concanavalin-a and Chemical-and-Drug-Induced-Liver-Injury--Chronic

A previous study revealed that treatment with the anticoagulant heparin attenuated concanavalin A (ConA)-induced liver injury. The administration of spermidine (SPD) increased urokinase-type plasminogen activator (uPA) levels in the serum. uPA is clinically used for the treatment of some thrombotic diseases such as cerebral infarction. Therefore, SPD may attenuate ConA-induced liver injury that is exacerbated by blood coagulation. The present study investigated the effect of SPD on liver injury in mice with autoimmune hepatopathy induced by ConA. A model of liver injury was created by intravenous injection of ConA into mice. SPD was administered in free drinking water and was biochemically and pathologically examined over time. The administration of SPD to ConA-treated mice significantly reduced liver injury. However, SPD treatment upregulated the mRNA expression of TNF-α and IFN-ϒ in the livers of ConA-treated mice. In contrast, the mRNA expression of tissue factor in the livers of SPD-treated mice was decreased after ConA injection. The frequency of lymphocytes and lymphocyte activation were not affected by SPD administration in ConA-treated mice. SPD treatment increased uPA levels in the serum and decreased the level of D-dimer in ConA-treated mice. Moreover, SPD decreased fibrin in the livers of ConA-treated mice. These results indicated that SPD treatment increased anticoagulant ability by increasing of uPA and attenuated ConA-induced liver injury.

Topics: Animals; Anticoagulants; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Liver; Mice; RNA, Messenger; Spermidine

Tripterygium wilfordii tablets (TWT) is widely used to treat autoimmune diseases such as rheumatoid arthritis. Celastrol, one main active ingredient in TWT, has been shown to produce a variety of beneficial effects, including anti-inflammatory, anti-obesity, anti-cancer, and immunomodulatory. However, whether TWT could protect against Concanavalin A (Con A)-induced hepatitis remains unclear.. This study aims to investigate the protective effect of TWT against Con A-induced hepatitis and elucidate the underlying mechanism.. Metabolomic analysis, pathological analysis, biochemical analysis, qPCR and Western blot analysis and the Pxr-null mice were used in this study.. The results indicated that TWT and its active ingredient celastrol could protect against Con A-induced acute hepatitis. Plasma metabolomics analysis revealed that metabolic perturbations related to bile acid and fatty acid metabolism induced by Con A were reversed by celastrol. The level of itaconate in the liver was increased by celastrol and speculated as an active endogenous compound mediating the protective effect of celastrol. Administration of 4-octanyl itaconate (4-OI) as a cell-permeable itaconate mimicker was found to attenuate Con A-induced liver injury through activation of the pregnane X receptor (PXR) and enhancement of the transcription factor EB (TFEB)-mediated autophagy.. Celastrol increased itaconate and 4-OI promoted activation of TFEB-mediated lysosomal autophagy to protect against Con A-induced liver injury in a PXR-dependent manner. Our study reported a protective effect of celastrol against Con A-induced AIH via an increased production of itaconate and upregulation of TFEB. The results highlighted that PXR and TFEB-mediated lysosomal autophagic pathway may offer promising therapeutic target for the treatment of autoimmune hepatitis.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Hepatitis, Autoimmune; Mice; Models, Animal; Pentacyclic Triterpenes; Tripterygium; Triterpenes

Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)-17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL-17A in a mice model of immune-mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A-induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then, the natural killer (NK) T cells were overactivated by the accumulated IL-17A in the liver in the Con A and S. typhimurium administration group. IL-17A could activate NKT cells by inducing CD178 expression via IL-4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal-associated invariant T (MAIT)-cell-derived IL-17A could be the original driver of NKT cell overactivation in intragastric administration of S. typhimurium and Con A injection. In IL-17A-deficient mice, Con A-induced liver injury and NKT cell activation were alleviated. However, when AAV-sh-mIL-17a was used to specifically knock down IL-17A in liver, it seemed that hepatic IL-17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A-induction, laminae propria MAIT-derived IL-17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Hepatitis, Autoimmune; Interleukin-17; Mice; Mice, Inbred C57BL; Mucous Membrane; Natural Killer T-Cells

