BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Chuan-Jian Shi,Shi-Ying Li,Chun-Hui Shen,Fei-Fei Pan,Li-Qiang Deng,Wei-Ming Fu,Ji-Yong Wang,Jin-Fang Zhang
Icariside II, a flavonol glycoside, one of the major components of Traditional Chinese Medicine Herba epimedii. In the present study, we found that Icariside II suppressed the proliferation of CRC by inducing cell cycle arrest and apoptosis in vitro and inhibited tumor growth in vivo . The further mechanism investigation showed that Icariside II suppressed the expression of β-catenin and led to the functional inactivation of Wnt/β-catenin signaling. Circβ-catenin was considered as a promising candidate for mediating the tumorigenesis and the activation of Wnt/β-catenin signaling in CRC cells. Furthermore, Icariside II has been proven to suppress the biogenesis of circβ-catenin via epigenetically targeting DNA methyltransferases (DNMTs) to decrease global DNA methylation levels in CRC cells. Taken together, our results indicated that Icariside II suppressed tumorigenesis by epigenetically silencing the activation of circβ-catenin-Wnt/β-catenin axis in colorectal cancer. More importantly, the information gained from this study suggest that Icariside II may have great potential to be developed as a therapeutic drug for CRC patients.
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Cancer Management and Research
·
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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Current Computer-Aided Drug Design
·
2026
·Vol. 22
·期 3
·180-194
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IF 1.5
Siluo Wu,Jiayang Wang,Ziheng Luo,Bifeng Li,Liangliang Xu,Liuchao Hu,Rihe Hu
Background Qi-Gui-Jian-Gu decoction (QGJG), as a clinical empirical formula, has clinical benefits in promoting bone formation, but the underlying mechanism for its application in treating fractures has not been investigated. Methods The potential therapeutic target and signaling pathway of QGJG for treating fractures were analyzed by network pharmacology. In vitro, we used bone marrow mesenchymal stem cells (MSCs) to evaluate osteogenic differentiation and mineralization by alizarin red staining, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence staining. In vivo, the 8w male SPF C57BL/6J mouse femoral fracture model was constructed, and the therapeutic effects of QGJG were evaluated. Results and Discussion By network pharmacology analysis, we found that glycogen synthase kinase 3 beta (GSK3β) was a potential therapeutic target of QGJG for treating fractures. The canonical Wnt signaling pathway was selected as the potential molecular mechanism. QGJG was confirmed to upregulate the mRNA levels of alkaline phosphatase (ALP) and bone morphogenetic protein 2 (BMP2), thereby promoting osteogenic differentiation and mineralization. Mechanistically, QGJG inhibited GSK3β while increasing p-Ser9-GSK3β to increase β-catenin protein expression and its nuclear translocation, implying the activation of the canonical Wnt signaling pathway. In vivo, QGJG administration promoted fracture healing, as demonstrated by the up-regulation of OPN and Osx, and accelerated the progression of ossification at 2 and 3 weeks after surgery. Conclusion QGJG promotes osteogenic differentiation and fracture healing by activating the canonical Wnt pathway.
