Journal of Cell Communication and Signaling最新文献

This study aimed to investigate the therapeutic effects and underlying mechanisms of adipose-derived stem cell exosomes (ADSCs-exo) in ameliorating fibrosis in a rat model. ADSCs were isolated and cultured from rat adipose tissue, and ADSCs-exo were extracted via ultracentrifugation. Urethral fibrosis was induced by local injection of TGF-β1 (10 μg), followed by ADSCs-exo treatment. Urodynamic parameters were evaluated, and histological changes were evaluated using hematoxylin and eosin and Masson staining. Transcriptomic analysis and pathway enrichment were performed to identify signaling pathways regulated by ADSCs-exo. In vitro, urinary fibroblasts were stimulated with TGF-β1 and treated with ADSCs-exo alone or in combination with PDGF-BB (agonist) or imatinib (inhibitor). ADSCs-exo treatment significantly improved urodynamic function, reduced collagen deposition, and suppressed fibrosis-related protein expression in vivo. Transcriptomic analysis revealed platelet-derived growth factor and TGF-β pathways as major contributors to fibrosis. In vitro, ADSCs-exo significantly reduced TGF-β1-induced fibroblast proliferation, migration, and fibrosis-related protein expression, effects that were reversed by PDGF-BB and enhanced by imatinib. These findings were consistent in vivo, further supporting the hierarchical regulation of fibrosis-related signaling by ADSCs-exo. ADSCs-exo mitigates urethral stricture fibrosis by primarily suppressing the TGF-β/Smad pathway, thereby downregulating the downstream PDGFR-β/RAS/ERK axis, highlighting its therapeutic potential as a cell-free therapeutic approach for fibrotic urethral disease.

Atherosclerosis (AS) is a prevalent cardiovascular disease, and emerging evidence highlights the critical role of gut microbiota in its development. Trimethylamine-N-oxide (TMAO), a metabolite derived from gut microbiota, is thought to promote AS progression by regulating smooth muscle protein 22-alpha (SM22α)-mediated inflammation in vascular smooth muscle cells. This study aims to explore the molecular mechanisms of TMAO in AS through multi-omics analysis, particularly its effects on SIRT1 inhibition and SM22α modulation. 16S ribosomal RNA sequencing revealed an altered gut microbiota composition in AS mice, characterized by increased Bacteroides and decreased Firmicutes. Metabolomics analysis indicated elevated levels of TMAO in AS mice. Transcriptomic data and cell experiments further confirmed that TMAO promotes AS by regulating SM22α-mediated inflammation via SIRT1 regulation. These findings suggest that TMAO accelerates progression through the SIRT1 and SM22α-related pathways, offering novel therapeutic targets for AS intervention.

Endometriosis (EMs) is a disease that adversely affects women's health. Immune imbalance is an important factor contributing to EMs, and exosomes (Exo) play an important role in immunomodulation. The purpose of this study was to investigate the effect of exosomes derived from the blood of patients with EMs on macrophage polarization and elucidate the underlying mechanisms. Exosomes were isolated from the serum of healthy controls (control exosomes) and patients with EMs (EMs exosomes). Macrophage polarization levels were detected using flow cytometry (FCM), RT-qPCR, and Western blot. Subsequently, we used RNA sequencing to analyze differential microRNAs (miRNA) and associated pathways. Electroporation techniques were used to modify the exosomes. The associated pathways were analyzed by Western blot. Finally, 12Z cells were co-cultured with macrophages of different polarizations, and the viability and metastasis of 12Z cells were calculated by cell counting kit-8 (CCK-8), scratch, and Transwell. EMs exosomes induced M2-type polarization in macrophages. RNA sequencing results showed that miR-196a-5p was dramatically decreased in EMs exosomes, whereas overexpression of miR-196a-5p in EMs exosomes could inhibit the M2-type polarization of macrophages and activate the Hippo pathway. In addition, M2-type macrophages promoted 12Z cell proliferation and metastasis. These findings suggest that serum-derived exosomes encapsulating miR-196a-5p alleviate endometriosis by promoting M1-type macrophage polarization via Hippo pathway activation.

