TOXICOLOGY LETTERS
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2021
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IF 4.374
Xing Ma,Xiaowei Yu,Jialing Min,Xin Chen,Ren Liu,Xueqing Cui,Jing Cheng,Mingyong Xie,Patrick Diel,Xiaojuan Hu
Genistein (GEN) has been demonstrated to interfere with antitumor effects of cisplatin (CIS) in vitro . To analyze whether these findings are also relevant in vivo , we examined the effects of combined GEN and CIS treatment in an ovariectomized nude mouse breast cancer xenograft model. Tumor growth and markers for antitumor activity were determined after three weeks of treatment. Furthermore, the concentrations of GEN metabolites were measured in serum, liver, and xenograft tumor tissues using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Three weeks’ oral exposure to GEN at a dose of 5 mg kg −1 ·d -1 resulted in an average concentration of total GEN metabolite equivalent as high as 0.2729 nmol g −1 wet weight in xenograft tumor tissues. At this dosage, GEN significantly antagonized the antitumor effects of CIS. Mechanistically, GEN blocked both the inhibition of cell proliferation and induction of apoptosis triggered by CIS. Moreover, GEN concentrations in xenograft tumor tissues were found to be significantly higher than in serum and liver. In conclusion, our findings suggested that oral GEN exposure at a level comparable to dietary exposure in humans could interfere with CIS chemotherapy.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
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2020
·Vol. 11
·期 1
·1-15
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IF 5.116
Shen Ying-Shan,Chen Xiao-Jun,Wuri Sha-Na,Yang Fan,Pang Feng-Xiang,Xu Liang-Liang,He Wei,Wei Qiu-Shi
Objectives Polydatin (PD), extracted from Polygonum cuspidatum , has shown potential therapeutic applications due to its antiosteoporotic and anti-inflammatory activities. Our previous study suggested that PD promotes the osteogenesis of human bone marrow stromal cells (hBMSCs) via the BMP2-Wnt/β-catenin pathway. The aim of our present study was to further explore the role of PD-mediated regulation of Tafazzin (TAZ), a transcriptional coactivator with a PDZ-binding motif, in osteogenesis. Materials and methods hBMSCs were isolated and treated with PD at various concentrations. Alizarin red staining and RT-qPCR were performed to identify calcium complex deposition in hBMSCs as well as the expression of specific osteoblast-related markers, respectively, in each group. Next, TAZ-silenced hBMSCs were generated by lentivirus-produced TAZ shRNA. After treatment with PD, the osteogenic abilities of the TAZ-silenced and control hBMSCs were estimated by ALP activity assay, and expression of the TAZ protein was detected by Western blot analysis and immunofluorescence staining. In vitro, an ovariectomized (OVX) mouse model was established and used to evaluate the effect of PD on bone destruction by micro-CT, immunohistochemistry, and ELISA. Results In vitro, 30 μM PD significantly improved the proliferation and calcium deposition of hBMSCs and markedly stimulated the expression of the mRNAs RUNX2 , Osteopontin , DLX5 , β-catenin , TAZ , and Osteocalcin ( OCN ). Osteogenic differentiation induced by PD was blocked by lentivirus-mediated TAZ shRNA. Furthermore, Noggin (a regulator of bone morphogenic protein 2 (BMP2)) and DKK1 (an inhibitor of the Wnt/β-catenin pathway) were found to inhibit the increase in TAZ expression induced by PD. In vivo, PD prevented estrogen deficiency-induced bone loss in the OVX mouse model. Conclusion Taken together, our findings suggest that PD improved the osteogenic differentiation of hBMSCs and maintained the bone matrix in the OVX mouse model through the activation of TAZ, a potential target gene of the BMP2-Wnt/β-catenin pathway.
研究领域:
药理学
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干细胞生物学
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骨骼生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
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2024
·Vol. 27
·期 11
·1611-1628
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IF 1.6
Pan Chengzhen,Zhang Chi,Lin Zonghan,Liang Zhou,Cui Yinhang,Shang Zhihao,Wei Yuanxun,Chen Feng
Background: Osteoporosis (OP) is an age-related skeletal disease. Kaempferol can regulate bone mesenchymal stem cells (BMSCs) osteogenesis to improve OP, but its mechanism related to disulfidptosis, a newly discovered cell death mechanism, remains unclear. Objective: The study
aimed to investigate the biological function and immune mechanism of disulfidptosis- related ribophorin I (RPN1) in OP and to experimentally confirm that RPN1 is the target for the treatment of OP with kaempferol. Methods: Differential expression analysis was conducted on disulfide-related
genes extracted from the GSE56815 and GSE7158 datasets. Four machine learning algorithms identified disease signature genes, with RPN1 identified as a significant risk factor for OP through the nomogram. Validation of RPN1 differential expression in OP patients was performed using the GSE56116
dataset. The impact of RPN1 on immune alterations and biological processes was explored. Predictive ceRNA regulatory networks associated with RPN1 were generated via miRanda, miRDB, and TargetScan databases. Molecular docking estimated the binding model between kaempferol and RPN1. The targeting
mechanism of kaempferol on RPN1 was confirmed through pathological HE staining and immunohistochemistry in ovariectomized (OVX) rats. Results: RPN1 was abnormally overexpressed in the OP cohort, associated with TNF signaling, hematopoietic cell lineage, and NF-kappa B pathway. Immune
infiltration analysis showed a positive correlation between RPN1 expression and CD8+ T cells and resting NK cells, while a negative correlation with CD4+ naive T cells, macrophage M1, T cell gamma delta, T cell follicular helper cells, activated mast cells, NK cells, and dendritic cells, was
found. Four miRNAs and 17 lncRNAs associated with RPN1 were identified. Kaempferol exhibited high binding affinity (-7.2 kcal/mol) and good stability towards the RPN1. The experimental results verified that kaempferol could improve bone microstructure destruction and reverse the abnormally
high expression of RPN1 in the femur of ovariectomized rats. Conclusion: RPN1 may be a new diagnostic biomarker in patients with OP, and may serve as a new target for kaempferol to improve OP.
研究领域:
医学研究
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药理学
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分子生物学
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免疫学
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生物信息学
✓ 已验证
DOI
PubMed
高影响因子
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