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PHYTOMEDICINE
·
2026
·
IF 11.3
Zhuorui Li,Ningbo Zhang,Limei Dai,Xiangzhen Meng,Jiaqi Huang,Qingwen Hei,Zhinan Mei,Hui Xiong
Bairesi Pills promote repigmentation in hydroquinone-induced vitiligo mice. • Bairesi Pills reduce hippuric acid levels and restore gut-skin axis homeostasis. • Bairesi Pills and their active constituents including piperine and quercitrin, enhance melanogenesis through modulation of the MAPK14/β-catenin pathway. Background Bairesi Pills is a traditional Uyghur medicinal formula prescribed for vitiligo. However, its bioactive constituents and specific pharmacological mechanisms remain to be fully elucidated. Purpose This study aims to elucidate the underlying mechanisms and identify the active constituents of Bairesi Pills in the treatment of vitiligo. Methods A hydroquinone-induced vitiligo mouse model was established to evaluate the effects of Bairesi in vivo. Serum untargeted metabolomics and gut microbiome analyses were integrated to identify key differential metabolites and explore the association between gut dysbiosis and skin depigmentation. In vitro, melanocyte oxidative injury models were established using H₂O₂ or hippuric acid. Transcriptome sequencing was performed to screen differentially expressed genes and related signaling pathways. MAPK14 overexpression and pharmacological inhibition were further used to verify the effects and mechanisms of Bairesi and its active constituents in alleviating hippuric acid-induced oxidative stress. Results In vivo, Bairesi ameliorated oxidative stress and promoted pigment deposition in vitiligo-like mice, which was associated with enhanced intestinal mucus barrier integrity, reshaped gut microbiota, and reduced hippuric acid accumulation. In vitro, H₂O₂ or hippuric acid induced oxidative injury and MAPK activation in melanocytes, whereas Bairesi, piperine, and quercitrin suppressed MAPK14 activation, alleviated oxidative stress, and restored melanin synthesis, but these protective effects were attenuated by MAPK14 overexpression. Conclusion Bairesi Pills ameliorates vitiligo-like depigmentation by reshaping the gut microbiota–metabolite profile, reducing hippuric acid accumulation, and reversing HA-induced oxidative stress through inhibition of MAPK14 phosphorylation. Download: Download high-res image (219KB) Download: Download full-size image
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JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2026
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IF 4
Zhewen Deng,Mengyuan Zhang,Senqiang Zhu,Yunlong Zhang,Haitao Liao,Jiaqi Li,Peiyu Yan,Qi Zhang,Rui Liu,Bo Ma
Osteosarcoma (OS), a highly aggressive bone cancer with a dismal prognosis in the metastatic setting, urgently demands novel therapeutic modalities. While phototherapy offers a promising, minimally invasive strategy, its clinical efficacy is often hampered by the poor aqueous solubility of photosensitizers and the development of multidrug resistance. In response, we constructed the dual-modal nanoplatform BDP-NPs by leveraging a multifunctional F127/TPGS mixed micelle to encapsulate a cationic BODIPY photosensitizer, thereby creating a system engineered for enhanced tumor accumulation and to overcome multidrug resistance. Benefiting from their uniform size, colloidal stability, and hypoxia-responsive properties, the BDP-NPs demonstrate potent reactive oxygen species generation and high photothermal conversion efficiency under 525 nm laser irradiation. This dual-modal action induces severe mitochondrial dysfunction, thereby triggering apoptosis in both 3D tumor spheroids and tumor tissues. The synergistic phototherapy elicited profound mitochondrial-targeted cytotoxicity, inhibited clonogenic survival, and significantly suppressed tumor growth in human osteosarcoma models, all while maintaining a favorable biosafety profile. Mechanistic analyses revealed that this synergistic phototherapy plays a pivotal role in suppressing the YAP1/β-catenin axis, thereby reversing the epithelial-mesenchymal transition (EMT) program and consequently inhibiting OS cell proliferation, migration and invasion. This study not only establishes BDP-NPs as a potent and biocompatible nanotherapeutic for OS but also presents a groundbreaking phototherapeutic strategy to disrupt the YAP1/β-catenin axis-a key signaling network driving tumorigenesis and malignant progression. This approach provides a robust conceptual foundation for devising next-generation phototherapeutics that precisely target oncogenic signaling in aggressive cancers.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
