ACS Applied Materials & Interfaces
·
2026
·Vol. 18
·期 30
·40218-40231
·
IF 7.8
Xu Tianyu,Zhong Jun,Dai Chengbai,Du Yimin,Lyu Xinzhe,Ma Tian,Zhang Panpan,Zhu Xiaojia,Li Zheng,Quan Cheng,Hu Yuting
Osteoarthritis (OA) is a chronic degenerative disease causing bone and cartilage deterioration, joint deformity, and functional loss. The initiation and progression of OA are primarily driven by oxidative stress and the abnormal activation of the Wnt/β-catenin signaling pathway. This study involved loading Resveratrol (Res) and platinum (Pt) nanozymes, which exhibit superoxide dismutase (SOD) and catalase (CAT), onto a metal-organic framework (MOF) due to its distinctive porosity and high loading capacity. The system was further modified with hyaluronic acid (HA) to synthesize Pt-MOF/Res@HA (PMRH) nanoparticles. The PMRH nanoparticles improve early OA prevention and treatment by concurrently inhibiting the Wnt/β-catenin signaling pathway and eliminating reactive oxygen species (ROS). Experimental results, both in vitro and in vivo, indicate that PMRH nanoparticles efficiently scavenge ROS within the OA microenvironment. The PMRH nanoparticles inhibit the overactive Wnt/β-catenin signaling pathway in chondrocytes affected by osteoarthritis. This dual-target approach, which addresses oxidative stress and inhibits the Wnt/β-catenin signaling pathway, shows promising therapeutic potential for OA.
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Advanced Science
·
2022
·Vol. 9
·期 28
·2200750
·
IF 17.521
Shaoqin Zheng,Jiahui Lin,Zhongqiu Pang,Hui Zhang,Yinuo Wang,Lanjing Ma,Haijiao Zhang,Xi Zhang,Maorong Chen,Xinjun Zhang,Chao Zhao,Jun Qi,Liu Cao,Min Wang,Xi He,Ren Sheng
Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the elusiveness of the in-depth mechanism, it is well-established that pancreatic cancer specially requires abnormal cholesterol metabolism levels for growth. In this study, it is unexpectedly found that among ten Fzds, Fzd5 has a unique capacity to bind cholesterol specifically through its conserved extracellular linker region. Cholesterol-binding enables Fzd5 palmitoylation, which is indispensable for receptor maturation and trafficking to the plasma membrane. In Wnt-addicted pancreatic ductal adenocarcinoma (PDAC), cholesterol stimulates tumor growth via Fzd5-mediated Wnt/ β -catenin signaling. A natural oxysterol, 25-hydroxylsterol competes with cholesterol and inhibits Fzd5 maturation and Wnt signaling, thereby alleviating PDAC growth. This cholesterol-receptor interaction and ensuing receptor lipidation uncover a novel mechanism by which Fzd5 acts as a cholesterol sensor and pivotal connection coupling lipid metabolism to morphogen signaling. These findings further suggest that cholesterol-targeting may provide new therapeutic opportunities for treating Wnt-dependent cancers.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2023
·
IF 3.6
Chen Min,Huang Shanjiao,Weng Shuoyun,Weng Junting,Guo Rongjie,Shi Bingbing,Liu Danjuan
Septic cardiomyopathy (SCM) is manifested by impairment of cardiac contractile function with myocardial mitochondrial dysregulation. Natural product, songorine (SGR), a diterpenoid alkaloid derived from the lateral root of Aconitum carmichaeli , has been reported for the treatment of heart failure. Here, the protective role of SGR in heart injury of SCM was investigated and its underlying action of mechanism was explored. Firstly, the mouse and cardiomyocytes (H9C2 cell) SCM model induced by LPS were established to evaluate the therapeutic effect of SGR. The in vivo results exhibited that SGR rescued the survival rate of SCM mice, restored the loss of ejection fraction (EF) and fractional shortening (FS), and reduced left ventricular systolic diameter and left ventricular diastole diameter (LVIDs, LVIDd) by echocardiography. SGR improved the mitochondrial biosynthesis and myocardial fiber structure and arranged them neatly by transmission