Experimental and Therapeutic Medicine
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2019
·Vol. 18
·期 5
·3643-3649
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IF 1.448
Cui Huang,Jing Ma,Bai‑Xiang Li,Yan Sun
Wingless (Wnt) signaling regulates the proliferation and differentiation of midbrain dopamine (DA) neurons. Paraquat (PQ) and maneb (MB) are environmental pollutants that can be used to model Parkinson's disease (PD) in rodents. A previous study demonstrated that developmental exposure to PQ and MB affects the expression of Wnt1, Wnt5a, nuclear receptor‑related factor 1 (NURR1) and tyrosine hydroxylase (TH). However, how Wnt signaling regulates these developmental factors in vitro is yet to be determined. To explore this, SH‑SY5Y cells were exposed to PQ and MB. The results of the current study indicated that exposure to PQ and MB decreased Wnt1, β‑catenin, NURR1 and TH levels and increased Wnt5a levels. Furthermore, Wnt1 silencing has the same effect as exposure to PQ and MB. Additionally, the neurotoxicity induced by PQ and MB is more severe in siWnt1‑SH‑SY5Y cells compared with normal SH‑SY5Y cells. Therefore, Wnt1 may serve an important role in regulating developmental DA factors, and may be a candidate gene for PD diagnosis or gene therapy.
研究领域:
神经科学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BONE AND MINERAL RESEARCH
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2024
·
IF 5.1
Tan Zhijia,Chen Peikai,Zhang Jianan,Shek Hiu Tung,Li Zeluan,Zhou Xinlin,Zhou Yapeng,Yin Shijie,Dong Lina,Feng Lin,Wong Janus Siu Him,Gao Bo,Tsun To Michael Kai
Osteogenesis imperfecta (OI) is a group of severe genetic bone disorders characterized by congenital low bone mass, deformity and frequent fractures. Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST was dramatically reduced in type XV patients when comparing to the patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from the human tibia samples of patients diagnosed with type XV OI and leg-length-discrepancy respectively, revealed aberrant differentiation trajectory of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes and existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV osteogenesis imperfecta and relative low bone mass diseases such as early onset osteoporosis.
研究领域:
遗传学
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骨生物学
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医学遗传学
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蛋白质组学
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转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2017
·
IF 3.778
Xiayun Yang,Shusheng Tang,Chongshan Dai,Daowen Li,Shen Zhang,Sijun Deng,Yan Zhou,Xilong Xiao
Quinocetone (QCT) has been used as an animal feed additive in China since 2003. However, investigations indicate that QCT has potential toxicity due to the fact that it shows cytotoxicity, genotoxicity , hepatotoxicity, nephrotoxicity and immunotoxicity in vitro and animal models. Although QCT-induced mitochondrial apoptosis has been established, the molecular mechanism remains unclear. This study was aimed to investigate the role of voltage-dependent anion channel 1 (VDAC1) oligomerization and Wnt/β-catenin pathway in QCT-induced mitochondrial apoptosis. The results showed VDAC inhibitor 4, 4-diisothiocyano stilbene-2, 2-disulfonic acid (DIDS) partly compromised QCT-induced cell viability decrease (from 34.1% to 68.5%) and mitochondrial apoptosis accompanied by abating VDAC1 oligomerization, cytochrome c (Cyt c ) release and the expression levels of cleaved caspase-9, -3 and poly (ADP-ribose) polymerase (PARP). Meanwhile, overexpression VDAC1 exacerbated QCT-induced VDAC1 oligomerization and Cyt c release. In addition, lithium chloride (LiCl), an activator of Wnt/β-catenin pathway, markedly attenuated QCT-induced mitochondrial apoptosis by partly restoring the expression levels of Wnt1 and β-catenin. Finally, reactive oxygen species (ROS) scavenger N -acetyl- l -cysteine (NAC) obviously blocked QCT-induced VDAC1 oligomerization and the inhibition of Wnt1/β-catenin pathway. Taken together, our results reveal that QCT induces mitochondrial apoptosis by ROS-dependent promotion of VDAC1 oligomerization and suppression of Wnt1/β-catenin pathway.
