BMC Complementary Medicine and Therapies
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2020
·Vol. 20
·期 1
·1-10
·
IF 0
Liu Shou Gang,Luo Guang Pu,Qu Yong Bin,Chen Yong Feng
Background Psoriasis is a common inflammatory skin disease. Abnormal proliferation of keratinocytes is one of the psoriatic histopathological features. Indirubin has an essential effect on the proliferation and activation of keratinocytes; however, in psoriasis, the specific mechanism of action of indirubin on keratinocytes is unclear. In the present study, we revealed the effects of indirubin on DNA methyltransferase 1 (DNMT1), wnt inhibitory factor 1 (wif-1), and wnt/β-catenin signal pathway, in the meantime, we explored the effects of indirubin on proliferation, cell cycle and the apoptosis of HaCaT cells.Methods The expression of DNMT1, wif-1, Frizzled2, Frizzled5, and β-catenin in HaCaT cells treated with different concentrations of indirubin were detected by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of DNMT1 and wif-1 were observed after treated with different concentrations of indirubin by enzyme-linked immunosorbent assay (ELISA). The wif-1 promoter methylation status was detected by DNA methylation-specific PCR (MSP). The transcriptional activities of wif-1 and β-catenin were discovered by a luciferase reporter gene system. Cell viability was determined by Cell Counting Kit-8 (CCK8) method. The cell cycle was detected by flow cytometry. The apoptotic cells were surveyed by the apoptosis kit. The expression of Inolucrin, Loricrin, Filaggrin, Keratin 17, and transcriptional activation of transglutaminase 1(TGase1) were detected by Western blotting.Results Indirubin inhibited the expression of DNMT1 and the methylation of the wif-1 promoter. In the wnt signal pathway, indirubin restored the protein expression of wif-1 and inhibited expression of Frizzled2, Frizzled5, and β-catenin. Besides, indirubin inhibited the proliferation of HaCaT cells, induced apoptosis, and arrest cell cycle. We also reported that indirubin could down-regulate the expression of Involucrin, TGase 1, and keratin 17, but the expression of Filaggrin and Loricrin had no significant effect.Conclusion Our research showed that indirubin promoted the demethylation of wif-1 and suppressed the wnt/β-catenin signal pathway, thereby exerted an anti-proliferative effect. This study reveals the anti-proliferation mechanism of indirubin, which may provide an effective option for the treatment of proliferative diseases.
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3 Biotech
·
2021
·Vol. 11
·期 8
·1-11
·
IF 2.406
Wang Dekang,Hu Aili,Peng Hao,Li Dongbo,Zhang Li
Glioma is the most common primary brain tumor in adults with an adverse prognosis and obscure pathogenesis. PICALM interacting mitotic regulator protein (PIMREG) functions as an oncogene in multiple types of cancer, but its function in glioma remains unknown. The Gene Expression Profiling Interactive Analysis 2 (GEPIA2, http://gepia2.cancer-pku.cn/#index ) showed that PIMREG expression in the glioma tissues was higher than that in normal brain tissues. Herein, cell counting kit-8 assay and flow cytometry analysis exhibited that overexpression of PIMREG significantly promoted the proliferation of glioma cells and the transition from G1 phase of the cell cycle to S phase. Wound-healing and transwell assays showed that overexpression of PIMREG markedly enhanced the migration and invasion of glioma cells. Western blot analysis revealed that overexpression of PIMREG increased the expression of cyclin D1, cyclin E, Vimentin, matrix metalloproteinase (MMP)-2, and MMP-9, but reduced the expression of E-cadherin. In addition, overexpression of PIMREG activated the β-catenin signaling pathway, as evidenced by the increased total and nuclear expression of β-catenin and the up-regulated expression of its downstream target c-myc. Furthermore, immunofluorescence staining further indicated the increased nuclear translocation of β-catenin in PIMREG-overexpressing cells. However, knockdown of PIMREG exerted opposite effects on glioma cells. Blockade of the β-catenin signaling by ICG-001 markedly impeded the promoting effects of PIMREG on glioma cell proliferation and invasion. In conclusion, PIMREG acts as a tumor promoter in glioma at least partly via activating the β-catenin signaling pathway. This study provides new insights into the molecular mechanism for glioma pathogenesis and treatment.
