Cell Biology and Toxicology最新文献

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.

Renal cell carcinoma (RCC) is a type of renal malignancy originated from the urinary tubular epithelial system. Despite its high incidence, the molecular mechanisms driving its pathogenesis remain poorly understood, limiting therapeutic advancements. This study explored the link between MCM8 and RCC progression. MCM8 displays significantly high expression in RCC tissues and was closely associated with RCC pathological staging. Knocking down endogenous MCM8 in RCC cells significantly suppressed malignant phenotypes, while simultaneously inducing apoptosis. Similarly, in vivo experiments confirmed these findings, showing a pronounced reduction in tumor growth upon MCM8 silencing. Mechanistic investigations revealed that MCM8 regulates E2F1 expression by interacting with the transcription factor NR4A1, thereby affecting E2F1 transcriptional activity. Additionally, MCM8 and E2F1 collaboratively influence aerobic glycolysis and the cellular behavior of RCC cells. In conclusion, this study identifies MCM8 as a tumor-promoting factor in RCC, with its oncogenic role potentially mediated by its regulation of E2F1 expression.

Nephrotoxicity caused by drug or chemical exposure involves complex mechanisms as well as a temporal integration of injury and repair responses in different nephron segments. Distinct cellular transcriptional programs regulate the time-dependent tissue injury and regeneration responses. Whole kidney transcriptome analysis cannot dissect the complex spatio-temporal injury and regeneration responses in the different nephron segments. Here, we used laser capture microdissection of formalin-fixed paraffin embedded sections followed by whole genome targeted RNA-sequencing-TempO-Seq and co-expression gene-network (module) analysis to determine the spatial-temporal responses in rat kidney glomeruli (GM), cortical proximal tubules (CPT) and outer-medulla proximal tubules (OMPT) comparison with whole kidney, after a single dose of the nephrotoxicant cisplatin. We demonstrate that cisplatin induced early onset of DNA damage in both CPT and OMPT, but not GM. Sustained DNA damage response was strongest in OMPT coinciding with OMPT specific inflammatory signaling, actin cytoskeletal remodeling and increased glycolytic metabolism with suppression of mitochondrial activity. Later responses reflected regeneration-related cell cycle pathway activation and ribosomal biogenesis in the injured OMPT regions. Activation of modules containing kidney injury biomarkers was strongest in OMPT, with OMPT Clu expression highly correlating with urinary clusterin biomarker measurements compared the correlation of Kim1. Our findings also showed that whole kidney responses were less sensitive than OMPT. In conclusion, our LCM-TempO-Seq method reveals a detailed spatial mechanistic understanding of renal injury/regeneration after nephrotoxicant exposure and identifies the most representative mechanism-based nephron segment specific renal injury biomarkers.

Methamphetamine (Meth) is a potent central nervous system stimulant with high addictive potential and neurotoxic effects. Chronic use results in significant damage in various brain functions, including cognition, memory, and sensory perception. Olfactory dysfunction is a notable yet often overlooked consequence of Meth abuse, and its underlying mechanisms are not fully understood. This study investigates the mechanisms of Meth-induced olfactory impairment through a thorough examination of olfactory bulb (OB) neurogenesis. We found that chronic Meth abuse impaired olfactory function in mice by not only reducing the self-renewal of subventricular zone (SVZ) neural stem cells (NSCs) but also altering their differentiation potential, leading their differentiation into astrocytes at the expense of neurons. Mechanistically, Meth inhibits autophagosome-lysosome fusion by downregulating Syntaxin 17 (Stx17), which reduces autophagic flux. In NSCs, autophagy tightly regulates Notch1 levels, and impaired autophagic degradation of Notch1 leads to its abnormal activation. This alters NSCs fate determination, ultimately affecting OB neurogenesis. Our study reveals that Meth impairs olfactory function through autophagic dysfunction and aberrant Notch1 signaling. Understanding these mechanisms not only provides new insights into Meth-induced olfactory dysfunction but also offers potential targets for developing therapies to alleviate Meth-induced neurotoxicity and sensory damage in the future.

This study investigated ERS-related gene expressions in CESC, identifying two molecular subtypes, P1 and P2, and constructing a precise prognostic model based on these subtypes. TCGA's whole-genome expression profiles were used to recognize these subtypes through the ConsensusClusterPlus method, further refining prognostic models with univariate and Lasso Cox regression analyses validated by the GSE39001 dataset. The study analyzed the expression distribution of ERS marker genes within T cell subgroups using scRNA-seq data (GSE168652), highlighting T cell diversity. The critical role of the CCL3 gene in prognostic models was examined explicitly in CD8 + T cells from healthy individuals and CESC patients. Elevated CCL3 levels were observed in patients' CD8 + T cells compared to healthy controls. Functional experiments involving CCL3 knockdown and overexpression in HeLa and SiHa CESC cell lines were conducted to investigate its impact on cell proliferation, migration, and invasion. These findings were subsequently validated in a nude mouse model. The results demonstrated that suppressing CCL3 inhibited cell proliferation, migration, and invasion significantly, while its overexpression promoted these processes. In the mouse model, CCL3 silencing reduced tumor growth and decreased Ki-67 labeling within the tumor tissues, indicating the therapeutic potential of targeting CCL3 in CESC treatment, possibly through CD8 + T cell regulation. This study contributes new prognostic assessment tools and personalized treatment options for CESC patients, paving the way for more targeted therapies in CESC by discovering the CCL3 gene, presenting significant clinical implications.

