International Journal of Biological Sciences
·
2022
·Vol. 18
·期 16
·6008-6019
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IF 10.75
Li Chao,Lv Li-fang,Qi-Li Mu-ge,Yang Rui,Wang Yu-jing,Chen Shuang-shuang,Zhang Ming-xiu,Li Tian-yu,Yu Tong,Zhou Yu-hong,Liang Hai-hai,Shan Hong-li,Li Xue-lian
Cardiac fibrosis is one of the common pathological processes in many cardiovascular diseases characterized by excessive extracellular matrix deposition. SerpinE2 is a kind of protein that inhibits peptidase in extracellular matrix and up-regulated tremendously in mouse model of cardiac fibrosis induced by pressure-overloaded via transverse aortic constriction (TAC) surgery. However, its effect on cardiac fibroblasts (CFs), collagen secretion and the underlying mechanism remains unclear. In this study, DyLight® 488 green fluorescent dye or His-tagged proteins were used to label the exogenous serpinE2 protein. It was showed that extracellular serpinE2 translocated into CFs by low-density lipoprotein receptor-related protein 1 (LRP1) and urokinase plasminogen activator receptor (uPAR) of cell membrane through endocytosis. Knockdown of LRP1 or uPAR reduced the level of serpinE2 in CFs and down-regulated the collagen expression. Inhibition of the endocytosis of serpinE2 could inhibit ERK1/2 and β-catenin signaling pathways and subsequently attenuated collagen secretion. Knockdown of serpinE2 attenuates cardiac fibrosis in TAC mouse. We conclude that serpinE2 could be translocated into cardiac fibroblasts due to endocytosis through directly interact with the membrane protein LRP1 and uPAR, and this process activated the ERK1/2, β-catenin signaling pathways, consequently promoting collagen production.
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Journal of Advanced Research
·
2022
·
IF 12.822
Weiwei Tao,Jie Ruan,Ruyan Wu,Min Zhao,Tong Zhao,Mingming Qi,Sonata S.Y. Yau,Guangda Yao,Hongru Zhang,Yue Hu,Gang Chen
Introduction Adult hippocampal neurogenesis (AHN) is acknowledged to play a critical role in depression. Emerging evidence suggests that the Wnt/β-catenin pathway can modulate hippocampal neurogenesis. Crocin, a natural carotenoid, possesses antidepressant property. Yet, how it affects neurogenesis and exerts antidepressant response remains unknown. Objective To explore the role of AHN and Wnt/β-catenin in the antidepressant action of crocin. Methods Depressive-related behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and sexual behaviors were performed following crocin treatment. Neurogenesis was characterized via immunohistochemistry, immunofluorescence, Golgi staining and electrophysiology approach. Wnt/β-catenin signaling was examined with western blot analysis. The role of AHN Wnt/β-catenin cascade in crocin’s antidepressant response was assessed by conditional removal of glial fibrillary acidic protein (GFAP)-expressing newborn neural cells, temozolomide administration, microinfusion of Dkk1 or viral-mediated shRNA of Wnt3a. Results Crocin decreased the immobility duration in TST and FST without impairing the performance in sexual behaviors. Crocin boosted the proliferation and differentiation of progenitors, and promoted dendritic maturation and functional integration of hippocampal newborn neurons. Conditional removal of GFAP-expressing neural cells or temozolomide administration impaired the antidepressant response of crocin. Additionally, Wnt/β-catenin signaling was promoted following crocin treatment. In chronic unpredictable mild stress (CUMS) murine model, crocin treatment displayed antidepressant response in SPT, FST and TST, and restored the neurogenesis levels and Wnt/β-catenin signaling impaired by CUMS. Infusion of Dickkopf-1 (DKK1) or knockdown of Wnt3a in the hippocampus impaired the antidepressant response of crocin. Conclusion Crocin exerted antidepressant response, which was dependent on enhancement of AHN and activation of the Wnt/β-catenin pathway.
