JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Chenxi Yan,Guilan Li,Lian Huang,Zhaohui Zhang
Beryllium (Be) is a recognised environmental toxicant associated with pulmonary fibrosis. Epithelial–mesenchymal transition (EMT), a critical process in cell phenotype conversion, plays a key role in its pathophysiology. Methyltransferase-like 3 (METTL3), a major N6-methyladenosine methyltransferase, regulates gene expression and cellular functions. However, its role in Be-induced EMT remains unclear. In this study, human bronchial epithelial cell line (16HBE cells) were exposed to varying concentrations of beryllium sulphate (BeSO 4 ) to assess changes in METTL3 expression. METTL3 overexpression vectors were constructed, and quantitative reverse transcription-polymerase chain reaction, western blotting and immunofluorescence were used to detect METTL3, EMT markers and Wingless/Integrated (Wnt)/β-catenin pathway proteins. The Wnt/β-catenin pathway inhibitor ICG-001 was also employed to explore the role of the Wnt/β-catenin pathway in BeSO 4 -induced EMT. The study demonstrated that BeSO 4 suppressed METTL3 expression, induced EMT and activated the Wnt/β-catenin pathway in 16HBE cells. Both METTL3 overexpression and ICG-001 pretreatment mitigated BeSO 4 -induced EMT and Wnt/β-catenin pathway activation. These findings suggest that METTL3 inhibits BeSO 4 -induced EMT by suppressing the Wnt/β-catenin pathway, offering novel mechanistic insights into beryllium toxicity and a potential therapeutic target for Be-related pulmonary fibrosis.
研究领域:
细胞生物学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Jun Li,Meixin Hu,Yingying Liu,Rongrong Lu,Weijun Feng
Heavy metals, such as Lead (Pb), are ubiquitous environmental pollutants that is a considerable problem worldwide. Increasing evidences suggest that Pb exposure negatively impact central nervous system. However, the exact toxic mechanism of Pb on early human brain development remain unclear due to the limitations of animal models and 2D cell models. In this study, we used human cortical organoids to reveal that Pb had specific early neurodevelopmental toxicity during the neural differentiation stage. We observed that short-term Pb exposure (10 days) is sufficient to induce premature neuronal differentiation. Mechanistically, Pb exposure downregulates the Wnt signaling in cortical organoids, and the activation of Wnt signaling reverses the neurodevelopmental phenotype. In support, Pb exposure during pregnancy lead to premature neuronal differentiation and reduced neurogenesis in mice. In conclusion, our study reveals the neuropathogenesis of Pb exposure and uncovers the potential intervention role of Wnt activation.
研究领域:
毒理学
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神经科学
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发育生物学
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DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2023
·Vol. 46
·期 1
·74-85
·
IF 2
Jianchao He,Yuhui Bu,Xiaolong Li,Xiaojun Zhang,Li Ma
Breast cancer (BC) is the most generally diagnosed cancer and the driving cause of cancer-related death. Transmembrane (TMEM) proteins have been reported to serve as prognostic indicators in a variety of cancers, and it can offer therapeutic targets for carcinoma. However, the function of TMEM in BC remains unclear. In this study, TMEM9A, a member of TMEM family, was screened as the candidate gene after analyzing the profiles of GSE42568 and GEPIA-BRCA database via bioinformatic method. The upregulated expression of TMEM9A was confirmed in BC samples compared with the paired normal tissues. Hence, we speculated that TMEM9A might promote BC progression. To test the hypothesis, we performed a series of loss/gain-of-function experiments and found that BC cells with TMEM9A deletion inhibited cell proliferation, migration, and invasion along with induced apoptosis. Conversely, TMEM9A overexpression reversed the trend. Mechanically, TMEM9A knockdown blocked the Wnt/β-catenin signaling pathway as evidenced by the increased adenomatous polyposis coli (APC) expression and decreased β-catenin, cyclin D1, and axis inhibition protein 2 (AXIN2) expression. Furthermore, over-activation of the Wnt/β-catenin pathway by transfecting BC cells with β-Catenin-S33Y (β-Catenin tyrosine for serine at codon 33) plasmids reversed the effects caused by TMEM9A knockdown. In conclusion, TMEM9A may play a tumor-promoting role in BC progression via activating the Wnt/β-catenin signaling pathway. Therefore, TMEM9A may be an effective therapeutic option for BC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Current Medical Science
·
2022
·Vol. 42
·期 5
·1022-1032
·
IF 2.64
Chen Xue-qi,Mao Jia-yu,Wang Chun-saier,Li Wen-bin,Han Tao-tao,Lv Ke,Li Jing-nan
Objective While the upregulation of cytochrome P450 family 24 subfamily A member 1 ( CYP24A1 ) gene expression has been reported in colon cancer, its role in tumorigenesis remains largely unknown. In this study, we aimed to investigate the involvement of CYP24A1 in Wnt pathway regulation via the nuclear factor kappa B (NF-κB) pathway. Methods The human colon cancer cell lines HCT-116 and Caco-2 were subjected to stimulation with interleukin-6 (IL-6) as well as tumor necrosis factor alpha (TNF-α), with subsequent treatment using the NF-κB pathway-specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). Furthermore, CYP24A1 expression was subjected to knockdown via the use of small interfering RNA (siRNA). Subsequently, NF-κB pathway activation was determined by an electrophoretic mobility shift assay, and the transcriptional activity of β-catenin was determined by a dual-luciferase reporter assay. A mouse ulcerative colitis (UC)-associated carcinogenesis model was established, wherein TNF-α and the NF-κB pathway were blocked by anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides, respectively. Then the tumor size and protein level of CYP24A1 were determined. Results IL-6 and TNF-α upregulated CYP24A1 expression and activated the NF-κB pathway in colon cancer cells. PDTC significantly inhibited this increase in CYP24A1 expression. Additionally, knockdown of CYP24A1 expression by siRNA could partially antagonize Wnt pathway activation. Upregulated CYP24A1 expression was observed in the colonic epithelial cells of UC-associated carcinoma mouse models. Anti-TNF-α monoclonal antibody and NF-κB antisense oligonucleotides decreased the tumor size and suppressed CYP24A1 expression. Conclusion Taken together, this study suggests that inflammatory factors may increase CYP24A1 expression via NF-κB pathway activation, which in turn stimulates Wnt signaling.
研究领域:
肿瘤学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2024
·
IF 6.9
Zhang Tingting,Zhao Faming,Zhang Yi,Shi Ji-Hua,Cui Fengzhen,Ma Weixiang,Wang Kai,Xu Chuanrui,Zeng Qingping,Zhong Rong,Li Ningning,Liu Yong,Jin Yang,Sheng Xia
Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of β-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.
研究领域:
癌症生物学
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分子生物学
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遗传学
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转化医学
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DOI
PubMed
高影响因子
Cell Regeneration
·
2023
·Vol. 12
·期 1
·1-18
·
IF 0
Liu WenYe,Lin ShuHui,Li LingYa,Tai ZhiPeng,Liu Jing-Xia
EAF1 and EAF2, the eleven-nineteen lysine-rich leukemia (ELL)-associated factors which can assemble to the super elongation complex (AFF1/4, AF9/ENL, ELL, and P-TEFb), are reported to participate in RNA polymerase II to actively regulate a variety of biological processes, including leukemia and embryogenesis, but whether and how EAF1/2 function in hematopoietic system related hypoxia tolerance during embryogenesis remains unclear. Here, we unveiled that deletion of EAF1/2 (eaf1−/− and eaf2−/−) caused reduction in hypoxia tolerance in zebrafish, leading to reduced erythropoiesis during hematopoietic processes. Meanwhile, eaf1−/− and eaf2−/− mutants showed significant reduction in the expression of key transcriptional regulators scl, lmo2, and gata1a in erythropoiesis at both 24 h post fertilization (hpf) and 72 hpf, with gata1a downregulated while scl and lmo2 upregulated at 14 hpf. Mechanistically, eaf1−/− and eaf2−/− mutants exhibited significant changes in the expression of epigenetic modified histones, with a significant increase in the binding enrichment of modified histone H3K27me3 in gata1a promoter rather than scl and lmo2 promoters. Additionally, eaf1−/− and eaf2−/− mutants exhibited a dynamic expression of canonical WNT/β-catenin signaling during erythropoiesis, with significant reduction in p-β-Catenin level and in the binding enrichment of both scl and lmo2 promoters with the WNT transcriptional factor TCF4 at 24 hpf. These findings demonstrate an important role of Eaf1/2 in erythropoiesis in zebrafish and may have shed some light on regeneration medicine for anemia and related diseases and on molecular basis for fish economic or productive traits, such as growth, disease resistance, hypoxia tolerance, and so on.
研究领域:
发育生物学
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血液学
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分子生物学
✓ 已验证
DOI
Biomed Research International
·
2018
·
IF 2.583
Xinggui Tian,Huaji Jiang,Yuhui Chen,Xiang Ao,Chuan Chen,Wentao Zhang,Feilin He,Xiaoqing Liao,Xiaocheng Jiang,Tao Li,Zhongmin Zhang,Xintao Zhang
Background. Tendon-bone healing is a reconstructive procedure which requires a tendon graft healing to a bone tunnel or to the surface of bone after the junction injury between tendon, ligament, and bone. The surgical reattachment of tendon to bone often fails due to regeneration failure of the specialized tendon-bone junction. Materials and Methods. An extra-articular tendon-bone healing rat model was established to discuss the effect of the baicalein 10 mg/(kg·d) in accelerating tendon-bone healing progress. Also, tendon-derived stem cells (TDSCs) were treated with various concentrations of baicalein or dickkopf-1 (DKK-1) to stimulate differentiation for 14 days. Results. In vivo, tendon-bone healing strength of experiment group was obviously stronger than the control group in 3 weeks as well as in 6 weeks. And there were more mature fibroblasts, more Sharpey fibers, and larger new bone formation area treated intragastrically with baicalein compared with rats that were treated with vehicle for 3 weeks and 6 weeks. In vitro, after induction for 14 days, the expressions of osteoblast differentiation markers, that is, alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix (OSX), and collagen I, were upregulated and Wnt/β-catenin signaling pathway was enhanced in TDSCs. The effect of DKK-1 significantly reduced the effect of baicalein on the osteogenic differentiation. Conclusion. These data suggest that baicalein may stimulate TDSCs osteogenic differentiation via activation of Wnt/β-catenin signaling pathway to accelerate tendon-bone healing.
研究领域:
骨科
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干细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Zhize Liu,Weitao He,Jingwei Zhang,Bo Su,Jiang Mu,Xintao Wang
Introduction: Paederia scandens (Lour.) Merr. (P. scandens), a widely consumed edible wild botanical drug in East Asia, has traditionally been used in folk medicine for its purported health-promoting effects, including the relief of fractures, rheumatoid arthritis, and pain. Despite its common use, the bioactive metabolites and underlying mechanisms of action remain insufficiently understood. This study investigates the pharmacological effects and molecular mechanisms of P. scandens in the context of osteoporosis.Methods: An ovariectomized (OVX) rat model of osteoporosis was used to evaluate the effects of P. scandens extract on bone health. Network pharmacology analysis identified candidate metabolites related to osteoblast differentiation. Paederoside, the primary plasma-absorbed metabolite, was validated in OVX rats via HPLC-Q-TOF-MS. In vitro experiments assessed osteogenesis and osteoclast activity using an osteoblast-osteoclast co-culture system, while in vivo studies evaluated serum calcium and phosphorus levels, bone morphology, and bone mass.Results: P. scandens extract significantly improved bone mass, bone mineral density (BMD), and the trabecular bone microstructure in the OVX rat model. Paederoside promoted osteogenesis and suppressed osteoclast activity in vitro. In vivo, paederoside demonstrated pronounced anti-osteoporotic effects, as evidenced by elevated serum calcium and phosphorus levels, improved bone morphology, and increased bone mass. Paederoside upregulated osteogenesis-related markers (BMP2, Smad1, Col1a1, Bglap, Osterix, and Runx2) and downregulated osteoclastogenesis-related markers (RANKL, NFATc1, Acp5, Ctsk, and Mmp9). Transcriptomic analysis revealed that paederoside modulated the Wnt/β-catenin signaling pathway, inducing Wnt3a expression, inhibiting GSK-3β and β-catenin phosphorylation, and upregulating downstream targets such as Cyclin D1 and c-Myc.Discussion: In conclusion, P. scandens exerts protective effects against osteoporosis, and paederoside, identified as a primary plasma-absorbed metabolite, enhances osteoblastogenesis and suppresses osteoclastogenesis, likely through the upregulation of the Wnt/β-catenin signaling pathway. This study elucidates the health benefits of P. scandens and paederoside in the prevention and treatment of osteoporosis.
研究领域:
药理学
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分子生物学
·
骨生物学
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天然产物化学
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药物代谢
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转化医学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE REPORTS
·
2019
·Vol. 39
·期 1
·
IF 2.535
Chen Gang,Chen Weicheng,Ye Ming,Tan Weiqiang,Jia Bing
Neuroblastoma is the most common tumor in children, with a very poor prognosis. It is urgent to identify novel biomarkers to treat neuroblastoma, together with surgery, chemotherapy, and radiation. Human tripartite motif 59 (TRIM59), a member of the TRIM family, has been reported to participate in several human tumors. However, the exact role of TRIM59 in neuroblastoma is unknown. In the present study, real-time PCR and Western blot were used to measure mRNA and protein levels of TRIM59 in four neuroblastoma cell lines and in neuroblastoma tissues. Lentiviruses targeting TRIM59 were used to up/down-regulate TRIM59 expression levels. Cell Counting Kit-8 and Annexin-V/PI were used to analyze cell proliferation and apoptosis in neuroblastoma cell lines. Our data showed that TRIM59 knockdown inhibits cell proliferation while inducing apoptosis in SH-SY5Y and SK-N-SH neuroblastoma cell lines. TRIM59 knockdown up-regulated expression of Bax and Bim and down-regulated levels of Survivin, β-catenin, and c-myc. Interestingly, the inhibition of cell proliferation caused by TRIM59 knockdown could be blocked by LiCl, which is an agonist of Wnt/β-catenin signaling pathway. In contrast, TRIM59 overexpression could increase cell proliferation, up-regulate Survivin, β-catenin and c-myc, down-regulate Bax and Bim, and these effects could be blocked by XAV939, which is an inhibitor of Wnt/β-catenin signaling pathway. In addition, TRIM59 was up-regulated and positively related with β-catenin in neuroblastoma tissues. In conclusion, TRIM59 was up-regulated in neuroblastoma, and TRIM59 knockdown inhibited cell proliferation by down-regulating the Wnt/β-catenin signaling pathway in neuroblastoma.
研究领域:
肿瘤学
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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
PHYTOMEDICINE
·
2021
·
IF 5.34
Yongmei Li,Zean Zhao,Jian Luo,Yanqing Jiang,Lu Li,Yanyu Chen,Leqi Zhang,Qinghua Huang,Ying Cao,Pingzheng Zhou,Ting Wu,Jianxin Pang
Background Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. Purpose To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. Methods The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro . Results The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro , API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC 50 values of 0.64 ± 0.14 μM and 2.63 ± 0.69 μM, respectively. Conclusions API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN.
研究领域:
药理学
·
肾病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2023
·Vol. 50
·期 7
·561-572
·
IF 2.9
Yawei He,Wanjing Chen,Liang Yu,Yanwei Liu,Yunsheng Cheng,Xianghua Li,Gang Yu
Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
转录调控
·
代谢途径
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DOI
PubMed
高影响因子
Frontiers in Physiology
·
2021
·
IF 4.566
Wangzhou Kaixin,Lai Zhiying,Lu Zishao,Fu Wanren,Liu Cheng,Liang Zhengeng,Tan Yi,Li Conghui,Hao Chunbo
Human periodontal ligament cells (hPDLCs) play a vital role in cell regeneration and tissue repair with multi-directional differentiation potential. microRNAs (miRs) are implicated in the osteogenesis of hPDLCs. This study explored the mechanism of miR-143-3p in osteogenesis of hPDLCs. Osteogenic differentiation of isolated hPDLCs was induced. KLF5 expression during osteogenic differentiation of hPDLCs was detected and then silenced in hPDLCs. Binding relationship between KLF5 and miR-143-3p was predicted and verified. hPDLCs were treated with miR-143-3p mimic or overexpressing KLF5, and then osteogenic specific markers and mineralized nodules were measured. The key factors of the Wnt/β-catenin pathway during osteogenesis of hPDLCs were measured. KLF5 expression was upregulated during osteogenesis of hPDLCs. KLF5 silencing or miR-143-3p mimic reduced osteogenic specific markers and mineralized nodules. Overexpression of KLF5 could reverse the inhibitory effect of miR-143-3p on osteogenic differentiation. miR-143-3p mimic and KLF5 silencing inactivated the Wnt/β-catenin pathway. Activation of the Wnt/β-catenin pathway reversed the repression effect of miR-143-3p mimic on osteogenesis of hPDLCs. In conclusion, miR-143-3p inhibited osteogenic differentiation of hPDLCs by targeting KLF5 and inactivating the Wnt/β-catenin pathway.
研究领域:
牙科学
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分子生物学
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细胞生物学
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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）