electron microscope (TEM). Further, SGR inhibited inflammatory targets myeloperoxidase (MPO) and tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and plasminogen activator inhibitor-1 (PAI-1). And SGR activated the mitochondrial biosynthesis–related peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), β-catenin, and matrix metallopeptidase 2 (MMP2) proteins. Meanwhile, the in vitro results showed that SGR promoted the increased the myocardial H9C2 cell viability, and mitochondrial biosynthesis and structure. SGR also blocked the inflammatory factors and reversed PGC-1α, β-catenin, and MMP2 in vitro, while SGR alleviated the myocardial cell apoptosis via flow cytometry. The findings indicate that SGR mitigates sepsis-caused myocardial damage by Wnt/β-catenin signaling pathway–mediated mitochondrial biosynthesis. SGR may be a promising candidate for treatment of SCM. Graphical Abstract
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JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
·
2026
·
IF 4
Lei Gong,Zhenghang Wang,Hao Chen,Kaili Xuan,Yuchen Ding,Junqiang Zhang,Mengqi Wang,Qingxi Wu,Yan Chen
BACKGROUND Cacumen Platycladi (CP), the dried twigs and leaves of Platycladus orientalis , is a food-related botanical with potential hair health-promoting activity. However, the principal bioactive constituent responsible for its anti-alopecia effect and the underlying mechanism remain unclear. This study aimed to identify the key anti-alopecia constituent of CP and investigate its mechanism of action against androgenetic alopecia. RESULTS Six major candidate compounds were identified from CP by fractionated extraction, gas chromatography–mass spectrometry, liquid chromatography–mass spectrometry, and network pharmacology analysis. Among them, amentoflavone showed the strongest anti-alopecia activity. In a testosterone-induced mouse model, amentoflavone increased mean hair length by 1.10-fold and hair density by 1.33-fold versus the model group, improved follicular morphology, reduced the proportion of vellus hair by 50.8%, and regulated serum hormone levels. Western blot analysis further showed that amentoflavone increased β-catenin and cyclin D1 expression while decreasing GSK-3β expression. CONCLUSION Amentoflavone was identified as the principal anti-alopecia constituent of CP. Its beneficial effect was associated with activation of the Wnt/β-catenin signaling pathway, suggesting that CP is a promising source of functional bioactive compounds for hair health-related applications. © 2026 Society of Chemical Industry.
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PHYTOTHERAPY RESEARCH
·
2019
·Vol. 34
·期 4
·817-824
·
IF 3.766
Mingming Zhu,Xi Yu,Zongmei Zheng,Jiaming Huang,Xuepan Yang,Hongfei Shi
Cancer stem cells (CSCs) are considered as the origin and driving cells of cancer, and play a key role in the progress of cancer. Studies have shown that capsaicin exerted inhibitory effect on prostate cancer cells, however, the effects of capsaicin on prostate CSCs remain undefined. In the present study, we showed that capsaicin could downregulate prostate CSCs markers and inhibit the growth of PC-3 and DU145 prostate cancer stem cells. Further, we found capsaicin suppressed the expression of Wnt-2, p-GSK3β and β-catenin, along with downregulation of Wnt/β-catenin pathway target genes c-myc and cyclinD1. Using LiCl, a activator of Wnt/β-catenin pathway, we found activation of Wnt/β-catenin pathway could ameliorate the downregulation of prostate CSCs markers and the growth inhibition induced by capsaicin in prostate cancer stem cells. Those data suggested that the inhibition effect of capsaicin on prostate cancer stem cells and the anti-cancer effect of capsaicin on prostate cancer stem cell may be mediated by Wnt/β-catenin pathway. Findings from this study reveals for the first time the potential role and mechanisms of capsaicin on prostate cancer stem cells.
