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Abstract: Chronic obstructive pulmonary disease (COPD) ranks as the third most common contributor to global mortality. Oxidative stress has been recognized as a critical driver of multiple interacting mechanisms in COPD development. This research investigated the potential of oxidative stress-related genes (OSRGs) biomarkers and their potential molecular mechanisms for COPD clinical diagnosis and treatment through bioinformatics analyses. As a result, 5 hub genes, CA3, PPP1R15B, MAPT, MMP9, and ECT2, were yielded by LASSO, Boruta, and SVM-RFE, and the performance of the nomogram constructed based on hub genes was favorable. Correlation analyses between hub genes and oxidative stress biomarkers showed that MMP9 and MAPT genes had a high association with oxidative stress biomarkers. Immune cell infiltration identified follicular helper T cells, Γδ T cells, M0 macrophages, and CD8 T cells as significantly different in COPD. ROC of ECT2 and MMP9 showed a higher capability to discriminate COPD patients from normal samples. In addition, we collected clinical samples and analyzed the core gene expression, which revealed that the hub genes ECT2 and MMP9 had high discriminatory ability in the COPD samples. The epistasis of ECT2 and MMP9 was further verified by constructing animal models, pathological sections, qPCR, immunoblotting, immunohistochemistry, etc. The data indicated the crucial function of MMP9 in CSC-induced oxidative stress injury. Deprivation of MMP9 attenuated CSC-induced injury and promoted macrophage polarisation to M2 macrophages. MMP9 deprivation protected against CSC-induced injury, mainly related to the reduction of cell apoptosis, cell inflammation, and ROS injury in BEAS-2B. It promoted macrophage polarization from M1 to M2. In summary, we found ECT2 and MMP9 are related to oxidative stress in COPD, and MMP9 was related to cell apoptosis, cell inflammation, and ROS injury in BEAS-2B, and the macrophage polarization from M1 to M2. PubDate: 2025-04-11
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Abstract: This paper aimed to address the function of the MIAT/miR-130a-3p/Pdgfra axis in retinal microglia activation in chronic retinal hypoperfusion injury (CRHI) mice. CRHI mouse models were constructed through bilateral common carotid artery occlusion (BCCAO). MIAT, Pdgfra, and miR-130a-3p expression levels in retinal tissues and cells were assessed. The expression of genes linked to the Nlrp3 inflammatory vesicle pathway (Gsdmd, Asc, Tlr4, Casp1, and Casp8) was assessed. Serum contents of inflammatory cytokines IL-18 and IL-1β were determined. Iba-1/Casp1/Csdmd expression was tested. Moreover, the interplay between miR-130a-3p and MIAT, as well as associations between Pdgfra and miR-130a-3p were verified. MIAT and Pdgfra expression was enhanced and miR-130a-3p diminished in BCCAO mouse models. MIAT downregulation reduced IL-18 and IL-1β contents and repressed microglia activation in BCCAO mice, and histopathological results also displayed raised mouse retinal thickness and diminished apoptosis. Both inhibiting miR-130a-3p and overexpressing Pdgfra can reverse the delayed effects of MIAT interference on CRHI. MIAT regulates miR-130a-3p to stimulate the expression of Pdgfra, thereby further promoting retinal microglia activation in CRHI mice. This provides potential targets for the development of innovative treatment approaches for retinal disorders. Graphical Abstract Mechanism of the MIAT/miR-130a-3p/Pdgfra axis in retinal microglia in CRHI mice. PubDate: 2025-04-11
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Abstract: Embryo implantation relies on complex mother-fetus interactions. Abnormal decidualization can cause various pregnancy complications such as placental abnormalities, preeclampsia, and fetal growth restriction. circRNAs play a key role in various cellular processes. This study focuses on the role of circ-Hdac4, a circRNA derived from the Hdac4 gene, in decidualization and placental function. Mouse models revealed a spatiotemporally regulated expression of circ-Hdac4 in the endometrium during early pregnancy, with enhanced expression surrounding implantation sites. In vitro and in vivo assays confirmed that circ-Hdac4 is crucial for stromal cell decidualization, as its knockdown resulted in reduced expression of decidualization markers and disrupted endometrial