生物学最新文献

Adipose tissue is central to energy homeostasis and endocrine function, and its dysregulation is a key driver of metabolic disorders. Exosomes, serving as critical intercellular messengers, mediate systemic metabolic responses by delivering bioactive cargo, including nucleic acids, proteins, and lipids. Mounting evidence identifies adipose-derived exosomes as potent mediators of obesity-related inflammation and glucose metabolic dysfunction, thereby contributing to insulin resistance and diabetic complications. This review summarizes the pivotal roles of exosomal microRNAs (miRNAs) and highlights their significant potential as a novel class of small RNA therapeutics. Unlike synthetic delivery systems, exosomal miRNAs constitute an inherent delivery vehicle that synergizes natural targeting efficiency with potent gene regulatory functions. This unique combination enables the precise coordination of complex gene networks involved in metabolic disease, offering a distinct advantage over conventional single-target approaches. Consequently, exosomal miRNAs are positioned as promising candidates for pioneering RNA-based therapies against pervasive conditions such as diabetes and cardiovascular disease.

This study investigated mitochondrial permeability transition-driven necrosis-related genes (MPTDNRGs) and its association with lung adenocarcinoma (LUAD). We systematically investigated their genetic variation, expression patterns, and prognostic value. A risk prediction model for MPTDNRGs was contrasted using Cox regression and least absolute shrinkage and selection operator regression analyses. MPTDNRG scores were used to quantify LUAD subtypes. We evaluated their value in the tumor microenvironment (TME), tumor mutational burden (TMB), prognostic prediction, and drug sensitivity in LUAD. The expression level, copy number variation, methylation, and microRNA (miRNA) status of PSMB7 were analyzed. We also analyzed the expression and knockdown efficiency of PSMB7 in LUAD by immunohistochemical staining, real-time fluorescence quantitative polymerase chain reaction, and western blotting. PSMB7 function in LUAD cells and in vivo was assayed using Cell Counting Kit 8, colony formation, wound healing, Transwell assays, flow cytometry, and mouse models. Seven MPTDNRG features were successfully constructed to predict LUAD prognosis and validated in an external cohort. Patients were categorized into high- and low-risk groups based on risk scores. The high-risk group exhibited shorter survival times, lower TME scores, weaker TME cell infiltration, and higher TMB scores than the low-risk group. Cancer stem cell index, mutation frequency, and drug sensitivity significantly differed between the two groups. MPTDNRG score could independently predict LUAD. PSMB7 was highly expressed in various tumors, and copy number variation, methylation, and miRNA expression significantly differed among different cancers. PSMB7 was highly expressed in LUAD tissues and cell lines. PSMB7 knockdown inhibited cancer cell proliferation, migration, invasion, and epithelial - mesenchymal transition, and promoted apoptosis. PSMB7 exerted tumorigenic effects in mice. In conclusion, we comprehensively demonstrated the characterization of MPTDNRGs in LUAD and constructed a new risk prediction model. Meanwhile, PSMB7 was shown to be a possible new target for LUAD treatment.

Small non-coding RNAs, such as microRNAs and tRNA-derived fragments, are key regulators of cellular processes, but the functions of small intronic RNAs (sinRNAs), a recently identified RNA class, remain largely unknown. Here, we report that two sinRNAs, sinR-D and sinR-T, are upregulated in pancreatic β-cells of NOD mice, a well-established model of type 1 diabetes. Using in vivo RNA-tagging, we demonstrate that these sinRNAs are packaged into extracellular vesicles released by infiltrating CD4⁺ T lymphocytes and subsequently delivered to β-cells during the early stages of autoimmune attack. Functional analyses revealed that overexpression of sinR-T has little effect on β-cell viability, whereas sinR-D markedly increases β-cell apoptosis. This finding suggests that the transfer of sinR-D contributes to β-cell destruction and the onset of type 1 diabetes. Furthermore, pull-down experiments with biotinylated sinRNAs identified Ago2, a core component of the RNA-induced silencing complex (RISC), as a binding partner of sinR-D, indicating mechanistic parallels with microRNA-mediated regulation. Collectively, our data uncover a novel role for sinRNAs as extracellularly transferred regulators of β-cell fate, expanding the repertoire of small RNAs implicated in the initiation of type 1 diabetes.