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Journal of Natural Medicines
·
2026
·
IF 2.6
Chen Peiyao,Wan Baolian,Yu Fei,Zhang Yanqiu,He Mengmeng,Wu Enyi,He Yanjun,Zhong Hui,Zhang Hao
Liver aging is a critical contributor to metabolic dysregulation and the development of various liver diseases. Currently, there is no approved therapy specifically targeting liver aging. The potential of medicinal and edible herbs in preventing and treating liver aging has attracted increasing attention. Accordingly, we constructed a self-built compound library containing 87 bioactive constituents isolated from these herbs. This study aimed to identify the potential compound capable of alleviating hepatic senescence from the constructed library and to elucidate the underlying mechanism. Isomucronulatol (Iso), a bioactive isoflavone isolated from Astragalus membranaceus , exhibited potential anti-hepatic senescence activity in a p21 promoter-driven luciferase reporter assay. Iso exhibited significant anti-hepatic senescence activity in H₂O₂-stimulated and doxorubicin (DOX)-stimulated HepG2 cells, as well as in mitomycin C (MC)-exposed AML12 cells, as evidenced by reduced SA-β-Gal positivity, downregulated p21 and p16 expression, and decreased secretion of SASP factors (IL-6, IL-1β, CCL2). In a D-galactose (D-gal)-induced mouse aging model, Iso treatment attenuated liver histological damage, lowered serum ALT and AST levels, and suppressed senescence markers in liver tissues. Transcriptomic and network pharmacology analyses revealed that Iso could activate Wnt/β-catenin signaling pathway to delay hepatic senescence. Mechanistically, Iso could facilitate nuclear accumulation of β-catenin by inhibiting GSK-3β acetylation, thereby restoring Wnt signaling. Collectively, these findings highlight Iso as a potential therapeutic agent against hepatic senescence. Graphical abstract
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CELL BIOLOGY INTERNATIONAL
·
2026
·Vol. 50
·期 2
·e70136
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IF 3.1
Guansheng Hu,Laiai Fang,Xiang Ding,Qingjun Zeng,Youwu Wen,Dongyang Cheng,Yonggui Zhou
Replication factor C (RFC), a multimeric protein with ATPase activity, plays a crucial role in DNA replication and repair. RFC4, one of its subunits, is aberrantly expressed in various malignant tumors, including colorectal cancer (CRC). Nevertheless, the impact of RFC4 on CRC metastasis remains to be elucidated. In this study, we systematically examined the effects of RFC4 silencing on the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and Wnt/β-catenin signaling pathway in CRC cells in vitro. Additionally, we further explored the regulatory role of RFC4 in liver metastasis of CRC cells in vivo. Finally, BML-284, a known activator of the Wnt/β-catenin signaling pathway, was employed to validate the underlying mechanism by which RFC4 modulates the invasive phenotype of CRC cells. The results demonstrated that RFC4 was significantly overexpressed in CRC cell lines. Upon silencing of RFC4, the proliferation, migration, and invasion capabilities of CRC cells were markedly attenuated, and the EMT process as well as Wnt/β-catenin signaling pathway activity were effectively suppressed. Notably, RFC4 silencing significantly reduced liver metastasis of CRC cells in a nude mouse model. However, the inhibitory effects of RFC4 silencing on CRC cells proliferation, migration, invasion, and EMT were partially reversed by the intervention of the Wnt/β-catenin signaling pathway activator BML-284. Altogether, these results indicate that RFC4 plays a critical role in promoting CRC metastasis, and its mechanism of action may involve the regulation of Wnt/β-catenin signaling pathway activation to facilitate EMT.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2025
·Vol. 48
·期 10
·1503-1513
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IF 1.7
Xinyue Zhou,Wei Zhou,Changhong Qu,Yisha Jiang,Wenzhu Liu,Lipeng Pei
