (UVB) environment.
Collapse
Affiliation(s)
- Hongce Song
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Lei Wei
- School of Agriculture, Ludong University, Yantai 264025, PR China.
| | - Mingyu Zhong
- Ocean School, Yantai University, Yantai 264005, PR China
| | - Xi Chen
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Chaoyi Xie
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Xiao Chen
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Xiaona Wang
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Baoyu Huang
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Yaqiong Liu
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Meiwei Zhang
- School of Agriculture, Ludong University, Yantai 264025, PR China
| | - Yitao Qi
- Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, PR China
| | - Xiaotong Wang
- School of Agriculture, Ludong University, Yantai 264025, PR China.
| |
Collapse
|
|
3
|
Tamai Y, Chen Z, Wu Y, Okabe J, Kobayashi Y, Chiba H, Hui SP, Eguchi A, Iwasa M, Ito M, Takei Y. Branched-chain amino acids and l-carnitine attenuate lipotoxic hepatocellular damage in rat cirrhotic liver. Biomed Pharmacother 2021; 135:111181. [PMID: 33395607 DOI: 10.1016/j.biopha.2020.111181] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 01/06/2023] Open
Abstract
Branched-chain amino acids (BCAA) reverse malnutrition and l-carnitine leads to the reduction of hyperammonemia and muscle cramps in cirrhotic patients. BCAA and l-carnitine are involved in glucose and fatty acid metabolism, however their mechanistic activity in cirrhotic liver is not fully understood. We aim to define the molecular mechanism(s) and combined effects of BCAA and l-carnitine using a cirrhotic rat model. Rats were administered carbon tetrachloride for 10 weeks to induce cirrhosis. During the last 6 weeks of administration, cirrhotic rats received BCAA, l-carnitine or a combination of BCAA and l-carnitine daily via gavage. We found that BCAA and l-carnitine treatments significantly improved hepatocellular function associated with reduced triglyceride level, lipid deposition and adipophilin expression, in cirrhotic liver. Lipidomic analysis revealed dynamic changes in hepatic lipid composition by BCAA and l-carnitine administrations. BCAA and l-carnitine globally increased molecular species of phosphatidylcholine. Liver triacylglycerol and phosphatidylcholine hydroperoxides were significantly decreased by BCAA and l-carnitine. Furthermore, serum and liver ATP levels were significantly increased in all treatments, which were attributed to the elevation of mature cardiolipins and mitochondrial component gene expressions. Finally, BCAA and l-carnitine dramatically reduced hepatocellular death. In conclusion, BCAA and l-carnitine treatments attenuate hepatocellular damage through the reduction of lipid peroxides and the overall maintenance of mitochondrial integrity within the cirrhotic liver. These effectiveness of BCAA and l-carnitine support the therapeutic strategies in human chronic liver diseases.
Collapse
Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Zhen Chen
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Yue Wu
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Jun Okabe
- Epigenetics in Human Health and Diseases, Department of Diabetes, Central Clinical School, Monash University, Australia
| | - Yoshinao Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan; Center for Physical and Mental Health, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Hitoshi Chiba
- Department of Nutrition, Sapporo University of Health Sciences, Sapporo, Japan
| | - Shu-Ping Hui
- Faculty of Health Sciences, Hokkaido University, Sapporo, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan; PRETO, JST, Saitama, Japan.
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| |
Collapse
|
|
4
|
Ansari MA, Raish M, Bin Jardan YA, Ahmad A, Shahid M, Ahmad SF, Haq N, Khan MR, Bakheet SA. Sinapic acid ameliorates D-galactosamine/lipopolysaccharide-induced fulminant hepatitis in rats: Role of nuclear factor erythroid-related factor 2/heme oxygenase-1 pathways. World J Gastroenterol 2021; 27:592-608. [PMID: 33642831 PMCID: PMC7901048 DOI: 10.3748/wjg.v27.i7.592] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/30/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sinapic acid (SA) has been shown to have various pharmacological properties such as antioxidant, antifibrotic, anti-inflammatory, and anticancer activities. Its mechanism of action is dependent upon its ability to curb free radical production and protect against oxidative stress-induced tissue injuries. AIM To study the hepatoprotective effects of SA against lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF) in rats. METHODS Experimental ALF was induced with an intraperitoneal (i.p.) administration of 8 μg LPS and 800 mg/kg D-GalN in normal saline. SA was administered orally once daily starting 7 d before LPS/D-GalN treatment. RESULTS Data showed that SA ameliorates acute liver dysfunction, decreases serum levels of alanine transaminase (ALT), and aspartate aminotransferase (AST), as well as malondialdehyde (MDA) and NO levels in ALF model rats. However, pretreatment with SA (20 mg/kg and 40 mg/kg) reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and levels of inflammatory cytokines (tumor necrosis factor-α and interleukin 6). Also, SA increased the activity of the nuclear factor erythroid-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway. CONCLUSION In conclusion, SA offers significant protection against LPS/D-GalN-induced ALF in rats by upregulating Nrf2/HO-1 and downregulating NF-κB.
Collapse
Affiliation(s)
- Mushtaq Ahmad Ansari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Yousef A Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mudassar Shahid
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sheikh Fayaz Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nazrul Haq
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Rashid Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Saleh A Bakheet
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| |
Collapse
|
|
5
|
Stremmel W, Staffer S, Fricker G, Weiskirchen R. The Bile Acid-Phospholipid Conjugate Ursodeoxycholyl-Lysophosphatidylethanolamide (UDCA-LPE) Disintegrates the Lipid Backbone of Raft Plasma Membrane Domains by the Removal of the Membrane Phospholipase A2. Int J Mol Sci 2019; 20:ijms20225631. [PMID: 31717968 PMCID: PMC6888454 DOI: 10.3390/ijms20225631] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/28/2019] [Accepted: 11/06/2019] [Indexed: 01/07/2023] Open
Abstract
The bile acid-phospholipid conjugate ursodeoxycholyl-lysophosphatidylethanolamide (UDCA-LPE) was shown to have anti-inflammatory, antisteatotic, and antifibrotic properties, rendering it as a drug targeting non-alcoholic steatohepatitis (NASH). On a molecular level, it disrupted the heterotetrameric fatty acid uptake complex localized in detergent-resistant membrane domains of the plasma membrane (DRM-PM). However, its mode of action was unclear. Methodologically, UDCA-LPE was incubated with the liver tumor cell line HepG2 as well as their isolated DRM-PM and all other cellular membranes (non-DRM). The membrane cholesterol and phospholipids were quantified as well as the DRM-PM protein composition by Western blotting. The results show a loss of DRM-PM by UDCA-LPE (50 µM) with a 63.13 ± 7.14% reduction of phospholipids and an 81.94 ± 8.30% reduction of cholesterol in relation to mg total protein. The ratio of phospholipids to cholesterol changed from 2:1 to 4:1, resembling those of non-DRM fractions. Among the members of the fatty acid uptake complex, the calcium-independent membrane phospholipase A2 (iPLA2β) abandoned DRM-PM most rapidly. As a consequence, the other members of this transport system disappeared as well as the DRM-PM anchored fibrosis regulating proteins integrin β-1 and lysophospholipid receptor 1 (LPAR-1). It is concluded that UDCA-LPE executes its action by iPLA2β removal from DRM-PM and consequent dissolution of the raft lipid platform.
Collapse
Affiliation(s)
- Wolfgang Stremmel
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany;
- Correspondence: ; Tel.: +49-152-34349907
| | - Simone Staffer
- Department of Internal Medicine IV, University Hospital of Heidelberg, 69120 Heidelberg, Germany;
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, 52074 Aachen, Germany;
| |
Collapse
|
|
6
|
Li Y, Wang N, Jiang Y. Geraniol protects against lipopolysaccharide and D-galactosamine-induced fulminant hepatic failure by activating PPARγ. Microb Pathog 2018; 128:7-12. [PMID: 30550845 DOI: 10.1016/j.micpath.2018.11.054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 11/16/2018] [Accepted: 11/30/2018] [Indexed: 12/18/2022]
Abstract
Geraniol (GOH), a natural component of plant essential oils, exhibits potent antioxidant and anti-inflammatory properties. The aim of this study was to assess the protective effects and mechanisms of GOH on lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). Mice were treated with GOH (12.5, 25, and 50 μg/kg) 1 h before challenging LPS (60 mg/kg) and D-GalN (800 mg/kg). 8 h later LPS/D-GlaN treatment, mice were sacrificed and the serum and the liver tissues were collected for testing. The liver pathological changes were assessed by H & E staining. MPO activity, MDA level in liver tissues, and AST, ALT levels in serum were detected by specific detection kits. The levels of TNF-α and IL-1β were detected by ELISA. The expression of NF-κB and PPARγ were detected by western blot analysis and qRT-PCR. The results showed that GOH had a protective effect on LPS/D-GalN-induced FHF, as evidence by the attenuation of liver pathological injury, MPO activity, MDA level, and serum AST and ALT levels. GOH reduced liver TNF-α and IL-1β levels through inhibiting NF-κB signaling pathway activation. Furthermore, GOH increased PPARγ expression in FHF induced by LPS/D-GalN. In conclusion, the present study proved that GOH protects against LPS/D-GalN-induced FHF through inhibiting inflammatory response and increasing PPARγ expression.