architecture. Furthermore, we found that circ-Hdac4 functions as a microRNA sponge for miR-30c, which negatively regulates RBPJ, a critical protein for decidual remodeling. Proteomic analysis revealed that RBPJ was downregulated upon circ-Hdac4 silencing, and we validated the direct interaction between miR-30c and RBPJ using luciferase reporter assays. A mouse preeclampsia model showed that downregulation of circ-Hdac4 during decidualization exacerbated preeclampsia-related phenotypes, including reduced fetal counts, weights, and placental weights. In addition, we observed decreased expression of circ-Hdac4 and RBPJ in the decidual surface of placental tissues from preeclampsia patients, further supporting our findings in the mouse model. Collectively, our study provides evidence that circ-Hdac4 regulates decidualization through the miR-30c-RBPJ axis and that its abnormal expression during decidualization contributes to placental dysfunction in preeclampsia. This research offers novel insights into the molecular mechanisms underlying pregnancy complications and potential therapeutic targets for their prevention and treatment. Graphical Abstract 1. circ-Hdac4 can regulate endometrial decidualization by targeting Mir-30c-RBPJ axis in early pregnancy mice 2. circ-Hdac4/miR-30c/RBPJ axis regulating decidualization through miRNA sponging, 3. Reduced circ-Hdac4 and RBPJ expression in human preeclampsia decidua correlates with placental dysfunction PubDate: 2025-04-10
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Abstract: Lamin A/C is a nuclear type V intermediate filament protein part of the meshwork structure underlying the inner nuclear membrane (nuclear lamina), which plays numerous roles, including maintenance of nuclear shape, heterochromatin organization, and transcriptional regulation. Our group has demonstrated the role of Lamin A/C in different pathophysiological conditions. Here, we investigated for the first time how Lamin A/C affects neuronal maturation in rat cerebellar granule cells (GCs). Primary rat cerebellar GCs where we silenced the Lmna gene constituted our key model; this provided a rather homogeneous cellular system showing a neuronal population in vitro. We then validated our findings in another in vivo murine model with knock-out of the Lmna gene and in an in vitro human neuronal model with silencing of the LMNA gene. We observed across three different models that Lamin A/C down-regulation affects neurons maturation by protecting the cells from glutamate-evoked excitotoxicity and correlates with an inhibition of calcium influxes and a down-regulation of pro-inflammatory cytokine pathways. Consistent with previous findings from our group, this study corroborates that Lamin A/C plays a key role in neural development and opens new significant implications for a better comprehension of the mechanisms involved in neurodegenerative diseases, where changes in the nuclear envelope are linked to neuroinflammatory processes and damage. PubDate: 2025-04-05
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Abstract: Examining the communications in the tumor microenvironment (TME) specific to hepatocellular carcinoma (HCC), this exploration looks into the role played by beta-1,4-Galactosyltransferase III (B4GALT3) in bone marrow mesenchymal stromal cell-derived extracellular vesicles (BMSCs-EVs) regarding the NF-κB pathway and the triggering of cancer-associated fibroblasts (CAF). Through a multidisciplinary approach combining transcriptome sequencing, bioinformatic analysis, and various experimental models, the involvement of B4GALT3 in regulating CAF activity by modulating NF-κB signaling was brought to light in our study. The outcomes suggest that targeting B4GALT3 could impede HCC cell migration and invasion, promote apoptosis, and dampen tumor progression and metastasis, offering novel insights into potential therapeutic strategies for combating HCC. PubDate: 2025-04-05
