TP-58, a Novel Thienopyridine Derivative, Protects Mice from ConcanavalinA-Induced Hepatitis by Suppressing Inflammation

Li, Yang; Wang, Zhenling; He, Fang; Wu, Yang; Huang, Wenyu; He, Yijun; Tong, Qingyi; Wei, Yuquan; Qing, Yong; Yang, Li; Wu, Xiaohua

doi:10.1159/000337584

Cited by 11 publications

(6 citation statements)

References 36 publications

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“…Once activated, NF-jB is released from cytoplasm and translocated to nucleus, and where it binds the jB site of target genes and induces the overproduction and release of inflammatory cytokines, which can damage the liver and eventually cause cell necrosis and apoptosis [36]. It has demonstrated that Con A can up-regulate NF-jB expression in liver [37], whereas liver injury induced by Con A is significantly attenuated by inhibiting NF-jB activation [38,39]. Therefore, inhibition of the expression of TLRs and the activation of NF-jB are the effective therapeutic targets for immune-mediated hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

Sang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Immune hepatic injury is a liver disease closely related to an immune imbalance of T cells and macrophages. Our previous series of studies have demonstrated that taraxasterol isolated from Taraxacum possesses great anti-inflammatory and immunomodulatory effects in vivo and in vitro. In this study, we explored the preventive effects of taraxasterol and its underlying mechanisms on concanavalin A (Con A)-induced acute hepatic injury in mice. It was found that treatment with taraxasterol significantly decreased the Con A-induced increase of liver index, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and hepatic malondialdehyde (MDA) levels, and increased the Con A-induced decrease of hepatic glutathione (GSH) and superoxide dismutase (SOD) production. Taraxasterol also significantly inhibited the release of pro-inflammatory cytokines tumour necrosis factor-a (TNF-a), interleukin-6 (IL-6), IL-1b, interferon-c (IFN-c) and IL-4. In addition, treatment with taraxasterol alleviated the hepatic histopathological injury and apoptosis induced by Con A. Furthermore, taraxasterol dramatically down-regulated the expressions of T toll-like receptor (TLR2), TLR4 and nuclear factor-jappaB (NF-jB) p65, and decreased the expression ratio of Bax/Bc1-2 in hepatic tissues. These findings suggest that taraxasterol prevents Con A-induced acute hepatic injury in mice by inhibiting TLRs/NF-jB inflammatory signalling pathway and promoting Bax/Bc1-2 anti-apoptotic signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

Sang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Upon activation by LPS, phosphorylation of IκBα activates the NF-κB pathway, which results in NF-kB p65 dissociates from IκBα, then the released NF-κB p65 translocates into the nucleus, and triggers the transcription of related inflammatory genes (Sun and Andersson, 2002 ; Li et al, 2014 ). Some studies have reported that Con A could upregulate NF-kB expression in liver (Tiegs et al, 1998 ), and there was increasing evidence shown that Con A-induced liver injury was significantly attenuated via inhibiting NF-kB activation (Li Y. et al, 2012 ; Song et al, 2013 ). In the present study, the results showed that Baicalin obviously inhibited the protein levels of p-p65, p- IκBα and p65 induced by LPS in liver tissues.…”