Despite zygotic genome activation (ZGA) is crucial for early embryonic development, its regulatory mechanism is still unclear in mammals. In the present study, we demonstrate that TRPS1, a maternal factor, plays an essential role in mouse early embryogenesis by regulating the transition from 2-cell to 4-cell embryos during preimplantation development. The absence of Trps1 could leads to impaired ZGA through AKT/CREB signaling pathway. Furthermore, our findings suggest that TRPS1 may modulate the transcription of Pde4d to influence AKT and CREB phosphorylation. Interestingly, compared to Trps1 knockdown alone, co-injection of Trps1 siRNA and Pde4d mRNA significantly enhances the development rate of 4-cell embryos. Collectively, these results indicate a negative involvement of Trps1 in mouse preimplantation embryo development by targeting the PDE4D/AKT/CREB pathway to regulate ZGA.

Bone disorders affect more than half of the adult population worldwide who may have a poor quality of life and physical independence worldwide. Multi-omic techniques are increasingly adopted and applied to determine the molecular mechanisms of bone tissue repair, providing perspective towards personalized medical intervention. Data from genomics, epigenomics, transcriptomics, proteomics, glycomics, and lipidomics were combined to elucidate dynamic processes in bone repair. In this narrative review, the key role of genetic and epigenetic factors in regulating injured cellular responses is highlighted, and changes in RNA and protein expression during the healing phase, as well as glucolipid metabolism adaptation, are described in detail how the repair process is affected. In a word, the integration of multi-omic techniques in this review not only benefits the comprehensive identification of new biomarkers, but also facilitates the development of personalized treatment strategies of bone disorders to revolutionize regenerative medicine.

Objectives: The study examined the NDUFA1 expression and its prognostic value in pan-cancer, especially in esophageal cancer (ESCA). Its carcinogenic effect on ESCA was further elucidated.

Materials and methods: TCGA database was used to examine NDUFA1 expression and its prognostic value in 33 cancer types. GO and KEGG were performed for function and pathway enrichment of NDUFA1-related genes. The carcinogenic effect on ESCA was verified in both KYSE-30 cell and Xenograft mouse model.

Results: Abnormal high expression of NDUFA1 was detected in pan-cancer, and related to immune cell infiltration. TCGA database indicated an elevated value of NDUFA1 in ESCA tumor tissues, which was linked to patients' poor prognosis. NDUFA1-related genes were mainly enriched in oxidative stress and immune response in ESCA. NDUFA1 knockdown significantly suppressed ESCA cell proliferation, migration and invasion. Similarly, tumor growth of ESCA xenograft mice was inhibited by NDUFA1 knockdown. Activated PI3K-Akt signaling was detected in both ESCA cell lines and tumor tissues, which was reversed by NDUFA1 knockdown.

Conclusion: Multi-omics analysis showed that NDUFA1 might be adopted as a potential therapeutic goal and prognostic indicator for a variety of cancers, especially for ESCA. NDUFA1 knockdown inhibited ESCA tumor growth, which may have the participation of the PI3K/Akt signaling pathway.

Background and purpose: Significant advancements in therapeutic approaches are imperative to address the prevalent impact of myocardial infarction (MI) on morbidity and mortality rates worldwide. This study explores the therapeutic potential of GATM/Gel hydrogel, focusing on its ability to enhance cardiac repair and functionality after MI through modulation of inflammatory and repair pathways.

Experimental approach: The effects of GATM/Gel hydrogel on cardiac recovery were studied in a murine MI model. HA-CHO and gelatin solutions were mixed in situ using a dual syringe with a static mixing needle, and the resulting hydrogel was applied directly to the epicardium during MI modeling, followed by repositioning of the heart and closure of the thorax. Comprehensive in vivo assessments-including echocardiography, electrocardiography, and histopathological analysis-were combined with molecular techniques such as RT-qPCR, Western blotting, and immunofluorescence to elucidate the underlying mechanisms. Key cellular and molecular changes were tracked, focusing on macrophage polarization, angiogenesis, and modulation of the TNF/TNFR2 signaling pathway.

Key results: Employing the GATM/Gel hydrogel led to a substantial improvement in heart function, shown through enhanced ejection fraction and fractional shortening, and reduced infarction size compared to control groups. Mechanistically, the hydrogel promoted the polarization of anti-inflammatory M2 macrophages and stimulated angiogenesis. Moreover, treatment with GATM/Gel hydrogel altered the TNF/TNFR2 pathway, pivotal in mediating inflammatory responses and facilitating myocardial repair. The discoveries highlight the possibility of GATM/Gel hydrogels as an innovative remedy for MI, providing a twofold role in regulating inflammation and fostering recovery.

Carnitine palmitoyltransferase 1A (CPT1A), a succinylating enzyme, is highly expressed in various malignant tumors and promotes tumor progression. Succinylation is a posttranslational modification that has been reported in various diseases, but its role in NK/T-Cell lymphoma nasal type (ENKTL-NT) remains underexplored. In this study, bioinformatics analysis showed that glycolytic is a major metabolic pathway in ENKTL-NT as the expression of many glycolytic related kinases are increased. CPT1A probably mediates glycolytic process, as indicated by GO-enrichment analysis. Studies showed that CPT1A was upregulated in ENKTL-NT tissues, and that high CPT1A expression was associated with poor prognosis of ENKTL-NT. CPT1A promoted the proliferation, colony formation, invasion and glycolytic process of ENKTL-NT cells and suppresses apoptosis. Mechanistically, CPT1A promotes succinylation of LDHA at lysine 318 (K318), which increase the protein stability and the final protein level of LDHA. Both knockdown and mutation (K318R) of LDHA abolished the cancer-promoting effects of CPT1A in ENKTL-NT. In all, this study reveals the mechanism underlying the cancer-promoting effects of CPT1A via inducing LDHA succinylation and metabolic reprogramming in ENKTL-NT. These findings might provide potential targets for the diagnosis or therapy of ENKTL-NT.