WORLD JOURNAL OF GASTROENTEROLOGY
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2015
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IF 2.369
Gui-Li Huang,Dong-Yan Shen,Cheng-Fu Cai,Qiu-Yan Zhang,Hong-Yue Ren,Qing-Xi Chen
AIM: To develop a safe and effective agent for cholangiocarcinoma (CCA) chemotherapy. METHODS: A drug combination experiment was conducted to determine the effects of β-escin in combination with chemotherapy on CCA cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was performed to determine the effects of β-escin and common chemotherapeutics on the proliferation of human CCA cells (QBC939, Sk-ChA-1, and MZ-ChA-1). Immunocytochemistry was used to detect the expression of P-glycoprotein (P-gp) protein. Luciferase reporter assay was used to detect the activation of the Wnt/β-catenin pathway. The protein levels of P-gp, pS9-GSK3β, pT216-GSK3β, GSK3β, β-catenin, and p-β-catenin were further confirmed by western blotting. RESULTS: The drug sensitivity of QBC939 and QBC939/5-fluorouracil (5-FU) cells to 5-FU, vincristine sulfate (VCR), or mitomycin C was significantly enhanced by β-escin compared with either agent alone ( P < 0.05). In addition, the combination of β-escin (20 μmol/L) with 5-FU and VCR was synergic with a combination index < 1. Further investigation found that the mRNA and protein expression of P-gp was down-regulated by β-escin. Moreover, β-escin induced GSK3β phosphorylation at Tyr-216 and dephosphorylation at Ser-9, resulting in phosphorylation and degradation of β-catenin. Interestingly, activation of the GSK3β/β-catenin pathway induced by Wnt3a resulted in up-regulation of P-gp, which was effectively abolished by β-escin, indicating that β-escin down-regulated P-gp expression in a GSK3β-dependent manner. CONCLUSION: β-escin was a potent reverser of P-gp-dependent multidrug resistance, with said effect likely being achieved via inhibition of the GSK3β/β-catenin pathway and thus suggesting a promising strategy of developing combination drugs for CCA.
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JOURNAL OF CELLULAR PHYSIOLOGY
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2024
·
IF 4.5
Zhiguang Chen,Qi Zhao,Lianghong Chen,Songlan Gao,Lingshuai Meng,Yingjie Liu,Yu Wang,Tiegang Li,Jinqi Xue
Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating β-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and β-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, β-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with β-catenin/TCF4 to enhance β-catenin/TCF4's function and activate LRP5-activated β-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2018
·Vol. 22
·期 7
·3514-3525
·
IF 4.302
Wenhui Cui,Zhihui Zhang,Panpan Zhang,Jiao Qu,Cheng Zheng,Xiaoting Mo,Wencheng Zhou,Liang Xu,Hongwei Yao,Jian Gao
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and abnormal inflammatory response. Wnt/β-catenin and AMP-activated protein kinase (AMPK) have been shown to modulate lung inflammatory responses and injury. However, it remains elusive whether Wnt/β-catenin and AMPK modulate nuclear factor erythroid-2 related factor-2 (Nrf2)-mediated protective responses during the development of emphysema. Here we showed that treatment with a Wnt pathway activator (LiCl) reduced elastase-induced airspace enlargement and cigarette smoke extract (CSE)-induced lung inflammatory responses in WT mice, which was associated with increased activation of Nrf2 pathway. Interestingly, these effects of LiCl were not observed in Nrf2 −/− mice exposed to elastase. In normal human bronchial epithelial (NHBE) cells, Wnt3a overexpression up-regulated, whereas Wnt3a knockdown further down-regulated the levels of Nrf2 and its target proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by CSE treatment. In contrast, Nrf2 deficiency did not have any effects on Wnt/β-catenin pathway in mouse lungs and NHBE cells. Both elastase and CSE exposures reduced AMPK phosphorylation. A specific AMPK activator metformin increased Wnt3a, β-catenin, Nrf2 phosphorylation and activation but reduced the levels of IL-6 and IL-8 in NHBE cells and mouse lungs exposed to CSE. Furthermore, Nrf2 deficiency abolished the protection of metformin against CSE-induced increase in IL-6 and IL-8 in NHBE cells. In conclusion, Nrf2 mediates the protective effects of both Wnt3a/β-catenin and AMPK on lung inflammatory responses during the development of COPD/emphysema. These findings provide potential therapeutic targets for the intervention of COPD/emphysema.