Endometriosis, a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, demonstrates malignant tumor-like properties including aggressive adhesion and invasiveness. Emerging evidence implicates roundabout guidance receptor 3 (ROBO3) in cellular pathophysiology, yet its role in endometriosis remains unexplored. In this study, we first found abnormally high ROBO3 expression in endometriosis by bioinformatics analysis. Next, functional assays revealed that ROBO3 is a key regulator promoting the invasion and migration of endometriotic stromal cells (ESCs) in vitro. Mechanistically, ROBO3 activates the Wnt/β-catenin signaling pathway, evidenced by increased phosphorylation of glycogen synthase kinase 3β, nuclear β-catenin accumulation, and upregulated c-myc expression. Pharmacological inhibition of Wnt/β-catenin with MSAB (5 μM) reversed ROBO3-mediated pro-invasive and pro-migratory effects. Furthermore, we discovered that ROBO3 enhances the secretion of chemokines CCL2 and CCL5 in ESCs, which subsequently promote macrophage polarization toward the M2 phenotype, as indicated through elevated expression of interleukin-10 and Arg-1. Collectively, our findings elucidate a dual mechanism whereby ROBO3 drives endometriosis progression through both intrinsic activation of Wnt/β-catenin signaling and extrinsic modulation of tumor-associated macrophages, underscoring ROBO3 as a promising therapeutic target for endometriosis.
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Frontiers in Oncology
·
2023
·
IF 4.7
Song Jian,Ren Tingting,Duan Yanheng,Guo Haitao,Wang Gang,Gan Yu,Bai Mengcai,Dong Xiaotian,Zhao Zheng,An Jiaze
Background: Near-infrared fluorescence (NIRF) imaging has recently emerged as a promising tool for noninvasive cancer imaging. However, lack of tumor sensitivity and specificity restricts the application of NIRF dyes in surgical navigation.Methods: Herein, we investigated the imaging features of NIRF dye MHI-148 and indocyanine green (ICG) in live cell imaging and xenograft nude mice models. TCGA dataset analysis and immunohistochemistry were conducted to investigate the expression of OATPs or ABCGs in hepatocellular carcinoma (HCC) tissues. OATPs or ABCGs were knocked down and overexpressed in HCC cells using transient transfection by siRNA and plasmids or stable transfection by lentivirus. Further, qRT-PCR ,Western blotting and the use of agonists or inhibitors targeting β-catenin signaling pathway were applied to explore its important role in regulation of OATP2B1 and ABCG2 expression.Results: Here we demonstrated that NIRF dye MHI-148 was biocompatible as indocyanine green (ICG) but with higher imaging intensity and preferential uptake and retention in hepatocellular carcinoma (HCC) cells and tissues. Moreover, our data indicated that membrane transporters OATP2B1 and ABCG2, which regulated by β-catenin signaling pathway, mediated tumor-specific accumulation and retention of MHI-148 in HCC cells. In addition, the treatment with β-catenin inhibitor significantly enhanced the accumulation of MHI-148 in HCC tissues and improved the efficacy of tumor imaging with MHI-148 in vivo.Conclusions: Our study uncovers a mechanism that links the distribution and expression of the membrane transporters OATP2B1 and ABCG2 to the tumor-specific accumulation of MHI-148, and provides evidence supporting a regulating role of the β-catenin signaling pathway in OATP2B1 and ABCG2- induced retention of MHI-148 inHCC tissues, and strategy targeting key components of MHI-148 transport machinery may be a potential approach to improve HCC imaging.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Chen Bo,Li Xiaoli,Wu Lihong,Zhou Duanfang,Song Yi,Zhang Limei,Wu Qiuya,He Qichen,Wang Gang,Liu Xu,Hu Hui,Zhou Weiying
High invasiveness is a biological and clinical characteristic of glioblastoma and predicts poor prognosis of patients. Quercetin, a natural flavonoid compound, exhibits anticancer activity. However, we have a limited understanding of the possible underlying mechanism of quercetin in glioblastoma. In this study, we investigated the anticancer effect of quercetin in human glioblastoma cells. Our results showed that quercetin markedly suppressed the viability of glioblastoma cells in vitro and in vivo, and significantly inhibited glioblastoma cell migration and invasion. Moreover, quercetin reversed EMT-like mesenchymal phenotype and reduced the expression levels of EMT-related markers. Furthermore, we found that quercetin suppressed GSK-3β/β-catenin/ZEB1 signaling in glioblastoma. Taken together, our results demonstrate that quercetin inhibited migration and invasion of human glioma cells by suppressing GSK3β/β-catenin/ZEB1 signaling. Our study provides evidence that quercetin is a promising therapeutic natural compound to treat glioblastoma.