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Experimental and Therapeutic Medicine
·
2019
·Vol. 18
·期 2
·1285-1290
·
IF 1.448
Hanchun Chen,Qiong Lu,Chao Chen,Yunhai Di,Ya'nan Li,Weijie Min,Zhengquan Yu,Dongwei Dai
Mutations of the β‑catenin gene are common in various cancer types. MicroRNA (miR)‑24 suppresses gene expression during the cell cycle. However, the effects of miR‑24 on the cell viability and autophagy of glioma cells, and how these biological processes are regulated by β‑catenin are largely unclear. The current study aimed to investigate the role of β‑catenin in regulating the effects of miR‑24 on the cell viability and autophagy of glioma cells. The expression levels of microtubule‑associated proteins 1A/1B light chain 3B (LC3B) and Beclin1 were detected by immunohistochemistry and western blotting. Glioma C6 cells were transfected with miR‑24 mimics, miR‑24 inhibitors and negative control miRNAs. C6 cells transfected with miR‑24 mimics or negative control miRNAs were treated with the β‑catenin inhibitor, XAV‑939. An MTT assay was utilized to evaluate the viability of C6 cells. The expression of miR‑24 and mRNA expression of autophagy related 4a cysteine peptidase (ATG4A) were detected by quantitative polymerase chain reaction analysis. The protein expression of LC3B and Beclin1 decreased significantly in glioma tissue and glioma C6 cells compared with normal brain tissue. Compared with the negative control group, C6 cells transfected with miR‑24 mimics exhibited significantly higher cell viability at 24 and 48 h, and those transfected with miR‑24 inhibitors exhibited significantly lower cell viability at 48 h. XAV‑939 decreased the stimulatory effects of miR‑24 mimics on the viability of C6 cells. The expression of miR‑24 significantly decreased and ATG4A mRNA significantly increased in C6 cells transfected with XAV‑939 compared with those transfected with the negative control miRNA. XAV‑939 attenuated the miR‑24‑induced decrease of the protein expression of LC3B and Beclin1, and decreased the stimulatory effects of miR‑24 mimics on cell viability. In addition, XAV‑939 attenuated the miR‑24‑induced decrease of autophagy marker expression by attenuating miR‑24 expression and increasing ATG4A mRNA expression in glioma C6 cells. To the best of our knowledge, the present study is the first to demonstrate whether β‑catenin regulates the intracellular effects of miR‑24 on the viability and autophagy of glioma cells. The results also provide some mechanistic basis to the pharmaceutical targeting of WNT signaling in high grade glial tumors.
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Biomed Research International
·
2018
·
IF 2.583
Xinggui Tian,Huaji Jiang,Yuhui Chen,Xiang Ao,Chuan Chen,Wentao Zhang,Feilin He,Xiaoqing Liao,Xiaocheng Jiang,Tao Li,Zhongmin Zhang,Xintao Zhang
Background. Tendon-bone healing is a reconstructive procedure which requires a tendon graft healing to a bone tunnel or to the surface of bone after the junction injury between tendon, ligament, and bone. The surgical reattachment of tendon to bone often fails due to regeneration failure of the specialized tendon-bone junction. Materials and Methods. An extra-articular tendon-bone healing rat model was established to discuss the effect of the baicalein 10 mg/(kg·d) in accelerating tendon-bone healing progress. Also, tendon-derived stem cells (TDSCs) were treated with various concentrations of baicalein or dickkopf-1 (DKK-1) to stimulate differentiation for 14 days. Results. In vivo, tendon-bone healing strength of experiment group was obviously stronger than the control group in 3 weeks as well as in 6 weeks. And there were more mature fibroblasts, more Sharpey fibers, and larger new bone formation area treated intragastrically with baicalein compared with rats that were treated with vehicle for 3 weeks and 6 weeks. In vitro, after induction for 14 days, the expressions of osteoblast differentiation markers, that is, alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix (OSX), and collagen I, were upregulated and Wnt/β-catenin signaling pathway was enhanced in TDSCs. The effect of DKK-1 significantly reduced the effect of baicalein on the osteogenic differentiation. Conclusion. These data suggest that baicalein may stimulate TDSCs osteogenic differentiation via activation of Wnt/β-catenin signaling pathway to accelerate tendon-bone healing.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Pan Song,Dong Lv,Luchen Yang,Jing Zhou,Xin Yan,Zhenghuan Liu,Kai Ma,Yunfei Yu,Xiaoyang Liu,Qiang Dong
Di-(2-ethylhexyl) phthalate (DEHP) might led to chronic and long-term effects on human organs due to its widespread use and bioaccumulation. Despite some cohorts reporting an association between DEHP exposure and BPH, its underlying mechanisms have not been investigated. Our findings indicate that exposure to DEHP or MEHP (main metabolites of DEHP in the human body) leads to increased prostate weights, elevated prostate index, and notable epithelial thickening in rats. It has been observed to promote BPH-1 cell proliferation with effects ranging from low to high concentrations. Transcriptome sequencing analysis of rat prostate tissues identified KIF11 as the key hub gene. KIF11 is highly expressed after DEHP/MEHP exposure, and knocking down of KIF11 inhibits the MEHP-induced promotion of cell proliferation. Exposure to MEHP has been observed to increase the expression of p-GSK-3β and elevate the levels of β-catenin, thereby activating the Wnt/β-catenin signaling pathway. Knocking down of KIF11 significantly inhibits these effects. Histone H3 at Lysine 27 acetylation (H3K27ac) is implicated in the upregulation of KIF11 expression, as evidenced by the addition of the acetylation inhibitor C646. In summary, our findings established that DEHP exposure could promote BPH through H3K27ac regulated KIF11/Wnt/β-catenin signaling pathway.
