BIOORGANIC CHEMISTRY
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2023
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IF 5.1
Xuchen Feng,Jun Ge,Hui Fu,Lin Miao,Feng Zhao,Jingyu Wang,Yujiao Sun,Yingpeng Li,Yunfei Li
Small molecules directly downregulating β-catenin could potentially offer a more effective therapeutic approach for combating against cancer stem cells, as compared to targeting the downstream components of the Wnt/β-catenin pathway. The challenge, however, lies in the fact that very few β-catenin suppressors have proven clinically effective, leaving a significant gap in medical solutions. Given that E-cadherin has a natural affinity for β-catenin, it stands to reason that agents designed to increase E-cadherin expression might provide an alternative method of regulating β-catenin levels. In this study, we report our discovery of DSS-C12 and DSS-B8, specific ester-based drugs derived from Dan-Shen-Su (DSS) extracted from the herb Salvia miltiorrhiza . Remarkably, these compounds display a potent ability to downregulate β-catenin, while also improving overall survival in post-surgery mice. Additionally, when these drugs are used in combination with PD-L1 checkpoint blockade, they stimulate enhanced systemic immune responses leading to significant suppression of primary tumor growth. In-depth mechanistic studies revealed that DSS-B8 functions as a vitamin D receptor agonist without inducing hypercalcemic effects. Collectively, our findings indicate that DSS-derived small molecules have considerable potential as clinically viable therapeutic strategies for β-catenin deactivation.
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Frontiers in Bioscience-Landmark
·
2020
·Vol. 25
·期 3
·549-563
·
IF 2.747
Jun Shi,Qiuwei Zhu,Jianbo Wu,Ping Zhu
Gastric cancer (GC) is the most common cancer with a poor prognosis and the third leading cause of cancer death in the world, for which no effective therapeutic target exists. We tested the hypothesis that FAM46C might be involved in regulation of proliferation and apoptosis in GC. FAM46C was down-regulated and its expression negatively correlated with the expression of β-catenin that drives proliferation and apoptosis. Overexpression of FAM46C inhibited cell proliferation, induced G1 phase arrest and promoted apoptosis. Activation of Wnt/β-catenin signaling pathway in GC cell lines quenched the effect of FAM46C overexpression. On the other hand, FAM46C silencing attenuated DKK1-mediated inhibition of G1 phase, cessation of proliferation and induction apoptosis. Together, these data show that FAM46C shows tumor suppressor properties and such effects are mediated, at least in part, by Wnt/β-catenin in GC.
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Frontiers in Pharmacology
·
2020
·
IF 4.225
Jin Yinshan,Liu Jiannan,Liu Yadong,Liu Yang,Guo Guiying,Yu Shiliang,An Ruihua
Aims: Oxymatrine (OMT) has been identified to possess immunomodulatory, antiinflammatory and anticancer properties. This study aimed to investigate its precise function and the underlying molecular mechanisms in renal cell carcinoma progression.Methods: The antineoplastic effect of oxymatrine was investigated by CCK-8 assay, cell cycle analysis, apoptosis assay, wound healing experiment, transwell assay, and drug-sensitivity analysis in renal cancer cells following oxymatrine treatment. The modulation of oxymatrine on β-catenin was analyzed through western blot and immunofluorescence assay. β-catenin overexpression was employed to determine the key role of β-catenin in oxymatrine-inhibited renal cell carcinoma in vitro. In addition, animal model was established to investigate the effect of oxymatrine on tumor growth in vivo.Results: Oxymatrine inhibited renal cell carcinoma progression in vitro, including cell proliferation, apoptosis, migration, invasion and chemotherapy sensitivity. Further mechanistic studies demonstrated that oxymatrine exerted its antineoplastic effect through suppressing the expression of β-catenin. Moreover, in nude mice model, oxymatrine exhibited remarkable inhibition of tumor growth, which was consistent with our in vitro results.Conclusions: Our findings illuminate oxymatrine as an effective antitumor agent in renal cell carcinoma, and suggest it a promising therapeutic application in renal cell carcinoma treatment.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2018
·Vol. 42
·期 1
·61-70
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IF 2.784
Yuhuan Ma,Wenwei Zheng,Houhuang Chen,Xiang Shao,Pingdong Lin,Xianxiang Liu,Xihai Li,Hongzhi Ye
The present study investigated the mechanism underlying the effects of glucosamine (GlcN) on the proliferation of chondrocytes isolated from the knee cartilage of Sprague‑Dawley rats. Chondrocytes were treated with various concentrations of GlcN or without GlcN. The effects of GlcN on chondrocyte proliferation were determined using reverse transcription‑polymerase chain reaction, western blot analysis and immunohistochemistry. The results indicated that GlcN significantly improved chondrocyte viability, accelerated G1/S transition during progression of the cell cycle and promoted the expression of cell cycle regulatory proteins, including cyclin D1, cyclin‑dependent kinase (CDK)4 and CDK6, thus indicating that GlcN may promote chondrocyte proliferation. Furthermore, GlcN upregulated the expression levels of Wnt‑4, Frizzled‑2 and β‑catenin, and downregulated the expression of glycogen synthase kinase‑3. GlcN also promoted β‑catenin translocation; β‑catenin is able to activate numerous downstream target genes, including cyclin D1. To determine the role of the Wnt/β‑catenin signaling pathway in chondrocyte proliferation, the Wnt/β‑catenin signaling pathway was inhibited using Dickkopf‑1 (DKK‑1), after which chondrocytes were treated with GlcN. The results demonstrated that the expression levels of β‑catenin and cyclin D1 were decreased in chondrocytes treated with DKK‑1 and GlcN. These results suggested that GlcN may promote chondrocyte proliferation via the Wnt/β‑catenin signaling pathway.