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Abstract: The prevalence of contrast-enhanced magnetic resonance imaging (MRI) examinations and the absence of safer alternatives to gadolinium-based contrast agents (GBCAs) make the associated adverse effects of GBCAs much more concerning. Safety concerns arise from the toxic behavior of heavy metal gadolinium (Gd3+) and the potential release of the metal from the chelating ligand. Renal insufficiency and other patient factors increase the susceptibility to the toxic effects of GBCAs. It is, therefore, imperative that the molecular and cellular mechanisms underlying GBCA toxicity be defined. This study aims to determine GBCA-induced endolysosomal dysfunction in mouse renal proximal tubule epithelial cells. Loss of cell viability was agent- and time-dependent, and proximal tubule injury was detectable following 24 h linear GBCA exposure. Both classes of GBCAs displayed lysosomotropic behaviors, characterized by early lysosomal enlargement and lysosomal injury. Hijacking of the endolysosomal system by these agents inhibited cathepsin processing by blocking the transport and maturation of cathepsin B (CTSB) and cathepsin D (CTSD). Lysosomal enlargement coincided with the translocation of CTSB and CTSD from the lysosomal lumen to the cytosol, suggesting lysosomal membrane destabilization. Even though both agents displayed a similar response, linear exposures appeared to exhibit a greater effect. Disturbance of mitochondrial activity and loss of cell viability occurs downstream of early lysosome damage. This effect was partially restored by lysosomal protease inhibitor co-treatment. This data suggests that GBCA exposures induce a lysosomal stress response, and partial LMP occurs upstream of mitochondrial dysfunction and resultant cellular injury. Graphical abstract PubDate: 2025-04-03
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Abstract: Sodium fluoride-induced ocular damage constitutes a significant public health concern globally; however, the precise molecular mechanisms underlying this issue remain obscure. This study aims to investigate the effects of sodium fluoride on myopia and to offer novel theoretical foundations for future strategies in myopia prevention and control. The experimental data showed that sodium fluoride could promote myopia progression, and through bioinformatics analysis, we found that sodium fluoride could affect the ferroptosis pathway. Western blotting and redox kit assays further confirmed that sodium fluoride activates the ferroptosis pathway. We also demonstrated that PIEZO1 plays a crucial role in sodium fluoride-induced myopia, and that the PIEZO1 inhibitor (GsMTx4) can inhibit the ferroptosis pathway. Subsequently, we identified PIEZO1 as a potential target of baicalin, which inhibited PIEZO1 expression in vivo and in vitro, as confirmed by molecular docking modeling and CETSA assays. Finally, we found that baicalin inhibited sodium fluoride-induced myopia via PIEZO1. Taken together, our findings indicate that sodium fluoride can promote myopia progression by activating the ferroptosis pathway through PIEZO1, and that targeting PIEZO1 expression can delay myopia progression, which may provide a new drug target for myopia treatment in the future. PubDate: 2025-04-02
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Abstract: Bone marrow-derived cells in the tumor microenvironment, including macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, eosinophils and basophils, participate in the generation, development, invasion and metastasis of tumors by producing different cytokines and interacting with other cell types, and play a pro-tumor or anti-tumor role in regulating tumor immunity. Due to the complexity of cell types in the tumor microenvironment and the unknown process of tumor development and metastasis, cancer treatment to achieve better survival status remains challenging. In this article, we summarize the effects of myeloid cells in tumor microenvironment on tumor immunity, cancer migration, and crosstalk with metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism), which will help to further study the tumor microenvironment and seek targeted therapeutic strategies for patients. Graphical abstract Myeloid cells in the tumor microenvironment exhibit diverse biological functions, influencing tumor initiation and progression. Myeloid cells are involved in tumor immunity and metastasis processes, interacting with other immune cell types to affect the tumor immune response. The crosstalk between glucose metabolism, lipid metabolism, amino acid metabolism, and myeloid cells impacts tumor immunity and metastasis. PubDate: 2025-03-25