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PHYTOMEDICINE
·
2024
·
IF 6.7
Qinwei Lu,Junlin Zhu,Linxin Teng,Cuihua Chen,Lei Bi,Weiping Chen
Background Hepatocellular carcinoma (HCC) stands out as a significant contributor of cancer-related death. Traditional Chinese Medicine (TCM) presents numerous advantages in the treatment of HCC. Britannin, a pivotal compound found in Inulae Flos, demonstrates pharmacological effects against various cancers, yet research on its specific impact on anti-hepatocellular carcinoma remains limited. Purpose This study aims to explore both the anti-hepatocellular carcinoma effects of britannin and its underlying mechanism of action. Methods MTT assay, clone formation assay and flow cytometry were utilized to detect the cell activity, proliferation ability and apoptosis of britannin against HCC cell lines. Cell migration and invasion abilities of britannin on HCC cell lines were evaluated by wound-healing assay and transwell migration and invasion assay. H22 xenografted tumor mouse model was constructed and britannin treatment was performed to observe the effect of britannin on HCC tumor. The expression levels of liver cancer biomarkers AFP, AFP-L3, APT and TGF-β were detected by Elisa, and the histopathology was observed by HE staining. Network pharmacology and molecular docking were used to predict the possible signaling pathway of anti- hepatocellular carcinoma effect of britannin. The surface plasmon resonance (SPR) experiments was used to verify the interaction between britannin and proteins. The cell kinase activity function experiment was employed to detect the effect of britannin on enzyme activity. RT-qPCR and Western-Blot were used to verify the effect of britannin on the mRNA expressions of key genes and protein levels related to GSK-3β/β-catenin pathway in hepatocellular carcinoma cells and tumor tissues in mice. Results In vitro experiments showed that britannin could inhibit the activity, proliferation, migration and invasion abilities of HCC cells, while promoting their apoptosis. In vivo experiments revealed that britannin exerted inhibitory effects on the growth of transplanted liver cancer tumors, reducing the inflammatory infiltration and the expression levels of AFP, AFP-L3, APT and TGF-β of liver cancer markers in transplanted mice. Network pharmacology and molecular docking predicted that cell adhesion factors and GSK-3β/β-catenin pathway might be the related signaling pathway and had potential docking activity with key proteins. The SPR experiments elucidated the molecular interaction between britannin and GSK-3β. Enzyme activity assays indicated that britannin could modulate the functional activity of GSK-3β kinase. RT-qPCR suggested britannin could regulate the mRNA expressions of β-catenin, GSK-3β, E-cadherin and N-Cadherin. Western-Blot further verified that britannin could significantly up-regulate the expression of GSK-3β and down-regulate the expression of p -GSK-3β and β-catenin. At the same time, the expression of E-cadherin increased and N-Cadherin decreased, thereby reducing the occurrence of EMT and inhibiting the metastasis of hepatocellular carcinoma. Conclusion In conclusion, britannin could inhibit the growth, development and metastasis of HCC, and its mechanism may be related to the regulation of GSK-3β/β-catenin signaling pathway to inhibit epithelial-mesenchymal transition of HCC.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 7
·e70539
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IF 4.2
Tianyi Ji,Xiangying Li,Jiachen Li,Guan Wang
