ABSTRACTLiver injury‐induced activation of hepatic stellate cells (HSCs) is a crucial step in the progression of liver fibrosis. The aryl hydrocarbon receptor (AHR), a ligand‐activated transcription factor, is highly expressed in the liver. However, the role of AHR in liver fibrosis remains controversial. Our study revealed that the nontoxic ligand YH439 directly activated the AHR and regulated the expression of multidrug‐resistant protein 1 (Mrp1) in mouse hepatic stellate cells (mHSCs), thereby diminishing the antioxidant capacity of mHSCs by promoting GSH efflux, and specifically inducing mHSCs ferroptosis without affecting hepatocytes. In a chronic liver fibrosis model, YH439 activated AHR to promote mHSC ferroptosis without causing hepatocyte ferroptosis, thereby alleviating liver fibrosis. Conclusively, this study shows that AHR alleviates liver fibrosis in mice by selectively inducing mHSC ferroptosis without causing hepatocyte ferroptosis and suggests that AHR is a potential target for the treatment of liver fibrosis.

01 Sep 2024·Heliyon

AHR regulates liver enlargement and regeneration through the YAP signaling pathway

Article

Author: Liu, Shenghui

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligands that participates in many important physiological processes. Although AHR activation is associated with hepatomegaly, the underlying mechanism remains unclear. This study evaluated the effects of AHR activation on liver enlargement and regeneration in various transgenic mice and animal models. Activation of AHR by the non-toxic ligand YH439 significantly induced liver/body weight ratio in wild-type mice (1.37-fold) and AHR^{fl/fl.ALB-CreERT2} mice (1.54-fold). However, these effects not present in AHR^ΔHep mice. Additionally, the activation of AHR promotes hepatocyte enlargement (1.43-fold or 1.41-fold) around the central vein (CV) and increases number of Ki67⁺ cells (42.5-fold or 48.8-fold) around the portal vein (PV) in wild-type mice and AHR^{fl/fl.ALB-CreERT2} mice. In the 70 % partial hepatectomy (PHx) model, YH439 significantly induced hepatocyte enlargement (1.40-fold) and increased number of Ki67⁺ cells (3.97-fold) in AHR^{fl/fl.ALB-CreERT2} mice. However, these effects were not observed in AHR^ΔHep mice. Co-immunoprecipitation results suggested a potential protein-protein interaction between AHR and Yes-associated protein (YAP). Disruption of the association between YAP and transcription enhancer domain family member (TEAD) significantly inhibited AHR-induced liver enlargement and regeneration. Furthermore, AHR failed to induce liver enlargement and regeneration in YAP^ΔHep mice. Blocking the YAP signaling pathway effectively eliminated AHR-induced liver enlargement and regeneration. This study revealed the molecular mechanism of AHR regulation of liver size and regeneration through the activation of AHR-TEAD signaling pathway, thereby offering novel insights into the physiological role of AHR. These findings provide a theoretical foundation for the prevention and treatment of disorders associated with liver regeneration.

01 Feb 2024·Science of The Total Environment

Predictive metabolomic signatures for safety assessment of three plastic nanoparticles using intestinal organoids

Article

Author: Luo, Jinhua ; Yan, Yuhui ; Yi, Wensen ; Xuan, Lihui ; Guo, Peiyu ; Yang, Jingjing ; Zhou, Pingkun ; Guan, Hua ; Qu, Can ; Huang, Ruixue

Nanoplastic particles are pervasive environmental contaminants with potential health risks, while mouse intestinal organoids provide accurate in vitro models for studying these interactions. Metabolomics, especially through LC-MS, enables detailed cellular response studies, and there's a novel interest in comparing metabolic changes across nanoparticle species using gut organoids. This study used a mouse intestinal organoid combined with cell model to explore the differences in metabolites and toxicity mechanisms induced by exposure to three nanoplastics (PS, PTFE, and PMMA). The results showed that PS, PTFE, and PMMA exposure reduced mitochondrial membrane potential, intracellular ROS accumulation and oxidative stress, and inhibited the AKT/mTOR signaling pathway. Non-targeted metabolomics results confirmed that three types of nanoplastic particles regulate cellular status by regulating fatty acid metabolism, nucleotide metabolism, necroptosis and autophagy pathways. More importantly, these representative metabolites were further validated in model groups after mouse intestinal organoids and HCT116 cells were exposed to the respective NPs, indicating that organoid metabolomics results can be used to effectively predict toxicity. Untargeted metabolomics is sensitive enough to detect subtle metabolomic changes when functional cellular analysis shows no significant differences. Overall, our study reveals the underlying metabolic mechanism of NPs-induced intestinal organoid toxicity and provides new insights into the possible adverse consequences of NPs.

100 Deals associated with Mivotilate

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Indication	Country/Location	Organization	Date
Hepatitis B	South Korea	-	01 May 1999
Liver Diseases	South Korea	-	01 May 1999
Neoplasms	South Korea	-	01 May 1999

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B	Phase 2	Germany	Yuhan Corp.	-
Neoplasms	Phase 2	United States	-	-

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