Human Cell
·
2022
·Vol. 35
·期 5
·1535-1546
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IF 4.374
Mao Dong,Zhang Xiaowei,Wang Zhaoping,Xu Guannan,Zhang Yun
Transmembrane protein 97 (TMEM97) is a conserved integral membrane protein highly expressed in various human cancers, including colorectal cancer (CRC), and it exhibits pro-tumor roles in breast cancer, gastric cancer, and glioma. However, whether TMEM97 participates in CRC progression is not fully understood. The expression of mRNA and protein was evaluated by real-time qPCR, western blotting, immunofluorescent, and immunohistochemical staining. TMEM97 functions in cell proliferation, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and transwell assays. The roles of TMEM97 in CRC cells in vivo was investigated using a subcutaneous xenograft model. The transcriptional regulation of TMEM97 was explored by luciferase reporter and ChIP assays. The silencing of TMEM97 inhibited migration and invasion of CRC cells in vitro and led to suppressed growth and enhanced apoptosis in CRC cells and xenografts, whereas overexpression of TMEM97 displayed opposite effects. Mechanistically, TMEM97 knockdown caused a reduction of the proliferating marker PCNA and an increase of pro-apoptotic proteins (cleaved caspase 8/3/7 and cleaved PARP) in CRC cells. TMEM97 also positively regulated the β-catenin signaling pathway in CRC cells and xenografts by modulating the phosphorylated-GSK-3β and active (non-phospho) β-catenin levels. Interestingly, YY1, a well-recognized oncogenic transcription factor, was identified to bind to the TMEM97 promoter and enhance its transcriptional activity, and silencing of TMEM97 abolished YY1-mediated pro-tumor effects on CRC cells. Our results suggest that TMEM97 is transcriptionally activated by YY1 and promotes CRC progression via the GSK-3β/β-catenin signaling pathway, providing that TMEM97 might be a novel therapeutic target for preventing CRC development.
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BIOLOGICAL TRACE ELEMENT RESEARCH
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2026
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IF 4.3
Liu Bai Han,Zhang Jin Ge,Peng Dong Qiao,Jin Yong Cheng
Copper is an essential trace element for beef cattle, yet its muscle developmental regulatory mechanism remains unclear. This study investigated the effects of copper sulfate (CuSO₄) on myogenic differentiation of bovine skeletal muscle-derived cells (BSMC) and the underlying molecular mechanisms. BSMC were isolated from the longissimus thoracis muscle of three 30-month-old crossbred steers, with each steer defined as an independent experimental unit corresponding to a separate biological replicate ( n = 3). Based on cell viability, CuSO₄ was used at 0, 0.1, 1, and 10 µM. All cell samples were harvested at differentiation day 6 (D6). The 0.1 µM CuSO₄ treatment during cell growth significantly promoted D6 myotube formation ( P = 0.049), and upregulated mRNA and protein expression of myogenic differentiation 1 (MyoD) ( P = 0.044, P = 0.030), as well as protein expression of hypoxia-inducible factor-1α (HIF-1α) ( P = 0.037) and β-catenin ( P = 0.050). During differentiation, 1 µM CuSO₄ significantly facilitated D6 myotube formation ( P = 0.0004), increased myogenic factor 5(Myf5) mRNA and protein expression ( P = 0.030, P = 0.006), and elevated HIF-1α ( P = 0.025) and β-catenin ( P = 0.004) protein levels, whereas Wnt10b protein expression remained unaltered ( P = 0.930). Single or combined pharmacological inhibition of HIF-1α and β-catenin markedly reversed copper’s pro-myogenic effect on BSMC. In conclusion, copper modulates BSMC myogenic differentiation via the HIF-1α/β-catenin axis by enhancing β-catenin protein stability independent of Wnt10b transcription. HIF-1α acts upstream to drive β-catenin, and a reciprocal regulatory relationship may exist in which β-catenin in turn helps sustain HIF-1α abundance, thereby supporting cascade signaling and downstream myogenic transcription. This study elucidates copper’s molecular mechanism governing muscle development and provides theoretical support for precise copper supplementation to improve beef production performance.
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MOLECULAR BIOTECHNOLOGY
·
2023
·
IF 2.6
Lv Chen-Guang,Cheng Yao,Zhang Lei,Wu Guo-Gang,Liang Chun-Yan,Tao Zuo,Chen Bo
BC (breast cancer) is the leading cause of cancer death in women. Exosome component 2 (EXOSC2), an RNA exosome component, is elevated in BC tissues and may relate to BC carcinogenesis. In this work, the high EXOSC2 expression was correlated with TNM (Tumor Node Metastasis) stage. Moreover, overexpression of EXOSC2 enhanced tumorigenic capacity of BC cells via facilitating cell proliferation and cell cycle progression, increasing migration and angiogenesis, as well as exacerbating xenograft formation in vivo. Whereas, EXOSC2 knockdown showed anti-cancer effects, including inhibition of cell proliferation and angiogenesis. Mechanistically, EXOSC2 activated the wnt/β-catenin pathway, which was also abolished by EXOSC2 knockdown. In addition, there were m6A methylation modification sites in the mRNA of EXOSC2. WTAP (Wilms tumor 1-associated protein) bound to EXOSC2 mRNA and increased its m6A methylation, resulting in extending the half-life of EXOSC2 mRNA. Luciferase data also confirmed that WTAP enhanced EXOSC2 mRNA stability through binding with the 3′-UTR containing m6A sites. Furthermore, WTAP silencing exhibited cancer-inhibiting effects on cell viability, cell cycle progression and tube formation, which was effectively reversed by EXOSC2 overexpression. In conclusion, our results demonstrate that EXOSC2 promotes the malignant behaviors of BC cells via activating the wnt/β-catenin pathway. In addition, EXOSC2 mediates the function of WTAP which contributes to the m6A modification of EXOSC2. Totally, this study suggested that EXOSC2 mediated the pro-tumor role of WTAP via activating the wnt/β-catenin signal.
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Human Cell
·
2023
·
IF 4.3
Hu Lianying,Cheng Zhen,Wu Lunan,Luo Liangliang,Pan Ping,Li Shujin,Jia Qiyu,Yang Ning,Xu Bin
Osteogenic differentiation plays important roles in the pathogenesis of osteoporosis. In this study, we explored the regulatory mechanism of histone methyltransferase SET domain bifurcated 1 (SETDB1) underlying the osteogenic differentiation in osteoporosis. The common osteoporosis-related genes were retrieved from the GeneCards, CTD, and Phenolyzer databases. The enrichment analysis was conducted on the candidate osteoporosis-related genes using the PANTHER software, and the binding site between transcription factors and target genes predicted by hTFtarget. The bioinformatics analyses suggested 6 osteoporosis-related chromatin/chromatin binding protein or regulatory proteins (HDAC4, SIRT1, SETDB1, MECP2, CHD7, and DKC1). Normal and osteoporosis tissues were collected from osteoporosis patients to examine the expression of SETDB1. It was found that SETDB1 was poorly expressed in osteoporotic femoral tissues, indicating that SETDB1 might be involved in the development of osteoporosis. We induced SETDB1 overexpression/knockdown, orthodenticle homeobox 2 (OTX2) overexpression, activation of Wnt/β-catenin or BMP-Smad pathways alone or in combination in osteoblasts or ovariectomized mice. The data indicated that SETDB1 methylation regulated H3K9me3 in the OTX2 promoter region and inhibited the expression of OTX2. Besides, the BMP-Smad and Wnt/β-catenin pathways were inhibited by OTX2, thereby resulting in inhibited osteogenic differentiation. Animal experiments showed that overexpressed SETDB1 could promote the increase of calcium level and differentiation of femoral tissues. In conclusion, upregulation of SETDB1 promotes osteogenic differentiation by inhibiting OTX2 and activating the BMP-Smad and Wnt/β-catenin pathways in osteoporosis.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Hanxiao Zheng,Limin Qu,Lei Yang,Xianmin Xie,Ling Song,Qiuen Xie
