Publications by authors named "Mengli Yan"

5 Publications

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Dopamine receptor D2 antagonization normalizes profibrotic macrophage-endothelial crosstalk in non-alcoholic steatohepatitis.

J Hepatol 2021 Oct 11. Epub 2021 Oct 11.

Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610064, China. Electronic address:

Background & Aims: Fibrosis in the liver is the main histological determinant of non-alcoholic steatohepatitis (NASH), a disease that parallels the worldwide surge in metabolic syndromes. Currently, there is no effective treatment for liver fibrosis. While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberrant activation frequently leads to fibrosis and tumorigenesis. Unravelling "context-specific" contributions of YAP in liver repair might help selectively bypass fibrosis and preserve the pro-regenerative YAP function in hepatic diseases.

Methods: We used murine liver fibrosis and minipig NASH models, liver biopsies from cirrhotic patients, single-cell RNA sequencing (scRNA-Seq) and a G-protein-coupled receptor (GPCR) ligand screening system.

Results: YAP levels in macrophages are increased in the livers of humans and mice with liver fibrosis. The fibrogenic role of macrophage YAP was evidenced via boosting type I interferon and attenuating liver fibrosis in mice specifically lacking Yap1 in myeloid cells. scRNA-Seq further showed that defecting YAP pathway in macrophages diminished a fibrogenic vascular endothelial cell subset exhibiting pro-fibrotic molecular signatures such as CTGF and VCAM1 expression. To specifically target fibrogenic YAP in macrophages, we utilized a GPCR ligand screening system and identified a dopamine receptor D2 (DRD2) antagonist that selectively blocked YAP in macrophages but not hepatocytes. Genetic and pharmacological targeting of macrophage DRD2 attenuated liver fibrosis. In a large animal (minipig) NASH model recapitulating human pathology, DRD2 antagonist blocked fibrosis and restored hepatic architecture.

Conclusions: DRD2 antagonization selectively targets YAP-dependent fibrogenic crosstalk between macrophages and CTGFVCAM1 endothelial cells, promoting liver regeneration over fibrosis in both rodent and large animal models.

Lay Summary: Fibrosis in the liver is one of the main histological determinants of non-alcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes. Our study demonstrates that myeloid-specific YAP deficiency attenuates liver fibrosis. Dopamine receptor D2 (DRD2) antagonization selectively blocks YAP in macrophages and thwarts liver fibrosis in both rodent and large animal models, showing the potential for the GPCR targeting-based NASH therapies.
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http://dx.doi.org/10.1016/j.jhep.2021.09.032DOI Listing
October 2021

Selective Targeting of Vascular Endothelial YAP Activity Blocks EndMT and Ameliorates Unilateral Ureteral Obstruction-Induced Kidney Fibrosis.

ACS Pharmacol Transl Sci 2021 Jun 5;4(3):1066-1074. Epub 2021 Apr 5.

National Traditional Chinese Medicine Clinical Research Base, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.

Kidney fibrosis is accompanied by vascular dysfunction. Discovering new ways to ameliorate dysfunctional angiogenesis may bypass kidney fibrosis. YAP (Yes-associated protein) plays a multifaceted role during angiogenesis. Here, we found that selectively targeting YAP signaling in the endothelium ameliorates unilateral ureteral obstruction (UUO)-induced kidney fibrosis. Genetic deletion of , encoding YAP protein, in VE-cadherin endothelial cells inhibited endothelial-to-mesenchymal transition (EndMT) and dysfunctional angiogenesis and improved obstructive nephropathy and kidney fibrosis. Treatment with the systemic YAP inhibitor verteporfin worsened kidney fibrosis symptoms because of its lack of cell specificity. In an attempt to identify endothelial-specific YAP modulators, we found that G-protein-coupled receptor coagulation factor II receptor-like 1 (F2RL1) was highly expressed in vessels after UUO-induced kidney fibrosis. The F2RL1 peptide antagonist FSLLRY-NH2 selectively blocked YAP activity in endothelial cells and ameliorated kidney fibrosis. Thus, selective antagonization of endothelial YAP activity might bypass kidney fibrosis and provide new avenues for the design of antifibrotic therapies.
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http://dx.doi.org/10.1021/acsptsci.1c00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204321PMC
June 2021

Sodium iodate induces ferroptosis in human retinal pigment epithelium ARPE-19 cells.

