Short-term use of MyD88 inhibitor TJ-M2010-5 prevents d-galactosamine/lipopolysaccharide-induced acute liver injury in mice

Ding, Zeyu; Du, Dunfeng; Yang, Yang; Yang, Min; Yan, Miao; Zou, Zhimiao; Zhang, Xiaoqian; Li, Zeyang; Zhang, Xue; Zhang, Limin; Wang, Xinqiang; Zhao, Yuanyuan; Jiang, Jianzhong; Jiang, Fan; Zhou, Ping

doi:10.1016/j.intimp.2018.11.051

Cited by 14 publications

(8 citation statements)

References 36 publications

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“…MyD88 −/− MDSCs fail to suppress the tumor antigen-specific T cell immune response [26]. Moreover, our previous study proved that the administration of a novel MyD88 inhibitor, TJ-M2010-5 (a patented small-molecule compound synthesized by Dr. Zhou's group), which has been proven to be effective in suppressing the innate immune response in many animal models of diseases (such as hepatocellular carcinoma [27], acute liver injury [28], tracheal, cardiac and skin transplantation [29,30], graft-versus-host disease [31] and myocardial ischemia reperfusion injury [32]), may completely prevent the development of colitis-associated colorectal cancer (CAC) in mice by controlling inflammation and carcinogenesis [33]. Therefore, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSCs in mice with CAC.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

Wang

Xie

et al. 2022

Invest New Drugs

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SummaryBackground. In cancer, myeloid-derived suppressor cells (MDSCs) are known to escape the host immune system by developing a highly suppressive environment. However, little is known about the molecular mechanism behind MDSC-mediated tumor cell evasion of the immune system. Toll-like receptor (TLR) signaling elicited in the tumor microenvironment has the potential to induce MDSC differentiations in different organs. Therefore, MDSC elimination by blocking the action of myeloid differentiation factor 88 (MyD88), which is a key adaptor-signaling molecule that affects TLR activity, seems to be an ideal tumor immunotherapy. Previous studies have proven that blocking MyD88 signaling with a novel MyD88 inhibitor (TJ-M2010-5, synthesized by Zhou’s group) completely prevented colitis-associated colorectal cancer (CAC) development in mice. Methods. In the present study, we investigated the impact of the novel MyD88 inhibitor on the number, phenotype, and function of MDSC in the mice model of CAC. Results. We showed that CAC growth inhibition was involved in diminished MDSC generation, expansion, and suppressive function and that MDSC-mediated immune escape was dependent on MyD88 signaling pathway activation. MyD88 inhibitor treatment decreased the accumulation of CD11b+Gr1+ MDSCs in mice with CAC, thereby reducing cytokine (GM-CSF, G-CSF, IL-1β, IL-6 and TGF-β) secretion associated with MDSC accumulation, and reducing the expression of molecules (iNOS, Arg-1 and IDO) associated with the suppressive capacity of MDSCs. In addition, MyD88 inhibitor treatment reduced the differentiation of MDSCs from myeloid cells and the suppressive capacity of MDSCs on the proliferation of activated CD4+ T cells in vitro. Conclusion. MDSCs are primary cellular targets of a novel MyD88 inhibitor during CAC development. Our findings prove that MyD88 signaling is involved in the regulation of the immunosuppressive functions of MDSCs. The novel MyD88 inhibitor TJ-M2010-5 is a new and effective agent that modulates MyD88 signaling to overcome MDSC suppressive functions, enabling the development of successful antitumor immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

Wang

Xie

et al. 2022

Invest New Drugs

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“…In our previous studies ( Ding et al, 2019 ; Liu et al, 2019a; Xie et al, 2016 , Zou et al, 2020 ), we designed, synthesized and characterized a novel small MyD88 inhibitor, TJ-M2010-5, which specifically interacts with the MyD88 TIR domain and interferes with MyD88 dimerization. In vitro , we sought to validate the effect of TJ-M2010-5 on MyD88-related inflammatory pathways.…”