·
IF 6.8
Jiao Kong,Yujia Chen,Shuanghui Lu,Lvexiang Yuan,Tao He,Minlei Dong,Yingqiong Zhang,Xiaoyi Pan,Hui Zhou,Huidi Jiang
Ethnopharmacological relevance The pollen of Brassica campestris L. (BCP, syn. Brassica rapa L. subsp. oleifera (DC.) Metzg.), included in the Chinese Pharmacopoeia as a licensed patent medicine (Pule'an tablets), is used clinically for kidney-qi deficiency-related lower urinary tract symptoms in chronic prostatitis and benign prostatic hyperplasia. Prostatic obstruction is a common cause of obstructive uropathy that may progress to renal fibrosis. However, the renoprotective effects and the underlying mechanism remain to be fully elucidated. Aim of the study To study the renoprotective effects, the active fraction, the effective components of BCP and the underlying mechanisms. Materials and methods Mouse models of hyperuricemic nephropathy (HN) and unilateral ureteral obstruction (UUO) were established to evaluate the renoprotective effects of BCP. Transcriptomics and liquid chromatography-mass spectrometry were applied to explore potential mechanisms and intrarenal constituents. Erastin- and uric acid (UA)-induced HK-2 cells were employed to validate the cytoprotective effects of the potential active compounds, whose binding capability with direct target was confirmed by CETSA/SPR. Results BCP dose-dependently reduced UA levels and reversed the protein expression of UA-producing enzymes and renal transporters (for reabsorption and excretion) in HN mice. Additionally, BCP improved renal injury and fibrosis in HN mice and UUO mice by reducing UA and direct renoprotection, in which the flavonoids of BCP played a crucial role. Meanwhile, BCP alleviated renal fibrosis by inhibiting the β-catenin/TCF4-ferroptosis axis, which was achieved mainly by its bioactive components, kaempferol and kaempferol-3-glucuronide (K-3-G), in HK-2 cells. Furthermore, kaempferol and K-3-G were demonstrated to directly bind with β-catenin, block the transcriptional activation of β-catenin, and subsequently suppress ferroptosis. Conclusions BCP and its major bioactive compounds, kaempferol and K-3-G, exert nephroprotective effects by inhibiting the β-catenin/TCF4-ferroptosis axis.
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JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
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2026
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IF 3.5
Xiaoran Sun,Yifan Chen,Kunyi Liu,Yi Si,Mingda Xuan,Rui Zhang,Jiao Jiao,Ting Liu,Shuangshuang Han,Jia Wang,Weifang Yu
Objective Gastric cancer remains a major global health burden. This study aimed to investigate the biological function, clinical significance, and underlying molecular mechanism of the RNA-binding protein YTHDF3 in gastric cancer (GC) progression. Methods YTHDF3 expression was analyzed using public databases (TCGA, GEO), clinical GC specimens (IHC, RT-qPCR), and GC cell lines. Functional roles were assessed through in vitro proliferation, migration, invasion, and apoptosis assays following YTHDF3 knockdown or overexpression, and via an in vivo subcutaneous tumor model. Mechanistic insights were gained through RNA sequencing, RIP-qPCR, dual-luciferase reporter assay, co-immunofluorescence, rescue experiments, and western blotting to identify downstream targets and signaling pathways. Results YTHDF3 was significantly upregulated in GC tissues, correlating with lymph node metastasis and advanced TNM stage. In vitro, YTHDF3 knockdown inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas its overexpression had the opposite effects. In vivo, YTHDF3 knockdown suppressed tumor growth. Mechanistically, YTHDF3 directly bound to and stabilized NEK7 mRNA. NEK7 was highly expressed in GC and crucial for YTHDF3-mediated oncogenic effects. Furthermore, YTHDF3 promoted GC progression by activating the Wnt/β-catenin signaling pathway via NEK7, which was validated using a pathway inhibitor (IWR-1-endo). Conclusion This study identifies the YTHDF3/NEK7 axis as a key regulator of GC progression via activation of the Wnt/β-catenin pathway. YTHDF3 represents a potential prognostic biomarker and a promising therapeutic target for GC. Graphical YTHDF3 binds to and stabilizes NEK7 mRNA in an m6A-dependent manner, thereby activating the Wnt/β-catenin signaling pathway and promoting gastric cancer progression. This study identifies the YTHDF3/NEK7 axis as a potential prognostic biomarker and therapeutic target in gastric cancer.
