BACKGROUNDStatic magnetic field (SMF) as an effective physical stimulus is capable of osteogenic differentiation for multiple mesenchymal stem cells, including human periodontal ligament stem cells (hPDLSCs). However, the exact molecular mechanism is still unknown. Therefore, this study intends to excavate molecular mechanisms related to SMF in hPDLSCs using functional experiments.METHODShPDLSCs were treated with different intensities of SMF, H19 lentivirus, and Wnt/β-catenin pathway inhibitor (XAV939). Changes in osteogenic markers (Runx2, Col Ⅰ, and BMP2), Wnt/β-catenin markers (β-catenin and GSK-3β), and calcified nodules were examined using RT-qPCR, western blotting, and alizarin red staining in hPDLSCs.RESULTSSMF upregulated the expression of H19, and SMF and overexpressing H19 facilitated the expression of osteogenic markers (Runx2, Col Ⅰ, and BMP2), activation of the Wnt/β-catenin pathway, and mineralized sediment in hPDLSCs. Knockdown of H19 alleviated SMF function, and treatment with XAV939 limited SMF- and H19-mediated osteogenic differentiation of hPDLSCs. Notably, the expression of hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p in hPDLSCs was regulated by SMF, and may form an endogenous competitive RNA mechanism with H19 and β-catenin.CONCLUSIONSMF contributes to the osteogenic differentiation of hPDLSCs by mediating the H19/Wnt/β-catenin pathway, and hsa-miR-532-3p, hsa-miR-370-3p, hsa-miR-18a-5p, and hsa-miR-483-3p may be the key factors in it.

01 Dec 2024·Toxicology and Applied Pharmacology

Network toxicology and cell experiments reveal the mechanism of DEHP-induced diabetic nephropathy via Wnt signaling pathway

Article

Author: Zhang, Wang ; Hu, Xin-xin ; Hu, Xin-Xin ; Xu, Peng ; Yin, Ying-chuan ; Yin, Ying-Chuan ; Wei, Min

Di(2-ethylhexyl) phthalate (DEHP), a widely recognized endocrine disruptor, has been linked to the pathogenesis of diabetic nephropathy (DN) through its interference with hormonal and metabolic homeostasis. This study integrates network toxicology with cell-based assays to elucidate the molecular mechanisms of DEHP-induced DN, seeking to identify novel targets for toxicity assessment and therapeutic intervention. Through comprehensive screening across multiple toxicology and disease-related databases, six core genes (CTNNB1, EGFR, TNF, CCND1, BCL2, CASP3) were identified as shared mediators of DEHP exposure and DN. These genes are predominantly associated with the Wnt signaling pathway, a pivotal regulator of podocyte function, including cellular adhesion, differentiation, apoptosis, and inflammatory response. Mouse glomerular podocytes (MPC-5) exposed to graded concentrations of DEHP, with or without the Wnt pathway inhibitor XAV-939, displayed significant DEHP-induced disruptions: reduced cell adhesion, proliferation, and differentiation; increased autophagy, apoptosis, and migratory activity; elevated inflammatory mediator release; and pronounced activation of the Wnt signaling pathway, evidenced by upregulation of β-catenin, EGFR, TNF, CCND1, BCL2 and downregulation of CASP3. DEHP exposure further altered transcriptional activity and chromatin structure at key loci (CTNNB1, EGFR, and TNF). XAV-939 effectively mitigated these effects, underscoring the Wnt pathway's central role in DN progression under DEHP influence. These findings highlight the complex multi-target, multi-pathway interactions of DEHP in DN pathophysiology, offering deeper mechanistic insights and potential targets for therapeutic intervention against DEHP-induced nephrotoxicity.

01 Dec 2024·International Immunopharmacology

The effects of therapeutic hypothermia on the expression of DKK3 and myocardial ischemia-reperfusion injury

Article

Author: Ma, Yanfeng ; Chen, Hongping ; Qian, Wei ; Zhou, Ran ; Chen, Tao ; Su, Mingyu ; Zhang, Xueshan

BACKGROUNDThe impact and mechanisms of therapeutic hypothermia (TH) on myocardial ischemia-reperfusion (I/R) injury are still unknown.METHODSSprague-Dawley (SD) rat model and primary cardiomyocytes were applied in our study. TTC staining evaluated myocardial infarction, while H&E staining assessed myocardial injury. ELISA quantified lactate dehydrogenase (LDH), IL-1β, IL-6, and TNF-α. Blood serum concentrations of CK, CK-MB, and cTnT were detected using a biochemical assay. TUNEL assay, flow cytometry and western blot were used to detect cell apoptosis. EdU assay was applied to examine cell proliferation. The expression of DKK3 and β-catenin protein was analyzed using Realtime PCR and Western blot.RESULTSTH alleviated myocardial infarction size and injury in rat models of I/R, and reduced serum levels of myocardial injury markers and inflammatory factors in animal and cell models. In addition, TH inhibited the increased apoptosis and β-catenin expression as well as decreased DKK3 expression caused by I/R in I/R cell models, while si-DKK3 reversed the changes brought by TH, and XAV939 inhibited the effects of si-DKK3.CONCLUSIONTH may reduce myocardial infarction size, myocardial injury, inflammatory response and apoptosis through DKK3/Wnt/β-catenin pathway, thereby alleviating myocardial I/R injury.

100 Deals associated with XAV-939

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	CN	Beijing Novartis Pharma Co. Ltd.	30 Sep 2009
Neoplasms	Preclinical	DE	Cellzome AG	30 Sep 2009

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