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Oncology Letters
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2021
·Vol. 21
·期 3
·1-1
·
IF 2.967
Jiaxue Hao,Xufen Dai,Juan Gao,Yuexuan Li,Zhaoling Hou,Zhongman Chang,Yuxin Wang
Colorectal cancer (CRC) is the third most common cancer worldwide, with high incidence and mortality rates. Conventional therapies, including surgery, chemotherapy and radiation, are extensively used for the treatment of CRC. However, patients present with adverse effects, such as toxicity, hepatic injury and drug resistance. Thus, there is an urgent requirement to identify effective and safe therapy for CRC. Curcumin (CUR), a polyphenol substrate extracted from the rhizome of Curcuma longa, has been extensively studied for the treatment of CRC due to its high efficacy and fewer side effects. Previous studies have reported that several signaling pathways, such as NF‑κB, Wnt/β‑catenin, are involved in the antitumor effects of CUR in vitro. However, the effect and mechanisms in vivo are not yet fully understood. The present study aimed to determine the molecular mechanism of colorectal cancer in vivo. Reverse transcription‑quantitative PCR, western blot and immunohistochemistry analyses were performed to determine the underlying molecular mechanism of curcumin's anti‑cancer effect in azoxymethane‑dextran sodium sulfate induced colorectal cancer. The results of the present study demonstrated that CUR suppressed tumorigenesis in AOM‑DSS induced CRC in mice, and anticancer effects were exerted by suppressing the expression of pro‑inflammatory cytokines, and downregulating Axin2 in the Wnt/β‑catenin signaling pathway. Taken together, these results exhibit the potential in vivo mechanisms of the anticancer effects of CUR, and highlight Axin2 as a potential therapeutic target for CRC.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Yongkui Wang,Jian Chen,Jing Chen,Chao Dong,Xu Yan,Zhongpei Zhu,Pan Lu,Zongmian Song,Hongjian Liu,Songfeng Chen
Glucocorticoids have been widely used in multiple inflammatory and autoimmune diseases. However, long-term glucocorticoid therapy may result in osteoporosis. The present study aimed to evaluate the potential therapeutic effects and investigate the underlying mechanisms of Daphnetin (Daph) on glucocorticoid-induced osteoporosis (GIOP). In vivo, male Sprague Dawley rats were intramuscularly injected with dexamethasone (DEX) to induce GIOP and Daph was given intraperitoneally. Bone histological changes, mineral content, microstructure parameters and bone turnover markers were detected. Gut microbiota composition and intestinal barrier function were further assessed. In vitro, MC3T3-E1 pre-osteoblasts were treated with DEX and the abilities of Daph on osteoblast proliferation, differentiation and mineralization were assessed. A Wnt signaling inhibitor, XAV939 , was added additionally to evaluate the effect of Daph on Wnt signaling. The results showed that in vivo, Daph increased the DEX-induced reduction in body weight gain, bone mineral content and microstructure parameters and restored the levels of bone turnover markers in GIOP rats. In vitro, Daph promoted osteoblast proliferation, differentiation and mineralization in DEX-treated MC3T3-E1 pre-osteoblasts. Moreover, Daph activated the Wnt/GSK-3β/β-catenin signaling pathway. XAV939 successfully abolished the beneficial effects of Daph on GIOP in vitro . Besides, Daph showed improvement on gut microbiota disorder and intestinal barrier dysfunction post GIOP. Collectively, these data demonstrated that Daph effectively ameliorates GIOP and the possible mechanism may be that Daph activated Wnt/GSK-3β/β-catenin signaling.