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Abstract: Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of iron-dependent lipid peroxides, which has been implicated in the pathogenesis of various diseases, and therapeutic agents targeting ferroptosis are emerging as promising tools for cancer treatment. Current research reveals that ferroptosis-targeted therapies can effectively inhibit tumor progression or delay cancer development. Notably, natural product-derived compounds—such as artemisinin, baicalin, puerarin, quercetin, kaempferol, and apigenin—have demonstrated the ability to modulate ferroptosis, offering potential anti-cancer benefits. Mechanistically, ferroptosis exhibits negative glutathione peroxidase 4 (GPX4) regulation and demonstrates a positive correlation with plasma membrane polyunsaturated fatty acid (PUFA) abundance. Moreover, the labile iron pool (LIP) serves as the redox engine of ferroptosis. This review systematically analyzes the hallmarks, signaling pathways, and molecular mechanisms of ferroptosis, with a focus on how natural product-derived small molecules regulate this process. It further evaluates their potential as ferroptosis inducers or inhibitors in anti-tumor therapy, providing a foundation for future clinical translation. PubDate: 2025-03-25
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Abstract: Sorafenib has demonstrated great efficacy in liver cancer, however, its application as first-line treatment has been hampered due to the emerging drug resistance. This study is aimed to investigate the mechanism underlying acquired sorafenib resistance in liver cancer. Based on GSE109211 and TCGA datasets, bioinformatics analysis was conducted to find the potential genes implicated in the sorafenib resistance in liver cancer. mCherry-/eGFP-LC3B dual-fluorescent system was used to assess autophagic state. Wild and mutant types of HA-labeled ubiquitin (K27, K29, K33, K48, K63, K29R and K48R) were used to identify the type of polyubiquitin chains added to p27 by CUL1. Herein, we identified that F-box protein (SCF) ubiquitin ligase complexes (CUL1 and SKP2) and NEDD8 were highly expressed in sorafenib-resistant tissues using both the public data and clinical samples. NEDD8-mediated CUL1 neddylation enhanced SCF ubiquitin ligase complex to target p27 and subsequently linked K29-linked polyubiquitin chains to p27. Furthermore, NBR1 facilitated the degradation of ubiquitinated p27 protein by enhancing autophagy flux. Knocking down of CUL1 could prevent ubiquitination- and autophagy-mediated p27 protein degradation. The resistance to sorafenib was suppressed with CUL1 knockdown both in vitro and in vivo. In conclusion, our findings indicated that blocking neddylation or autophagy can restore drug sensitivity, thus providing a potential strategy for overcoming sorafenib resistance in the future. PubDate: 2025-03-20
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Abstract: Background Exosome Lnc A2M-AS1 from olfactory mucosa mesenchymal stem cells (OM-MSCs) can ameliorate oxidative stress by improving mitophagy in cardiomuscular cells; however, it remains unclear whether this effect exists in the brain tissues of patients with Parkinson’s disease (PD). Methods OM-MSC–Exosomes were isolated and verified based on morphology and specific biomarkers. The effects of OM-MSC-Exo on mitochondrial autophagy, oxidative stress, and lncRNA A2M-AS1 were detected in MPP+-treated HT22 cells. The effects of OM-MSC-Exos on mitochondrial autophagy and oxidative stress were detected in an MPTP-induced Parkinson's disease (PD) model in C57BL/6 mice. The interaction between IGF2BP1, A2M-AS1, and TP53INP1 was assessed via RNA pull-down/RNA Immunoprecipitation and RNA stability assays. The effects of lnc A2M-AS1 on IGF2BP1/TP53INP1-mediated mitochondrial autophagy and oxidative stress were verified in MPP+-treated HT22 cells and MPTP-induced PD mouse models. Results Exosomes isolated from olfactory mucosa mesenchymal stem cells were found to be rich in Lnc A2M-AS1. Lnc A2M-AS1 was proved to be able to ameliorate oxidative stress induced by MPP+ in HT22 cells. lncRNA A2M-AS1 regulates oxidative stress by enhancing mitophagy in HT22 cells. In addition, lncRNA A2M-AS1 induced mitophagy through TP53INP1 and mediated TP53INP1 expression by binding to IGF2BP1. Furthermore, OM-MSC-Exo and Lnc A2M-AS1 treatment improved symptoms and ameliorated oxidative stress in MPTP-induced PD mouse models. Conclusion Collectively, lncRNA A2M-AS1 from OM-MSC-derived exosomes regulates TP53INP1 expression by targeting IGF2BP1 to induce mitophagy and ameliorate oxidative stress. OM-MSC-derived exosomes could potentially serve as promising candidates for new treatment methods for PD. Graphical Abstract PubDate: 2025-03-20