Section: Resultsmentioning

confidence: 99%

“…TJ-M2010-5 can bind to the TIR domain of MyD88 and inhibit MyD88 dimerization ( Xie et al, 2016 ), thus disrupting myddosome formation. TJ-M2010-5 has been demonstrated to be effective in the treatment of acute liver injury ( Ding et al, 2019 ), transplant rejection ( Li et al, 2017 ), and colitis-associated colorectal cancer ( Xie et al, 2016 ). Here, we found that TJ-M2010-5 at a moderate dose, but not the highest dose, exerted a better antidepressant effect, indicating that the highest dose of TJ-M2010-5 may produce side effects that counteracted the behavior benefits.…”

Section: Discussionmentioning

confidence: 99%

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals

Yao¹,

Ye²,

Tian³

et al. 2023

Brain, Behavior, and Immunity

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“… 18 NF-κB is a downstream signaling molecule of MyD88 and an upstream regulator of various inflammation-related genes. 19 NF-κB is retained in an inactive form in the cytoplasm of hepatocytes that interact with IκB inhibitors. However, some stimulants, such as LPS, proinflammatory cytokines, viruses and other substances, can trigger NF-κB activation.…”

Section: Discussionmentioning

confidence: 99%

UMSCs Attenuate LPS/D-GalN-Induced Acute Liver Failure in Mice by Down-regulating the MyD88/NF-κB Pathway

Liao¹,

Du²,

Jiang³

et al. 2021

Journal of Clinical and Translational Hepatology

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Background and Aims: Acute liver failure (ALF) is an inflammatory process of acute liver cell injury. Mesenchymal stem cells (MSCs) are undifferentiated, primitive cells with antiinflammatory, anti-apoptotic, and multi-directional differentiation abilities. This study aimed to explore the therapeutic mechanism of umbilical cord (U)MSCs in ALF. Methods: Dgalactosamine (D-GalN) combined with lipopolysaccharide (LPS) was used to establish an ALF model. After model establishment, UMSCs were injected via the tail vein. After UMSC transplantation, the number of mouse deaths was monitored every 12 h. A fully automatic biochemical analyzer was used to detect changes in biochemical analysis. Pathological changes was observed by stained with hematoxylin and eosin.The expression of My D88 was detected by immunohistochemical analysis, quantitative reverse transcription, and western blotting. The expression of NF-κB was detected by quantitative reverse transcription, western blotting.The expression of Bcl-2,Bax were detected by quantitative reverse transcription, western blotting.The expression of TNF-α, IL-1β, IL-6 were detected by enzyme-linked immunosorbent assay. Results: The 48-h survival rate of the UMSC-treated group was significantly higher than that of the LPS/D-GalNexposed group. After 24 h of LPS/D-GalN exposure, UMSCs reduced serum alanine aminotransferase and aspartate aminotransferase levels and improved the liver structure. Western blot and real-time fluorescence quantitative nucleic acid amplification analyses showed that UMSCs decreased MyD88 expression, thereby inhibiting LPS/GalN-induced phosphorylation and degradation of inhibitor of nuclear factor (NF)-κB (IκB). Additionally, NF-κB p65 underwent nuclear translocation, inhibiting the production of the inflammatory factors interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and played a protective role in ALF by down-regulating the pro-apoptotic gene Bax and up-regulating the anti-apoptotic gene Bcl-2. In summary, these findings indicate that UMSCs play a protective role in LPS/GalN-induced acute liver injury via inhibition of the MyD88 pathway and subsequent inhibition of NF-κB-mediated cytokine production. Conclusions: Through the above mechanisms, UMSCs can effectively reduce LPS/D-GalN-induced ALF, reduce mouse mortality, and restore damaged liver function and damaged liver tissue.

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Short-term use of MyD88 inhibitor TJ-M2010-5 prevents d-galactosamine/lipopolysaccharide-induced acute liver injury in mice

Cited by 14 publications

References 36 publications

Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

Blockade of Myd88 signaling by a novel MyD88 inhibitor prevents colitis-associated colorectal cancer development by impairing myeloid-derived suppressor cells

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals

UMSCs Attenuate LPS/D-GalN-Induced Acute Liver Failure in Mice by Down-regulating the MyD88/NF-κB Pathway

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