6 results on '"Fan, Jinjin"'
Search Results
2. A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42‐mediated GSK‐3β/β‐catenin Signaling.
- Author
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Hu, Xinrong, Gan, Lu, Tang, Ziwen, Lin, Ruoni, Liang, Zhou, Li, Feng, Zhu, Changjian, Han, Xu, Zheng, Ruilin, Shen, Jiani, Yu, Jing, Luo, Ning, Peng, Wenxing, Tan, Jiaqing, Li, Xiaoyan, Fan, Jinjin, Wen, Qiong, Wang, Xin, Li, Jianbo, and Zheng, Xunhua
- Subjects
RENAL fibrosis ,CATENINS ,SMALL molecules ,CHRONIC kidney failure ,KIDNEY diseases ,CELL cycle proteins - Abstract
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay‐guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti‐renal fibrotic lead. DA shows significant anti‐kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down‐regulates its downstream phospho‐protein kinase Cζ(p‐PKCζ)/phospho‐glycogen synthase kinase‐3β (p‐GSK‐3β), thereby promoting β‐catenin Ser33/37/Thr41 phosphorylation and ubiquitin‐dependent proteolysis to block classical pro‐fibrotic β‐catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation
- Author
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Wang Xin, Ning Luo, Fan Jinjin, Xiaoyan Li, Qiong Wen, and Shaozhen Feng
- Subjects
Models, Molecular ,0301 basic medicine ,Pyridines ,Recombinant Fusion Proteins ,Ubiquitin-Protein Ligases ,Amino Acid Motifs ,Kidney ,Ligands ,urologic and male genital diseases ,Biochemistry ,Pentapeptide repeat ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ubiquitin ,Western blot ,Cell Line, Tumor ,MG132 ,medicine ,Renal fibrosis ,Humans ,Protein Interaction Domains and Motifs ,Molecular Targeted Therapy ,Smad3 Protein ,Renal Insufficiency, Chronic ,Benzofurans ,Pharmacology ,Binding Sites ,biology ,medicine.diagnostic_test ,Ubiquitination ,Surface Plasmon Resonance ,Hypoxia-Inducible Factor 1, alpha Subunit ,Fibrosis ,Molecular biology ,Peptide Fragments ,Ubiquitin ligase ,Cell biology ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Drug Design ,030220 oncology & carcinogenesis ,Proteolysis ,Proteasome inhibitor ,biology.protein ,Target protein ,medicine.drug - Abstract
Purpose Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel–Lindau (VHL) ubiquitin ligase (E3). Methods Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC’s specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL − ) and ACHN (VHL + ), and its anti-fibrosis effect was tested in renal fibrosis cell models. Results Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 ( K D = 4.547 × 10 −5 M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-β1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. Conclusion The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation.
- Published
- 2016
4. Combined Blockade of Smad3 and JNK Pathways Ameliorates Progressive Fibrosis in Folic Acid Nephropathy.
- Author
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Jiang, Mengjie, Fan, Jinjin, Qu, Xinli, Li, Songhui, Nilsson, Susan K., Sun, Yu Bo Yang, Chen, Yaping, Yu, Di, Liu, Dan, Liu, Bi-Cheng, Tang, Mingliang, Chen, Wei, Ren, Yi, Nikolic-Paterson, David J., Jiang, Xiaoyun, Li, Jinhua, and Yu, Xueqing
- Subjects
FOLIC acid ,FIBROSIS ,RENAL fibrosis - Abstract
Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signaling pathways promote interstitial fibrosis; however, effective suppression of fibrosis may require blockade of more than one pathway. This study investigated whether blockade of Smad3 and c-Jun N-terminal kinase (JNK) signaling gives added suppression of interstitial fibrosis in folic acid nephropathy. A single high dose of folic acid (FA) causes acute tubular damage in C57BL/6J mice followed by interstitial fibrosis and chronic renal impairment. Co-activations of Smad3 and JNK signaling occur in both tubular epithelial cells and myofibroblasts in areas of tubulointerstitial damage and fibrosis in both murine FA-induced nephropathy and human IgA nephropathy. Groups of mice were treated with a Smad3 inhibitor (SIS3), a JNK inhibitor (SP600125), or a combination from day 6 after FA administration until being killed on day 28. Each drug efficiently inhibited its specific target (Smad3 phosphorylation or c–Jun phosphorylation) without affecting the other pathway. Given alone, each drug partially reduced renal fibrosis, whereas the combination therapy gave an additive and profound protection from renal fibrosis and improved renal function. Inhibition of Smad3 and/or JNK signaling activities prevented down-regulation of PGC-1α in tubular epithelial cells and up-regulation of PGC-1α in myofibroblasts during FA-induced renal fibrosis and inflammation. The expression of PGC-1α was upregulated in Smad3
−/− NRK52E cells while downregulated in Smad3−/− NRK49F cells, suggesting that Smad3 signaling may regulate expression of PGC-1α in renal tubular epithelial cells and fibroblasts in distinct fashion. In vivo and cell culture studies also indicate that Smad3 and JNK signaling cooperate to cause mitochondrial dysfunction and cell damage in tubular epithelial cells via direct actions on the transcription of PGC-1α. These pathways also act cooperatively to promote renal fibroblast proliferation in tempo-spatial fashion. In conclusion, we have identified a potential combination therapy for progressive renal fibrosis which operates, in part, through modifying mitochondrial function. [ABSTRACT FROM AUTHOR]- Published
- 2019
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5. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G 2 /M arrest and renal fibrosis.
- Author
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Li, Huiyan, Peng, Xuan, Wang, Yating, Cao, Shirong, Xiong, Liping, Fan, Jinjin, Wang, Yihan, Zhuang, Shougang, Yu, Xueqing, and Mao, Haiping
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- 2016
- Full Text
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6. Altered tight junctions and fence function in NRK-52E cells induced by aristolochic acid.
- Author
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Liu, Mei, Yang, Xiao, Fan, Jinjin, Zhang, Rui, Wu, Jun, Zeng, Youjia, Nie, Jing, and Yu, Xueqing
- Subjects
TIGHT junctions ,ARISTOLOCHIA ,RENAL fibrosis ,CELL-mediated cytotoxicity ,CELL culture - Abstract
Aristolochic acid (AA) can accumulate in the tubulointerstitium and cause kidney-specific injuries. However, the mechanism by which AA induces nephropathy remains largely unknown. This study explored the effect of AA-I on tight junctions (TJs), and the fence function in a renal epithelial cell (REC). NRK-52E cells were exposed to different concentrations of AA-I for 4 h or 25 μM AA-I for different time. Cell viability was detected by MTT, cell apoptosis by flow cytometric analysis, the expression of zonula occludens-1 (ZO-1), E-cadherin and polarity scaffold (Par3) by western blot and immunofluorescence, cell membrane permeability by transepithelial electrical resistance (TEER). It was found that AA-I reduced the expression of ZO-1, E-cadherin, and Par3 in a concentration- and time-dependent fashion, and altered the distribution of ZO-1 and Par3 from cell membrane to cell plasma. In parallel to the reduced expression of TJ proteins, TEER exhibited a significant reduction in response to AA-I treatment in a time- and concentration-dependent manner. Meanwhile, α-SMA expression in cells was increased following AA-I treatment. In contrast, cell viability and apoptosis were unaltered with the doses of AA-I tested. Our findings show for the first time that AA-I treatment in cultured RECs induced a rapid disruption of TJ and the fence function preceding apoptosis, which indicated that aberrant expression of TJ proteins within RECs may be involved in initiating the renal tubulointerstitial disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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