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Abstract: The progression of coronary artery disease atherosclerosis (CAD) is closely associated with cardiomyocyte apoptosis and inflammatory responses. This study focused on investigating the impact of BRCA1 in exosomes (Exo) derived from M1 macrophages on CAD. Through the analysis of single-cell RNA-seq datasets, significant communication between macrophages and cardiomyocytes in CAD patients was observed. BRCA1, identified as a significant apoptosis-related gene, was pinpointed through the assessment of differential gene expression and weighted gene co-expression network analysis (WGCNA). Experimental procedures involved BRCA1 lentivirus transfection of M1 macrophages, isolation of Exo for application to cardiomyocytes and smooth muscle cells, cell viability assessments, and characterization of Exo. The results showed that BRCA1-Exo from M1 macrophages induced cardiomyocyte apoptosis and affected smooth muscle cell behavior. In vivo studies further supported the exacerbating effects of BRCA1-Exo on CAD progression. Overall, the involvement of Exo carrying BRCA1 from M1 macrophages is evident in the induction of cardiomyocyte apoptosis and the regulation of smooth muscle cell behaviors, thereby contributing to CAD atherosclerosis progression. These findings unveil novel molecular targets that could have potential implications for CAD treatment strategies. Graphical Abstract PubDate: 2025-03-13
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Abstract: Triple-negative breast cancer (TNBC) poses as a daunting and intricate manifestation of breast cancer, highlighted by few treatment options and a poor outlook. The crucial element in fostering tumor growth and immune resistance is the polarization of tumor-associated macrophages (TAMs) into the M2 state within the tumor microenvironment (TME). To address this, we developed M2 targeting peptide-chitosan-curcumin nanoparticles (M2pep-Cs-Cur NPs), a targeted delivery system utilizing chitosan (Cs) as a carrier, curcumin (Cur) as a therapeutic agent, and targeting peptides for specificity. These NPs effectively inhibited TNBC cell proliferation (~ 70%) and invasion (~ 70%), while increasing the responsiveness of tumors to anti-PD-L1 treatment (~ 50% survival enhancement) in vitro and in vivo. Bioinformatics analysis suggested that Cur modulates TAM polarization by influencing key genes such as COX-2, offering insights into its underlying mechanisms. This study highlights the potential of M2pep-Cs-Cur NPs to reverse M2 polarization in TAMs, providing a promising targeted therapeutic strategy to overcome immunotherapy resistance and improve TNBC outcomes. PubDate: 2025-03-08
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Abstract: As legalization of cannabis increases worldwide, vaping cannabis is gaining popularity due to the belief that it is less harmful than smoking cannabis. However, the safety of cannabis vaping remains untested. To address this, we developed a physiologically relevant method for in vitro assessment of cannabis vapor on alveolar epithelial cell cultures. We compared the transcriptional response in three in vitro models of cannabis vapor exposure using A549 epithelial cells in submerged culture, pseudo-air liquid interface (ALI) culture, and ALI culture coupled with the expoCube™ advanced exposure system. Baseline gene expression in ALI-maintained A549 cells showed higher expression of type 2 alveolar epithelial (AEC2) genes related to surfactant production, ion movement, and barrier integrity. Acute exposure to cannabis vapor significantly affected gene expression in AEC2 cells belonging to pathways related to cancer, oxidative stress, and the immune response without being associated with a DNA damage response. This study identifies potential risks of cannabis vaping and underscores the need for further exploration into its respiratory health implications. Graphical Abstract • Vaporizing cannabis is increasingly popular but remains largely untested. • We used three in vitro models to assess the effects of cannabis vapor on alveolar epithelial cells. • Cannabis vapor exposure alters pathways linked to cancer and metabolism, without causing DNA damage. PubDate: 2025-03-08