Osteogenic differentiation of mesenchymal stem cells (MSCs) was strongly correlated with the progression of congenital tibial pseudoarthrosis (CPT). Activation of ferroptosis inhibited osteogenic differentiation of MSCs. ELAV-like RNA binding protein 1 (ELAVL1) is a key factor in promoting ferroptosis. This study aimed to elucidate the mechanism of ELAVL1 in the osteogenic differentiation of CPT periosteum-derived MSCs. Osteogenic differentiation of CPT periosteum-derived MSCs was detected by ARS and ALP staining. Fe²⁺ content and lipid reactive oxygen species content were measured using commercial kits. Molecular interactions were verified using RIP, RNA pulldown, and Co-IP. The ubiquitination level of homeobox gene D8 (HOXD8) was detected using Co-IP. Expression of ELAVL1 and tripartite motif containing 21 (TRIM21) was upregulated in CPT periosteum-derived MSCs, whereas HOXD8 expression was downregulated. Moreover, knockdown of ELAVL1 or TRIM21 inhibited ferroptosis and promoted osteogenic differentiation of CPT MSCs. TRIM21 overexpression reversed the effect caused by knockdown of ELAVL1. Mechanistically, ELAVL1 upregulated TRIM21 by increasing the stability of TRIM21, which ubiquitinated and degraded HOXD8. ELAVL1 bound to TRIM21, which promoted ubiquitination and degradation of HOXD8, thereby promoting ferroptosis to inhibit osteogenic differentiation of CPT MSCs.

Gouty arthritis (GA) is an inflammatory disease resulting from monosodium urate (MSU) crystal deposition in joints and surrounding tissues. Daphnetin (DAP) is a coumarin derivative with potent anti-inflammatory activity. Nonetheless, whether DAP can protect against MSU-induced acute GA remains unclarified. In this study, C57BL/6 mice were injected intra-articularly with MSU crystal suspension to induce acute GA. THP-1 cells were stimulated with MSU to mimic the microenvironment of GA in vitro. Hematoxylin–eosin staining was conducted to observe the pathological changes in mouse synovial tissues. ELISA and RT-qPCR were employed for inflammatory cytokine level determination. Immunofluorescence staining was performed to estimate LC3 expression in THP-1 cells. Western blotting was used for protein expression analysis. The results showed that DAP pretreatment mitigated MSU-elicited ankle joint swelling and synovial damage in mice. Moreover, DAP hindered proinflammatory factor expression and promoted autophagy in MSU-stimulated GA mice and THP-1 cells. Mechanistically, DAP induced AMPK activation and mTOR inactivation. Blocking AMPK signaling counteracted DAP-mediated effects on inflammation and autophagy in MSU-stimulated THP-1 cells. In conclusion, DAP prevents MSU-elicited GA by alleviating inflammation and enhancing autophagy via AMPK/mTOR signaling transduction.

CEP162, a 162-kDa centrosome protein, is a crucial centrosomal adapter, mediating cell differentiation and polarization. CEP162 maintains mitosis by dynamically stabilizing microtubules. CEP162 promotes the transition zone (TZ) assembly in the basal body through interaction with CEP131, CEP290, and axoneme microtubules as well as the distal centriole. TZ ensures the normal distribution of soluble proteins between the cytoplasm and cilia. It also facilitates retinal development and sperm flagellar motility. However, fluctuations in TZ permeability caused by abnormal expression of CEP162, including truncated mutations and naturally occurring mutations, lead to cilia abnormality and dysfunction in ciliogenesis through the regulation of intraflagellar transport, resulting in retinal degeneration and infertility. LncRNAs can induce SNP events in the CEP162 transcript by altering alternative splicing. Naturally occurring mutations are closely linked to retinal ciliopathy and diabetic retinopathy. This review summarizes the latest research progress to better understand the biology and pathophysiology of CEP162 and the clinical manifestations caused by CEP162 variants.

Small extracellular vesicles (sEVs) are considered promising gene-delivery vehicles for the treatment of osteoarthritis (OA). This study aimed to explore the molecular mechanism by which M2 macrophage-derived sEVs (M2-sEVs) modulate chondrocyte proliferation and apoptosis, thereby affecting OA progression. M2 macrophages were successfully induced, and M2-sEVs were successfully isolated. The sEVs were small vesicles with diameters ranging from 50 to 150 nm. The exosomal markers, including CD9, CD63, and CD81, were highly expressed, whereas the negative marker calnexin was absent in M2-sEVs. M2-sEVs effectively alleviated OA tissue and chondrocyte damage in both in vivo and in vitro models, evidenced by reduced rat knee joint injury, increased chondrocyte viability, and decreased chondrocyte apoptosis and extracellular matrix (ECM) degradation. Furthermore, M2-sEVs decreased the levels of pro-inflammatory cytokines IL-6 and TNF-α. Osteopontin (OPN) was upregulated within rats with OA and IL-1β-induced chondrocytes. Silencing of OPN exacerbated IL-1β-induced chondrocyte damage and partially abrogated the therapeutic effects of M2-sEVs. Additionally, M2-sEVs enhanced OPN expression and activated CD44 and the PI3K/AKT signaling pathway. In conclusion, M2-sEVs promoted OPN expression to improve knee joint tissue damage in rats with OA and chondrocyte damage. This protective effect of M2-sEVs might be associated with the activation of CD44 and the PI3K/AKT signaling.

Chemoresistance and immune evasion remain significant barriers to effective esophageal cancer (EC) treatment. This study explores the mechanistic role of extracellular vesicles (EVs) delivering LncRNA HOTAIR in modulating these processes. Using transcriptomic profiling, LncRNA HOTAIR was identified as a critical factor in EC progression. Its interaction with miR-375 was examined via luciferase reporter assays and RNA immunoprecipitation. Paclitaxel-resistant EC cells were treated with EVs containing HOTAIR, and the functional impact on proliferation, migration, invasion, and immune response was assessed through in vitro and in vivo models. LncRNA HOTAIR in EVs enhanced paclitaxel resistance by suppressing miR-375 and increasing CDH2 expression. Furthermore, HOTAIR promoted immune escape by upregulating PD-L1, impairing T-cell-mediated cytotoxicity. These changes were validated in patient-derived EC models. This study demonstrates that EV-LncRNA HOTAIR mediates chemoresistance and immune evasion in EC by targeting the miR-375/CDH2 axis. These findings provide a foundation for novel therapeutic interventions targeting EV-HOTAIR.

Hepatocellular carcinoma (HCC), a severe consequence of hepatitis C virus infection, is significantly influenced by the virus’s non-structural protein 3 (NS3). This study employed transcriptome sequencing to explore the role of NS3 in promoting HCC progression by comparing gene expression profiles between HCV-infected HCC tissues and healthy liver controls. Key genes regulated by NS3 were identified and validated with quantitative reverse transcription PCR (RT-qPCR) and western blot analyses. Functionality assays, including CCK-8, BrdU, and Transwell migration and invasion tests, were performed to evaluate the effects of NS3 on HCC cell proliferation, migration, and invasion. Further investigation through a dual-luciferase reporter and RNA pull-down assays revealed that NS3 specifically upregulates circ_0001175. This circular RNA interacts with and inhibits miR-130a-5p, diminishing its regulatory impact on P53 by modulating the MDM4 pathway, thereby promoting oncogenic characteristics. The findings highlight the NS3-induced circ_0001175/miR-130a-5p/MDM4/P53 pathway as a potential therapeutic target, offering promising directions for treatment strategies in HCV-related HCC.

This study explored the possible effect of transcription factor GTF2I on the differentiation of osteoclasts and its regulation on the miR-134-5p/MAT2A axis. RANKL-induced osteoclasts were measured for expressions of GTF2I, miR-134-5p, and MAT2A. The number and size of osteoclasts were assessed after TRAP staining. The expressions of osteoclast differentiation biomarkers, NFATC1, TRAP, and CTSK, were detected as well. The relationships of the GTF2I/miR-134-5p/MAT2A axis were verified by ChIP, dual luciferase, and RNA pull-down assay. In vivo experiments were conducted on ovariectomized (OVX)-treated mice to determine the effect of GTF2I overexpression on osteoclast differentiation and bone loss. RANKL-induced osteoclasts had suppressed expressions of GTF2I and miR-134-5p and increased expression of MAT2A. GTF2I overexpression or miR-134-5p overexpression contributed to decreased cell number and size and suppressed cell differentiation, whereas such an effect can be abolished by overexpression of MAT2A. GTF2I can bind the miR-134-5p promoter to regulate its expression, whereas miR-134-5p can negatively regulate MAT2A expression. The protective effect of GTF2I overexpression against bone loss and cell differentiation was verified by in vivo experiments. Collectively, these results indicate that GTF2I can mediate miR-134-5p expression to increase MAT2A expression, contributing to the suppression of osteoclast differentiation.