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New Compounds, Novel Targets and Mechanism Study in Inflammation-Associated Liver Diseases

Cover image for Research Topic "New Compounds, Novel Targets and Mechanism Study in Inflammation-Associated Liver Diseases"
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Editorial09 December 2022
Editorial: New compounds, novel targets and mechanism study in inflammation-associated liver diseases
Baoming Wu

1 Authors

Total of 18 manuscripts were submitted and reviewed, with 9 manuscripts accepted and others rejected. Scopes of accepted manuscripts involved liver injury, autoimmune hepatitis, liver ischemia/reperfusion injury and liver fibrosis. There were 3 manuscripts that discussed effects of Chinese traditional medicine on liver diseases: paeoniflorin alleviates liver injury in hypercholesterolemic rats through the ROCK/AMPK pathway, mechanism of Hydroxysafflor yellow A on acute liver injury based on transcriptomics, and saikosaponin d alleviates liver fibrosis by negatively regulating the ROS/NLRP3 inflammasome through activating the ERβ pathway. There were 2 manuscripts that studied the effects and mechanism of chemical medicine on liver diseases: hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes, and roxadustat, a hypoxia-inducible factor 1α activator, attenuates both long-and short-term alcohol induced alcoholic liver disease. There were 3 manuscripts that revealed the effects and mechanism of cytokines on liver diseases: inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury, human umbilical cord blood mononuclear cells ameliorate CCl4 induced acute liver injury in mice via inhibiting inflammatory responses and up-regulating interleukin-22, and interleukin-6 receptor blockade can increase the risk of nonalcoholic fatty liver disease: indications from Mendelian randomization. There was 1 review manuscript in this research topic, which summarized the current literature regarding FAT10 role in developing liver diseases and potential therapeutic targets for nonalcoholic/alcoholic fatty liver disease and hepatocellular carcinoma.In the end, I would like to first thank our guest editors, because they worked very hard to organize the research topic and review manuscripts assigned to them. Second, I would like to thank all the contributors who submitted their great work to this topic. Last but not the least, we would like to thank Frontier in Pharmacology for giving us this opportunity to learn a great deal from this special issue.

1,953 views

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes
ORIGINAL RESEARCH
15 September 2022
Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes
Chao Jin, 7 more and Ting-Ting Liu

9 Authors

Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

7,451 views

21 citations

ORIGINAL RESEARCH
23 August 2022
Paeoniflorin alleviates liver injury in hypercholesterolemic rats through the ROCK/AMPK pathway
Tong Liu, 7 more and Zhihong Ma

9 Authors

3,994 views

29 citations

ORIGINAL RESEARCH
8 September 2022
Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury
Sanyang Chen, 7 more and Changju Zhu

9 Authors

5,056 views

14 citations

ORIGINAL RESEARCH
2 September 2022
Mechanism of hydroxysafflor yellow A on acute liver injury based on transcriptomics
Xiangmei Hou, 5 more and Lijie Ma

7 Authors

  • XH

    Xiangmei Hou

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • ZZ

    Ziying Zhang

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • YM

    Yuehong Ma

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • RJ

    Rong Jin

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • BY

    Bing Yi

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • DY

    Dongdong Yang

    Inner Mongolia Key Laboratory of Molecular Biology, China

  • LM

    Lijie Ma

    Inner Mongolia Key Laboratory of Molecular Biology, China

4,967 views

13 citations

ORIGINAL RESEARCH
22 July 2022
Human Umbilical Cord Blood Mononuclear Cells Ameliorate CCl4-Induced Acute Liver Injury in Mice via Inhibiting Inflammatory Responses and Upregulating Peripheral Interleukin-22
Jinming Zhang, 8 more and Xiaogang Xiang

10 Authors

4,593 views

9 citations

Saikosaponin d Alleviates Liver Fibrosis by Negatively Regulating the ROS/NLRP3 Inflammasome Through Activating the ERβ Pathway
ORIGINAL RESEARCH
25 May 2022
Saikosaponin d Alleviates Liver Fibrosis by Negatively Regulating the ROS/NLRP3 Inflammasome Through Activating the ERβ Pathway
Kehui Zhang, 4 more and Yong Li

6 Authors

Saikosaponin d (SSd) has a steroidal structure and significant anti-inflammatory effects. The purpose of this study was to explore the mechanism underlying SSd’s inhibitory effects on liver fibrosis. Methods: Wild-type and estrogen receptor knockout (ERKO) mice were treated with CCl4 to establish liver fibrosis mouse models. The effects of SSd on hepatic fibrogenesis were studied in these mouse models. Hepatic stellate cells (HSCs) were activated by H2O2 to investigate the potential molecular mechanisms. The establishment of the models and the degrees of inflammation and liver tissue fibrosis were evaluated by detecting changes in serum liver enzymes and liver histopathology. The expression of α-SMA and TGF-β1 was determined by immunohistochemistry. The expression and significance of NLRP3 inflammasome proteins were explored by RT-PCR and Western blotting analyses. The mitochondrial ROS-related indexes were evaluated by MitoSOX Red. Results: Fibrous hyperplasia, infiltration of inflammatory cells and fat, and deposition of collagen in the vessel wall of portal area were observed in the liver of wild-type and ERKO mice treated with CCL4. The expression levels of α-SMA and TGF-β1 in the vascular wall and portal area were obviously increased. SSd treatment significantly reduced the degree of fibrosis in wild-type and αERKO mice, but not in βERKO mice. Compared with untreated mice, treatment with SSd significantly downregulated the mRNA and protein levels of NLRP3 inflammatory and fibrosis-related indicators in wild-type and αERKO mice, but not in βERKO mice. Conclusion: SSd alleviated liver fibrosis by negatively regulating the ROS/NLRP3 inflammasome through activating the ERβ pathway.

5,507 views

39 citations

ORIGINAL RESEARCH
10 May 2022
Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
Yongyao Gao, 11 more and Xiaoxiao Yang

13 Authors

Roxadustat, a Hypoxia-Inducible Factor 1α Activator, Attenuates Both Long- and Short-Term Alcohol-Induced Alcoholic Liver Disease
Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS) and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1α (HIF-1α), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remains to be elucidated. In this study, we used the chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation and morphology changes, which were reversed by roxadustat. Roxadustat reduced fatty liver was mainly contributed by reducing sterol-responsive element binding protein 1c (SREBP1c) pathway, and enhancing β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophage to hepatocytes, as well as inflammatory cytokines expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol-caused ROS generation in liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro, we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1α regulation. Taken together, our study demonstrates that activation of HIF-1α can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation and oxidative stress. This study suggests roxadustat could be a potential drug for ALD treatment.

6,207 views

15 citations