Liver injury is a serious threat to human health that has become a worldwide problem. To date, there is still no effective treatment strategy. In the present study, we examined the protective effects of Human liver stem cells (HLSCs) against concanavalin A (Con A)-induced acute liver injury.. Isolated HLSCs were characterized by microscopy, functional assays, and gene expression. HLSCs or HLSCs culture medium were transplanted in mice for 12 h and subsequently challenged with Con A via tail-vein injection. The effects were evaluated through survival rate, histology, blood tests, TUNEL assay, quantitative RT-PCR and flow cytometry. CellTracker™ CM-Dil labled HLSCs were tracked by fluorescence microscope.. Transplantation of HLSCs reduced the mortality rate, reduced the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), narrowed the area of liver necrosis, and inhibited hepatocyte apoptosis induced by Con A. Injection of HLSCs culture medium could also alleviate Con A-induced liver injury. Of note, HLSCs-transplanted mice exhibited lower frequencies of Th17 cells and higher frequencies of Tregs in their liver and spleen following Con A injection. Moreover, transplantation of HLSCs significantly reduced the expression of IL-17A, IL-17F and ROR-γt induced by Con A, while reversed Con A-induced downregulation of Foxp3 expression and IL-10.. HLSCs protect mice from immune-mediated liver injury by regulating the balance of Treg/Th17 cells, suggesting that transplantation of HLSCs is a potential and effective therapeutic method for amelioration of liver injury.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Humans; Liver; Mice; Stem Cells; T-Lymphocytes, Regulatory; Th17 Cells

To evaluate the preventive effect of SPRC on concanavalin A (Con A)-induced liver injury and uncover the underlying mechanisms.. Mice were randomly divided into five groups: control, Con A, SPRC (5 and 10 mg/kg injected intravenously once a day for 7 days), and propargylglycine (PAG; 50 mg/kg injected intraperitoneally 0.5 h before SPRC for 7 days). All mice except the controls were intravenously injected with Con A (20 mg/kg) on day 7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using kits. Inflammatory cytokines (TNF-α and IFN-γ) in the blood and in the liver were detected by ELISA Kit and real-time PCR, respectively. The expression of mitogen-activated protein kinase (MAPK) pathway proteins (p-JNK and p-Akt) and apoptosis proteins (Bax and Bcl-2) was detected using western blotting.. SPRC reduced the levels of AST (. SPRC prevents Con A-induced liver injury in mice by promoting CSE expression and producing endogenous H

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Cysteine; Cytokines; Hydrogen Sulfide; Mice; Neurodegenerative Diseases

Autoimmune hepatitis (AIH) is a heterogeneous immune-mediated chronic liver disease affecting children and adults. It is important to rely on a specific animal model to study the hepatic changes and to evaluate the roles played by pro-inflammatory cytokines such as tumor necrosis factor alpha "TNF-α" and transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells "NF-κβ" in the pathogenesis and outcome of the disease. This will help to identify specific targets for treatment of AIH. This study aimed at evaluating Concanavalin-A (Con A) as a model for induction of AIH and assessing splenocytes' TNF-α and hepatocytes' NF-κβ levels at comparable durations after induction of hepatitis with Con A to evaluate the relationship between both factors. Materials and methods: A total of 130 outbreed CD1 mice were divided into group (1) which included 100 mice with induced AIH and group (2) included 30 normal mice as negative controls. Intra-peritoneal injection of Concanavalin-A was used to induce hepatitis. Hepatic injury was evaluated by the levels of liver enzymes, histopathological evidence for hepatic inflammatory infiltrate and/or apoptosis. Splenocytes and hepatocytes were cultured for assessment of TNF-α and NF-κβ levels, respectively. Results: Con A injection caused a significant elevation in ALT and AST levels, portal inflammatory infiltrate, remarkable hepatocytes degeneration and marked increase of TNF-α levels, particularly within 24 hours, but all returned to normal within 1 week. Administration of another dose of Con A resulted in sharp significant elevation of liver enzymes, inflammatory infiltrate and hepatocyte apoptosis after 24 hours and sustained till the end of the study. There was a significant increase in NF-κβ throughout most of the study duration following Con A injection as compared to that of normal mice. In conclusions, intra-peritoneal administration of Con A, particularly two doses, represents an efficient approach for induction of immune-mediated hepatitis. T-cells play a major role in AIH through release of TNF-α. Coincidently, hepatitis seems to be associated with elevation of NF-κβ to protect hepatocytes. Thus TNF-α and NF-κβ can represent targets for treatment of AIH either through inhibition or augmentation, respectively.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Cytokines; Disease Models, Animal; Hepatitis, Autoimmune; Liver; Mice; NF-kappa B; Spleen; Tumor Necrosis Factor-alpha

