eLife
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2018
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IF 7.616
Dao-Lai Zhang,Yu-Jing Sun,Ming-Liang Ma,Yi-jing Wang,Hui Lin,Rui-Rui Li,Zong-Lai Liang,Yuan Gao,Zhao Yang,Dong-Fang He,Amy Lin,Hui Mo,Yu-Jing Lu,Meng-Jing Li,Wei Kong,Ka Young Chung,Fan Yi,Jian-Yuan Li,Ying-Ying Qin,Jingxin Li,Alex R B Thomsen,Alem W Kahsai,Zi-Jiang Chen,Zhi-Gang Xu,Mingyao Liu,Dali Li,Xiao Yu,Jin-Peng Sun
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.
研究领域:
分子生物学
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生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Xu Lu,Ma Yan,Yao Wang,Qiu Ya-ju,Xu Chao,Xu Fang-yue,Zou Zhi-miao,Dai Wu-min,Gong Wan-gang,Ma De-ning,Chen Xiao-wan,Ye Wen-kai,Huang Yi-yun,Chen Hai-tao,Hong Lue,Mo Jia-ping,Feng Jian-guo,Yu En-yan,Chen Wei,Zhang Yu-hua,Yao Qing-hua,Li Xia
5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC) involves oxidative stress mechanisms, but the role of epitranscriptomic regulation remains unclear. This study investigates how oxidative post-translational modifications of the N6-methyladenosine (m 6 A) methyltransferase METTL16 contribute to 5-FU resistance. Parental (HCT8, HCT15) and 5-FU-resistant CRC cells were compared using redox proteomics, m 6 A-seq, RNA-seq, and functional assays. METTL16 S-glutathionylation was assessed via streptavidin pulldown and mass spectrometry. IGF2BP3’s role was validated through knockdown/overexpression, patient-derived organoids (PDOs), and xenograft models. Clinical relevance was evaluated in 112 CRC patient tissues and data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug synergy was tested using isoliquiritigenin (ISO) combined with 5-FU. Resistant cells exhibited elevated global protein S-glutathionylation and reduced m 6 A RNA methylation. METTL16 underwent site-specific S-glutathionylation at Cys548, leading to its degradation and subsequent m 6 A loss. Integrative omics identified IGF2BP3 as a key METTL16 target: reduced m 6 A on IGF2BP3 mRNA enhanced its nuclear export, splicing, and overexpression. IGF2BP3 knockdown sensitized resistant cells to 5-FU in vitro and in vivo, while overexpression conferred resistance. Mechanistically, IGF2BP3 destabilized CFTR mRNA (an ABC transporter), reducing 5-FU uptake. Clinically, high IGF2BP3 correlated with poor survival and 5-FU resistance in CRC patients. Targeting IGF2BP3 with ISO synergized with 5-FU, overcoming resistance in cells and xenografts. Oxidative stress-induced METTL16 S-glutathionylation drives 5-FU resistance by reducing m 6 A modification, enabling IGF2BP3 overexpression and CFTR suppression. IGF2BP3 is a biomarker of clinical resistance, and its targeting with ISO represents a promising combinatorial strategy to restore 5-FU efficacy in CRC.
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Yang Xiang,Yuanhui Gao,Qiuhua Cheng,Zhongwen Lei,Xiaoyu Zhang,Yijun Yang,Jianquan Zhang
Bile duct injury presents a significant clinical challenge following hepatobiliary surgery, necessitating advancements in the repair of damaged bile ducts is a persistent issue in biliary surgery. 3D printed tubular scaffolds have emerged as a promising approach for the repair of ductal tissues, yet the development of scaffolds that balance exceptional mechanical properties with biocompatibility remains an ongoing challenge. This study introduces a novel, bio-fabricated bilayer bile duct scaffold using a 3D printing technique. The scaffold comprises an inner layer of polyethylene glycol diacrylate (PEGDA) to provide high mechanical strength, and an outer layer of biocompatible, methacryloylated recombinant collagen type III (rColMA) loaded with basic fibroblast growth factor (bFGF)-encapsulated liposomes (bFGF@Lip). This design enables the controlled release of bFGF, creating an optimal environment for the growth and differentiation of bone marrow mesenchymal stem cells (BMSCs) into cholangiocyte-like cells. These cells are instrumental in the regeneration of bile duct tissues, evidenced by the pronounced expression of cholangiocyte differentiation markers CK19 and CFTR. The PEGDA//rColMA/bFGF@Lip bilayer bile duct scaffold can well simulate the bile duct structure, and the outer rColMA/bFGF@Lip hydrogel can well promote the growth and differentiation of BMSCs into bile duct epithelial cells. In vivo experiments showed that the scaffold did not cause cholestasis in the body. This new in vitro pre-differentiated active 3D printed scaffold provides new ideas for the study of bile duct tissue replacement.
