BIOORGANIC CHEMISTRY
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2025
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IF 4.7
Nan Li,Feng-xiang Pang,Yu-wan Zhou,Shou-chang Ding,Chuan-jian Shi,Rui-jia Wen,Yong-xin Mai,Xian-lin Wu,Jin-fang Zhang
Background Osteosarcoma (OS) is a malignant primary tumor in bone tissues, and Methotrexate (MTX) is widely used as a chemotherapeutic drug for OS in clinical treatment. However, MTX resistance is a major challenge for OS patients. Polydatin (PD) is an extract derived from Reynoutria japonica Houtt and has been identified as a potential agent for reversing chemotherapy resistance in cancer. We therefore wondered whether PD could alleviate MTX resistance in OS. Methods The effect of PD on MTX resistance was investigated. And H19 expression was examined in the PD-treated OS cells. The association between H19 and MTX resistance in osteosarcoma was investigated.The effects of H19 on MTX resistance in osteosarcoma were evaluated by cell proliferation, colony formation, ChIP and western blotting assays. In order to investigate the molecular mechanism of PD underlying methotrexate resistance in OS, the cell proliferation, colony formation, q-PCR and western blotting were examined. Results In the present study, PD was found to act as a novel MTX sensitizer, and significantly enhanced the suppressive effects of MTX on OS in vitro and in vivo . Mechanically, PD was demonstrated to suppress the expression of long non-coding RNA H19 as well as its binding protein histone methyltransferase Enhancer of zeste homolog 2 (EZH2), and thus reduced the trimethylation of histone H3K9 (H3K9me3) and K27 (H3K27me3). Furthermore, H19 knowndown increased the binding ability of H3K9me3 and H3K27me3 with the folate metabolism-related genes RFC-1 and PCFT's promoter, and influenced folate metabolism and MTX resistance. Conclusion In conclusion, our results indicated that PD alleviated MTX resistance in OS via the H19/H3K27me3/H3K9me3 mediated folate metabolism regulatory axis. The translational potential of this article The findings of this study validate the function of PD in alleviating MTX resistance, and provide the new insight into developing PD as a promising drug candidate for the MTX resistant OS patients.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Human Cell
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2023
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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.
研究领域:
分子生物学
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细胞生物学
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医学遗传学
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骨骼生物学
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
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2024
·Vol. 81
·期 1
·1-14
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IF 6.2
Ren Xuan,Huang Shihai,Xu Jianchun,Xue Qingsong,Xu Tairan,Shi Deshun,Ma Shinan,Li Xiangping
BRG1 has been found to promote the generation of induced pluripotent stem cells (iPSCs) by regulating epigenetic modifications or binding to transcription factors, however, the role of BRG1 on the cellular metabolism during reprogramming has not been reported. In this study, we found that BRG1 improved the efficiency of porcine iPSC generation, and upregulated the expression of pluripotency-related factors. Further analysis revealed that BRG1 promoted cellular glycolysis, and increased levels of glycolysis-related metabolites. It enhanced the transcriptional activity of glycolysis-related gene HK2, PKM2, and PFK-1 promoters, and decreased the enrichment of H3K9me3 in glycolysis- and pluripotency-related gene promoters. BRG1 also increased the phosphorylation level at the Ser473 site of AKT protein. The specific PI3K/AKT signaling pathway inhibitor, LY294002, impaired the generation of porcine iPSCs, downregulated the expression of pluripotency-related factors, and inhibited cellular glycolysis, overexpressing BRG1 rescued those changes caused by LY294002 treatment. In addition, the glycolysis inhibitor 2-DG and BRG1 inhibitor PFI-3 had similar effects to LY294002. The above results suggest that overexpression of BRG1 promotes the generation of porcine iPSCs by facilitating glycolytic reprogramming through the PI3K/AKT signaling pathway.
研究领域:
干细胞生物学
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代谢
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表观遗传学
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细胞重编程
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DOI
PubMed
高影响因子
American Journal of Translational Research
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2023
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IF 2.2
Ting Xie,Xunshan Ren,Huangming Zhuang,Fuze Jiang,Yuelong Zhang,Panghu Zhou
Objective: Osteoarthritis (OA) is the most common degenerative joint disease leading to disability worldwide. Cellular senescence is considered to be a fundamental pathogenic mechanism in the development of OA and has attracted increasing attention. However, regulatory mechanisms underlying chondrocyte senescence in OA remain unclear. Methods: Bioinformatic methods were used to screen key genes. Immunohistochemistry and the quantitative reverse transcription polymerase chain reaction were used to evaluate gene expression. RNA intervention experiments were performed to explore the functions of key genes. Results: We used 494 aging-associated genes provided by the Aging Atlas to identify the co-expression modules associated with age and OA. Thirty age-associated differentially expressed genes (ASDEGs) were identified. Using cytoHubba in Cytoscape, we identified Jun as the hub-ASDEG for OA chondrocytes. We confirmed the downregulation of Jun in OA rats and senescent chondrocytes by immunohistochemistry and quantitative reverse transcription polymerase chain reaction, respectively. Inhibition of proliferation and accelerated senescence were observed in chondrocytes treated with siRNA against Jun. Mechanistically, we observed micronuclei formation and reduced expression of H3K9me3 and heterochromatin protein 1gamma in siRNA-Jun-treated chondrocytes, indicating that destabilization of chromatin occurred during this treatment. Conclusion: Jun plays a crucial role in OA development and causes senescence by destabilizing chromatin in chondrocytes. These findings provide new insights into OA progression and suggest promising therapeutic targets.
研究领域:
风湿病学
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分子生物学
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细胞生物学
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老年学
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DOI
PubMed
高影响因子
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