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Frontiers in Pharmacology
·
2025
·
IF 4.8
Eryang Chen,Lei Wang,Qu Wang,Yan Cai,Yaning Dou,Hongyan Qu,Junyi Zhu,Haiyang Zhao,Suqing Zheng,Chengguang Zhao,Bin Chen
Background: Psoriasis, an immune-mediated chronic inflammatory skin disease, is characterized by keratinocyte proliferation and inflammatory cell infiltration. T ripterygium wilfordii is a potential treatment option for psoriasis, and triptolide (TP) is one of its active components. TP may possess the potential to treat psoriasis; however, its mechanism of action remains unknown.Objective: The research aims to explore the therapeutic effect of TP on psoriasis and elucidate its potential targets.Methods: The imiquimod-induced psoriasis-like lesion mouse model was used to identify the mechanism underlying the therapeutic effect of TP.RNA-seq strategy was utilized to forecast the targets and mechanisms of TP in the context of psoriasis.Finally, we verify the effect of TP in the IL-17A-induced keratinocyte hyperproliferation and inflammation model.Results: TP reduced epidermal hyperplasia as well as psoriasis area and severity index scoring. Moreover, treatment with TP inhibited IMQ-induced splenomegaly and T-helper 17 cell differentiation in the psoriatic mice. Additionally, the treatment reduced the serum levels of pro-inflammatory cytokines such as interleukin (IL)-17A, IL-22, IL-23, IL-6, and tumor necrosis factor-α in the mice. The sequencing of RNA obtained from skin lesions of the psoriatic mice indicated that treatment with TP significantly downregulated Wnt5a RNA levels. Moreover, the Wnt5a/β-catenin pathway upregulated by IMQ was downregulated by treatment with TP. Additionally, IL-17A induced and upregulated Wnt5A and β-catenin mRNA expression, and TP inhibited this upregulated expression in HaCaT cells. Furthermore, TP inhibited proliferation, promoted apoptosis, and arrested the cell cycle in the IL-17A-induced keratinocyte hyperproliferation and inflammation model, thereby exhibiting its anti-inflammatory properties.Conclusion: TP alleviated psoriasis in mice by exerting anti-inflammatory effects and inhibited keratinocyte proliferation, which was partly achieved by regulating the Wnt5a/β-catenin signaling pathway.
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THERIOGENOLOGY
·
2023
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IF 2.8
Xuan Ren,Jianchun Xu,Qingsong Xue,Yi Tong,Tairan Xu,Jinli Wang,Ting Yang,Yuan Chen,Deshun Shi,Xiangping Li
Brahma-related gene 1 (BRG1) enhances the pluripotency of embryonic and adult stem cells , however, its effect on induced pluripotent stem cell (iPSC) pluripotency has not been reported. The aim of this study was to investigate the effect of BRG1 on porcine iPSC pluripotency and its mechanisms. The effect of BRG1 on porcine iPSC pluripotency was explored by positive and negative control it. The mechanism was investigated by regulating the WNT/β-catenin signaling pathway and autophagy flux. The results showed that inhibition of BRG1 decreased pluripotency-related gene expression in porcine iPSCs; while its overexpression had the opposite effect, the expression of WNT/β-catenin signaling pathway- and autophagy-related genes was significantly up-regulated ( P < 0.05) in the BRG1 overexpressed group when compared to the control group. Inhibited pluripotency-related gene or protein expression , decreased autophagy flux, and increased mitochondrial length and mitochondrial membrane potential (MMP) were observed when porcine iPSCs were treated with the WNT/β-catenin signaling pathway inhibitor IWR-1. Forced BRG1 expression restored porcine iPSC pluripotency, increased autophagy flux, shortened mitochondria, and reduced MMP. Lastly, Compound C was used to activate porcine iPSC autophagy, and it was found that the expression of BRG1 and β-catenin increased, and pluripotency-related gene and protein expression was up-regulated; these effects were reversed when the BRG1 inhibitor PFI-3 and IWR-1 were added. These results suggested that BRG1 enhanced the pluripotency of porcine iPSCs through WNT/β-catenin and autophagy pathways.