Knee osteoarthritis (KOA) is a chronic disease characterized by joint wear and cartilage degeneration. Current clinical treatments are based on symptomatic relief and are not effective in regenerating cartilage, and inflammation-induced cartilage damage accelerates the progression of osteoarthritis, making the protection of articular cartilage important for controlling the development of knee osteoarthritis. In this study, a biodegradable hydrogel (HA-Ca-Alg@Ica) loaded with Icariin (Ica) was prepared by in situ cross-linking of hyaluronic acid-calcium complex (HA-Ca) and sodium alginate (Alg-Na) for local sustained delivery of Ica. The hydrogel promoted chondrocyte proliferation and inhibited the degradation of cartilage matrix by regulating key factors (Wnt3a, β-catenin and GSK-3β) in the Wnt/β-catenin signaling pathway. In addition, the hydrogel reduced the expression of inflammatory factors, including IL-1β, IL-6, TNF-α, COX-2, and MMP13, leading to a reduction in inflammation and pain relief. In summary, this hydrogel containing Icariin has shown significant effects in reducing chondrocyte degradation and promoting chondrocyte proliferation, which can play a role in delaying osteoarthritis by protecting chondrocytes. These findings offer innovative prospects for the therapeutic management of knee osteoarthritis.
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EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Zhen Xu,Yilin Guo,Lu Wang,Jinquan Cui
HECW1 belongs to ubiquitin ligase (E3) HECT family, and is found to be involved in tumorigenesis and tumor progression. However, the function of HECW1 in cervical cancer (CC) remains unknown. Clinical analysis showed that HECW1 is significantly decreased in CC tumor tissues. Ectopic expression of HECW1 suppressed cell growth, promoting cell cycle arrest and apoptosis in CC cells, while downregulation of HECW1 reversed these trends, impeded proliferation and accelerated cell cycle progression of CC cells. Overexpressing of HECW1 reduced mitochondrial membrane potential and the protein expression of voltage-dependent anion channel 1 (VDAC1). In addition, upregulation of HECW1 inhibited nuclear β-catenin accumulation, downregulated β-catenin/TCF/LEF-mediated transcriptional activity and the expression of downstream gene c-Myc, whereas inhibition of HECW1 received opposite results. Further results confirmed HECW1 affects the protein expression of dishevelled-1 (DVL1), a potent activator of Wnt/β‐catenin, and inhibition of HECW1 inhibited the ubiquitination of DVL1, upregulating its expression. Inhibition of DVL1 restrained the promotion effect of HECW1 suppression on cell proliferation. In vivo experiments also verified that HECW1 suppression promoted the tumor formation of CC cells. Summary, we demonstrated that HECW1 inhibits CC cell proliferation and tumor formation by downregulating DVL1 induced Wnt/β‐catenin signaling pathway activation.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yue Xiong,Chao He,Xun Lin,Ke Cheng,Fumei He,Jingxin Zhao,Mengjie Yang,Hong Gao,Fangjie He,Xiaopei Zhang,Zeqi Liu,Gan Liu,Wenbin Deng
Black phosphorus nanosheet (BPNS) has recently demonstrated intrinsic anti-tumor bioactivity, but its underlying molecular mechanism remains unclear, limiting its potential applications in biomedicine. In this study, we investigated the impact of BPNS on glioblastoma cells and observed a significant dose-dependent inhibition of invasion and migration. RNA sequencing analysis revealed downregulation of genes associated with the WNT/β-catenin and NOTCH signaling pathways, both linked to invasion and migration. Mechanistically, BPNS directly binds to CSNK2A2, reducing its kinase activity, which indirectly enhances GSK-3β kinase activity. As a result, GSK-3β increases the phosphorylation level of β-catenin, leading to its degradation and subsequent inhibition of downstream molecules in the WNT/β-catenin signaling pathway. Our study uncovers the inherent biological activity of BPNS in hindering glioblastoma invasion and migration and sheds light on the molecular mechanisms, offering new directions for the nanomaterial’s biomedical applications.