研究领域:
组织工程
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生物医学工程
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再生医学
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外科研究
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产品关联
DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
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2026
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IF 3.9
Zhen-ye Luo,Zhe Chen,Feng-lin Zhang,Chang-shun Liu,Fei-long Chen,Ze-zhong Zheng,Xiao-mei Tan
Bacterial diarrhea involves colonic water absorption dysfunction and gut microbiota disruption. Gegen Qinlian decoction (GQD) is clinically used to treat infectious diarrhea, yet its mechanisms remain incompletely understood. This study aimed to investigate how GQD modulates gut microbiota and enhances colonic water absorption in E. coli -induced diarrhea. Using an E. coli -induced piglet diarrhea model together with a rat colonic perfusion model, results show that GQD alleviates diarrhea-associated intestinal injury and inflammation and improves colonic water absorption. Mechanistically, GQD was associated with increased colonic aquaporin-3 (AQP3) expression and attenuation of the cAMP-protein kinase A-cystic fibrosis transmembrane conductance regulator (cAMP-PKA-CFTR) secretory signaling axis. 16S rRNA sequencing indicated enrichment of Lactobacillus amylovorus after GQD treatment, and administration of L. amylovorus partially reproduced the anti-diarrheal phenotype and transport-related signaling changes. In vitro assays further suggested that GQD suppresses E. coli growth while promoting L. amylovorus metabolic activity, and molecular docking provided hypothesis-generating predictions of candidate phytochemicals and bacterial targets. Overall, GQD may improve bacterial dysbiosis by enriching L. amylovorus and inhibiting E. coli , thereby restoring colonic water transport via the cAMP/CFTR/AQP3 pathway and ultimately improving bacterial diarrhea.
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DOI
高影响因子
JOURNAL OF INFECTION
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2022
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IF 38.637
Zhuo-Er Qiu,Lei Chen,Xiao-Chun Hou,Jie Sheng,Jian-Bang Xu,Jia-Wen Xu,Dong-Dong Gao,Ze-Xin Huang,Tian-Lun Lei,Zi-Yang Huang,Lei Peng,Hai-Long Yang,Qin-Hua Lin,Yun-Xin Zhu,Wei-Jie Guan,Zhao-Rong Lun,Wen-Liang Zhou,Yi-Lin Zhang
Summary Toxoplasma gondii is a widespread parasitic protozoan causing toxoplasmosis including pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii , the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl − concentration ([Cl − ] i ) was consequently elevated, leading to activation of nuclear factor-κB (NF-κB) signaling via serum/glucocorticoid regulated kinase 1. Furthermore, the heightened [Cl − ] i and activated NF-κB signaling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP level through NF-κB-mediated up-regulation of phosphodiesterase 4. Conversely, the sulfur-containing compound allicin conferred anti-inflammatory effects on pulmonary toxoplasmosis by decreasing [Cl − ] i via activation of CFTR. These results suggest that the intracellular Cl − dynamically modulated by T. gondii mediates sustained airway inflammation, which provides a potential therapeutic target against pulmonary toxoplasmosis.
研究领域:
传染病学
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免疫学
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呼吸病学
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寄生虫学
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产品关联
DOI
PubMed
高影响因子
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