Journal of Pharmaceutical Analysis
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2025
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IF 8.9
Na Liu,Yuzhen Tu,Hanyu Wang,Xiaoqiang Zheng,Fanpu Ji,Mingsha Geng,Xin Wei,Jingman Xin,Wangxiao He,Qian Zhao,Tianya Liu
The Wnt/β-catenin signaling pathway is renowned for its contribution to the immunosuppressive microenvironment in non-small cell lung cancer (NSCLC). Consequently, inhibiting this pathway has emerged as a promising strategy to enhance immune activation and reinstate T cell responses in cancer treatment. In this study, we initially investigate the metabolic characteristics of Wnt-hyperactivated NSCLC using mass spectroscopic detection in a mouse in-situ model and unveil its significant feature of acid accumulation at tumor sites. Building upon this discovery, we design an acid-sensitive peptide-carnosic acid (CA) supramolecular droplet, Pep1@CA, which leverages the acidic microenvironment characteristic of NSCLC for controlled release. By doing so, we aim to enhance targeting efficiency while minimizing off-target effects. As anticipated, Pep1@CA demonstrates potent tumor-specific inhibition of the Wnt signaling pathway and effectively reactivates T cell immunity in Wnt-hyperactivated NSCLC. Importantly, comprehensive in vivo evaluations reveal significant antitumor efficacy alongside excellent biosafety profiles. Collectively, this study provides a therapeutic strategy with promising clinical translational potential for targeting the Wnt signaling pathway and offers theoretical support for its application in immunotherapy. This innovative approach underscores that targeting pathways beyond traditional immunotherapy can also activate tumor immunity, thereby expanding the potential of cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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DOI
PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
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2025
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IF 3.2
Ting-Ting Yang,Xin-Xin Ma,Xuan Zhang,Zhen-Qing Han,Shuang Zhang,Qi Wang,Hong-Wei Dong,Jia-Ren Liu
β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe 2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 ( P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells ( P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β ( P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BONE
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2022
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IF 4.626
Senxin Cai,Yuchun Zou,Yong Zhao,Hanyu Lin,Dali Zheng,Linyu Xu,Youguang Lu
Aims Mechanical stress overload in the temporomandibular joint (TMJ) is an important cause of TMJ osteoarthritis (TMJOA). Whether secreted frizzled-related proteins (SFRPs) play important roles in the development of mechanical stress-induced TMJOA remains controversial. In this study, we investigated the roles of the Wnt/β-catenin signaling and SFRPs in the progression of mechanical stress-induced TMJOA. Methods We investigated the progression of mechanical stress-induced TMJOA using an in vivo model via modified increased occlusal vertical dimension (iOVD) malocclusion and an in vitro model in which isolated chondrocytes were subjected to mechanical stress. The effects of inhibition of Wnt/β-catenin signal on TMJOA induced by mechanical stress were studied by in vitro drug added and in vivo intra-articular injection of XAV-939. TMJOA progression, Wnt/β-catenin signaling and SFRPs was assessed by Cone beam computed tomography (CBCT) analysis, histochemical and immunohistochemical (IHC) staining, quantitative real-time PCR (qRT–PCR), Western blotting (WB), and immunofluorescence (IF) staining. Results Our in vivo results showed that iOVD-induced mechanical stress in the TMJ disrupted mandible growth, induced OA-like changes in TMJ cartilage, and increased OA-related cytokine expression. In addition, iOVD activated Wnt/β-catenin signaling and suppressed Sfrp1 , Sfrp3 , and Sfrp4 expression in condylar cartilage. Moreover, our in vitro study showed that stress disrupted homeostasis , activated Wnt/β-catenin signaling and inhibited SFRP3 and SFRP4 expression in chondrocytes. Suppression of Wnt/β-catenin signaling with XAV-939 promoted SFRP3 and SFRP4 expression and rescued mechanical stress-induced cartilage degeneration in vivo and in vitro. Conclusions Our work suggests that mechanical stress reduces SFRPs expression both in vivo and in vitro and promotes TMJOA via Wnt/β-catenin signaling. Suppression of Wnt/β-catenin signaling promotes SFRPs expression, especially SFRP3 and SFRP4 expression, and rescues mechanical stress-induced cartilage degeneration. Wnt/β-catenin signaling and SFRPs may represent potential therapeutic targets for TMJOA.