Wnt signalling is a highly conserved signalling pathway that plays an important role in a variety of biological processes. Frizzled (Fzd) family proteins are receptors for Wnt ligands. The physiological processes involved in mature trafficking of Fzd proteins remain elusive. Here, we identified asparagine residues 59 and 144 as the N-glycosylation modification sites of Fzd4. Sequence analysis of Fzd4 in different species showed that the two asparagine residues were highly conserved. N-glycosylation modification of Fzd4 is indispensable for its maturation and transport to the plasma membrane. N-glycosylation modification enhances the stability of Fzd4 and is also necessary for Fzd4 activity, which promotes Fzd4 interaction with Wnt ligands and co-receptor Norrin. Knockout of Fzd4 in the non-small cell lung cancer (NSCLC) cell line A549 followed by replenishment of Fzd4 glycosylation site mutants inhibited the growth and migration ability of A549 cells in vitro and in vivo. In summary, we identified N-glycosylation modification sites of Fzd4. N-glycosylation modification of Fzd4 is necessary for its stability and activity. When N-glycosylation modification is absent, Fzd4 cannot mediate the Wnt/β-catenin signalling pathway, which can inhibit the proliferation and migration of NSCLC and provide new targets and strategies for the treatment of NSCLC.
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International Journal of Biological Sciences
·
2024
·
IF 8.2
Zuodong Xuan,Chen Chen,Huimin Sun,Kunao Yang,Jinxin Li,Meilin Fu,Yang Bai,Zeyuan Zheng,Yue Zhao,Chunlan Xu,Bin Liu,Tian Li,Chen Shao
Background: Prostate cancer progression hinges on β-catenin's stability and activity, a key factor in epithelial-mesenchymal transition (EMT) and metastasis. This study delves into NDR1-dependent phosphorylation's impact on β-catenin via FBXO11, an E3 ubiquitin ligase, in prostate cancer cells. Methods: Human prostate cancer cell lines underwent various in vitro assays, including real-time PCR, Western blotting, immunoprecipitation, immunofluorescence, and protein stability assays, to explore β-catenin's interactions and post-translational modifications. NDR1 modulation's in vivo efficacy was assessed using a nude mice lung metastasis model. Small-molecule screening identified a potential NDR1 activator, aNDR1, tested for its effects on metastasis via in vitro and in vivo assays. Results: NDR1 phosphorylated β-catenin at Ser33/37, facilitating its interaction with FBXO11. This led to FBXO11-mediated ubiquitination and cytoplasmic degradation of β-catenin, while the NDR1-FBXO11 complex impeded β-catenin nuclear translocation by inducing JNK2 ubiquitination. Thus, NDR1 and FBXO11 jointly regulate β-catenin activity in prostate cancer cells through dual phosphorylation-driven ubiquitination, potentially suppressing EMT. Reduced NDR1 expression inhibited FBXO11 and β-catenin phosphorylation, diminishing β-catenin and JNK2 ubiquitination, promoting EMT and enhancing prostate cancer cell metastasis. The inhibitory effects of aNDR1 on prostate cancer metastasis were validated. Conclusion: The NDR1/FBXO11 axis outlines a non-canonical β-catenin degradation pathway crucial in regulating EMT and prostate cancer cell metastasis. NDR1 activation, particularly with aNDR1, could offer a promising therapeutic avenue against prostate cancer metastasis.
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Advanced Science
·
2024
·
IF 14.3
Lijiao He,Xiao Zhang,Shengwei Zhang,Yi Wang,Weichao Hu,Jie Li,Yunyi Liu,Yu Liao,Xue Peng,Jianjun Li,Haiyan Zhao,Liting Wang,Yang-Fan Lv,Chang-Jiang Hu,Shi-Ming Yang
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA -positive H. pylori . Tert knockout significantly ameliorated H. pylori -induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
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