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Journal of Cardiovascular Translational Research
·
2024
·
IF 2.4
Hu Guangquan,Chen Jin,Chen Min,Yang Kai,Wang Yuchen,Ma Ziyang,Bao Huangxin,Ding Xiaojie
Cardiac fibrosis following myocardial infarction (MI) seriously affects the prognosis and survival rate of patients. This study aimed to determine the effect and regulation mechanism of the dedicator of cytokinesis 2 (DOCK2) during this process. Experiments were carried out in mice in vivo, and in Ang II treated cardiac fibroblasts (CFs) in vitro. DOCK2 was increased in mouse myocardial tissues after MI and Ang II-treated CFs. In MI mice, DOCK2 silencing improved cardiac function, and ameliorated cardiac fibrosis. DOCK2 knockdown suppressed the activation of CFs and decreased the expression of α-SMA, collagen I, and collagen III. Suppression of DOCK2 mitigated Ang II induced migration of CFs. DOCK2 inhibition reduced the activity of the PI3K/Akt and Wnt/β-catenin pathways, while this change could be reversed by the pathway activators, SC79 and SKL2001. In summary, DOCK2 suppression improves cardiac dysfunction and attenuates cardiac fibrosis after MI via attenuating PI3K/Akt and Wnt/β-catenin pathways.
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MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-16
·
IF 6
Fang Lini,Tao Yang,Che Guoying,Yun Yongzi,Ren Min,Liu Yujie
Background Reperfusion is the most effective strategy for myocardial infarct, but induces additional injury. WD repeat and SOCS box containing protein 1 (WSB1) plays a protective role in ischemic cells. This study aims to investigate the effects of WSB1 on myocardial ischemia–reperfusion (IR) injury.Methods The myocardial IR was induced by left anterior descending (LAD) ligation for 45 min and subsequent reperfusion. The overexpression of WSB1 was mediated by tail vein injection of AAV9 loaded with WSB1 encoding sequence two weeks before IR surgery. H9c2 myocardial cells underwent oxygen-sugar deprivation/reperfusion (OGD/R) to mimic IR, and transfected with WSB1 overexpression or silencing plasmid to alter the expression of WSB1.Results WSB1 was found highly expressed in penumbra of myocardial IR rats, and the WSB1 overexpression relieved IR-induced cardio dysfunction, myocardial infarct and pathological damage, and cardiomyocyte death in penumbra. The ectopic expression of WSB1 in H9c2 myocardial cells mitigated OGD/R-caused apoptosis, and silencing of WSB1 exacerbated the apoptosis. In addition, WSB1 activated β-catenin signaling, which was deactivated under the ischemic condition. The co-immunoprecipitation results revealed that WSB1 mediated ubiquitination and degradation of glycogen synthase kinase 3 beta (GSK3β) as an E3 ligase in myocardial cells. The effects of WSB1 on myocardial cells under ischemic conditions were abolished by an inhibitor of β-catenin signaling.Conclusion WSB1 activated β-catenin pathway by promoting the ubiquitination of GSK3β, and restrained IR-induced myocardial injury. These findings might provide novel insights for clinical treatment of myocardial ischemic patients.
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Food Bioscience
·
2024
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IF 4.8
Yiming Ren,Liang Li
Probiotics have numerous biological functions and clinical studies have reported that consuming probiotic foods could promote hair growth and hair follicle health. Bifidobacterium longum BB536 was selected to investigate the possibility of treating hair loss with Cell-Free Supernatant (CFS) of B. longum BB536 and the alleviation mechanism of CFS on dihydrotestosterone (DHT)-damaged human dermal papilla cells (HDPCs). The results showed that HDPCs treated with 10% CFS of B. longum BB536 for 24 h could significantly promote cell proliferation, repair cell damage, accelerate the process of cell cycle and increase the secretion of VEGF. The CFS of B. longum BB536 reduced the apoptosis rate of DHT-damaged HDPCs. In addition, it could reduce the level of pro-inflammatory factors and improve the alkaline phosphatase (ALP) activity. Metabolites of B. longum BB536 may increase the protein expression of Wnt10b, β-catenin and LEF-1 by activating Wnt/β-catenin signaling pathway and inhibit the expression of DHT-induced negative feedback factors DKK1 and GSK-3β, which alleviates the damage of DHT on HDPCs, some protein expression levels such as LEF-1 are close to minoxidil (common drugs for hair loss). So, metabolites of B. longum BB536 can be used as new treatment for hair loss due to its safety. This study provides theoretical basis for probiotics to prevent androgenic alopecia.