Collapse
Affiliation(s)
- Yi Li
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
| | - Nian Wang
- Department of Pathophysiology, School of Basic Medical Science Central South University, Changsha, Hunan, 410083, China
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
| |
Collapse
|
|
7
|
Bivalent Ligand UDCA-LPE Inhibits Pro-Fibrogenic Integrin Signalling by Inducing Lipid Raft-Mediated Internalization. Int J Mol Sci 2018; 19:ijms19103254. [PMID: 30347788 PMCID: PMC6214129 DOI: 10.3390/ijms19103254] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/08/2018] [Accepted: 10/10/2018] [Indexed: 01/07/2023] Open
Abstract
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48 and primary human hepatic stellate cells induced a non-classical internalization of integrin β1 resulting in dephosphorylation and inhibition of SRC and focal adhesion kinase (FAK). Signalling analyses suggested that UDCA-LPE may act as a heterobivalent ligand for integrins and lysophospholipid receptor1 (LPAR1) and co-immunoprecipitation demonstrated the bridging effect of UDCA-LPE on integrin β1 and LPAR1. The disruption of either the UDCA-moiety binding to integrins by RGD-containing peptide GRGDSP or the LPE-moiety binding to LPAR1 by LPAR1 antagonist Ki16425 reversed inhibitory functions of UDCA-LPE. The lack of inhibitory functions of UDCA-PE and UDCA-LPE derivatives (14:0 and 12:0, LPE-moiety containing shorter fatty acid chain) as well as the consistency of the translocation of UDCA-LPE and integrins, which co-fractionated with LPE but not UDCA, suggested that the observed UDCA-LPE-induced translocation of integrins was mediated by LPE endocytic transport pathway.
Collapse
|
|
8
|
Ludwig JM, Zhang Y, Chamulitrat W, Stremmel W, Pathil A. Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. PLoS One 2018; 13:e0197836. [PMID: 29795632 PMCID: PMC5967712 DOI: 10.1371/journal.pone.0197836] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 05/09/2018] [Indexed: 01/04/2023] Open
Abstract
AIM Endotoxin-mediated liver inflammation is a key component of many acute and chronic liver diseases contributing to liver damage, fibrosis and eventually organ failure. Here, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate regarding its anti-inflammatory and anti-fibrogenic properties. METHODS Anti-inflammatory properties of UDCA-LPE were evaluated in a mouse model of D-galactosamine/lipopolysaccharide (GalN/LPS)-induced acute liver injury, LPS treated RAW264.7 macrophages and murine primary Kupffer cells. Furthermore, anti-inflammatory and anti-fibrotic effects of UDCA-LPE were studied on primary hepatic stellate cells (HSC) incubated with supernatant from LPS±UDCA-LPE treated RAW264.7 cells. RESULTS UDCA-LPE ameliorated LPS-induced increase of IL-6, TNF-α, TGF-β, NOX-2 in the GalN/LPS model by up to 80.2% for IL-6. Similarly, UDCA-LPE markedly decreased the expression of inflammatory cytokines IL-6, TNF-α and TGF-β as well as the chemokines MCP1 and RANTES in LPS-stimulated RAW 264.7 cells. Anti-inflammatory effects were also observed in primary murine Kupffer cells. Mechanistic evaluation revealed a reversion of LPS-activated pro-inflammatory TLR4 pathway by UDCA-LPE. Moreover, UDCA-LPE inhibited iNOS and NOX-2 expression while activating eNOS via phosphorylation of AKT and pERK1/2 in RAW264.7 cells. HSC treated with conditioned medium from LPS±UDCA-LPE RAW264.7 cells showed lower fibrogenic activation due to less SMAD2/3 phosphorylation, reduced expression of profibrogenic CTGF and reduced pro-inflammatory chemokine expression. CONCLUSION In the setting of endotoxin-mediated liver inflammation, UDCA-LPE exerts profound anti-inflammatory and anti-fibrotic effect implying a promising potential for the drug candidate as an experimental approach for the treatment of acute and chronic liver diseases.
Collapse
Affiliation(s)
- Johannes Maximilian Ludwig
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany
| | - Yuling Zhang
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | - Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
- * E-mail:
| |
Collapse
|
|
9
|
Utaipan T, Suksamrarn A, Kaemchantuek P, Chokchaisiri R, Stremmel W, Chamulitrat W, Chunglok W. Diterpenoid trigonoreidon B isolated from Trigonostemon reidioides alleviates inflammation in models of LPS-stimulated murine macrophages and inflammatory liver injury in mice. Biomed Pharmacother 2018; 101:961-971. [PMID: 29635906 DOI: 10.1016/j.biopha.2018.02.144] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/25/2018] [Accepted: 02/28/2018] [Indexed: 12/13/2022] Open
|
|
10
|
Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis. Shock 2018; 48:251-259. [PMID: 28060213 DOI: 10.1097/shk.0000000000000831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.
Collapse
|
|
11
|
Yang Y, Zhong Z, Ding Y, Zhang W, Ma Y, Zhou L. Bioinformatic identification of key genes and pathways that may be involved in the pathogenesis of HBV-associated acute liver failure. Genes Dis 2018; 5:349-357. [PMID: 30591937 PMCID: PMC6303483 DOI: 10.1016/j.gendis.2018.02.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 02/13/2018] [Indexed: 02/07/2023] Open
Abstract
In order to explore the molecular mechanisms behind the pathogenesis of acute liver failure (ALF) associated with hepatitis B virus (HBV) infection, the present study aimed to identify potential key genes and pathways involved using samples from patients with HBV-associated ALF. The GSE38941 array dataset was downloaded from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) between 10 liver samples from 10 healthy donors and 17 liver specimens from 4 patients with HBV-associated ALF were analyzed using the Linear Models for Microarray Data package. Gene Ontology and KEGG pathway enrichment analyses of the DEGs were performed, followed by functional annotation of the genes and construction of a protein–protein interaction (PPI) network. Subnetwork modules were subsequently identified and analyzed. In total, 3142 DEGs were identified, of which 1755 were upregulated and 1387 were downregulated. The extracellular exosome, immune response, and inflammatory response pathways may potentially be used as biomarkers of ALF pathogenesis. In total, 17 genes (including CCR5, CXCR4, ALB, C3, VGEFA, and IGF1) were identified as hub genes in the PPI network and may therefore be potential marker genes for HBV-associated ALF.