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Abstract: Andrographolide (AP) has been shown to possess anti-inflammatory activities. In this study, the impact of AP in sepsis-induced acute liver injury (ALI) and the molecules involved were dissected. FKBP1A was predicted to be the sole target protein of AP that was also differentially expressed in the GSE166868 dataset. AP induced the protein expression of FKBP1A and suppressed that of NOTCH1 in a dose-dependent manner. AP ameliorated ALI in mice induced by D-galactosamine and LPS and inhibited LPS-induced liver parenchymal cell injury in vitro. By contrast, the protective effect of AP was significantly lost after the knockdown of FKBP1A. As a positive control, the therapeutic effect of dexamethasone on ALI may be related to NOTCH1, which was not related to FKBP1A. NOTCH1 promoted AK2 transcription in liver parenchymal cells, and FKBP1A inhibited endoplasmic reticulum (ER) stress by impairing NOTCH1/AK2 signaling. Restoration of NOTCH1 significantly reversed the hepatoprotective effect of AP in ALI mice and LPS-induced liver parenchymal cell injury by activating the ER stress pathway. Therefore, AP-promoted FKBP1A expression inhibits ALI progression by blocking the NOTCH1/AK2-mediated ER pathway. Graphical Abstract PubDate: 2025-03-07
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Abstract: Acute lung injury (ALI), which poses a significant public health threat, is commonly caused by sepsis. ALI is associated with permeability and glycolysis changes in pulmonary microvascular endothelial cells. Our study demonstrates that heparin-binding protein (HBP), released from neutrophils during sepsis, exacerbates endothelial permeability and glycolysis, thereby triggering ALI. Through coimmunoprecipitation and mass spectrometry, TRIM21 was identified as a HBP interaction partner. Notably, HBP enhances the protein stability of TRIM21 by inhibiting K48 ubiquitination. TRIM21 binds to and promotes K63-linked ubiquitination of P65, facilitating its nuclear translocation. TRIM21 regulates HPMEC permeability and glycolysis in a manner dependent on P65 nuclear translocation. HBP stabilizes TRIM21 and enhances TRIM21 interactions with P65. Rescue experiments conducted in vivo and in vitro demonstrate that modulation of endothelial permeability and glycolysis by HBP is predominantly mediated through the TRIM21-P65 axis. Our results suggest that targeting the HBP/TRIM21/P65 axis is a novel therapeutic strategy to ameliorate ALI. PubDate: 2025-03-05
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Abstract: Recently, infertility has emerged as a significant and prevalent public health concern warranting considerable attention. Apoptosis, recognized as programmed cell death, constitutes a crucial process essential for the maintenance of normal spermatogenesis. Multiple investigations have illustrated that the dysregulated apoptosis of reproductive cells, encompassing spermatogonial stem cells, Sertoli cells, and Leydig cells, serves as a causative factor in male infertility. MicroRNAs represent a class of small RNA molecules that exert negative regulatory control over gene expression using direct interaction with messenger RNA transcripts. Previous studies have established that aberrant expression of miRNAs induces apoptosis in reproductive tissues, correlating with reproductive dysfunctions and infertility. In this review, we offer a comprehensive overview of miRNAs and their respective target genes implicated in the apoptotic process. As well, miRNAs are involved in multiple apoptotic signaling pathways, namely the PI3K/AKT, NOTCH, Wnt/β-catenin, and mTOR signaling cascades, exerting both negative and positive effects. We additionally elucidate the significant functions played by lncRNAs and circular RNAs as competing endogenous RNAs in the process of apoptosis within reproductive cells. We further illustrate that external factors, including silica nanoparticles, Cyclosporine A, and smoking, induce dysregulation of miRNAs, resulting in apoptosis within reproductive cells and subsequent male reproductive toxicity. Further, we discuss the implication of heat stress, hypoxia, and diabetes in reproductive cell apoptosis induced by miRNA dysregulation in male infertility. Finally, we demonstrate that the modulation of miRNAs via traditional and novel medicine could protect reproductive cells from apoptosis and be implemented as a therapeutic approach in male infertility. PubDate: 2025-03-05