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Cells
·
2025
·Vol. 14
·期 6
·394
·
IF 5.2
Min Jiang,Jiaqi Hou,Qianqian Chai,Shihao Yin,Qian Liu
Pulmonary fibrosis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the leading cause of death in patients with COVID-19. β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, has been shown to be involved in the development of pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, silicosis). In this study, we developed a SARS-CoV-2-infected A549-hACE2 cell model to evaluate the efficacy of the A549-hACE2 monoclonal cell line against SARS-CoV-2 infection. The A549-hACE2 cells were then subjected to either knockdown or overexpression of the effector β-catenin, and the modified cells were subsequently infected with SARS-CoV-2. Additionally, we employed transcriptomics and raw letter analysis approaches to investigate other potential effects of β-catenin on SARS-CoV-2 infection. We successfully established a model of cellular fibrosis induced by SARS-CoV-2 infection in lung-derived cells. This model can be utilized to investigate the molecular biological mechanisms and cellular signaling pathways associated with virus-induced lung fibrosis. The results of our mechanistic studies indicate that β-catenin plays a significant role in lung fibrosis resulting from SARS-CoV-2 infection. Furthermore, the inhibition of β-catenin mitigated the accumulation of mesenchymal stroma in A549-hACE2 cells. Additionally, β-catenin knockdown was found to facilitate multi-pathway crosstalk following SARS-CoV-2 infection. The fact that β-catenin overexpression did not exacerbate cellular fibrosis may be attributed to the activation of PPP2R2B.
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CELL BIOLOGY INTERNATIONAL
·
2023
·
IF 3.9
Hongyang Xie,Junyu Chen,Changyan Ma,Jingjing Zhao,Manhua Cui
Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial–mesenchymal transition by inducing the nuclear transport of β-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that β-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of β-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the β-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.
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Biochemistry and Cell Biology
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2025
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IF 2.1
Hongyu Wang,Liyang Liang,Yanfei Wang,Xuan Zhong,Chao Zhang,Zhipeng Liu,Jinzhong Liu,Wanning Hu
WD repeat domain 4 (WDR4) has been reported to promote tumor metastasis in various cancers. However, its precise function in colorectal cancer (CRC) has not been reported yet. Herein, the expression pattern of WDR4 in CRC was determined by analyzing Gene Expression Omnibus datasets (GSE110225, GSE127069, GSE156355, and GSE184093) and GEPIA online dataset. In vitro and in vivo experiments, including CCK-8, colony formation, flow cytometry, wound healing, transwell assays, and xenograft mouse models, were used to investigate the role of WDR4 in CRC. Firstly, data from Kaplan–Meier database showed that high expression of WDR4 was associated with the poor prognosis of CRC patients. Then, upregulation of WDR4 was confirmed in clinical CRC tissues. In vitro functional experiments suggested that overexpression of WDR4 promoted cell proliferation, migration, and invasion, while knockdown of WDR4 has the opposite effects. Also, the oncogenic role of WDR4 was also verified in in vivo experiments. CO-IP-LC/MS analysis uncovered that glycogen synthase kinase 3β (GSK3β) is the central protein that binds to WDR4. Mechanistically, WDR4 activated the β-catenin pathway by promoting GSK3β phosphorylation. This study demonstrates that WDR4 promotes CRC progression through activating GSK3β/β-catenin pathway, indicating that WDR4 might be a potential therapeutic target for CRC treatment.
