scholarly journals mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway

2016 ◽  
Vol 100 (6) ◽  
pp. 1349-1362 ◽  
Author(s):  
Xi Chen ◽  
Zhengguo Zhang ◽  
Yujing Bi ◽  
Zan Fu ◽  
Pingsheng Gong ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Mtor Signaling ◽  
Glycolytic Pathway ◽  
Immune Mediated

scholarly journals Corilagin Ameliorates Con A-Induced Hepatic Injury by Restricting M1 Macrophage Polarization

2022 ◽  
Vol 12 ◽  
Author(s):  
Fenglian Yan ◽  
Dalei Cheng ◽  
Haiyan Wang ◽  
Min Gao ◽  
Junfeng Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Hepatic Injury ◽  
Mononuclear Cells ◽  
Macrophage Polarization ◽  
Treatment Choice ◽  
Control Group ◽  
Con A ◽  
Immune Mediated ◽  
M1 Macrophage ◽  
Mitogen Activated Protein

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.

scholarly journals Glomerular Damage in Trichloroethylene-Sensitized Mice: Targeting Cathepsin L-Induced Hyperactive mTOR Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Feng Wang ◽  
Yuying Dai ◽  
Meng Huang ◽  
Chenchen Zhang ◽  
Liping Huang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Structural Integrity ◽  
Health Hazard ◽  
Cathepsin L ◽  
Mtor Signaling ◽  
Transmission Electron ◽  
Immune Mediated ◽  
Mtorc1 Signaling ◽  
Podocyte Loss ◽  
Glomerular Damage

Trichloroethylene (TCE) is a serious health hazard for workers with daily exposure, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and glomerular damage. Recent studies suggest that mTORC1 signaling is activated in various glomerular disorders; however, the role of mTORC1 signaling in TCE-induced glomerular damage remains to be explored. In the present study, 6 OMDT patients were enrolled and a TCE-sensitized mouse model was established to investigate molecular mechanisms underlying the glomerular damage associated with OMDT. Glomerular damage was assessed by levels of urine nephrin, H&E staining, and renal function test. Ultrastructural change of podocyte was investigated by transmission electron microscopy. The podocyte-related molecules including nephrin, α-actinin-4, and integrin β1 were visualized by immunofluorescence. The activation of mTORC1 signaling was confirmed by Western blot. Glomerular apoptosis was examined by the TUNEL test and Western blotting. Expression and location of cathepsin L (CTSL) were assessed by RT-PCR and immunofluorescence. Our results showed that TCE sensitization caused damage to glomerular structural integrity and also increased the activation of mTORC1 signaling, which was accompanied by podocyte loss, hypertrophy, and glomerular apoptosis. Importantly, we also found that over-expressed CTSL was mainly located in podocyte and CTSL inhibition could partially block the activation of mTORC1 signaling. Thus, our findings suggested a novel mechanism whereby hyperactive mTOR signaling contributes to TCE sensitization–induced and immune-mediated glomerular damage via CTSL activation.

Deficiency of TGR5 Exacerbates Immune-Mediated Cholestatic Hepatic Injury by Stabilizing the β-Catenin Destruction Complex

2018 ◽  
Author(s):  
Jianhua Rao ◽  
Chao Yang ◽  
Hao Lu ◽  
Yuanchang Hu ◽  
Shikun Yang ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Immune Mediated

scholarly journals Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex

2020 ◽  
Vol 32 (5) ◽  
pp. 321-334 ◽  
Author(s):  
Jianhua Rao ◽  
Chao Yang ◽  
Shikun Yang ◽  
Hao Lu ◽  
Yuanchang Hu ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Hepatic Injury ◽  
Inflammatory Responses ◽  
Therapeutic Implications ◽  
Immune Mediated ◽  
Duct Ligation ◽  
G Protein Coupled ◽  
Therapeutic Perspective

Abstract Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5−/−) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5−/− bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5−/− macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5−/− BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5−/− BMDMs. From a therapeutic perspective, TGR5−/− BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI.

scholarly journals Diclofenac Synthesis

2021 ◽  
Author(s):  
Aymen Labidi
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Hepatic Injury ◽  
Liver Toxicity ◽  
Reactive Intermediates ◽  
The United States ◽  
Hepatocellular Injury ◽  
Hepatocellular Damage ◽  
Immune Mediated ◽  
Inflammatory Drugs

Diclofenac is an NSAID, Non-Steroidal Anti-Inflammatory Drugs, widely used clinically in the treatement of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and has been available in the United States since 1988 (Banks et al. 1995). Diclofenac can cause hepatotoxicity, and despite the rare nature of these events, affects a large number of people due to its widespread usage. It is one of the most common drugs associated with idiosyncratic hepatic injury (Daly et al. 2007). From November 1988 to June 1991 the FDA received 180 cases of diclofenac-induced adverse hepatic injury of which 79% were female, 71% were elderly patients (above the age of 60), and 77% of the patients had osteoarthritis. In most of the cases the liver injury was characterized by hepatocellular damage or mixed hepatocellular injury, and there were some cases of cholestasis (Banks et al. 1995). The incidence of diclofenac hepatotoxicity has been reported to be 6.3 per 100 000 patients (DeAbajo et al. 2004). Bioactivation to reactive intermediates, their disposition, the production of oxidative stress, mitochondrial damage, and immune-mediated mechanisms have been suggested to play a role in diclofenac-mediated liver toxicity

Allicin, the active component of garlic, prevents immune-mediated, concanavalin A-induced hepatic injury in mice.

2005 ◽  
Vol 25 (3) ◽  
pp. 613-621 ◽  
Author(s):  
Rafael Bruck ◽  
Hussein Aeed ◽  
Eli Brazovsky ◽  
Talia Noor ◽  
Rami Hershkoviz
Keyword(s):  
Concanavalin A ◽  
Active Component ◽  
Hepatic Injury ◽  
Immune Mediated

scholarly journals Corrigendum to: Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex

2021 ◽  
Author(s):  
Jianhua Rao ◽  
Chao Yang ◽  
Shikun Yang ◽  
Hao Lu ◽  
Yuanchang Hu ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Immune Mediated

scholarly journals Overexpression of KLF14 protects against immune-mediated hepatic injury in mice

2018 ◽  
Vol 99 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Xiaoyan Chen ◽  
Qinghai Tan ◽  
Yunwu Wang ◽  
Huijie Lv ◽  
Zhihui Wang ◽  
...  
Keyword(s):  
Hepatic Injury ◽  
Immune Mediated

scholarly journals 24-Nor-Ursodeoxycholic acid reshapes immunometabolism in CD8+ T cells and alleviates hepatic inflammation

2021 ◽  
Author(s):  
Ci Zhu ◽  
Nicole Boucheron ◽  
André C. Müller ◽  
Peter Májek ◽  
Thierry Claudel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Diseases ◽  
Hepatic Injury ◽  
Cell Function ◽  
Cell Immune Response ◽  
Immune Mediated ◽  
Mtorc1 Signaling ◽  
Lcmv Infection

AbstractBackground & Aims24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8+ T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects.MethodsNorUDCA effects on CD8+ T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8+ T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8+ T cells in vitro. Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8+ T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients.ResultsIn vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8+ T cells. With MS, we identified that NorUDCA regulates CD8+ T cells via targeting mTORC1. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating human CD8+ T cells.ConclusionsNorUDCA possesses a yet-unrecognized direct modulatory potency on CD8+ T cells and attenuates excessive CD8+ T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

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