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Aging-US
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2020
·
IF 4.831
Xin Zhang,Jiapeng Xu,Ronglin Yan,Yu Zhang,Zunqi Hu,Hongbing Fu,Qing You,Qingping Cai,Dejun Yang
Altered expression of family with sequence similarity 84, member B (FAM84B) has been found in various human cancers. However, the expression and function of FAM84B in pancreatic ductal adenocarcinoma (PDAC) has not been studied. Here, by analyzing The Cancer Genome Atlas cohort, we found that FAM84B amplification was observed in 11% of 141 PDAC patients, and FAM84B amplification was correlated with higher mRNA expression of FAM84B. FAM84B amplification and overexpression was significantly correlated with poor overall survival. Moreover, knockdown of FAM84B in PDAC cell lines suppressed cell proliferation and induced apoptosis. FAM84B knockdown also suppressed mitochondrial function and glycolysis of PDAC cells. Interestingly, knockdown of FAM84B decreased the nuclear accumulation of β-catenin, and the expression of c-Myc and lactate dehydrogenase A, but enhanced the expression of Survivin. On the contrary, FAM84B overexpression displayed reversed effects in cell proliferation, apoptosis, mitochondrial function, and glycolysis, which was blocked by the Wnt/β-catenin pathway inhibitor (XAV939). In addition, PDAC cells with lower expression of FAM84B were more sensitive to gemcitabine-induced cell proliferation inhibition both in vitro and in vivo . In conclusion, FAM84B plays an important role in aerobic glycolysis and tumorigenesis in PDAC and Wnt/β-catenin may be involved in this process.
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PLoS One
·
2016
·Vol. 11
·期 3
·e0149257
·
IF 3.057
Chao Fang,Weihong Lu,Chengyan Li,Xi Peng,Yang Wang,Xiulan Huang,Zhihong Yao,Nali Cai,Yuge Huang,Xingliang Zhang,Jianxin Tan
Asthma is a common chronic respiratory disease. In a previous study, we found several circulating microRNA signatures associated with childhood asthma and selected miR-3162-3p for subsequent studies. Since the target proteins and underlying molecular mechanisms of miR-3162-3p in asthma etiopathogenesis are not well characterized, we designed this study to clarify its role. We employed bioinformatics and quantitative PCR methods as a first step to determine the target of miR-3162-3p, and we elucidated β-catenin. Luciferase assays and western blot analysis confirmed β-catenin as a direct target of miR-3162-3p as the 3’-untranslated region of β-catenin mRNA possesses a specific miR-3162-3p pairing site. The correlation between the expression levels of miR-3162-3p and β-catenin is confirmed by quantitative PCR and western blot studies in A549, Beas-2B and H1299 cell lines and OVA-induced asthma mouse model. Of note, upregulation of the endogenous miR-3162-3p level is concomitant with the reduction of β-catenin mRNA and protein expression levels. MiR-3162-3p antagomir treatment antagonizes the endogenous miR-3162-3p and effectively rescues the attenuation of endogenous β-catenin in OVA-induced asthmatic mice, which alleviates airway hyperresponsiveness and ameliorates airway inflammation. Collectively, our findings suggest a novel relationship between miR-3162-3p and β-catenin and clarify their mechanistic role in asthma etiopathogenesis.
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JOURNAL OF MEDICINAL CHEMISTRY
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2024
·
IF 6.8
Feng-Yang Wang,Liang-Mei Yang,Xiao-Lin Xiong,Jing Yang,Yan Yang,Jiu-Qin Tang,Lei Gao,Yuan Lu,Yuan Wang,Taotao Zou,Hong Liang,Ke-Bin Huang
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/β-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in β-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
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