Section: Discussionmentioning

confidence: 99%

Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-κB Pathway

et al. 2017

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As a kind of potent stimulus, lipopolysaccharide (LPS) has the ability to cause cell damage by activating toll-like receptor(TLR)4, then nuclear factor kappa B (NF-κB) translocates into the nucleus and changes the expression of related inflammatory genes. Baicalin is extracted from Radix Scutellariae, which possesses anti-inflammation, antioxidant and antibacterial properties. However, the effects of it on LPS-induced liver inflammation have not been fully elucidated. This study aims to investigate the anti-inflammatory effects of Baicalin on the LPS-induced liver inflammation and its underlying molecular mechanisms in chicken. The results of histopathological changes, serum biochemical analysis, NO levels and myeloperoxidase activity showed that Baicalin pretreatment ameliorated LPS-induced liver inflammation. ELISA and qPCR assays showed that Baicalin dose-dependently suppressed the production of IL-1β, IL-6, and TNF-α. Furthermore, the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were significantly decreased by Baicalin. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by Baicalin pretreatment. In addition, Baicalin pretreatment inhibited NF-kB signaling pathway activation. All results demonstrated the protective effects of Baicalin pretreatment against LPS-induced liver inflammation in chicken via negative regulation of inflammatory mediators through the down-regulation of TLR4 expression and the inhibition of NF-kB activation.

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“…ConA stimulation has been reported to significantly increase TNF-α [25], IL-18 [5], IL-12p70 [26] and MCP-1 [27] in serum, and depletion of these mediators decreases hepatic damage. TNF-α is a proinflammatory cytokine that plays a crucial role in the response to tissue injury, infection, and inflammation [28].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Intrasplenic Transplantation of Ad-IL-18BP/IL-4 Gene-Modified Fetal Hepatocytes on ConA-Induced Hepatitis in Mice

Shao

Qian

et al. 2013

PLoS ONE

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BackgroundConcanavalin A (ConA)-induced hepatitis is an experimental murine model mirroring the pathology of human autoimmune hepatitis.AimTo investigate the effects of intrasplenically transplanted fetal hepatocytes (BNL.CL2) transfected with recombinant adenovirus vector expressing the IL-18 binding protein (IL-18BP) and IL-4 fusion protein on ConA-induced hepatitis in mice.MethodsAd-IL-18BP/IL-4 was used to infect BNL.CL2 cells. IL-4 and IL-18BP fusion protein expression were detected by ELISA and Western blotting. BNL.CL2 cells infected with Ad-IL-18BP/IL-4 were intrasplenically transplanted into mice. After 10 days, mice were injected with ConA (15 mg/kg), and sacrificed 18 hours later. Liver injury was assessed by serum transaminase and liver histology. TNF-α, IL-18, IL-4, IL-10, IL-12p70 and monocyte-chemoattracting protein (MCP)-1 levels in serum and liver homogenates were detected by ELISA. Signaling molecules in liver homogenates were analyzed by Western blotting.ResultsAd-IL-18BP/IL-4 effectively expressed the IL-18BP/IL-4 fusion protein for more than 14 days in BNL.CL12 cells. Treatment of mice with Ad-IL-18BP/IL-4-BNL.CL2 before ConA injection significantly reduced the elevated plasma levels of transaminases compared with ConA control groups. TNF-α, IL-18, IL-12p70 and MCP-1 levels in serum and liver homogenates from mice transplanted with Ad-IL-18BP/IL-4-BNL.CL2 were lower and IL-4 and IL-10 levels were higher than control groups. Phosphorylation levels of NF-κB p65, AKT, p38 and JNK1/2 in liver homogenates were markedly suppressed by Ad-IL-18BP/IL-4.ConclusionsAd-IL-18BP/IL-4 was effectively transfected into mouse BNL.CL2 cells. Intrasplenic transplantation of Ad-IL-18BP/IL-4-BNL.CL12 cells alleviated the severity of inflammation in ConA-induced experimental hepatitis and provides a useful basis for the targeted gene therapy of liver disease.

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TP-58, a Novel Thienopyridine Derivative, Protects Mice from ConcanavalinA-Induced Hepatitis by Suppressing Inflammation

Cited by 11 publications

References 36 publications

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

Taraxasterol from Taraxacum prevents concanavalin A-induced acute hepatic injury in mice via modulating TLRs/NF-κB and Bax/Bc1-2 signalling pathways

Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-κB Pathway

The Protective Effect of Intrasplenic Transplantation of Ad-IL-18BP/IL-4 Gene-Modified Fetal Hepatocytes on ConA-Induced Hepatitis in Mice

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