Collapse
Key Words
- ALF, acute liver failure
- BP, biological processes
- CC, cell components
- DEGs, differentially expressed genes
- Differentially expressed genes
- Function enrichment analysis
- GEO, Gene Expression Omnibus
- GO, Gene Ontology
- HBV, Hepatitis B Virus
- HBV-associated ALF
- HSPC, hepatic stem/progenitor cells
- KEGG, Kyoto Encyclopedia of Genes and Genomes
- MF, molecular functions
- Module analysis
- OLT, orthotopic liver transplantation
- PPI, protein–protein interaction
- Protein–protein interaction network
- STRING, the Search Tool for the Retrieval of Interacting Genes
Collapse
Affiliation(s)
- Yalan Yang
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Zhaohui Zhong
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Yubin Ding
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Wanfeng Zhang
- Department of Bioinformatics, Chongqing Medical University, Chongqing, 400016, China
| | - Yang Ma
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| | - Li Zhou
- School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.,Research Center for Medicine and Social Development, Chongqing, 400016, China.,Innovation Center for Social Risk Governance in Health, Chongqing, 400016, China
| |
Collapse
|
|
12
|
Horvatova A, Utaipan T, Otto AC, Zhang Y, Gan-Schreier H, Pavek P, Pathil A, Stremmel W, Chamulitrat W. Ursodeoxycholyl lysophosphatidylethanolamide negatively regulates TLR-mediated lipopolysaccharide response in human THP-1-derived macrophages. Eur J Pharmacol 2018; 825:63-74. [PMID: 29475064 DOI: 10.1016/j.ejphar.2018.02.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/15/2018] [Accepted: 02/19/2018] [Indexed: 11/26/2022]
Abstract
The bile acid-phospholipid conjugate ursodeoxycholyl oleoyl-lysophophatidylethanolamide (UDCA-18:1LPE) is an anti-inflammatory and anti-fibrotic agent as previously shown in cultured hepatocytes and hepatic stellate cells as well as in in vivo models of liver injury. We hypothesize that UDCA-18:1LPE may directly inhibit the activation of immune cells. We found that UDCA-18:1LPE was capable of inhibiting the migration of phorbol ester-differentiated human THP-1 cells. We examined anti-inflammatory activity of UDCA-18:1LPE during activation of THP1-derived macrophages. Treatment of these macrophages by bacterial lipopolysaccharide (LPS) for 24 h induced the release of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. This release was markedly inhibited by pretreatment with UDCA-18:1LPE by ~ 65-90%. Derivatives with a different fatty-acid chain in LPE moiety also exhibited anti-inflammatory property. Western blotting and indirect immunofluorescence analyses revealed that UDCA-18:1LPE attenuated the expression of phosphorylated p38, MKK4/MKK7, JNK1/2, and c-Jun as well as nuclear translocation of NF-κB by ~ 22-86%. After LPS stimulation, the Toll-like receptor adaptor proteins, myeloid differentiation factor 88 and TNF receptor associated factor 6, were recruited into lipid rafts and UDCA-18:1LPE inhibited this recruitment by 22% and 58%, respectively. Moreover, LPS treatment caused a decrease of the known cytoprotective lysophosphatidylcholine species containing polyunsaturated fatty acids by 43%, and UDCA-18:1LPE co-treatment reversed this decrease. In conclusion, UDCA-18:1LPE and derivatives inhibited LPS inflammatory response by interfering with Toll-like receptor signaling in lipid rafts leading to an inhibition of MAPK and NF-κB activation. These conjugates may represent a class of lead compounds for development of anti-inflammatory drugs.
Collapse
Affiliation(s)
- Alzbeta Horvatova
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyorovskeho 1203, 500 05 Hradec Kralove, Czech Republic
| | - Tanyarath Utaipan
- Department of Pre-Clinic, Faculty of Sciences and Technology, Prince of Songkla University, Pattani Campus, 94000 Pattani, Thailand
| | - Ann-Christin Otto
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Yuling Zhang
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Petr Pavek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyorovskeho 1203, 500 05 Hradec Kralove, Czech Republic
| | - Anita Pathil
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| |
Collapse
|
|
13
|
Park CH, Shin MR, An BK, Joh HW, Lee JC, Roh SS, Yokozawa T. Heat-Processed Scutellariae Radix Protects Hepatic Inflammation through the Amelioration of Oxidative Stress in Lipopolysaccharide-Induced Mice. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2017; 45:1233-1252. [DOI: 10.1142/s0192415x17500689] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The present study evaluated the effects of heat-processed Scutellariae Radix (Scutellaria baicalensis) on lipopolysaccharide (LPS)-induced liver injury in mice. Scutellariae Radix heat-processed at 160[Formula: see text]C or 180[Formula: see text]C was orally administered at a dose of 100 mg/kg body weight for three days before the intraperitoneal injection of LPS, and the effects were compared with those of vehicle-treated LPS administered to control mice. The administration of Scutellariae Radix decreased the elevated serum monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), reactive oxygen species (ROS), nitrite/nitrate, peroxynitrite, and hepatic functional parameters, and reduced the increased ROS in the liver. The augmented expressions of hepatic oxidative stress and inflammation-related proteins, phospho-p38, phosphorylated extracellular signal-regulated kinase, phosphorylated c-Jun N-terminal kinase, nuclear factor-[Formula: see text] B p65, activator protein-1, cyclooxygenase-2, inducible nitric oxide synthase, MCP-1, intercellular adhesion molecule-1, tumor necrosis factor-[Formula: see text], and IL-6, were downregulated by the heat-processed Scutellariae Radix. Hematoxylin-eosin staining showed that the increased hepatocellular damage in the liver of LPS-treated mice improved with the administration of heat-processed Scutellariae Radix. Overall, the ameliorative effects of Scutellariae Radix were superior to those when heat-processed at 180[Formula: see text]C. Our results indicate that heat-processed Scutellariae Radix acts as an anti-inflammatory agent by ameliorating oxidative stress in the liver of mice with LPS-induced liver injury.
Collapse
Affiliation(s)
- Chan Hum Park
- Department of Medicinal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong 369-873, Republic of Korea
- College of Korean Medicine, Daegu Haany University, Daegu 706-060, Republic of Korea
| | - Mi-Rae Shin
- College of Korean Medicine, Daegu Haany University, Daegu 706-060, Republic of Korea
| | - Byung Kwan An
- School of Korean Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea
| | - Hyun Woo Joh
- School of Korean Medicine, Pusan National University, Gyeongnam 626-870, Republic of Korea
| | - Jang Cheon Lee
- Jeollanamdo Development Institute for Korean Traditional Medicine, Jeollanamdo 529-851, Republic of Korea
| | - Seong-Soo Roh
- College of Korean Medicine, Daegu Haany University, Daegu 706-060, Republic of Korea
| | - Takako Yokozawa
- Graduate School of Science and Engineering for Research, University of Toyama, Toyama 930-8555, Japan
| |
Collapse
|
|
14
|
Hu K, Gong X, Ai Q, Lin L, Dai J, Cai L, Jiang R, Ge P, Zhang L. Endogenous AMPK acts as a detrimental factor in fulminant hepatitis via potentiating JNK-dependent hepatocyte apoptosis. Cell Death Dis 2017; 8:e2637. [PMID: 28252653 PMCID: PMC5386558 DOI: 10.1038/cddis.2017.62] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 01/19/2017] [Accepted: 01/24/2017] [Indexed: 02/06/2023]
Abstract
The energy sensor AMP-activated protein kinase (AMPK) is crucial for energy homeostasis. Recent studies have revealed that AMPK is involved in various energy-intensive pathological processes such as inflammation and apoptosis. The physiological functions of hepatic AMPK have been well studied, but the pathological significance of AMPK in liver disorders remains largely unknown. In the present study, the phosphorylation status and the roles of AMPK were investigated in mice with lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced fulminant hepatitis. The experimental data indicated that the phosphorylation of hepatic AMPK increased in mice with LPS/D-Gal-induced fulminant hepatitis. Pretreatment with the AMPK inhibitor compound C enhanced the early production of pro-inflammatory cytokines but suppressed the late activation of the caspase cascade, reduced the number of TUNEL-positive cells, decreased the elevation of aminotransferases, alleviated the histological abnormalities and improved the survival rate of LPS/D-Gal-insulted mice. Pretreatment with compound C suppressed LPS/D-Gal-induced phosphorylation of JNK. Inhibition of JNK alleviated LPS/D-Gal-induced liver injury, but the level of p53 remained unchanged in mice exposed to LPS/D-Gal. Post-insult treatment with the AMPK activator A-769662 further increased the phosphorylation levels of AMPK and JNK, enhanced hepatocyte apoptosis and deteriorated liver injury, all of these effects could be reversed by co-administration of the AMPK inhibitor or JNK inhibitor. Interestingly, post-insult treatment with the AMPK inhibitor also resulted in beneficial outcomes. These data suggested that AMPK might be a late detrimental factor in LPS/D-Gal-induced hepatitis via potentiating JNK-dependent hepatocyte apoptosis and AMPK might become a pharmacological target for the intervention of fulminant hepatitis.