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Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Mengyi Yan,Xiayun Chen,Xiaotong Li,Qianqian Liu,Baixue Yu,Yi Cen,Wei Zhang,Yibin Liu,Xinxuan Li,Ying Chen,Tao Wang,Shiying Li
The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments. In this work, a transferrin receptor (TfR) targeted immunostimulant (PTI) is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β -catenin signal pathway. To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001. On the one hand, the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumor-associated antigens. On the other hand, PTI will interrupt the binding between β -catenin and cAMP response element-binding protein (CREB), regulating the gene transcription to downregulate programmed death ligand 1 (PD-L1) while upregulating C–C motif chemokine ligand 4 (CCL4). Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.
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Frontiers in Pharmacology
·
2025
·
IF 4.8
Zhize Liu,Weitao He,Jingwei Zhang,Bo Su,Jiang Mu,Xintao Wang
Introduction: Paederia scandens (Lour.) Merr. (P. scandens), a widely consumed edible wild botanical drug in East Asia, has traditionally been used in folk medicine for its purported health-promoting effects, including the relief of fractures, rheumatoid arthritis, and pain. Despite its common use, the bioactive metabolites and underlying mechanisms of action remain insufficiently understood. This study investigates the pharmacological effects and molecular mechanisms of P. scandens in the context of osteoporosis.Methods: An ovariectomized (OVX) rat model of osteoporosis was used to evaluate the effects of P. scandens extract on bone health. Network pharmacology analysis identified candidate metabolites related to osteoblast differentiation. Paederoside, the primary plasma-absorbed metabolite, was validated in OVX rats via HPLC-Q-TOF-MS. In vitro experiments assessed osteogenesis and osteoclast activity using an osteoblast-osteoclast co-culture system, while in vivo studies evaluated serum calcium and phosphorus levels, bone morphology, and bone mass.Results: P. scandens extract significantly improved bone mass, bone mineral density (BMD), and the trabecular bone microstructure in the OVX rat model. Paederoside promoted osteogenesis and suppressed osteoclast activity in vitro. In vivo, paederoside demonstrated pronounced anti-osteoporotic effects, as evidenced by elevated serum calcium and phosphorus levels, improved bone morphology, and increased bone mass. Paederoside upregulated osteogenesis-related markers (BMP2, Smad1, Col1a1, Bglap, Osterix, and Runx2) and downregulated osteoclastogenesis-related markers (RANKL, NFATc1, Acp5, Ctsk, and Mmp9). Transcriptomic analysis revealed that paederoside modulated the Wnt/β-catenin signaling pathway, inducing Wnt3a expression, inhibiting GSK-3β and β-catenin phosphorylation, and upregulating downstream targets such as Cyclin D1 and c-Myc.Discussion: In conclusion, P. scandens exerts protective effects against osteoporosis, and paederoside, identified as a primary plasma-absorbed metabolite, enhances osteoblastogenesis and suppresses osteoclastogenesis, likely through the upregulation of the Wnt/β-catenin signaling pathway. This study elucidates the health benefits of P. scandens and paederoside in the prevention and treatment of osteoporosis.
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CURRENT ISSUES IN MOLECULAR BIOLOGY
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2026
·Vol. 48
·期 10
·1066
·
IF 4.1
Taomei Yang,Xiangyun Chen,Chunwei Chu,Yonghu Wan
Limited docetaxel efficacy in triple-negative breast cancer (TNBC) necessitates chemosensitizers. Baicalein is a potential chemosensitizer, but its synergy with docetaxel in TNBC is unclear. Here, we investigated the combined effects and underlying mechanisms. The concentrations of baicalein (80 μM) and docetaxel (20 nM) were tested on TNBC cells; synergy was assessed by CCK-8 and Chou–Talalay analysis. Proliferation, migration, invasion, and apoptosis were assessed by colony formation, wound healing, Transwell, Matrigel, and flow cytometry assays. Protein levels of p-AKT, p-GSK3β and β-catenin were determined by western blot, and HSP90AA1 mRNA by qPCR. Baicalein–HSP90AA1 binding was analyzed by molecular docking. The prognostic value of HSP90AA1 was analyzed by Kaplan–Meier Plotter. The combination exhibited synergistic anti-tumor activity (CI < 0.9), significantly suppressed proliferation, migration and invasion, and enhanced apoptosis. Mechanistically, the combination reduced p-AKT, p-GSK3β, and β-catenin protein levels without affecting HSP90AA1 mRNA. Molecular docking indicated a potential interaction between baicalein and HSP90AA1. High HSP90AA1 expression correlated with shorter distant metastasis-free survival (HR = 1.71,p= 0.0046) and worse overall survival (HR = 2.15,p= 0.021). Thus, baicalein synergizes with docetaxel to suppress TNBC in vitro, accompanied by suppression of AKT/GSK3β/β-catenin signaling, potentially through interaction with HSP90AA1, a proposed upstream target.