Cell Death Dis 2021 03 3;12(3):230. Epub 2021 Mar 3.

Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610065, Sichuan, PR China.

Sodium iodate (SI) is a widely used oxidant for generating retinal degeneration models by inducing the death of retinal pigment epithelium (RPE) cells. However, the mechanism of RPE cell death induced by SI remains unclear. In this study, we investigated the necrotic features of cultured human retinal pigment epithelium (ARPE-19) cells treated with SI and found that apoptosis or necroptosis was not the major death pathway. Instead, the death process was accompanied by significant elevation of intracellular labile iron level, ROS, and lipid peroxides which recapitulated the key features of ferroptosis. Ferroptosis inhibitors deferoxamine mesylate (DFO) and ferrostatin-1(Fer-1) partially prevented SI-induced cell death. Further studies revealed that SI treatment did not alter GPX4 (glutathione peroxidase 4) expression, but led to the depletion of reduced thiol groups, mainly intracellular GSH (reduced glutathione) and cysteine. The study on iron trafficking demonstrated that iron influx was not altered by SI treatment but iron efflux increased, indicating that the increase in labile iron was likely due to the release of sequestered iron. This hypothesis was verified by showing that SI directly promoted the release of labile iron from a cell-free lysate. We propose that SI depletes GSH, increases ROS, releases labile iron, and boosts lipid damage, which in turn results in ferroptosis in ARPE-19 cells.
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http://dx.doi.org/10.1038/s41419-021-03520-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930128PMC
March 2021

mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway.

Aging (Albany NY) 2019 10 3;11(19):8418-8432. Epub 2019 Oct 3.

Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu 610064, Sichuan, China.

Endogenous hydrogen sulfide mediates anti-aging benefits of dietary restriction (DR). However, it is unclear how HS production is regulated by pathways related to DR. Due to the importance of mTORC1 pathway in DR, we investigated the effects of Sch9, a yeast homolog of mammalian S6K1 and a major substrate of mTORC1 on HS production in yeast . We found that inhibition of the mTORC1-Sch9 pathway by deletion, rapamycin or myriocin treatment resulted in a dramatic decrease in HS production. Although deficiency of did not alter the intracellular level of methionine, the intracellular level of cysteine increased in cells. The expression of and , two transsulfuration pathway genes encoding cystathionine gamma-lyase (CGL) and cystathionine beta-synthase (CBS), were also decreased under mTORC1-Sch9 inhibition. Overexpression of or in cells or WT cells treated with rapamycin rescued the deficiency of HS production. Finally, we also observed a reduction in HS production and lowering of both mRNA and protein levels of CGL and CBS in cultured human cells treated with rapamycin to reduce mTORC1 pathway activity. Thus, our findings reveal a probably conserved mechanism in which HS production by the transsulfuration pathway is regulated by mTORC1-Sch9 signaling.
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http://dx.doi.org/10.18632/aging.102327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814617PMC
October 2019

Promoting Effect of Crystal Water Leading to Catalyst-Free Synthesis of Heteroaryl Thioether from Heteroaryl Chloride, Sodium Thiosulfate Pentahydrate, and Alcohol.

J Org Chem 2019 Sep 20;84(17):11294-11300. Epub 2019 Aug 20.

College of Chemistry and Materials Engineering , Wenzhou University , Wenzhou , Zhejiang 325035 , China.

It is observed the crystal water in sodium thiosulfate pentahydrate (NaSO·5HO) can promote its multicomponent reaction with heteroaryl chlorides and alcohols, providing a facile, green, and specific synthesis of unsymmetrical heteroaryl thioethers via one-step formation of two C-S bonds under catalyst-, additive-, and solvent-free conditions. Mechanistic studies suggest that the crystal water in NaSO·5HO is crucial in generating the key thiol intermediates and byproduct NaHSO, which then catalyzes the dehydrative substitution of alcohols with thiols to afford thioethers.
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http://dx.doi.org/10.1021/acs.joc.9b01670DOI Listing
September 2019
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