研究领域:
毒理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Stem Cells
·
2021
·
IF 2.5
Qiong Li,Lei Huang
Background and Objectives MiR-148a-3p has been reported to regulate the differentiation of marrow stromal cell osteoblast. In this study, whether miR-148a-3p regulated the odontoblastic differentiation of human dental pulp stem cells (hDPSCs) or not was explored. Methods and Results The hDPSCs were isolated and identified via flow cytometry. Targets of miR-148a-3p were identified via bioinformatics and dual-luciferase reporter assay. After the cell was cultured in the odontogenic differentiation medium or infected, cell viability, invasion, and odontoblastic differentiation were detected via MTT, transwell, and Alizarin Red S staining, respectively. The miR-148a-3p, Wnt1, β-catenin, DSPP, DMP-1, RUNX2, OCN, and Smad4 expressions were determined by RT-qPCR and Western blot. The hDPSCs odontoblastic differentiation downregulated the miR-148a-3p expression and upregulated Wnt1 expression. Wnt1 was determined as the target for miR-148a-3p. MiR-148a-3p mimic and siWnt1 suppressed the cell viability, invasion, and odontoblastic differentiation of hDPSCs and inhibited the Wnt1, β-catenin, DSPP, DMP-1, RUNX2, OCN, and Smad4 expressions. In contrast, miR-148a-3p inhibitor and overexpressed Wnt1 promoted the cell viability, invasion, and odontoblastic differentiation of hDPSCs, and upregulated the Wnt1, β-catenin, DSPP, DMP-1, RUNX2, OCN, and Smad4 expressions. Also, miR-148a-3p mimic and inhibitor reversed the effects of Wnt1 overexpression and siWnt1. Conclusions MiR-148a-3p modulated the invasion and odontoblastic differentiation of hDPSCs through the Wnt1/β-catenin pathway.
研究领域:
牙科研究
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干细胞生物学
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分子生物学
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细胞分化
✓ 已验证
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
·
2023
·
IF 5
Ying Li,Yu Wang,Qinguang Zou,Shouqing Li,Fan Zhang
The transcription factor Krüppel-like factor (KLF) 3 is one of the members of the KLF family, which plays an important role in tumor progression. Nevertheless, the role of KLF3 in the growth and metastasis of gastric cancer (GC) still needs to be elucidated. Bioinformatics analysis showed that KLF3 was overexpressed in patients with GC, and the high expression of KLF3 was correlated with poor survival. KLF3 was also overexpressed in GC clinical samples and cell lines. In vitro functional role of KLF3 in GC cells was explored by a gain-of-function and loss-of-function assay. Overexpressed KLF3 promoted the cell proliferation, migration, invasion, and epithelial-mesenchymal transition of GC cells, whereas suppressed KLF3 inhibited these biological behaviors. The clinical samples and bioinformatics analysis showed that WNT1 was also highly expressed in GC tumor tissues and positively correlated with KLF3 expression. The luciferase reporter assay and chromatin immunoprecipitation result confirmed that KLF3 could directly bind to the WNT1 promoter to increase the transcriptional activity of WNT1, thus regulating its expression. Overexpressed KLF3 enhanced the protein expression level of p-GSK3β(Ser9) and β-catenin, the key elements in the WNT/β-catenin signaling pathway. Repression of KLF3 decreased the level of p-GSK3β(Ser9) and β-catenin. Immunofluorescence images showed that KLF3 promoted nuclear β-catenin accumulation. Inhibition of WNT1 attenuated the proliferation, migration, and invasiveness of KLF3-overexpressing GC cells. Moreover, the xenograft mouse model confirmed that KLF3 promotes GC tumor growth and metastasis in vivo. Our results demonstrated that KLF3 activates the WNT/β-catenin signaling pathway via WNT1 to promote GC tumor growth and metastasis, indicating that repression of KLF3 may act as a potential therapeutic target for patients with GC.
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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生物信息学
✓ 已验证
DOI
PubMed
高影响因子
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