Collapse
Affiliation(s)
- Kai Hu
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China
| | - Xianqiong Gong
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China.,Hepatology Center, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian Province, China
| | - Qing Ai
- Department of Physiology, Chongqing Medical University, Chongqing, China
| | - Ling Lin
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China
| | - Jie Dai
- Hospital of Chongqing University of Arts and Sciences, Chongqing, China
| | - Lu Cai
- Department of Pathogenic Biology, Chongqing Medical University, Chongqing, China
| | - Rong Jiang
- Laboratory of Stem cell and Tissue Engineering, Chongqing Medical University, Chongqing, China
| | - Pu Ge
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China
| | - Li Zhang
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China.,Laboratory of Stem cell and Tissue Engineering, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
15
|
Xu T, Feng G, Zhao B, Zhao J, Pi Z, Liu S, Song F, Liu Z. A non-target urinary and serum metabolomics strategy reveals therapeutical mechanism of Radix Astragali on adjuvant-induced arthritis rats. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1048:94-101. [DOI: 10.1016/j.jchromb.2017.01.040] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 01/23/2017] [Accepted: 01/27/2017] [Indexed: 01/20/2023]
|
|
16
|
Abstract
PURPOSE OF REVIEW About 15-25% of patients with simple steatosis of non-alcoholic fatty liver disease progresses to non-alcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. RECENT FINDINGS Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development. FXR deficiency has shown to progress and exacerbate NASH development, and FXR activation has been protective against liver inflammation associated with NASH. The expression of factors in both the adaptive and innate immune response in the liver are regulated in a FXR-dependent and -independent manner. SUMMARY Therefore, understanding key signaling pathways of liver inflammation in NASH is important to determine essential components that predispose, progress, or exacerbate NASH. FXR has been identified as a therapeutic target for NASH to prevent liver inflammation.
Collapse
|
|
17
|
Caveolin-1 Function in Liver Physiology and Disease. Trends Mol Med 2016; 22:889-904. [DOI: 10.1016/j.molmed.2016.08.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 08/14/2016] [Accepted: 08/17/2016] [Indexed: 12/18/2022]
|
|
18
|
Shahbazov R, Kanak MA, Takita M, Kunnathodi F, Khan O, Borenstein N, Lawrence MC, Levy MF, Naziruddin B. Essential phospholipids prevent islet damage induced by proinflammatory cytokines and hypoxic conditions. Diabetes Metab Res Rev 2016; 32:268-77. [PMID: 26378630 DOI: 10.1002/dmrr.2714] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 07/10/2015] [Accepted: 08/03/2015] [Indexed: 01/19/2023]
Abstract
BACKGROUND The pancreatic islet damage that occurs through an inflammatory response and hypoxia after infusion is a major hurdle in islet transplantation. Because essential phospholipids (EPL) have been shown to exhibit anti-inflammatory properties in liver disease, we analysed their protective effect on islets in inflammatory or hypoxic conditions. METHODS We evaluated the viability of mouse and human islets cultured with cytokines or in hypoxic conditions for 48 h and measured cytokine expression in islets by quantitative polymerase chain reaction. We then employed an in vivo mouse assay, transplanting a marginal dose of human islets treated with or without EPL into the subcapsule of the kidney in diabetic nude mice and determining the cure rate. RESULTS The viability of mouse and human islets damaged by cytokines was significantly improved by supplementation of EPL in the culture (p = 0.003 and <0.001 for mouse and human islets respectively). EPL significantly inhibited intracellular expression of IL-1β and IL-6 in cytokine-damaged human islets (p < 0.001). The viability of human islets in hypoxic conditions was significantly better when treated with EPL (p < 0.001). In the in vivo mouse assay, the EPL-treated islet group had a higher cure rate than the untreated control, with marginal statistical significance (75 and 17% respectively, p = 0.07). CONCLUSIONS EPL could be a potent agent to protect islets from inflammatory and hypoxic conditions after isolation procedures. Further studies to clarify the effect of EPL in islet transplantation are warranted.
Collapse
Affiliation(s)
- Rauf Shahbazov
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | - Mazhar A Kanak
- The Institute of Biomedical Studies, Baylor University, Waco, TX, USA
| | - Morihito Takita
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | | | - Omar Khan
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | - Nofit Borenstein
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | | | - Marlon F Levy
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Bashoo Naziruddin
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| |
Collapse
|
|
19
|
Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia and reperfusion injury in mice. Shock 2016; 43:379-86. [PMID: 25526375 DOI: 10.1097/shk.0000000000000312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The ischemia and reperfusion (I/R) injury that occurs during liver transplantation causes severe complications leading to transplantation failure. We have designed a cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which promotes the survival of cultured hepatocellular cell lines and inhibits apoptosis and inflammation in the in vivo models of liver injury. Here, we show that UDCA-LPE increased the viability of mouse hepatocytes by activating the Akt/glycogen synthase kinase 3β survival signaling pathways. We further tested whether UDCA-LPE could protect hepatic I/R injury in mice by clamping liver lobes of C57/BL6 mice for 90 min of ischemia followed by unclamping and reperfusion for 2 h. Two regimens for UDCA-LPE treatment were carried out; with a single dose of 100 mg/kg UDCA-LPE intraperitoneally injected 30 min prior to ischemia and a double dose of 50 mg/kg UDCA-LPE given 30 min prior to ischemia and just prior to reperfusion. Using histology and liver enzyme determination, we observed that hepatic I/R caused significant hepatic necrosis, which was decreased in UDCA-LPE-treated mice undergoing I/R. Ursodeoxycholyl LPE concomitantly protected against I/R-induced apoptosis (cleaved caspase 3, cleaved poly[ADP-ribose] polymerase 1), inflammation (IL-1β, CD11b, chemokine ligands 2 and 3, chemokine receptor 2), and portal fibrogenesis (α-smooth muscle actin, plasminogen activator inhibitor 1), as determined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses. The protection by UDCA-LPE was found to be better in the double-dose than in the single-dose regimen. Thus, UDCA-LPE promoted the survival of mouse hepatocytes and protected against hepatic I/R injury and thus may be of therapeutic use in liver transplantation settings.
Collapse
|
|
20
|
Pathil A, Liebisch G, Okun JG, Chamulitrat W, Schmitz G, Stremmel W. Ursodeoxycholyl Lysophosphatidylethanolamide modifies aberrant lipid profiles in NAFLD. Eur J Clin Invest 2015; 45:925-31. [PMID: 26108973 DOI: 10.1111/eci.12486] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 06/20/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatic fat accumulation with disturbed lipid homoeostasis is a hallmark of nonalcoholic fatty liver disease (NAFLD). The bile acid phospholipid conjugate Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a novel anti-inflammatory agent with hepatoprotective effects in murine high-fat-diet (HFD)-induced NAFLD. The aim of this work was to study changes in the hepatic lipidome due to UDCA-LPE. MATERIALS AND METHODS High fat diet mouse model, mass spectometry, RT-PCR. RESULTS Hepatic lipid extracts of HFD mice were analysed by mass spectrometry. The results determined higher levels of total, saturated, mono- and diunsaturated fatty acids (FA) in HFD mice, which were decreased by UDCA-LPE predominantly by the reducing the most abundant FA species palmitic acid and oleic acid. Unlike other FA species, levels of long-chain polyunsaturated fatty acids (LCPUFA), which are composed of arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were increased in HFD mice upon UDCA-LPE treatment, mainly due to elevated hepatic ARA pools. Analysis of hepatic phospholipids species showed a decrease in total phosphatidylcholine (PC), especially monounsaturated PC (PUFA-PC) levels in HFD mice. Loss of total PC was reversed due to UDCA-LPE by increasing hepatic PUFA-PC pools. Gene expression analysis showed that UDCA-LPE upregulated PPARα, a key transcriptional regulator of fatty acid oxidation, as well as downstream target genes CPT1α and AOX, which are crucially involved in mitochondrial and peroxisomal fatty acid oxidation. CONCLUSION UDCA-LPE modulates defective fatty acid metabolism during experimental NAFLD thereby restoring altered lipid profiles in addition to its pronounced anti-inflammatory effects. Thus, UDCA-LPE may be a promising drug candidate for the management of NAFLD.
Collapse
Affiliation(s)
- Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
| | - Jürgen G Okun
- Department of General Pediatrics, Division of Inborn Metabolic Diseases, University of Heidelberg, Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | - Gerd Schmitz
- Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
21
|
Luo M, Zhao A, Li J, Chen Y, Tian D, Wang C, Hu Z, Gao J. Acute liver injury attenuation of a novel recombinant sTNFR through blocking hepatic apoptosis. Immunopharmacol Immunotoxicol 2015; 37:295-300. [PMID: 25982795 DOI: 10.3109/08923973.2015.1035390] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
CONTEXT Tumor necrosis factor (TNF) α plays a key role in acute liver injury (ALI) induced by injection of d-galactosamine (D-Gal)/lipopolysaccharide (LPS). A novel recombinant trimeric sTNFRII, sTNFRII-gAD, has been tested to be effective in ameliorating ALI, when administered prior to ALI establishment. This study aims to validate the protective effect of sTNFRII-gAD when given after ALI setup and further explore its effect on hepatic apoptosis. MATERIALS AND METHODS The treatments were carried out concomitantly with ALI establishment with clinically approved sTNFRII-Fc (the dimeric sTNFRII) as a positive control. Lethality, liver weight, and serum alanine transaminase were measured, and histological analysis was performed to evaluate liver injury induced by D-Gal/LPS. Additionally, Terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) and Western blot analyses of caspase-3 were used to examine hepatocellular apoptosis. RESULTS sTNFRII-gAD given after D-Gal/LPS injection turned out to attenuate animal mortality significantly (p < 0.01), and had better hepatic protection. In terms of apoptosis, both sTNFRII-gAD and sTNFRII-Fc displayed noticeable improvement of apoptosis evidenced by dramatic decline of active caspase-3 compared to the control group. CONCLUSIONS The results demonstrated that sTNFRII-gAD therapeutically diminished the lethality induced by D-Gal/LPS, possibly through blocking hepatic apoptosis initiated by TNFα. Of note, sTNFRII-gAD was superior to sTNFRII-Fc in some respects, indicating a promising alternative for the therapeutic strategy against the diseases associated with excessive TNFα.