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Aging-US
·
2021
·
IF 5.682
Feng Zhang,Feili Lin,Zhiwen Xu,Zheng Huang
Intervertebral disc degeneration (IDD) is the prevailing spine disorder and is associated with musculoskeletal disease. The extracellular matrix (ECM) degradation is an essential hallmark of IDD progression. Circular RNAs (circRNAs), as crucial cellular regulators, participate in multiple pathological processes including IDD. Here, we tried to explore the effect of circITCH on the ECM degradation of IDD and the underlying mechanism. Significantly, the expression levels of circITCH were elevated in the IDD patients’ nucleus pulposus (NP) tissues relative to that of normal cases. CircITCH promoted apoptosis and decreased proliferation of NP cells. CircITCH contributed to ECM degradation, as demonstrated by increased ADAMTS4 and MMP13 expression and decreased aggrecan and collagen II expression. Mechanically, miR-17-5p could be sponged by circITCH and miR-17-5p inhibited ECM degradation by repressing SOX4 in degenerative NP cells. CircITCH could activate Wnt/β-catenin pathway by targeting miR-17-5p/SOX4 signaling. SOX4 overexpression, miR-17-5p inhibitor, or Wnt/β-catenin signaling activator LiCl was able to reverse circITCH knockdown-inhibited apoptosis and ECM degradation, and circITCH knockdown-enhanced proliferation in NP cells. Thus, we conclude that circITCH promotes ECM degradation in IDD by activating Wnt/β-catenin through miR-17-5p/SOX4 signaling. Our finding presents novel insight into the mechanism that circITCH modulates the IDD progression. CircITCH and SOX4 may serve as potential targets for IDD therapy.
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Journal of Advanced Research
·
2023
·
IF 10.7
Wenjuan Tang,Yu Hu,Kaihui Tu,Zhengyan Gong,Man Zhu,Tianfeng Yang,Ammar Sarwar,Bingling Dai,Dongdong Zhang,Yingzhuan Zhan,Yanmin Zhang
Introduction Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. Objectives To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Methods Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Results Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. Conclusions These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 1
·74-85
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IF 2
Jianchao He,Yuhui Bu,Xiaolong Li,Xiaojun Zhang,Li Ma
Breast cancer (BC) is the most generally diagnosed cancer and the driving cause of cancer-related death. Transmembrane (TMEM) proteins have been reported to serve as prognostic indicators in a variety of cancers, and it can offer therapeutic targets for carcinoma. However, the function of TMEM in BC remains unclear. In this study, TMEM9A, a member of TMEM family, was screened as the candidate gene after analyzing the profiles of GSE42568 and GEPIA-BRCA database via bioinformatic method. The upregulated expression of TMEM9A was confirmed in BC samples compared with the paired normal tissues. Hence, we speculated that TMEM9A might promote BC progression. To test the hypothesis, we performed a series of loss/gain-of-function experiments and found that BC cells with TMEM9A deletion inhibited cell proliferation, migration, and invasion along with induced apoptosis. Conversely, TMEM9A overexpression reversed the trend. Mechanically, TMEM9A knockdown blocked the Wnt/β-catenin signaling pathway as evidenced by the increased adenomatous polyposis coli (APC) expression and decreased β-catenin, cyclin D1, and axis inhibition protein 2 (AXIN2) expression. Furthermore, over-activation of the Wnt/β-catenin pathway by transfecting BC cells with β-Catenin-S33Y (β-Catenin tyrosine for serine at codon 33) plasmids reversed the effects caused by TMEM9A knockdown. In conclusion, TMEM9A may play a tumor-promoting role in BC progression via activating the Wnt/β-catenin signaling pathway. Therefore, TMEM9A may be an effective therapeutic option for BC.
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Cell Death & Disease
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2024
·Vol. 15
·期 3
·1-16
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IF 8.1
Ma Lan,Zhou Xi,Yao Siyue,Zhang Xinyu,Mao Ji,Vona Barbara,Fan Liwen,Lou Shu,Li Dandan,Wang Lin,Pan Yongchu
Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m 6 A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3 -knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m 6 A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m 6 A-modified PSEN1 , while decreased METTL3-mediated m 6 A methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.