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MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Zhang Pan,Sun Xuelin,Liu Longteng,Zhang Yatong,Bo Jiaqi,Huang Wenli,Na Yifan,Zhang Jingyi,Qin Xiaoyun,Luo Qingfeng
Gastric precancerous lesions (GPLs) are a pivotal stage in the gastritis-gastric cancer sequence, and the absence of effective treatments presents a clinical challenge. Veratramine is a natural anti-inflammatory and analgesic steroid alkaloid; however, its effects on GPLs and the mechanisms have remained unexplored. This study investigated the effects of veratramine on GPLs using 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced GES-1 cells and rat models, utilizing RNA-seq to elucidate the underlying mechanisms. In vitro, veratramine inhibited malignant cells (MC) proliferation, induced apoptosis, and triggered G0/G1 cell cycle arrest. It also suppressed epithelial-mesenchymal transition (EMT), migration, and invasion by upregulating E‑cadherin and downregulating Slug and vimentin. Transcriptomic and molecular docking analyses highlighted the Wnt/β-catenin pathway as a key target, regulated via DDX60, MUC1, APOL1, and MSH5. Veratramine reduced Wnt10B, β-catenin, and cyclin D1 expression and blocked β‑catenin nuclear translocation; these effects were reversed by the Wnt activator BML-284. In vivo, treatment with veratramine ameliorated the GPLs-induced pathological changes in rats. It restored body weight and preserved gastric mucosal integrity, as evidenced by intact glandular and cellular morphology, reduced hyperplasia, and attenuated intestinal metaplasia. These improvements were associated with a modulation of key molecular markers, specifically a decrease in the expression of N-cadherin, Wnt10B, and β-catenin, alongside an increase in E-cadherin expression in gastric tissues. These results collectively indicate that veratramine exerts its therapeutic effects against GPLs primarily by suppressing the Wnt/β-catenin signaling pathway. Taken together, our findings suggest that veratramine is a promising candidate small-molecule drug for the treatment of GPLs.
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INTERNATIONAL DENTAL JOURNAL
·
2026
·Vol. 76
·期 5
·109801
·
IF 5.2
Yumeng Yang,Xin Li,Qianwen Tang,Chengfei Zhang,Zehao Chen,Wei Liu
Aim Punicalagin (PCG), a natural polyphenol derived from pomegranate peel, possesses well-established antibacterial and anti-inflammatory properties. However, whether PCG promotes odontogenic differentiation of human dental pulp stem cells (DPSCs) remains unclear. This study investigated the effects of PCG on odontogenic differentiation and reparative dentin formation and further explored the underlying molecular mechanism. Methods A rat pulpitis model was established to evaluate the effects of a PCG-loaded collagen sponge on pulpal repair. Pulpal inflammation and reparative dentin formation were assessed histologically. DPSCs were isolated and treated with PCG (5 μM). Cell viability, odontogenic differentiation, and Wnt/β-catenin signalling were evaluated using CCK-8, alkaline phosphatase (ALP) and Alizarin Red S staining, quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, and DKK-1 inhibition assays. Results PCG application significantly reduced inflammatory infiltration and stimulated reparative dentin formation in the rat pulpitis model. At the cellular level, PCG enhanced the odontogenic differentiation of DPSCs and upregulated key odontogenic markers (ALP, Runx2, DMP-1, and DSPP) at both the gene and protein levels. Mechanistically, PCG promoted the nuclear translocation of β-catenin, consistent with activation of the canonical Wnt/β-catenin signalling pathway. The pro-odontogenic effects of PCG were largely attenuated by DKK-1–mediated inhibition of canonical Wnt signalling. Conclusion PCG promoted the odontogenic differentiation of DPSCs at least in part through activation of the Wnt/β-catenin signalling pathway. These findings identify PCG as a promising modulator of odontogenic differentiation and provide mechanistic evidence supporting its further investigation for dentin-pulp repair. Clinical relevance These findings provide a biological rationale for further investigation of PCG-containing strategies for vital pulp therapy.
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Cell Death Discovery
·
2026
·
IF 10.4
Wang Wei,Wang Hui,Liu Yihan,Cui Siyuan,Tang Chuanxi,Wang Mengxue,Mu Chunyan,Li Jingyu,Ye Xianlong,Liang Xinmiao,Zhu Shenglong
The escalating global burden of metabolic diseases including obesity, type 2 diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD)-highlights an urgent need to identify new therapeutic targets. Although elevated hepatic de novo lipogenesis (DNL) is a hallmark of metabolic dysfunction, targeting its core transcriptional and enzymatic components has proven clinically challenging. Here, using a multi-model comparative transcriptomic strategy, we identify ubiquitin-specific protease 2 (Usp2) as a consistently upregulated gene strongly correlated with steatosis severity. Functional studies demonstrate that Usp2 promotes hepatic lipid accumulation both in vitro and in vivo. Mechanistically, Usp2 directly interacts with the RNA-binding protein G3bp2 and stabilizes it via K63-linked deubiquitination, leading to activation of β-catenin signaling and subsequent upregulation of key lipogenic genes, including Fasn, Scd1, and Plin2. These findings establish the Usp2-G3bp2-β-catenin axis as a previously unrecognized regulatory pathway driving hepatic lipogenesis and nominate Usp2 as a potential therapeutic target in metabolic disease.
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