This study investigated the immunoregulatory and protective roles of Yinchenhao decoction, a compound of Chinese herbal medicine, in a mouse model of concanavalin A (ConA)-induced chronic liver injury.. Female BalB/c mice were randomly divided into 4 groups: normal control, ConA model, ConA model treated with Yinchenhao decoction (400 mg/kg, orally), and ConA model treated with dexamethasone (0.5 mg/kg, orally). All treatments were given once a day for 28 d. Except of the normal control, mice received tail vein injection of ConA (10 mg/kg) on days 7, 14, 21, and 28, at 1 h after treatment with Yinchenhao decoction or dexamethasone or saline to induce chronic liver injury.. Repeated ConA injection induced chronic liver injury, which was evidenced by inflammatory cell infiltration and necrosis, increased serum alanine aminotranferease activities, decreased albumin levels, and an imbalanced expression of immunoregulatory genes in the liver tissues including significantly enhanced interferon-γ, interleukin-4, monocyte chemotactic protein-1, and cluster of differentiation 163 mRNA levels, and reduced tumor necrosis factor-α and interleukin-6 mRNA levels. Treatment with Yinchenhao decoction significantly reversed the ConA-induced changes in immunoregulatory gene expression in the liver tissues, reduced serum alanine aminotranferease activity, enhanced serum albumin level, and attenuated the extent of liver inflammation and necrosis. Furthermore, Yinchenhao decoction did not result in hepatocyte degeneration and spleen weight loss that were observed in mice received long-term treatment with dexamethasone.. Yinchenhao decoction treatment protected liver against the ConA-induced chronic liver damage and improved liver function, which were associated with the modulation of gene expression related to immune/inflammatory response.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Disease Models, Animal; Drugs, Chinese Herbal; Female; Immunomodulation; Mice; Mice, Inbred BALB C

Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4(+) T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; CD4-Positive T-Lymphocytes; Chemical and Drug Induced Liver Injury, Chronic; Chemokine CXCL10; Concanavalin A; Cytokines; Dexmedetomidine; Inflammation Mediators; Liver; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation

Interleukin-22 (IL-22), which acts as either a proinflammatory or anti-inflammatory cytokine in various disease models, is markedly up-regulated in chronic liver diseases, including hepatitis B and C. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 up-regulation in the pathogenesis of liver diseases, liver-specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4,000 to 7,000 pg/mL, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation (except for slightly thicker epidermis and minor inflammation of the skin) compared with wild-type mice. Interestingly, IL-22TG mice were completely resistant to concanavalin A-induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of antioxidant, mitogenic, acute phase genes were up-regulated in the livers of IL-22TG mice compared with those from wild-type mice.. These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation.

Topics: Animals; Cell Survival; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; Diethylnitrosamine; Disease Models, Animal; Disease Progression; Hepatectomy; Hepatitis B; Hepatitis C; Humans; Interleukin-22; Interleukins; Liver; Liver Diseases; Liver Neoplasms; Liver Regeneration; Mice; Mice, Inbred C57BL; Mice, Transgenic

Alpha-calcitonin gene-related peptide (alphaCGRP) is a 37-amino acid pleiotropic peptide that we previously showed to exert a hepatoprotective effect during concanavalin A (Con A)-induced acute hepatitis. In the present study, we used alphaCGRP(-/-) mice to further investigate the antifibrogenic and hepatoprotective effects of endogenous alphaCGRP in Con A-induced chronic hepatitis.. Chronic hepatitis was induced in alphaCGRP(-/-) and wild-type mice by repeated administration of Con A. Serum transaminases were measured to assess hepatic injury. The severity of fibrosis and the activation of hepatic stellate cells (HSCs) were analysed by Masson trichrome staining and immunohistochemical staining of alpha-smooth muscle actin (alpha-SMA) respectively. Altered expression of fibrosis- and inflammation-related genes was evaluated using a quantitative real-time polymerase chain reaction. Activation and proliferation of HSCs were analysed using both primary cultured HSCs from the mice and the LI90 HSC cell line.. alphaCGRP(-/-) mice showed more severe liver fibrosis than wild-type mice in a Con A-induced chronic hepatitis model. In histological and gene expression analyses, alphaCGRP(-/-) mice showed greater inflammatory and fibrotic changes, greater HSC activation and a higher incidence of apoptosis among nonparenchymal cells than wild-type mice.. Endogenous alphaCGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of Con A. alphaCGRP could be a useful therapeutic target for the treatment of chronic hepatitis.

Topics: Animals; Calcitonin Gene-Related Peptide; Cell Line; Chemical and Drug Induced Liver Injury, Chronic; Concanavalin A; DNA Primers; Hepatic Stellate Cells; Humans; Immunohistochemistry; Liver Cirrhosis; Mice; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction