Cellular signalling最新文献

Background: Silicosis, one of the serious occupational diseases, is mainly manifested by pulmonary fibrosis induced by long-term exposure to silica particles in workplace. Evidence demonstrates that circular RNAs (circRNAs) are interesting regulators of pulmonary fibrosis process. So, further elucidation of the role of circRNAs may provide a new perspective into mechanisms driving pulmonary fibrosis and silicosis.

Methods: The characteristics of circRNA homer scaffold protein 1 (hsa_circ_0006916, circHOMER1) was assessed using Actinomycin D, RNase R, and nucleoplasmic separation assay. The histopathological examination and Enzyme-linked immunosorbent assay (ELISA) were used to confirm circHOMER1 function in mouse lung tissues under silica particle exposure. The expression of circHOMER1, human antigen R (HuR) and NADPH oxidase 4 (NOX4) was identified by western blot or RT-qPCR assay. The RNA immunoprecipitation (RIP) assay and plasmid co-transfection were used to analyze the interaction between circHOMER1, HuR and NOX4.

Results: We confirmed an upregulated circHOMER1 in silicosis fibrosis. Functional assays showed that the knockdown of circHOMER1 suppressed the viability of fibroblasts and the production of fibrotic molecules and alleviated the histology fibrotic changes in lung tissues from mouse exposed to silica particles. Mechanistically, we found that circHOMER1 directly bound to HuR and promoted its protein expression in fibroblasts. And, circHOMER1 further regulated HuR/NOX4 signaling axis through HuR to stabilize NOX4 mRNA, which enhanced the production of reactive oxygen species (ROS), thereby promoting the silicosis fibrosis process.

Conclusion: This study revealed the role of circHOMER1 in silica-induced pulmonary fibrosis, suggesting that the inhibition of circHOMER1 may be a potential therapeutic approach to relieve the pathological process of silicosis.

Background: The osteogenic differentiation potential of bone marrow mesenchymal stem cells (BM-MSCs) is critical for bone regeneration and repair. In recent years, the role of protein succinylation modification in regulating cellular metabolism has garnered increasing attention. However, its mechanism in osteogenic differentiation remains unclear.

Methods: Oxygen consumption rate (OCR) and mitochondrial ROS (mtROS) were detected to assess mitochondrial function in BM-MSCs with successive passages. Alizarin red staining and western blot experiments were used to evaluate osteogenic differentiation capacity. .Succinylation modification omics and Co-IP detection were conducted to determine SIRT5-mediated desuccinylation of UQCRC2 .

Results: Bioinformatics analysis revealed that sirtuin 5 (SIRT5) expression is upregulated with multiple rounds of BM-MSCs' passages, and is associated with biological pathways such as oxidative phosphorylation (OXPHOS), cellular senescence, and inhibition of osteogenic differentiation. Experiments in vitro confirmed the up-regulation of SIRT5 and the suppression of osteogenic differentiation with the increased times of BM-MSCs' passages. Overexpression of SIRT5 enhanced OXPHOS and elevated mtROS levels, but reduced the expression of Runx2 and osteocalcin, and decreased calcified nodules, thereby inhibiting the osteogenic differentiation of BM-MSCs. SIRT5-mediated desuccinylation of ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) at the site of K250 promoted UQCRC2 translocation from cytoplasm to mitochondria, which enhanced the activity of mitochondrial respiratory complex III. It further increased mtROS, accelerated cellular senescence and inhibited the osteogenic differentiation of BM-MSCs.

Conclusion: SIRT5 reduces succinylation modification of UQCRC2, promotes mitochondrial respiration and mtROS, and thus reduces the osteogenic differentiation ability of BM-MSCs cells. SIRT5 might be a potential target to prevent the suppression of osteogenic differentiation of of BM-MSCs after multiple rounds passages.

Cuproptosis is a newly discovered form of non-apoptotic cell death. Cancer-associated fibroblasts (CAFs) can secrete various bioactive substances, including exosomes, to promote tumor progression. However, the impact of CAFs on the regulation of copper metabolism and cuproptosis in oral squamous cell carcinomas (OSCC) has not been investigated. In the present study, we revealed that up-regulated expression of ATP7A was correlated with reduced copper abundance, advanced clinicopathological characteristics and poor prognosis in OSCC. The knockdown of ATP7A significantly increased cuproptosis and inhibited malignant progression in vitro, as well as decreased tumor growth and metastasis in vivo. Furthermore, co-culture assays and dual-luciferase reporter demonstrated that upregulated expression of ATP7A in OSCC was due to a reduction of miR-148b-3p in CAF-derived exosomes. The downregulation of miR-148b-3p was observed to significantly elevate ATP7A expression, inhibit cuproptosis and increase malignant progression in vitro. Additionally, in vivo studies demonstrated that this process promoted tumor growth and metastasis. OSCC exhibit a low level of cuproptosis due to the uptake of miR-148b-3p-depleted exosomes from CAFs, leading to a more malignant phenotype in the tumor microenvironment by targeting ATP7A. The results of our experiments suggest that targeting the miR-148b-3p/ATP7A axis might be a promising therapeutic approach for the treatment of oral cancer.

Pre-eclampsia is a known hypertensive disorder of pregnancy. While abnormal placentation and poor trophoblast invasion into maternal endometrium during blastocyst implantation are primary causes of pre-eclampsia, the underlying mechanisms remain elusive. Hematopoietic PBX-Interacting protein (HPIP) is an estrogen receptor (ER) interacting protein that plays a pivotal role in cell proliferation, migration, and differentiation; however, its role in trophoblast functions is largely unknown. In this study, we used BeWo cells as a model system to investigate trophoblast fusion and syncytialization, focusing on the role of HPIP in regulating these critical aspects of trophoblast functions. Herein, we report that HPIP expression declines during forskolin-induced trophoblast fusion in BeWo cells. In support of these observations, HPIP depletion enhanced forskolin-induced human chorionic gonadotropin-β (β-hCG), ERVWE1, and GCM1 expression, markers for trophoblast fusion. Furthermore, silencing of HPIP decreased cell invasion and epithelial to mesenchymal transition (EMT), a prerequisite for syncytialization in BeWo cells. Functional genomic studies further revealed a regulatory role for HPIP in a subset of gene networks involved in trophoblast fusion and EMT. We also uncovered that HPIP is a proteolytic substrate of furin, which is known to promote trophoblast cell fusion. Clinical data further indicated a significantly lower expression level of HPIP in pre-eclampsia subjects than in normal subjects. These findings imply that HPIP inhibits trophoblast fusion while promoting invasion and EMT, and its downregulation in trophoblasts might have implications for pre-eclampsia development.