Dendrophenol inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating WNT3/b-catenin signaling pathway
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ABSTRACT:
PROVIDER: PRJNA981127 | ENA |
REPOSITORIES: ENA
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Project description:In this experiment,we used HASMCs cells to explore the mechanisms by which Dendrophenol affects smooth muscle cell osteogenic differentiation and related mechanisms. We found that IL13RA2 expression was significantly reduced during the induction of osteogenic differentiation in HASMCs, and normal levels were restored after Dendrophenol treatment, thus Dendrophenol may treat vascular calcification through IL13RA2. Further, we found that IL13RA2 interacts with the transcription factor STAT3, suggesting that the therapeutic effect of Dendrophenol may be mediated through STAT3. In addition, we further investigated the link between IL13RA2/STAT3 and the classical WNT/b-catenin pathway and found that WNT3 plays an important role in this process. The mechanism of action of Dendrophenol was further clarified.
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Project description:Oral squamous cell carcinoma (OSCC) represents a major malignancy in the oral and maxillofacial region. The primary therapeutic agents, 5-fluorouracil (5FU) and oxaliplatin (OXA), often encounter the challenge of chemoresistance, leading to treatment failure. The WNT/β-catenin signaling pathway, closely tied with chemoresistance, offers a promising therapeutic avenue. This study delves into this potential connection. 5FU-resistant and OXA-resistant cell lines were established by gradually elevating the drug concentration in the culture medium. Differential gene expressions between parental and resistant cells were analyzed by RNA sequencing analysis, which was then substantiated via RT-qPCR and western blot. The influence of the WNT signaling on OSCC drug resistance was ascertained through WNT3 knockdown or overexpression. The WNT inhibitor, MSAB, was probed for its capacity to boost the efficacy of 5FU or OXA. Through transcriptome sequencing, successfully derived 5FU-resistant and OXA-resistant cell lines revealed a conspicuous activation of the WNT/β-catenin signaling pathway in the drug-resistant cells. WNT3 was identified as a pivotal factor contributing to chemoresistance in OSCC. Counteracting β-catenin notably augmented the therapeutic potency of 5FU and OXA. Our study underscored the activation of the WNT/β-catenin signaling pathway in resistant OSCC cell lines. By modulating WNT signaling activity, drug resistance in OSCC cells may be effectively circumvented.
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Project description:Head regeneration in Hydra requires the transformation of gastric tissue into a head organizer that produces a head activator and a head inhibitor. Here we report the decipherment of a long-standing question in developmental biology, the identification of the transcription factor Sp5 as a key head inhibitory component. We show that Sp5 has an apical to basal graded expression pattern in intact Hydra, its expression is induced upon Wnt/β-catenin signaling activation and when knocked-down triggers the formation of multiple heads and axes in homeostatic and regenerative conditions. Our data indicate that Sp5 acts in a feed-forward loop to robustly regulate its own expression and that Sp5 prevents head formation by repressing the Wnt3 promoter. This Sp5 mediated Wnt antagonism is conserved and was invented early in metazoan evolution to set up axial patterning.
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Project description:Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced polyubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhanced VC. HDAC1 protein, but not mRNA, was reduced in cell and animal calcification models and in human calcified coronary artery. In the calcification-provoking condition, proteasomal degradation of HDAC1 preceded VC. The calcification-provoking condition induced MDM2 E3 ligase, which then resulted in HDAC1 K74 polyubiquitination. Overexpression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. Decoy peptides spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevented VC in vivo and in vitro. These results demonstrate a previously unknown ubiquitination pathway and suggest MDM2-mediated HDAC1 polyubiquitination as a new therapeutic target in VC. Calcification was induced in rat aorta vascular smooth muscle cells with inorganic phosphate (Pi). Total RNA were extracted from the cells 3 and 6 days later. mRNA profile of the sample was compared with normal control.
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