研究领域:
医学
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生物学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
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2025
·Vol. 23
·期 1
·1-18
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IF 7.5
Dong Rui,Li Meihui,Gu Xiu Feng,Gao Haiting,Wei Ziyi,Qi Houbao,Zhang Jun,Feng Qiang
Background Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying osteoblast dysfunction in periodontitis, with a focus on the role of Fusobacterium nucleatum (Fn) and its effector protein, D-galactose-binding periplasmic protein (Gbp).MethodSingle-cell RNA sequencing (scRNA-seq) data from human gingival tissues of periodontitis patients (PD) and healthy controls (HC) were analyzed to identify cellular heterogeneity and molecular pathways. An experimental periodontitis model in mice and primary osteoblast cultures were used to investigate the effects of Fn and Gbp on osteogenic differentiation. Transcriptomic analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were employed to explore the underlying mechanisms.Results scRNA-seq revealed a reduction in mesenchymal stem cells (MSCs) and osteoblastic lineage cells in PD tissues, with significant downregulation of osteogenic pathways such as Wnt signaling. Fn infection induced alveolar bone destruction in vivo and inhibited osteoblast proliferation, differentiation, and mineralization in vitro. Gbp, an Fn adhesin, similarly impaired osteogenic differentiation by downregulating key osteogenic genes and pathways. Transcriptomic analysis identified shared inflammatory and osteogenic pathways affected by Fn and Gbp, with NF-κB signaling activated and Wnt/β-catenin signaling inhibited. Mechanistically, Gbp interacted with the host protein ANXA2, disrupting the ANXA2/GSK3β complex and inhibiting Wnt/β-catenin signaling, a pivotal route for osteoblast differentiation. ANXA2 knockdown mitigated the Fn/Gbp-induced suppression of osteogenic activity, emphasizing its role in Fn-induced bone loss.Conclusion This study demonstrates that Fn and its effector Gbp disrupt osteogenic differentiation by inactivating the Wnt/β-catenin pathway binding to ANXA2.
研究领域:
微生物学
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分子生物学
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口腔健康
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干细胞研究
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产品关联
DOI
PubMed
高影响因子
TISSUE & CELL
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2022
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IF 2.586
Yuan Xu,Jian He,Jun He
Purpose The treatment of intervertebral disc degeneration is limited, cyanidin can protect chondrocytes from degeneration. This research investigated the effect of cyanidin on human nucleus pulposus cells (HNPC) metabolism and its mechanism. Methods HNPC were treated with cyanidin, XAV-939 (inhibitor of Wnt/β-catenin signaling) and SKL2001 (activator of Wnt/β-catenin signaling), and pressurized at 1, 3, and 30 atm. Quantitative real-time PCR and Western blot were used to assess the expressions of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-13 (MMP-13), Collagen-II, Aggrecan , Wnt-3a and β-catenin in treated HNPC. Cell counting kit-8 was used to detect the HNPC cell viability . Radioisotope incorporation method was used to assess the proteoglycan synthesis rate of HNPC. The level of cell matrix was detected by toluidine blue staining. Results Proper hydrostatic pressure of 3 atm could elevate cell viability, proteoglycan synthesis and the level of cell matrix of HNPC, while high hydrostatic pressure of 30 atm reduced the above effects. Cyanidin and XAV-939 reversed the promoting effect of 30 atm pressure on Wnt/β-catenin signaling pathway and the inhibiting effect on cell viability, proteoglycan synthesis and the level of cell matrix. Subsequently, SKL2001 further reversed the function of cyanidin on HNPC. Conclusion Cyanidin attenuated the high hydrostatic pressure-induced degradation of cellular matrix of HNPC via blocking the Wnt/β-catenin signaling pathway. Our findings in this research provided a basis for in vitro experiment of cyanidin and a theoretical fundament on this disease.
研究领域:
骨科
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cells
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2019
·Vol. 8
·期 8
·892
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IF 5.656
Dattatrya Shetti,Bao Zhang,Conghui Fan,Canlong Mo,Bae Hoon Lee,Kun Wei
Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.Keywords:breast cancer;XAV939;apoptosis;EMT;pristane;angiogenesis;combination treatment;Wnt signaling
研究领域:
肿瘤学
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药理学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
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2025
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IF 2.6
Bo Gao,Baokun Li,Jitao Hu,Xuhua Hu,Mingming Su
Purpose Colorectal cancer (CRC) is a prevalent cancer worldwide, with metastasis significantly contributing to its high mortality and poor prognosis. This study focuses on the impact of Alkaline Phosphatase, Placental (ALPP) on epithelial-mesenchymal transition (EMT) in colorectal cancer cells and its role in the Wnt/β-catenin signaling pathway.Patients and Methods Differential ALPP expression was first interrogated in metastatic versus non-metastatic CRC samples from The Cancer Genome Atlas (TCGA-CRC) cohort. Functional validation was subsequently performed in vitro with HT29 and HCT116 cell lines engineered for ALPP overexpression or CRISPR/Cas9-mediated knockdown. Proliferation, migration and invasion were quantified by CCK-8, wound-healing and Transwell assays; EMT and Wnt/β-catenin signaling were assessed by Western blot.Results Bioinformatics analysis revealed significantly different ALPP expression between metastatic and non-metastatic patients. In vitro experiments further revealed that ALPP overexpression drives proliferation, invasion, migration and, consequently, metastasis of HT29 and HCT116 colorectal cancer cells, whereas ALPP knockdown abolishes these EMT-dependent effects. Increased ALPP expression resulted in increased levels of N-Cadherin, Vimentin, and Snail proteins, along with a decrease in E-cadherin protein expression, in contrast to findings following ALPP knockdown. Furthermore, ALPP overexpression was also associated with Wnt/β-catenin signaling pathway activation.Conclusion ALPP was found to act as an oncogenic factor in colorectal cancer cell lines HT29 and HCT116, stimulating cell proliferation and facilitating EMT. Abnormal activation of the Wnt/β-catenin signaling pathway was also found to be linked to increased ALPP expression.