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MOLECULAR IMMUNOLOGY
·
2026
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IF 3.7
Zeyu Tao,Jingwei Gao,Hongbo Huang,Tao Xu,Tianqi Zhang,Jingtang Liang,Longkai Bao,Shaoping Liao,Long Mo,Jinyi Chi,Limin Li,Li Xie
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin signaling pathway is strongly associated with HIV infection. Our findings demonstrate that Wnt7a activates this pathway. Subsequently, β-catenin translocates to the nucleus, where it interacts with the transcription factor 4 (TCF4) to regulate ferroptosis in T lymphocytes from HIV-infected individuals. Analysis of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals revealed significantly decreased expression levels of Wnt7a, along with key Wnt/β-catenin pathway components (β-catenin, TCF4) and the ferroptosis regulator GPX4, compared to healthy controls. Concurrently, PBMCs from HIV-infected individuals exhibited elevated levels of ferroptosis. We established an in vitro HIV-infected T lymphocyte model by expanding patient-derived PBMCs using a CD3/CD28/CD2 T cell activator and IL-2. Lentiviral transduction was used to stably overexpress Wnt7a in this model. Wnt7a overexpression successfully activated the Wnt/β-catenin pathway and significantly reduced ferroptosis levels. Furthermore, pharmacological manipulation of ferroptosis modulated Wnt7a expression: treatment with the ferroptosis inhibitor Liproxstatin-1 and Ferrostatin-1 increased Wnt7a expression, while exposure to the ferroptosis inducer RSL-3 decreased it. Flow cytometry analysis confirmed that overexpressing Wnt7a significantly increased the number of CD4 + T cells compared to the control. In summary, Wnt7a activates the Wnt/β-catenin signaling pathway to reduce ferroptosis in T lymphocytes from HIV-infected individuals, likely by targeting GPX4, suggesting a potential new strategy for treating HIV infection by restoring the T lymphocyte population.
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PHYTOMEDICINE
·
2026
·
IF 11.3
Guoguo Zhi,Haiyu Shen,Zihao Li,Manju Che,Lin Cheng,Zhirui Du,Xueqiao Yan,Shaoyang Zhang,Ruichen Yang,Xiuying Ma,Huijuan Liu,Funeng Geng,Baojie Li
Background Cutaneous wound repair is a complex biological process that restores the integrity of the skin. Forsythia suspensa (LQ) is a traditional Chinese medicinal herb known for its anti-inflammatory and antimicrobial properties; however, its role and molecular mechanisms in promoting cutaneous tissue regeneration remain unclear. Objective This study aimed to evaluate the pharmacological efficacy of LQ and its bioactive compounds in treating acute skin injuries and to elucidate the underlying molecular mechanisms. Method Two distinct animal models, a full-thickness thermal injury wound (complex inflammatory damage) and a full-thickness excisional wound (mechanical trauma), were established to evaluate the therapeutic potential of LQ. Therapeutic effects were assessed by histopathological examination and immunofluorescence analysis of skin lesions. RNA sequencing and pathway-specific inhibitors were used to investigate and validate the molecular mechanisms involved. Active compounds were identified by UPLC-MS/MS, and their mechanisms of action were explored using molecular docking, molecular dynamics simulation, and experimental validation. Results LQ significantly accelerates cutaneous wound healing in both models. Mechanistically, LQ promotes tissue regeneration by suppressing neutrophil extracellular trap (NET) formation and activating Wnt/β-catenin signaling to drive epidermal cell proliferation, and these effects are reversed by the NET inhibitor GSK484 and the Wnt pathway inhibitor IWP2. Forsythoside A, an active component of LQ, similarly enhances wound closure, re-epithelialization, and cell proliferation, indicating that it is likely the key mediator. We further show that inhibition of NETs increases Wnt ligand production and β-catenin signaling, linking inflammatory responses to regenerative signaling. Conclusion LQ and forsythoside A promote skin wound healing by coordinately regulating NET-mediated inflammation and Wnt/β-catenin signaling–mediated cell proliferation, thereby highlighting their potential as therapeutic agents in regenerative medicine.