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JOURNAL OF ANIMAL SCIENCE
·
2024
·
IF 2.7
Ni Mengke,He Hui,Chen Mengjuan,Li Zhichao,Cai Hanfang,Chen Zhi,Li Ming,Xu Huifen
Acetic acid, which is one of the most abundant short-chain fatty acids (SCFA) in rabbits’ cecum, has been reported to play an important function during various physiological metabolic processes. The present study was conducted to elucidate the effects of sodium acetate on growth performance and intestinal health by evaluating feed intake and efficiency, diarrhoea score, serum and cecum metabolites, cecal pH and SCFA, histological staining, nutritional composition of meat and gene expression profile of cecum in rabbits. As a result of sodium acetate supplement, the feed conversion ratio, diarrhoea score, and diameter of muscle fiber were significantly decreased (P < 0.05). Additionally, dietary sodium acetate significantly increased in total area of muscle fibers and content of crude ash (P < 0.05). Dietary sodium acetate significantly increased serum glucose, total bile acid, and total cholesterol levels and decreased amylase, lipase, and tCO2 content (P < 0.05). Further examination suggested that sodium acetate supplementation enhanced the micro-environment of cecum, evidenced by significantly increased levels of total antioxidant capacity, total superoxide dismutase, and glutathione peroxidase, and decreased pH and amylase levels (P < 0.05). According to transcriptome sequencing of cecal tissues, differentially expressed genes were predominantly enriched in cell cycle, ABC transporters, and chemokine signaling pathways. Sodium acetate was further suggested to stimulate the proliferation and migration of rabbits’ cecum epithelial cells by activating Wnt/β-catenin pathway both in vivo and in vitro. In conclusion, dietary sodium acetate supplementation improved growth performance and intestinal health in rabbits.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Lulu Peng,Zhengwei Zou,Lin Zhou,Lincai Li,Wenming Lu,Cixiang Chen,Yan Xu,Yuyue Liu,Jing Lin,Junsong Ye
Hepatic fibrosis (HF) is a leading cause of death worldwide, yet there is currently no safe and effective treatment available. Canagliflozin, a novel glucose-lowering drug, has been shown to improve non-alcoholic steatohepatitis (NASH). However, its therapeutic effects on HF and the underlying molecular mechanisms remain unclear. In this study, HF was induced in mice via intraperitoneal injections of CCl 4 . Additionally, immortalized hepatic stellate cells (HSCs), including HSC-T6 and LX-2 cells, were used for in vitro experiments. Our findings revealed that Canagliflozin inhibited the activation and proliferation of HSCs, thereby downregulated the expression levels of fibrotic markers (α-SMA and Collagen I), ultimately alleviating HF. Further investigations demonstrated that Canagliflozin inhibits protein phosphatase 2 A (PP2A) activity in HSCs, which in turn prevents PP2A-mediated dephosphorylation of β-catenin and attenuates Wnt/β-catenin signaling. While the Wnt/β-catenin signaling is considered a key mechanism that promote the activation and proliferation of HSCs, it is also a crucial pathway in the development of HF. Moreover, increased activity of PP2A was found to promote the expression of fibrotic markers (α-SMA and Collagen I) in HSCs. In conclusion, our study indicates that Canagliflozin ameliorate HF via inhibiting PP2A-mediated dephosphorylation of β-catenin in HSCs. The inhibition of PP2A in HSCs may represent a potential therapeutic target not only for cancer treatment but also for the management of HF.
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