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Abstract: Abnormal embryonic development leads to the formation of cleft palate (CP) which is difficult to be detected by genetic screening and needs sequent treatment from infants to adults. There are no interceptive treatment about CP until now. Germline deletion of phosphatase and tensin homolog (Pten) was related to embryonic malformation and regulated tumor cell proliferation through glycolysis. However, the role of Pten in CP and the relationship between CP, Pten, and glycolysis are unknown. In our research, we constructed Pten knockdown models in vitro and in vivo. Our results provided preliminary evidence that blocking Pten by its inhibitor such as VO-OHpic might be an effective interceptive treatment in early period of palate development when pregnant mother expose in harmful environment during the early period of palate development to reducing CP occurring which was related with the crosstalk between Pten, and glycolysis in the process. Graphical Abstract PubDate: 2025-02-27
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Abstract: Background Triple negative breast cancer (TNBC) continues to be the most aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. Doxorubicin (DOX) belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. This study investigates the mechanism of m6A methyltransferase ZC3H13 in DOX resistance of TNBC. Methods ZC3H13, KCNQ1OT1, and TRABD expressions in TNBC tissues or cells were detected by RT-qPCR or Western blot. The effect of ZC3H13 on DOX resistance of TNBC cells was evaluated by CCK-8, clone formation, and EdU staining. RIP was performed to analyze the enrichment of YTHDF2 or m6A on KCNQ1OT1. RIP and RNA pull-down verified the binding between KCNQ1OT1 and MLL4. The enrichment of MLL or H3K9me1/2/3 on TRABD promoter was analyzed by ChIP. A nude mouse xenograft tumor model was established to verify the mechanism in vivo. Results ZC3H13 was poorly expressed in TNBC, and its expression further decreased in drug-resistant cells. Overexpression of ZC3H13 decreased the IC50 of drug-resistant TNBC cells to DOX, repressed proliferation, and induced ferroptosis. Mechanistically, ZC3H13-mediated m6A modification reduced the transcriptional stability of KCNQ1OT1 and inhibited its expression in a YTHDF2-dependent manner. KCNQ1OT1 enhanced the enrichment of H3K4me1/2/3 on TRABD promoter by recruiting MLL4, thus increasing TRABD expression. ZC3H13 induced ferroptosis by inhibiting KCNQ1OT1/TRABD, thereby restraining the growth of DOX-treated tumors in vivo. Conclusion ZC3H13-mediated m6A modification reduces DOX resistance in TNBC by promoting ferroptosis via KCNQ1OT1/TRABD axis. Graphical Abstract PubDate: 2025-02-26
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Abstract: Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEV) have recently garnered attention as a potential therapeutic approach for kidney diseases with anti-inflammatory effects. Infiltrated macrophages play an important role in facilitating tissue regeneration. However, the intricate regulatory effects of hucMSC-sEV on macrophages during cisplatin-induced acute kidney injury (AKI) remain unknown. In this study, we uncovered that hucMSC-sEV exhibited potent anti-inflammation and effectively inhibited the polarization of M1 phenotype macrophages. Mechanically, miRNA sequencing analysis and qRT-PCR indicated that a novel miRNA, named miR-13896, was enriched in hucMSC-sEV. When transfected with miR-13896 mimic, macrophages displayed M2 phenotype with elevated levels of Arg1 and IL-10, while miR-13896 inhibitor promoted M1 phenotype. Furthermore, we firstly established that miR-13896 repressed Tradd expression by targeting its 3' untranslated region and subsequently inhibited NF-κB signaling pathway in macrophages. Additionally, to improve therapeutic effects, hucMSC-sEV were engineered with elevated levels of miR-13896 through electroporation, which resulted in promoting M2 phenotype macrophages, inhibiting inflammatory factors, and enhancing kidney repair. Conclusively, our findings provide novel insights into the mechanisms underlying the effects of hucMSC-sEV on macrophages and AKI, while also highlighting electroporation as a promising strategy for treating cisplatin-induced AKI. PubDate: 2025-02-24
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