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DOI
PubMed
高影响因子
CELL
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2018
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IF 31.398
Qian Zhang,Xueying Wu,Peng Chen,Limeng Liu,Nan Xin,Ye Tian,Andrew Dillin
Summary The mitochondrial unfolded protein response (UPR mt ) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPR mt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPR mt . Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPR mt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the “mitokine” signal.
研究领域:
分子生物学
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细胞生物学
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遗传学
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神经科学
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产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2023
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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
研究领域:
药理学
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心脏病学
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免疫学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
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IF 3.263
Fei-fei Pan,Yan-Biao Zheng,Chuan-Jian Shi,Feng-wei Zhang,Jin-fang Zhang,Wei-ming Fu
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. However, the effective pharmacological approaches remain scanty in clinical practice. As a bioactive flavonoid , apigenin (API) is enriched in common fruits and vegetables. Although pharmacological activities of API have been widely investigated, its biological function in HCC remains obscure. In the present study, we found that API strongly suppressed cell growth and induced apoptosis in HCC cells. Using a xenograft mice model, API was demonstrated to inhibit the in vivo tumor growth. It is known that the long non-coding RNA H19, which is frequently elevated in HCC, plays a vital role in mediating tumorigenesis and cancer progression. Our results demonstrated that H19 was down-regulated by API, and thereby induced the inactivation of the canonical Wnt/β-catenin signaling. In conclusion, our results demonstrated that API was able to suppress tumor growth of HCC through H19-mediated Wnt/β-catenin signaling regulatory axis, suggesting that API may be a promising candidate for developing novel therapeutic approaches against liver cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Bone Reports
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2024
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IF 2.1
Qiang Chen,Shaoqin Tu,Dongxiao Tang,Jiaming Wei,Nan Wei,Hong Ai,Bu Yang,Zheng Chen
Objective To explore the effect of amyloid-β peptide (Aβ) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis. Methods A murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aβ. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aβ on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs). Results In vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aβ, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aβ promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1. Conclusion Aβ can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.
研究领域:
牙科学
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骨科学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
MEDICAL ENGINEERING & PHYSICS
·
2025
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IF 2.3
SHENGJIE WANG,WEI LIU,CHAO YANG,XIANLONG ZHANG,CHUNMING LYU
Prosthetic loosening represents a catastrophic postoperative complication in artificial joint replacement, resulting in severe patient morbidity and substantial healthcare costs. This investigation aimed to develop a novel strategy for preventing prosthetic loosening. Two-dimensional MXene V 2 C nanosheets were synthesized and subsequently immobilized onto three-dimensional porous sulfonated polyetheretherketone (SPEEK) surfaces with polydopamine (PDA) to form V 2 C-PDA@SPEEK (Abbrev. V 2 C-PS). The biocompatibility was systematically evaluated using rat bone marrow mesenchymal stem cells (rBMSCs) and murine models. The osteogenic differentiation potential of V 2 C-PS was assessed through real-time PCR analysis, Alkaline phosphatase (ALP) staining, and Alizarin Red staining. The in vivo osteogenic capacity of V 2 C-PS surrounding the implant material was evaluated in rat femoral models using micro-CT analysis, biomechanical pull-out testing, sequential fluorescent labeling of newly formed bone, and Van Gieson staining. The molecular mechanisms underlying V 2 C-PS -mediated osteogenic differentiation of rBMSCs were investigated both in vitro and in vivo using chemical inhibitors, β-catenin shRNA lentiviral silencing, and β-catenin mRNA lentiviral overexpression. The results demonstrated that V 2 C-PS exhibited excellent biocompatibility. Quantitative analysis revealed substantial upregulation (p<0.05) of critical osteogenic markers, including RUNX2 (4.4-fold), COL-1 (5.7-fold), OCN (3.3-fold), BMP-2 (4.4-fold), OPN (3.1-fold), BSP (3.3-fold), ON (4.3-fold), and OSX (2.83-fold), in the 25V 2 C-PS treatment group compared to PS group. The bone parameters were also remarkably enhanced in the 25V 2 C-PS group (BMD increased by 241 %, bone-implant contact by 159 %, BV/TV by 225 %, Tb.N by 281 %, Tb.Th by 214 %, maximum pull-out force by 250 %, and Tp.Sp decreased by 33 %). Furthermore, V 2 C-PS were found to enhance rBMSC osteogenic differentiation through activation of the Wnt/β-catenin signaling pathway. This study presents a promising approach for preventing orthopedic prosthetic loosening and demonstrates significant potential for clinical translation.
研究领域:
生物医学工程
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组织工程
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材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）