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Advanced Science
·
2025
·
IF 14.1
Xiaxia Fan,Dan Guo,Songtao Li,Jinmiao Tian,Chaotong Zhang,Zhuoyu Li
ABC transporter protein-mediated drug efflux is a significant contributor to induced resistance in breast cancer (BC). Novel therapies are therefore urgently needed to thwart chemoresistance. Herein, it is demonstrated that fusidic acid (FA) reduces the expression of ABC transporter proteins MRP1, P-gp, and BCRP, promotes the in vivo accumulation of agents, and exertes chemosensitizing effects. Further, DDX6 is identified as a direct target of FA by DARTS and biotin pull-down. Mechanistically, the results indicates that FA directly binds to H378 of DDX6, promotes its degradation, and downregulates its downstream p-GSK-3β, which in turn enhances the phosphorylation and ubiquitin-dependent hydrolysis of β-catenin S33/37/45/T41, blocks pro-resistance β-catenin signaling, and further prevents chemoresistance. The inhibitory effect of FA on chemoresistance is blocked following the knockout of DDX6 using CRISPR/Cas9. More importantly, FA also enhances the interaction between DDX6 and HSC70, while it facilitates DDX6 degradation via chaperone-mediated autophagy (CMA), thereby impairing the GSK-3β/β-catenin axis to enhance the efficacy of FA. Consistently, the effect of FA in combating chemoresistance by targeting DDX6 is evident in a xenograft mouse model. These findings reveal a direct protein target and molecular mechanism for FA to reverse chemoresistance, thus supporting the further development of FA as a chemosensitizing agent. Graphical FA directly binds to residue H378 of DDX6 and promotes its interaction with HSC70, leading to CMA degradation of DDX6, thereby impairing GSK-3β/β-catenin signaling, inhibiting ABC transporter proteins, and enhancing chemosensitivity.
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JOURNAL OF CELLULAR BIOCHEMISTRY
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2019
·Vol. 120
·期 10
·17273-17282
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IF 3.448
Min-yi Lv,Chuan-jian Shi,Fei-fei Pan,Jiang Shao,Lu Feng,Guoqin Chen,Caiwen Ou,Jin-fang Zhang,Wei-ming Fu
Consumption of dietary ellagitannins (ETs) has been proven to benefit multiple chronic health disorders including cancers and cardiovascular diseases. Urolithins, gut microbiota metabolites derived from ETs, are considered as the molecules responsible for these health effects. Previous studies have demonstrated that urolithins exhibit antiproliferative effects on prostate, breast, and colon cancers. However, as for hepatocellular carcinoma (HCC), it remains elusive. Herein, we aim to investigate the function of urolithin B (UB), a member of urolithins family, in HCC. The effects of UB on cell viability, cell cycle and apoptosis were evaluated in HCC cells, and we found UB could inhibit the proliferation of HCC cells, which resulted from cell cycle arrest and apoptosis. Furthermore, UB could increase phosphorylated β-catenin expression and block its translocation from nuclear to cytoplasm, thus inducing the inactivation of Wnt/β-catenin signaling. Using a xenograft mice model, UB was found to suppress tumor growth in vivo. In conclusion, our data demonstrated that UB could inhibit the proliferation of HCC cells in vitro and in vivo via inactivating Wnt/β-catenin signaling, suggesting UB could be a promising candidate in the development of anticancer drugs targeting HCC.
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BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
·
2019
·Vol. 66
·期 5
·787-793
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IF 1.559
Li Tao,Ying Gu,Jian Zheng,Jinkun Yang,Yingjie Zhu
Evidence suggests that Weichang'an (WCA) inhibited the metastasis of colorectal cancer (CRC) in vitro and downregulates oncogenic β-catenin; more intriguingly, we also found an upregulation of ARHGAP25 in this process. This study aimed to investigate the mechanisms by which WCA regulated CRC metastasis in vitro . Here, HCT116 cells were transfected with siRNAs to interfere ARHGAP25 expression. WCA decoction, XAV939 (a specific Wnt/β-catenin pathway inhibitor), and LiCl (an activator for Wnt/β-catenin pathway) were used for treatment. Cell migratory and invasive capacities were determined using Transwell chamber. The activation of Wnt/β-catenin pathway was assessed by determining the expression of MMP7, MMP9, ZEB1, and β-catenin. The study suggests that WCA inhibited the migration and invasion of HCT116 cells and suppressed the activation of Wnt/β-catenin pathway, as evidenced by retarding MMP7, MMP9, ZEB1, and β-catenin. However, siRNA–ARHGAP25 resulted in the opposite. In siRNA–ARHGAP25-transfected HCT116 cells, WCA (0.4 mg/mL) induced the antimetastatic effects and the inactivation of Wnt/β-catenin pathway was remarkably reversed with additional LiCl treatment. Our study concludes that inhibiting Wnt/β-catenin pathway while promoting ARHGAP25 was the mechanism, whereby WCA retarded migration and invasion of CRC in vitro .