Collapse
Affiliation(s)
- Mansheng Luo
- Department of Microbiology & Immunology, School of Medicine, JingGangShan University , Jian , China
| | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice. Exp Mol Med 2014; 46:e127. [PMID: 25523099 PMCID: PMC4274398 DOI: 10.1038/emm.2014.90] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 09/25/2014] [Accepted: 10/05/2014] [Indexed: 12/24/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen α1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor α showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH.
Collapse
|
|
23
|
Hepatitis B virus core protein sensitizes hepatocytes to tumor necrosis factor-induced apoptosis by suppression of the phosphorylation of mitogen-activated protein kinase kinase 7. J Virol 2014; 89:2041-51. [PMID: 25428880 DOI: 10.1128/jvi.03106-14] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
UNLABELLED Hepatitis B, which caused by hepatitis B virus (HBV) infection, remains a major health threat worldwide. Hepatic injury and regeneration from chronic inflammation are the main driving factors of liver fibrosis and cirrhosis in chronic hepatitis B. Proinflammatory tumor necrosis factor alpha (TNF-α) has been implicated as a major inducer of liver cell death during viral hepatitis. Here, we report that in hepatoma cell lines and in primary mouse and human hepatocytes, expression of hepatitis B virus core (HBc) protein made cells susceptible to TNF-α-induced apoptosis. We found by tandem affinity purification and mass spectrometry that receptor of activated protein kinase C 1 (RACK1) interacted with HBc. RACK1 was recently reported as a scaffold protein that facilitates the phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7) by its upstream activators. Our study showed that HBc abrogated the interaction between MKK7 and RACK1 by competitively binding to RACK1, thereby downregulating TNF-α-induced phosphorylation of MKK7 and the activation of c-Jun N-terminal kinase (JNK). In line with this finding, specific knockdown of MKK7 increased the sensitivity of hepatocytes to TNF-α-induced apoptosis, while overexpression of RACK1 counteracted the proapoptotic activity of HBc. Capsid particle formation was not obligatory for HBc proapoptotic activity, as analyzed using an assembly-defective HBc mutant. In conclusion, the expression of HBc sensitized hepatocytes to TNF-α-induced apoptosis by disrupting the interaction between MKK7 and RACK1. Our study is thus the first indication of the pathogenic effects of HBc in liver injury during hepatitis B. IMPORTANCE Our study revealed a previously unappreciated role of HBc in TNF-α-mediated apoptosis. The proapoptotic activity of HBc is important for understanding hepatitis B pathogenesis. In particular, HBV variants associated with severe hepatitis may upregulate apoptosis of hepatocytes through enhanced HBc expression. Our study also found that MKK7 is centrally involved in TNF-α-induced hepatocyte apoptosis and revealed a multifaceted role for JNK signaling in this process.
Collapse
|
|
24
|
Sayed RH, Khalil WKB, Salem HA, Kenawy SA, El-Sayeh BM. Sulforaphane increases the survival rate in rats with fulminant hepatic failure induced by D-galactosamine and lipopolysaccharide. Nutr Res 2014; 34:982-9. [PMID: 25439027 DOI: 10.1016/j.nutres.2014.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 09/28/2014] [Accepted: 10/02/2014] [Indexed: 12/14/2022]
Abstract
Fulminant hepatic failure (FHF) is a life-threatening clinical syndrome, with liver transplantation being the only effective therapy. Sulforaphane (SFN) is a natural compound that is extracted from cruciferous vegetables and possesses potent anti-inflammatory, antioxidant, and anticancer activities. This study was designed to test the hypothesis that SFN (3 mg/kg) may protect against FHF induced in rats by administering a combination of D-galactosamine (GalN; 300 mg/kg) and lipopolysaccharide (LPS; 30 μg/kg). The rats were given a single intraperitoneal injection of SFN, 1 hour before the FHF induction. Sulforaphane reduced the mortality and alleviated the pathological liver injury. In addition, SFN significantly reduced the increase in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in the GalN/LPS group, and this decrease was attenuated by SFN. Increases in serum tumor necrosis factor α, interleukin-6, and interleukin-10, which were observed in GalN/LPS-treated rats, were significantly reduced after using SFN. The GalN/LPS treatment increased the expression of superoxide dismutase-1, glutathione peroxidase 2, catalase, and heme oxygenase-1 genes. Sulforaphane inhibited the induction of reactive oxygen species scavenging proteins. Moreover, SFN inhibited GalN/LPS-induced caspase-3 activation and suppressed FAS and FASL expression. These findings suggest that SFN alleviates GalN/LPS-induced liver injury, possibly by exerting antioxidant, anti-inflammatory, and antiapoptotic effects and modulating certain antioxidant defense enzymes.
Collapse
Affiliation(s)
- Rabab H Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Wagdy K B Khalil
- Department of Cell Biology, National Research Centre, Cairo, Egypt
| | - Hesham A Salem
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Bahia M El-Sayeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| |
Collapse
|
|
25
|
Pathil A, Mueller J, Ludwig JM, Wang J, Warth A, Chamulitrat W, Stremmel W. Ursodeoxycholyl lysophosphatidylethanolamide attenuates hepatofibrogenesis by impairment of TGF-β1/Smad2/3 signalling. Br J Pharmacol 2014; 171:5113-26. [PMID: 25041068 DOI: 10.1111/bph.12837] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 06/10/2014] [Accepted: 06/23/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND PURPOSE Chronic hepatic inflammation results in liver fibrosis. As effective anti-fibrogenic agents are lacking, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate with anti-inflammatory and anti-apoptotic properties for tis effects on hepatic fibrogenesis. EXPERIMENTAL APPROACH To stimulate fibrogenesis, LX2 hepatic stellate cells were cultured with conditioned medium from CL48 liver cells after exposure to stress-inducing conditions - methionine-choline-deficient (MCD) medium or TNFα/cycloheximide (CHX) - with or without UDCA-LPE preincubation. Anti-fibrogenic effects of UDCA-LPE were further studied in CL48 and LX2 cells and in primary human hepatic stellate cells (HHStec) directly exposed to TGF-β1. To test UDCA-LPE in vivo, C57BL/6 mice were fed a MCD diet for 11 weeks followed by 30 mg·kg(-1) UDCA-LPE 3× per week for 2.5 weeks. KEY RESULTS Expression of α-smooth muscle actin (α-SMA), α1-collagen, vimentin and TGF-β1 was down-regulated by up to 93% by UDCA-LPE in LX-2 cells cultured with conditioned medium. Also, UDCA-LPE inhibited Smad3 phosphorylation in CL48 cells incubated with MCD medium or TNFα/CHX and in LX2 cells exposed to conditioned medium. UDCA-LPE also decreased phosphorylated Smad3 and Smad2 directly induced by TGF-β1. Inhibition of TGF-β1/Smad2/3 signalling with down-regulation of target genes was confirmed in HHStec. In vivo, UDCA-LPE decreased hepatic α-SMA, α1-collagen and TGF-β1 expression and markedly lowered α-SMA protein and collagen deposition in MCD mice. CONCLUSIONS AND IMPLICATIONS By blocking TGF-β1/Smad2/3 signalling, UDCA-LPE suppressed key mediators of hepatic fibrogenesis. Thus, UDCA-LPE could be suitable for prevention of fibrotic progression of chronic liver disease.