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American Journal of Cancer Research
·
2026
·Vol. 16
·期 3
·1115
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IF 3.1
Nan Liu,Mingyue Zhao,Lei Xu,Yeting Cui,Yu Tian,Juan Li,Xiaoyu Hu,Tongcun Zhang,Haining Zhen,Yanyang Tu
Glioma is the most aggressive tumor of the central nervous system and is associated with poor prognosis, especially in patients with high-grade gliomas. In this study, we investigated the biological role of inhibitor of kappa B kinase interacting protein (IKBIP) in promoting the progression of glioma. Analysis of the TCGA and GTEx databases revealed that IKBIP is upregulated in both lower-grade gliomas (LGG) and glioblastomas (GBM) compared with normal brain tissues. Kaplan-Meier survival analysis demonstrated that IKBIP upregulation is associated with shorter overall survival (OS) and disease-specific survival (DSS) in patients with LGG. Pan-cancer analysis indicated that IKBIP is aberrantly expressed in various malignant tumors, including gliomas. IKBIP knockdown inhibited the proliferation of glioma cells both in vitro and in vivo . Additionally, IKBIP knockdown in U251 and U87 glioma cell lines significantly suppressed their invasive capacity. Furthermore, IKBIP knockdown resulted in decreased expression of proteins associated with Wnt/β-catenin/epithelial-mesenchymal transition (EMT) pathway, including β-catenin, ZEB1, ZEB2, N-cadherin, whereas the expression of E-cadherin was increased. Conversely, IKBIP overexpression reduced the level of phosphorylated β-catenin (p-β-catenin) while increasing the expression of total β-catenin in glioma cells. Furthermore, we identified that transcription factor SP1 (Specificity Protein 1), which is also upregulated in glioma tissues and cell lines and is associated with the malignant phenotype of glioma, can bind to the promoter region of IKBIP. Upregulation of SPI in glioma cells significantly increased the expression level of IKBIP, while inhibiting the phosphorylation of β-catenin. These findings collectively suggest that upregulation of IKBIP promotes the proliferation and invasive behaviors of glioma cells by activating the Wnt/β-catenin/EMT pathway. Overall, our findings suggest that SP1-IKBIP axis facilitates the proliferation and invasion of glioma through Wnt/β-catenin-associated EMT, and SP1-IKBIP axis may represent a promising target for the clinical diagnosis and treatment of glioma.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
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IF 3.4
Zizheng Lu,Minxiao Lin
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro , SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re -expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.
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ONCOLOGY REPORTS
·
2023
·Vol. 49
·期 3
·1-14
·
IF 4.2
Sijia Han,Xueying Jin,Tianyu Hu,Feng Chi
Breast cancer remains the most common malignancy and the leading cause of cancer‑associated mortality in women worldwide. Lysosomal protein transmembrane 5 (LAPTM5), a lysosomal membrane protein, plays an important role in several human malignancies. However, the biological functions and mechanism of LAPTM5 in breast cancer remain unclear. In the present study, the potential tumor‑promoting effect of LAPTM5 was predicted by bioinformatics analysis. LAPTM5 was highly expressed in breast cancer clinical specimens. Moreover, in vitro studies demonstrated that cell proliferation, migration and invasion, as well as the process of epithelial‑mesenchymal transition (EMT) were promoted by LAPTM5 overexpression and were suppressed by LAPTM5 downregulation in vitro. The tumor‑promoting effects of LAPTM5 were also confirmed by xenograft tumor assay in vivo. It was found that the tumor‑promoting effects of LAPTM5 were partly dependent on the activation of the Wnt/β‑catenin signaling pathway. Furthermore, dual‑luciferase and chromatin immunoprecipitation assays verified that the transcription factor forkhead box protein 3 (FOXP3) directly bound to the promoter of LAPTM5 and negatively regulated its expression. Taken together, the present findings indicated that LAPTM5, negatively regulated by FOXP3, promoted the malignant phenotypes of breast cancer through activating the Wnt/β‑catenin signaling pathway.
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