HEPATOLOGY
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2024
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IF 12.9
Zhang Sitong,Sun Zhongquan,Chen Zhenhua,Bi Yanli,Wei Shenyu,Mao Zhengwei,Jin Jin,Ding Yuan,Wang Weilin
Background & Aims: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy, and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. Approach & Results: We enrolled recipients receiving orthotopic liver transplantation (OLT) and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, two cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In mice model, liver IRI mobilized MDSCs and promoted their infiltration in damaged liver, and intrahepatic MDSCs possessed with enhanced immunosuppressive function by up-regulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo , we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that CXCL17 was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs via binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated YAP/TEAD1 complex to promote CXCL17 transcription. Conclusions: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of a therapeutic potential for managing IRI in liver surgery. Export
研究领域:
医学
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免疫学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
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2022
·Vol. 58
·期 2
·96-108
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IF 2.723
Sun Xiaogang,Hou Zhiyun,Li Ning,Zhang Shuangwei
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high incidence and mortality. MiR-597-5p is downregulated in tumor tissues of HCC compared with non-tumor tissues. However, its role in HCC is still unknown. This study aims to assess the function of miR-597-5p in HCC development and investigate the underlying mechanism. To perform gain- and loss-of-function studies, SK-HEP-1 cells and Huh-7 cells were transfected with miR-597-5p mimics and inhibitor, respectively. MiR-597-5p markedly reduced the cell viability and the expression of Ki-67 in HCC cells. MiR-597-5p also repressed the cell cycle progression of HCC cells and the protein levels of cyclin D1 and CDK2. Moreover, miR597-5p inhibited the migration and invasion of HCC cells and decreased MMP2 and MMP9 levels. Transcriptional enhancer associate domain transcription factor 1 (TEAD1) was identified as a target of miR-597-5p by luciferase reporter assay. TEAD1 and its downstream target genes, CTGF and CYR61, were downregulated by miR-597-5p in HCC cells. Furthermore, miR-597-5p was demonstrated to function in HCC progression by targeting TEAD1 via TEAD1 expression gain and loss. Our study demonstrates that miR-597-5p represses the proliferation, migration, and invasion of HCC cells through targeting TEAD1, which provides a therapeutic target for HCC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2024
·Vol. 25
·期 10
·754-768
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IF 2.1
Xiaoyun Liu,Dafang Zhong,Chongzhuang Tang,Xiaofeng Xu,Hong Lan,Xingxing Diao
Background BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the transcriptional enhanced associate domain (TEAD) 1/3/4, which is currently in clinical development for the treatment of cancers with Hippo pathway alterations. Objectives This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, and in vitro and in vivo metabolic profile of BPI-460372. Methods The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes and rat and dog plasma was analyzed using ultra-high-performance liquid chromatography combined with Orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS). Results BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human-unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic site was 2-fluoro-acrylamide, and major metabolic pathways in hepatocytes, and rat and dog plasma involved oxidative defluorination, hydration, glutathione (GSH) conjugation, hydrolysis, cysteine conjugation, and N-acetyl cysteine conjugation. β-lyase pathway contributed to the metabolism of BPI-460372 in rats to a certain degree. Conclusion This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, and assessment of clinical co-administration limitations and possible metabolic pathways in humans.
研究领域:
药理学
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药物代谢
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肿瘤学
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生物化学
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临床药理学
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分析化学
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毒理学
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分子生物学
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DOI
高影响因子
JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2024
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IF 3.6
Qing Yang,Xiaosheng Jin,Yuansen Zhang,Xiaoqiu Wu,Haiying Lin,Tingting Ji,Rongzhou Li
The aim of this study is to investigate the impact of sh-LncRNA ASB16-AS1 on doxorubicin (DOX) resistance in colorectal cancer (CRC). First, an in vitro study was conducted to investigate the effects of LncRNA ASB16-AS1, miR-185-5p, and TEAD1 on drug resistance in CRC cells. Subsequently, utilizing nanotechnology, poly(beta amino esters) (PBAE)/zeolitic imidazolate framework-8 (ZIF-8)@sh-LncRNA ASB16-AS1 nanoparticles (PZSNP) were synthesized and characterized, evaluating their cellular toxicity and hemolytic activity. Finally, a mouse subcutaneous tumor model was established by subcutaneous injection of SW480/DOX cell suspension to investigate the impact of PZSNP on the tumor. Under DOX treatment, downregulation of LncRNA ASB16-AS1, overexpression of miR-185-5p, or downregulation of TEAD1 suppressed the viability and proliferation of drug-resistant CRC cells while promoting apoptosis. Conversely, overexpression of LncRNA ASB16-AS1, inhibition of miR-185-5p, or overexpression of TEAD1 enhanced the viability and proliferation of drug-resistant CRC cells while inhibiting apoptosis. The synthesized PZSNP exhibited a spherical shape with an average particle size of 123.6 nm, possessed positive charge, displayed good stability. It effectively encapsulated shRNA and displayed low cellular toxicity and hemolytic activity. Under DOX treatment, significant tumor necrosis was observed in the PZSNP group, and tumor growth was suppressed without causing weight loss. LncRNA ASB16-AS1, miR-185-5p, and TEAD1 are involved in regulating cell viability, proliferation, and apoptosis, contributing to drug resistance in CRC cells. sh-LncRNA ASB16-AS1 enhances the sensitivity of CRC cells to DOX during treatment, and in vivo delivery of PZSNP may serve as an effective strategy to overcome chemotherapy resistance in CRC.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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