Collapse
Affiliation(s)
- Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | | | | | |
Collapse
|
|
26
|
Kim JK, Lee KS, Chang HY, Lee WK, Lee JI. Progression of diet induced nonalcoholic steatohepatitis is accompanied by increased expression of Kruppel-like-factor 10 in mice. J Transl Med 2014; 12:186. [PMID: 24986741 PMCID: PMC4086692 DOI: 10.1186/1479-5876-12-186] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 06/24/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Kruppel-like-factor (KLF) 10 is identified as transforming growth factor (TGF) β inducible early gene and is reported to suppress lipogenic genes. Although previous studies report that TGFβ plays an important role in progression of nonalcoholic steatohepatitis (NASH) by regulating liver fibrosis, the association of KLF10 and NASH has never been explored. Thus we evaluated expressions and changes of KLF10 in diet induced NASH and in NASH which was alleviated by ursodeoxycholic acid (UDCA). We also assessed KLF10 in quiescent and activated hepatic stellate cells (HSCs). METHODS C57BL/6 mice were given high fat, sucrose diet (HFSD) at least for 12 weeks up to 48 weeks and sacrificed at 12, 24 and 48 weeks thereafter. In other groups, either standard diet (SD) or HFSD was given for 24 weeks at which point mice fed with HFSD were divided into two groups, and were given either UDCA in combination with HFSD or vehicle with HFSD. Mice under SD were given vehicle. HSCs were isolated from C57BL/6 mice in order to evaluated KLF10 expression in activated HSCs. RESULTS The mice were found to acquire liver steatosis and inflammation starting from week 12 of HFSD feeding, although significant liver fibrosis was noticed by week 24. Increased TGFβ and collagen α1(I) (Col1α(I)) expression was also apparent from week 24. However, expression of KLF10 mRNA started to increase from week 12, earlier than TGFβ gene. Up-regulation of KLF10 was accompanied by suppressed carbohydrate response element-binding protein (ChREBP) that is known to be protective against insulin resistance. The mice fed with HFSD and UDCA had decreased Colα(I) mRNA that was coincided with reduced TGFβ and KLF10 expression. Expression of ChREBP was also recovered by UDCA administration. Enhanced KLF10 was noticed in activated HSCs when quiescent cell showed minimal expression. CONCLUSIONS Our study demonstrated that KLF10 expression was significantly increased in diet induced NASH and collagen producing activated HSCs. We also noticed that this up-regulation of KLF10 was accompanied by increased TGFβ signaling genes and suppressed ChREBP expression. These observations suggest possible association of KLF10 and NASH progression.
Collapse
Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eunju-ro, Gangnam-gu, Seoul 135-720, Republic of Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eunju-ro, Gangnam-gu, Seoul 135-720, Republic of Korea
| | - Hye Young Chang
- Medical Research Center, Gangnam Severance Hospital, 211 Eunju-ro, Gangnam-gu, Seoul 120-752, Republic of Korea
| | - Woon Kyu Lee
- Laboratory of Developmental Genetics, Inha University School of Medicine, Incheon 400-712, Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eunju-ro, Gangnam-gu, Seoul 135-720, Republic of Korea
| |
Collapse
|
|
27
|
Stremmel W, Staffer S, Wannhoff A, Pathil A, Chamulitrat W. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis. FASEB J 2014; 28:3159-70. [PMID: 24719358 DOI: 10.1096/fj.14-249763] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Excess hepatic fat accumulation leads to nonalcoholic steatohepatitis (NASH), a serious threat to health for which no effective treatment is available. However, the mechanism responsible for fatty acid uptake by hepatocytes remains unclear. Using the human hepatocyte-derived tumor cell line HepG2, we found that fatty acid influx is mediated by a heterotetrameric plasma membrane protein complex consisting of plasma membrane fatty acid-binding protein, caveolin-1, CD36, and calcium-independent membrane phospholipase A2 (iPLA2β). Blocking iPLA2β with the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) caused the dissociation of the complex, thereby inhibiting fatty acid influx (IC50 47 μM), and suppressed the synthesis of all subunits through a reduction in lysophosphatidylcholine from 8.0 to 3.5 μmol/mg of protein and corresponding depletion of phosphorylated c-Jun N-terminal kinase. These findings were substantiated by an observed 56.5% decrease in fatty acid influx in isolated hepatocytes derived from iPLA2β-knockout mice. Moreover, steatosis and inflammation were abrogated by UDCA-LPE treatment in a cellular model of NASH. Thus, iPLA2β acts as an upstream checkpoint for mechanisms that regulate fatty acid uptake, and its inhibition by UDCA-LPE qualifies this nontoxic compound as a therapeutic candidate for the treatment of NASH.-Stremmel, W., Staffer, S., Wannhoff, A., Pathil, A., Chamulitrat, W. Plasma membrane phospholipase A2 controls hepatocellular fatty acid uptake and is responsive to pharmacological modulation: implications for nonalcoholic steatohepatitis.
Collapse
Affiliation(s)
- Wolfgang Stremmel
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Simone Staffer
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Andreas Wannhoff
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Anita Pathil
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
28
|
Wu F, Wang M, Tian D. Serum from patients with hepatitis E virus-related acute liver failure induces human liver cell apoptosis. Exp Ther Med 2013; 7:300-304. [PMID: 24348810 PMCID: PMC3861037 DOI: 10.3892/etm.2013.1398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 11/01/2013] [Indexed: 12/27/2022] Open
Abstract
The pathogenesis of acute liver failure has not been fully elucidated. The present study investigated the effects of the serum from patients with hepatitis E virus (HEV)-related acute liver failure on human liver cell survival and apoptosis, and evaluated the protective effects of anti-lipopolysaccharide(LPS) antibody recognizing core polysaccharide against acute liver failure serum-induced apoptosis. Serum was collected from patients with HEV-related acute liver failure. The levels of endotoxin (LPS) in the serum were measured using a quantitative tachypleus amebocyte lysate endotoxin detection kit with a chromogenic endpoint. Serum with a mean concentration of LPS was incubated with L02 human liver cells and the rate of apoptosis was detected by flow cytometry. The apoptotic rate was also evaluated in liver cells incubated with antibody and the HEV-related acute liver failure serum. The results indicated that the concentration of LPS in the serum of patients with HEV-related acute liver failure was 0.26±0.02 EU/ml, which was significantly higher than that of the control group (P<0.05). The rate of apoptosis in the human liver cells induced by acute liver failure serum was 5.83±0.42%, which was significantly increased compared with that in the cells treated with the serum of healthy individuals (P<0.05). The apoptotic rate of the cells incubated with antibody and the acute liver failure serum was 5.53±0.51%, which was lower than that of the cells incubated with acute liver failure serum alone (P>0.05). These results indicate that the serum of patients with HEV-related acute liver failure induces the apoptosis of human liver cells. LPS may be directly involved in the apoptosis of human liver cells. Moreover, the presence of the antibody did not significantly reduce the level of apoptosis of liver cells exposed to HEV-related acute liver failure serum.
Collapse
Affiliation(s)
- Fan Wu
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Minxin Wang
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Deying Tian
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| |
Collapse
|
|
29
|
Chamulitrat W, Liebisch G, Xu W, Gan-Schreier H, Pathil A, Schmitz G, Stremmel W. Ursodeoxycholyl lysophosphatidylethanolamide inhibits lipoapoptosis by shifting fatty acid pools toward monosaturated and polyunsaturated fatty acids in mouse hepatocytes. Mol Pharmacol 2013; 84:696-709. [PMID: 23974795 DOI: 10.1124/mol.113.088039] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a hepatoprotectant in inhibiting apoptosis, inflammation, and hyperlipidemia in mouse models of nonalcoholic steatohepatitis (NASH). We studied the ability of UDCA-LPE to inhibit palmitate (Pal)-induced apoptosis in primary hepatocytes and delineate cytoprotective mechanisms. We showed that lipoprotection by UDCA-LPE was mediated by cAMP and was associated with increases in triglycerides (TGs) and phospholipids (PLs). An inhibitor of cAMP-effector protein kinase A partially reversed the protective effects of UDCA-LPE. Lipidomic analyses of fatty acids and PL composition revealed a shift of lipid metabolism from saturated Pal to monounsaturated and polyunsaturated fatty acids, mainly, oleate, docosapentaenoate, and docosahexaenoate. The latter two ω-3 fatty acids were particularly found in phosphatidylcholine and phosphatidylserine pools. The catalysis of Pal by stearoyl-CoA desaturase-1 (SCD-1) is a known mechanism for the channeling of Pal away from apoptosis. SCD-1 protein was upregulated during UDCA-LPE lipoprotection. SCD-1 knockdown of Pal-treated cells showed further increased apoptosis, and the extent of UDCA-LPE protection was reduced. Thus, the major mechanism of UDCA-LPE lipoprotection involved a metabolic shift from toxic saturated toward cytoprotective unsaturated fatty acids in part via SCD-1. UDCA-LPE may thus be a therapeutic agent for treatment of NASH by altering distinct pools of fatty acids for storage into TGs and PLs, and the latter may protect lipotoxicity at the membrane levels.