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INTERNATIONAL UROLOGY AND NEPHROLOGY
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2026
·
IF 2.2
Liu Hong,Zhang Shuang,Zhao Xiu‑Nan,Wang Zhen‑Zhen,Song Jia‑Ni,Liu Shu‑Xin
Purpose Membranous nephropathy (MN) is the most common pathological type of primary nephrotic syndrome in adults. MicroRNAs (miRNAs) are involved in the pathogenesis of several renal diseases. Here we investigated the potential involvement of miRNAs in MN progression. Methods miRNA sequencing was performed in the urinary exosomes of MN patients and normal controls (three cases per group). An experimental mouse MN model induced by cationic bovine serum albumin (CBSA) and MPC5 podocytes intoxicated by puromycin aminonucleoside (PAN) were used in this study. Results Compared with the normal controls, 19 miRNAs were downregulated and 13 upregulated in the urinary exosomes of MN patients. In an expanded cohort, we confirmed that miR-423-5p was significantly upregulated in the urinary exosomes of MN patients. Urinary particle concentrations and size distribution were assessed using transmission electron microscopy and NanoSight. Similarly, upregulated miR-423-5p was observed in PAN-intoxicated MPC5 cells. Lentiviral vector-mediated inhibition of miR-423-5p suppressed podocyte apoptosis and inactivated β-catenin signaling. Upon miRNA database prediction, WT1 was identified as a target of miR-423-5p. Consistently, downregulated WT1 expression in PAN-intoxicated MPC5 cells was rescued by miR-423-5p inhibition. The target relationship between miR-423-5p and WT1 mRNA 3’UTR was validated by the dual luciferase reporter assay. Knockdown of WT1 reversed the inhibitory effect of LV-anti-miR-423-5p on podocyte apoptosis and β-catenin signaling. Notably, miR-423-5p inhibition and WT1 overexpression attenuated renal injury and podocyte apoptosis in MN mice. Conclusion Our study demonstrates that miR-423-5p expression is upregulated in urinary exosomes of MN patients and modulates WT1, affecting podocyte apoptosis by the β-catenin signaling pathway. Inhibition of miR-423-5p action may protect against MN.
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FASEB JOURNAL
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2026
·Vol. 40
·期 6
·e71634
·
IF 4.3
Wenyu Gao,Hao Chen,Fangyu Lin,Jialin Liu,Tingxuan Huang,Han Wang,Xiaojiao Weng,Xinli Wang,Xiaoyan Lin,Tao Jiang
Gastric cancer (GC) is a leading cause of cancer‐related deaths and has high recurrence rate. Although fibronectin domain‐containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi‐omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co‐IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β‐catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224–254) of Gβ2, disrupting Gβγ–Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β‐catenin–destruction complex (GSK3 β–APC–Axin1), leading to β‐catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the Gβ2–Dvl1 axis to activate Wnt/β‐catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target. FNDC1 competitively binds Gβ2 to suppress the β‐catenin–destruction complex and promote the malignant behavior of gastric cancer (GC) by the following mechanism: elevated FNDC1 competes with Dvl for binding to Gβ2, thereby reducing Dvl–Gβ2 interaction; this reduction inhibits Dvl degradation in the cytoplasm; increased Dvl recruits Axin1, thereby disrupting the β‐catenin–destruction complex (GSK3β–APC–Axin) and blocking ubiquitination and degradation of β‐catenin; accumulated β‐catenin in the cytoplasm translocates to the nucleus, where it activates Wnt target genes and promotes epithelial–mesenchymal transition (EMT) in GC cells.
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JOURNAL OF MEDICINAL CHEMISTRY
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2025
·
IF 6.8
Xing-Jie Dai,Leipeng Xue,Ying Liu,Shu-Wu Wang,Ying Li,Jia-Yi Yin,Hao-Zhe Long,Hui-Min Liu,Ning Wang,Guo-Liang Lu,Yan Li,Hong-Min Liu,Bo Wang,Yi-Chao Zheng
Lysine-specific demethylase 1 (LSD1) is a validated cancer therapeutic target, critically implicated in maintaining cancer stem cells (CSCs) across leukemia and solid tumors. Although numerous potent LSD1 inhibitors have been developed, none have reached clinical approval, underscoring the need for novel agents with improved efficacy. Using a scaffold-hopping strategy, we designed and synthesized a novel class of phenoxazine-based LSD1 inhibitors. Among them, X-1 (IC50 = 0.082 μM) emerged as the most potent, exhibiting a 3-fold improvement in activity over the previously reported compound 3s (IC50 = 0.247 μM). Mechanistic studies revealed that X-1 suppressed the stemness of gastric cancer cells by interrupting the β-catenin-mediated transcriptional program, thereby reducing the expression of stemness-related proteins. In vivo studies confirmed its robust antitumor efficacy by inhibiting tumor proliferation and stemness without significant toxicity. Our findings identify X-1 as a promising LSD1-targeted inhibitor, offering a potential therapeutic strategy for gastric cancer.