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PHYTOMEDICINE
·
2025
·
IF 8.3
Yigong Chen,Jie Liang,Meiqiu Yan,Lan Xu,Fanxiang Jin,Mingting Jiang,Dorota Kołodyńska,Guiyuan Lv,Suhong Chen
Background Changfa Zirong Powder (CFZRS) is a traditional Chinese medicine (TCM) formula from Imperial Medicine Formulas , primarily used to treat hair loss. It consists of a mixture of ginseng powder and roasted ginger peel powder, which is applied topically by rubbing fresh ginger slices. Modified Changfa Zirong Powder (MCFZRS) replaces roasted ginger peel powder with whole ginger powder for better accessibility, while retaining ginseng powder. This study is the first to examine and compare the efficacy and mechanisms of TCM formulations in treating androgenetic alopecia (AGA), providing a modern perspective on an ancient formula. Unlike existing literature, which mainly focuses on individual components or synthetic drugs, this research validates how these formulations regulate the Wnt/β-catenin pathway. Additionally, it emphasizes the thermoregulatory effects of topical ginger and its potential to enhance drug delivery. Purpose This study aims to assess the effects of MCFZRS and CFZRS treatments on AGA in mice, concentrating on the Wnt/β-catenin signaling pathway. Methods Male mice were induced with AGA via dorsal hair removal and testosterone propionate injections. MCFZRS and CFZRS were applied topically for 30 days using fresh ginger slices to rub the powders onto the skin. The treatment efficacy was assessed through hair growth scoring, skin darkening, dermatoscopy, histopathology, and enzyme-linked immunosorbent assays to measure androgen levels. Additionally, the proteins involved in the Wnt/β-catenin signaling pathway were analyzed using immunohistochemistry, immunofluorescence, and Western blot. Results MCFZRS and CFZRS significantly improved AGA symptoms, promoting hair regrowth, skin darkening, hair shaft elongation, dermal thickness, and local hormonal balance, without altering systemic levels. Both treatments activated the Wnt/β-catenin pathway, resulting in the upregulation of β-catenin and protein phosphatase 2A expression. Conclusions MCFZRS and CFZRS improved androgen-related profiles and normalized α-melanocyte-stimulating hormone and vascular endothelial growth factor levels in AGA model skin. MCFZRS revealed comparable or superior effects on hair growth, dermal thickness, follicle preservation, and Wnt/β-catenin modulation. This modified formula offers a safer and more accessible approach to topical TCM, with potential for clinical translation.
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JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Chenxi Yan,Guilan Li,Lian Huang,Zhaohui Zhang
Beryllium (Be) is a recognised environmental toxicant associated with pulmonary fibrosis. Epithelial–mesenchymal transition (EMT), a critical process in cell phenotype conversion, plays a key role in its pathophysiology. Methyltransferase-like 3 (METTL3), a major N6-methyladenosine methyltransferase, regulates gene expression and cellular functions. However, its role in Be-induced EMT remains unclear. In this study, human bronchial epithelial cell line (16HBE cells) were exposed to varying concentrations of beryllium sulphate (BeSO 4 ) to assess changes in METTL3 expression. METTL3 overexpression vectors were constructed, and quantitative reverse transcription-polymerase chain reaction, western blotting and immunofluorescence were used to detect METTL3, EMT markers and Wingless/Integrated (Wnt)/β-catenin pathway proteins. The Wnt/β-catenin pathway inhibitor ICG-001 was also employed to explore the role of the Wnt/β-catenin pathway in BeSO 4 -induced EMT. The study demonstrated that BeSO 4 suppressed METTL3 expression, induced EMT and activated the Wnt/β-catenin pathway in 16HBE cells. Both METTL3 overexpression and ICG-001 pretreatment mitigated BeSO 4 -induced EMT and Wnt/β-catenin pathway activation. These findings suggest that METTL3 inhibits BeSO 4 -induced EMT by suppressing the Wnt/β-catenin pathway, offering novel mechanistic insights into beryllium toxicity and a potential therapeutic target for Be-related pulmonary fibrosis.
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APOPTOSIS
·
2025
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IF 8.1
Miao Jintian,Jiang Xinyan,Wang Siyun
Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.
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