Collapse
Affiliation(s)
- Walee Chamulitrat
- Department of Internal Medicine IV, Gastroenterology and Infectious Diseases, Im Neuenheimer Feld, Heidelberg, Germany (W.C., H.G.-S., A.P., W.S.); Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany (G.L., G.S.); and Department of Gastroenterology, Hangzhou First People's Hospital, Hangzhou, Zhejiang, People's Republic of China (W.X.)
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Lysoglycerophospholipids in chronic inflammatory disorders: The PLA2/LPC and ATX/LPA axes. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:42-60. [DOI: 10.1016/j.bbalip.2012.07.019] [Citation(s) in RCA: 172] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Revised: 07/20/2012] [Accepted: 07/24/2012] [Indexed: 02/08/2023]
|
|
31
|
Abstract
Ursodeoxycholic acid (UDCA) is one of hepatologists'oldest friends, always ready to help, throughout the years, in numerous and various liver and biliary tract diseases. On paper, it has had an impeccable track record of cytoprotection in vitro and in vivo due to its pleiotropic effects on many pathways leading to cell injury. Most of its hepatoprotective effects demonstrated under experimental conditions proved able to counteract pathogenic mechanisms involved in the transition from steatosis to steatohepatitis, and early clinical studies suggested a potentially beneficial effect in non-alcoholic steatohepatitis (NASH) as well. Yet, only scant data on the efficacy of UDCA specifically in experimental models of steatosis/NASH are available, and the few available randomized controlled clinical studies have substantial methodological issues and are discussed in this review. Thus, at this point, there is not enough evidence to either confirm or reject the efficacy of UDCA in NASH, although many NASH patients clearly experience biochemical improvements with prolonged UDCA treatment. Also, a few new UDCA derivatives have shown promising activity in preclinical models and may be worth testing in clinical trials.
Collapse
Affiliation(s)
- Vlad Ratziu
- Service d'Hépato-gastro-entérologie, Hôpital Pitié-Salpêtrière, 47-83, boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
| |
Collapse
|
|
32
|
Yu J, Cao H, Yang J, Pan Q, Ma J, Li J, Li Y, Li J, Wang Y, Li L. In vivo hepatic differentiation of mesenchymal stem cells from human umbilical cord blood after transplantation into mice with liver injury. Biochem Biophys Res Commun 2012; 422:539-545. [PMID: 22580002 DOI: 10.1016/j.bbrc.2012.04.156] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 04/30/2012] [Indexed: 12/12/2022]
Abstract
AIM The aim of this study was to analyze the hepatic differentiation potential of human umbilical cord blood-derived mesenchymal stem cells (hUCBMSCs) after transplantation into severe combined immune deficiency (SCID) mice with liver injury induced by D-galactosamine/lipopolysaccharide (GalN/LPS) and to explore the possibility that cells can partially repair GalN/LPS-induced hepatic damage. METHODS Mononuclear cells (MNCs) were isolated from fresh human umbilical cord blood, characterized by flow cytometry, and then transplanted into GalN/LPS-injured mice. Specimens were collected at 7, 14, 21, and 28 days after hUCBMSC transplantation. Histopathological changes were analyzed by hematoxylin and eosin staining. Polymerase chain reaction (PCR) for a specific marker of human cells, the human Alu sequence, was performed to locate exogenous hUCBMSCs in mouse livers. Expression of human hepatocyte-specific markers such as human albumin (hALB), human alpha-fetoprotein (hAFP), human cytokeratin 18 (hCK18), and human cytokeratin 19 (hCK19) were analyzed by reverse transcriptase (RT)-PCR and immunohistochemical staining. RESULTS The hUCBMSCs were positive for the human MSC-specific markers CD271, CD29, CD90, CD105, and CD73, but negative for CD31, CD79b, CD133, CD34, and CD45. Histological findings showed that the hepatic damage in mice was attenuated after hMSC administration, and liver architecture was much better preserved. Human cells in the injured liver of recipient mice were detected by PCR for the human Alu sequence. In addition, expression of markers of hepatic lineage, including hALB, hAFP, hCK18, and hCK19, was detected by immunohistochemistry and RT-PCR in mouse livers after hUCBMSC transplantation, suggesting the formation of hepatocyte-like cells in vivo. CONCLUSION MSCs from hUCB exhibit the potential to differentiate into hepatocyte-like cells in the livers of hUCB-transplanted mice as well as partially repair the liver damage induced by GalN/LPS.
Collapse
Affiliation(s)
- Jiong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, PR China.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Pathil A, Mueller J, Warth A, Chamulitrat W, Stremmel W. Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease. Hepatology 2012; 55:1369-78. [PMID: 22183915 DOI: 10.1002/hep.25531] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 11/23/2011] [Indexed: 01/18/2023]
Abstract
UNLABELLED Hepatic fat accumulation and changes in lipid composition are hallmarks of nonalcoholic fatty liver disease (NAFLD). As an experimental approach for treatment of NAFLD, we synthesized the bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate in vitro and in vivo. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with hyperlipidemia. In a second model, mice received a methionin-choline-deficient (MCD) diet for up to 11 weeks, which induced advanced nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum triglyceride and cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic triglyceride and cholesterol levels. Additionally, the conjugate lowered serum caspase-8 activity in both models and decreased lipid hydroperoxides in MCD mice. Abundance of proinflammatory lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism. CONCLUSION The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of NAFLD. By concurrently lowering hepatic lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of NAFLD.
Collapse
Affiliation(s)
- Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | |
Collapse
|
|
34
|
Chamulitrat W, Zhang W, Xu W, Pathil A, Setchell K, Stremmel W. Hepatoprotectant ursodeoxycholyl lysophosphatidylethanolamide increasing phosphatidylcholine levels as a potential therapy of acute liver injury. Front Physiol 2012; 3:24. [PMID: 22363296 PMCID: PMC3282533 DOI: 10.3389/fphys.2012.00024] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2012] [Accepted: 02/03/2012] [Indexed: 11/13/2022] Open
Abstract
It has been long known that hepatic synthesis of phosphatidylcholine (PC) is depressed during acute such as carbon tetrachloride-induced liver injury. Anti-hepatotoxic properties of PC as liposomes have been recognized for treatment of acute liver damage. Ursodeoxycholate (UDCA) is a known hepatoprotectant in stabilizing cellular membrane. For therapeutic management of liver injury, we coupled UDCA with a phospholipid known as ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). UDCA-LPE has been shown to first-in-class hepatoprotectant being superior to UDCA or PC. It inhibits mitochondrial damage and apoptosis, elicits survival signaling pathway, and promotes regeneration of hepatocytes. We herein report that a unique contribution of UDCA-LPE in increasing concentrations of PC in vitro and in vivo. UDCA-LPE-treated hepatocytes contained significantly increased PC levels. UDCA-LPE underwent the hydrolysis to LPE which was not the precursor of the increased PC. The levels of PC in the liver and blood were increased rapidly after intraperitoneally administration UDCA-LPE, and were found to be sustained even after 24 h. Among PC synthesis genes tested, UDCA-LPE treatment of mouse hepatocytes increased transcription of CDP-diacylglycerol synthase 1 which is an enzyme catalyzing phosphatidic acid to generate intermediates for PC synthesis. Thus, UDCA-LPE as a hepatoprotectant was able to induce synthesis of protective PC which would supplement for the loss of PC occurring during acute liver injury. This property has placed UDCA-LPE as a candidate agent for therapy of acute hepatotoxicity such as acetaminophen poisoning.