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Journal of Orthopaedic Translation
·
2023
·
IF 6.6
Fengxiang Pang,Shouchang Ding,Nan Li,Zhipeng Li,Nannan Tian,Chuanjian Shi,Fengwei Zhang,Yongxin Mai,Jinfang Zhang,Junyan Wang
Background Osteosarcoma (OS) is the most common primary malignancy in bone tissues, and effective therapeutics remain absent in clinical practice. Traditional Chinese medicines (TCM) have been used for thousands of years, which provide great insights into OS management. Gallic acid (GA) is a natural phenolic acid enriched in various foods and herbs. Several pharmacological activities of GA such as anti-oxidation and anti-inflammation have been well-established. However, its biological function in OS remains not fully understood. Methods The potential anti-cancer properties of GA were evaluated in 143 B, U2OS and MG63 cells. Its effects on cell growth, cell cycle, apoptosis and migration were examined in these OS cells. The lncRNA H19 and Wnt/β-catenin signaling were detected by qPCR, luciferase activity and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using an orthotopic mouse model. Results In the present study, GA was found to suppress the tumor growth in vitro via inducing cell cycle arrest and apoptosis in OS cells, and inhibit the invasion and metastasis as well. Using the orthotopic animal model, GA was also found to suppress tumorigenesis in vivo . Long noncoding RNA (lncRNA) H19 was demonstrated to be down-regulated by GA, and thus disrupted the canonical Wnt/β-catenin signaling in OS cells. Furthermore, the ectopic expression of H19 rescued the GA-induced suppressive effects on tumor growth and metastasis, and partially reversed the inactivation of Wnt/β-catenin signaling. Conclusions Taken together, our results indicated that GA inhibited tumor growth through an H19-mediated Wnt/β-catenin signaling regulatory axis in OS cells. The translational potential of this article The information gained from this study provides a novel underlying mechanism of GA mediated anti-OS activity, suggesting that GA may be a promising drug candidate for OS patients.
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ONCOLOGY REPORTS
·
2023
·Vol. 50
·期 2
·1-13
·
IF 4.2
Xiao Wang,Simin Rong,Yunxiao Sun,Baohui Yin,Xiancong Yang,Xiaoqing Lu,Hongfang Sun,Yunfei Yan,Guangbin Sun,Yan Liang,Pingyu Wang,Shuyang Xie,Youjie Li
Imatinib resistance in chronic myelogenous leukemia (CML) is a clinical problem. The present study examined the role of N‑Myc downstream regulatory gene 3 (NDRG3) in imatinib resistance in CML. Quantitative PCR demonstrated that NDRG3 was highly expressed in patients with CML. Cell Counting Kit (CCK)‑8 experiments proved that NDRG3 promoted the proliferation of K562 CML cells and enhanced imatinib resistance. Dual‑luciferase assay showed that microRNA (miR)‑204‑5p inhibited expression of NDRG3 and immunofluorescence experiments showed that NDRG3 promoted accumulation of β‑catenin in the nucleus, thereby increasing the expression of downstream drug resistance‑ and cell cycle‑associated factors (c‑Myc and MDR1). At the same time, cell proliferation experiments showed that β‑catenin played a role in cell proliferation and drug resistance. Co‑transfection with small interfering (si)‑β‑catenin partially reversed the effect of NDRG3. This finding indicated that NDRG3 plays an important role in imatinib resistance and miR‑204‑5p and β‑catenin are involved in the biological behavior of NDRG3. The present results provide theoretical support for overcoming drug resistance in CML.
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BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Mengyan Wang,Xiaowei Wang,Wenxia Zhao,Yang Li,Meilian Cai,Kexin Wang,Xiaoming Xi,Cong Zhao,Huimin Zhou,Rongguang Shao,Guimin Xia,Yefan Zhang,Wuli Zhao
Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses , metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the β-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the β-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the β-catenin pathway induced by mutant β-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt’s anti-CSCs effect, elucidating the key role of the β-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of β-catenin and β-TrCP initiates ubiquitination and degradation of β-catenin induced by LMPt. In addition, the Apc Min/+ transgenic mouse model, in which colon tumors are spontaneously formed, demonstrates LMPt’s potent anti-non-CSCs activity in vivo.
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