Collapse
Affiliation(s)
- Walee Chamulitrat
- Department of Internal Medicine IV, University Heidelberg Hospital Heidelberg, Germany
| | | | | | | | | | | |
Collapse
|
|
35
|
Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice. Int Immunopharmacol 2012; 12:682-8. [PMID: 22330083 DOI: 10.1016/j.intimp.2012.01.015] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 01/19/2012] [Accepted: 01/31/2012] [Indexed: 02/08/2023]
Abstract
Metformin is a first-line antidiabetic drug in type 2 diabetes for its hypoglycemic activity, but recently researches also revealed the anti-inflammatory properties of metformin. In the present study, the pharmacological efficiency of metformin in lipopolysaccharide (LPS)-induced hepatic injury in D-galactosamine (D-Gal)-sensitized mice was investigated. We found that pretreatment with metformin significantly decreased serum ALT and AST levels in LPS/D-Gal-exposed mice. These were accomplished with improved histological alterations in liver sections, decreased myeloperoxidase (MPO) activity, reduced malondialdehyde (MDA) content in liver homogenates and increased survival rate of experimental animals. Metformin also markedly reduced hepatic TNF-α mRNA content and blood TNF-α level. Additional experiment showed that metformin significantly attenuated LPS/D-Gal-induced hepatic apoptosis as evidenced by decreased caspase activities in liver tissues and reduced number of TUNEL-positive cells in liver sections. Furthermore, therapeutic administration of metformin after LPS/D-Gal challenge also improved the survival rate of experimental animal. These results indicated that the hypoglycemic reagent metformin could also provide therapeutic benefits in endotoxin-induced hepatic injury, suggesting its pharmacological potential in inflammation-base disorders.
Collapse
|
|
36
|
Pathil A, Warth A, Chamulitrat W, Stremmel W. Comparison of different bile acid-phospholipid conjugates in acute hepatitis. Eur J Clin Invest 2012; 42:130-8. [PMID: 21707612 DOI: 10.1111/j.1365-2362.2011.02563.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION The bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a promising novel compound with profound hepatoprotective functions in vitro and in vivo. Because of high costs of LPE synthesis from hydrolysis of phosphatidylethanolamide (PE), costs for UDCA-LPE synthesis for in vivo and human use can become quite high. In this study, we evaluated whether ursodeoxycholyl phosphatidylethanolamide (udca-pe), which is more cost-effective, could replace udca-lpe in terms of protection from hepatocellular injury. MATERIALS AND METHODS Anti-apoptotic and anti-inflammatory properties of UDCA-PE and UDCA-LPE were compared in TNFα/cyclohexamide (CHX)-treated HepG2 cells as well as in a mouse model of d-galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver injury. RESULTS Ursodeoxycholyl lysophosphatidylethanolamide inhibited TNFα/CHX-induced apoptosis in HepG2 cells in a dose-dependent manner and markedly ameliorated Gal/LPS-mediated fulminant hepatitis in mice. In contrast, UDCA-PE showed weaker hepatoprotective functions at low concentrations, and protection was lost at higher dosage. Analysis of hepatic gene expression showed that both conjugates significantly reduced Gal/LPS-mediated expression of chemoattractants, such as monocyte chemotactic protein 1 (MCP1) and RANTES. These inhibitory effects by UDCA-PE were transient while those by UDCA-LPE were sustained in attenuating expression of inflammatory MCP1 and RANTES expression. CONCLUSIONS Our data underline the superiority of UDCA-LPE compared to UDCA-PE in ameliorating acute liver inflammation. This indicates the significance of the lyso-functional group of bile acid conjugate for optimal hepatoprotection and reduction in inflammation in vivo.
Collapse
Affiliation(s)
- Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Heidelberg, Germany
| | | | | | | |
Collapse
|
|
37
|
Park JH, Kim KH, Lee WR, Han SM, Park KK. Protective effect of melittin on inflammation and apoptosis in acute liver failure. Apoptosis 2012; 17:61-69. [PMID: 21928088 DOI: 10.1007/s10495-011-0659-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acute hepatic failure remains an extremely poor prognosis and still results in high mortality. Therefore, better treatment is urgently needed. Melittin, a major component of bee venom, is known to inhibit inflammatory reactions induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α in various cell types. However, there is no evidence of the anti-inflammatory and anti-apoptotic effect of melittin on liver cells. In the present study, we investigated the effects of melittin on D: -galactosamine (GalN)/lipopolysaccharide (LPS)-induced acute hepatic failure. Acute liver injury was induced with GalN/LPS to determine in vivo efficacy of melittin. Mice were randomly divided into four groups: sterile saline treated group (NC), melittin only treated group (NM), GalN/LPS-treated group (GalN/LPS), and GalN/LPS treated with melittin group (M+GalN/LPS). Mice were given intraperitoneal GalN/LPS with or without melittin treatment. Liver injury was assessed biochemically and histologically. Inflammatory cytokines in the serum, apoptosis of hepatocytes, and cleavage of caspase-3 in the liver were determined. The expression of TNF-α and interleukin (IL)-1β were increased in the GalN/LPS group. However, treatment of melittin attenuated the increase of inflammatory cytokines. The M+GalN/LPS group showed significantly fewer apoptotic cells compared to the GalN/LPS group. Melittin significantly inhibited the expression of caspase and bax protein levels as well as cytochrome c release in vivo. In addition, melittin prevented the activation of the transcription factor nuclear factor-kappa B (NF-κB) induced by GalN/LPS. These results clearly indicate that melittin provided protection against GalN/LPS-induced acute hepatic failure through the inhibition of inflammatory cytokines and apoptosis.
Collapse
Affiliation(s)
- Ji-Hyun Park
- Department of Pathology, College of Medicine, Catholic University of Daegu, Daemyung Nam-gu, Daegu, Republic of Korea
| | | | | | | | | |
Collapse
|
|
38
|
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver (NAFL) and especially its inflammatory variant nonalcoholic steatohepatitis (NASH) have become a major challenge to healthcare systems worldwide because of the increasing prevalence of its major risk factors obesity and type 2 diabetes, which are closely linked to overeating, physical inactivity, and the metabolic syndrome. RECENT FINDINGS Between 10 and 20% of patients with NAFL develop NASH, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The overall mortality in these patients is significantly increased because of both cardiovascular and liver-related complications. Sustained weight loss by diet and exercise, which is the most effective therapeutic measure, is only achieved by a minority of patients, having led to a great yet unmet need for medical therapies of NASH. SUMMARY Pharmacological therapies should target the underlying pathophysiology that involves insulin resistance, enhanced peripheral lipolysis and release of free fatty acids, oxidative stress, accumulation of toxic lipids, adipose tissue inflammation, sensitization of hepatocytes toward apoptotic cell death, and fibrogenesis. However, pharmacological therapy that is well tolerated, cost-effective, and poses an acceptable risk-to-benefit ratio has still to be identified. This review summarizes the current and promising treatment options and their implications for future research and clinical practice.
Collapse
Affiliation(s)
- Jörn M Schattenberg
- Department of Medicine I bCenter for Molecular and Translational Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, Mainz, Germany
| | | |
Collapse
|
|
39
|
Yuan H, Wan J, Li L, Ge P, Li H, Zhang L. Therapeutic benefits of the group B3 vitamin nicotinamide in mice with lethal endotoxemia and polymicrobial sepsis. Pharmacol Res 2011; 65:328-37. [PMID: 22154801 DOI: 10.1016/j.phrs.2011.11.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Revised: 11/22/2011] [Accepted: 11/22/2011] [Indexed: 12/14/2022]
Abstract
Nicotinamide (NAM) is a group B3 vitamin involved in a wide range of biological processes. Recently, the anti-inflammatory properties of NAM have been revealed. In this study, we investigated the therapeutic effects of NAM in murine models of endotoxemia and sepsis. Endotoxemic liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS) into D-galactosamine (D-Gal)-sensitized mice. Lethal endotoxemia was induced by intraperitoneal administration of LPS at a dose of 20 mg/kg. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). In mice challenged with LPS/D-Gal, treatment with NAM significantly deceased serum aminotransferases level and alleviated hepatic lesions. NAM also reduced serum tumor necrosis factor-α level and attenuated apoptosis in liver, as assessed by terminal deoxynucleotidyl transferase-mediated nucleotide nick end labeling (TUNEL) staining and measurements of caspases activities. Survival analysis indicated that NAM reduced the mortality rate of LPS/D-Gal-challenged mice. In mice with lethal endotoxemia, NAM reduced serum level of pro-inflammatory cytokines and multiple organ damage as evidence by improved morphological lesion, reduced lung wet to dry ratio as well as decreased serum level of aminotransferase and blood urea nitrogen. In survival analysis, treatment with NAM increased the survival rate of mice with lethal endotoxemia or CLP-induced polymicrobial sepsis. Taken together, treatment with NAM might provide therapeutic benefits in sepsis, which attenuated inflammatory injury and improved the survival rate.
Collapse
Affiliation(s)
- Hongmei Yuan
- Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, PR China
| | | | | | | | | | | |
Collapse
|