Ribosomal DNA copy number (rDNAcn) and DNA methylation are important modulators of the human genome, both studied in relation to overall cellular function, biological ageing, and disease development. Despite the overlapping roles, their relationship remains poorly understood, especially in the early stages of life, characterized by rapid growth and high cellular demands. Even though previous studies have associated rDNA methylation with cancer and ageing, no study to date has examined the interplay between rDNAcn and whole-genome DNA methylation. In an epigenome-wide association study of 45S rDNAcn variation in 194 newborns, we show strong positive associations between rDNAcn and single DNA methylated CpGs, measured with the Illumina EPIC array. Out of the 122 Bonferroni-significant CpGs, 63.5% were also Bonferroni-significant in a replication cohort of 167 newborns, in which a second EWAS was conducted using DNA methylation data from the Illumina 450K array. The identified CpGs were dispersed over the autosomes and were not functionally related to the rDNA-forming nucleolar-associated domains. The top CpGs were annotated to genes (GFI1, USP46, ABHD14B, CHL1, CGREF1) that are functionally linked to cancer and cellular proliferation. In downstream analyses, the 122 rDNAcn-related CpGs revealed 31 differentially methylated regions and 253 nominally significant correlations with cord blood gene transcripts in an eQTM analysis. Pathway enrichment analyses showed an overrepresentation of the following pathways: 'RNA Polymerase III transcription' (R-HSA-76071, R-HSA-76046, R-HSA-74158, R-HSA-749476, R-HSA-73780, R-HSA-73980, R-HSA-76066, R-HSA-76061, hsa03020), 'cytosolic sensors of pathogen-associated DNA' (R-HSA-1834949), 'RNA polymerase II transcribes snRNA genes' (R-HSA-6807505), and 'translation initiation' (R-HSA-72613, R-HSA-72737). Our findings reveal a close link between rDNAcn variation and DNA methylation in early life. Disruptions in this interplay may influence cellular functions critical for early development, potentially shaping health and disease trajectories later in life.

Advancing age and deregulated obesity are well-established risk factors for breast cancer risk. While epigenetic ageing, a measure of biological ageing, has been linked to breast cancer risk, prior studies have mainly focused on blood-based measures. We aimed to study well-established epigenetic age estimates in normal breast tissue in relation to obesity-related metabolic markers. We analysed breast tissue from 91 cancer-free women, using DNA methylation age (mAge) clocks, including first-generation clocks (Hannum, Horvath), mortality-related clocks (Grim, Pheno), and methylation-based telomere length (DNAmTL). Pearson correlations assessed relationships among the clocks. Linear regression was used to associate mAge clocks with obesity-related blood markers (leptin, adiponectin, IGF-1, IGFBP-3), adjusting for chronological age, race, body mass index (BMI), and smoking, applying a false discovery rate threshold of 0.1. We explored effect modification by menopausal status using interaction terms. In the normal breast tissue, the strongest correlation of mAge estimates was observed between Horvath-mAge and Grim-mAge (r = 0.85). BMI was positively associated with all mAge estimates except Pheno-mAge. Older Grim-mAge and longer DNAmTL were associated with higher levels of adiponectin, IGF-1, and IGFBP-3, while older Horvath-mAge was associated only with IGF-1. Associations of DNAmTL with IGF-1 and adiponectin differed statistically by menopausal status. Epigenetic age in breast tissue, particularly Grim and DNAmTL, is associated with obesity-related metabolic markers, independent of chronological age, BMI, and smoking. Although limited by a moderate sample size, our findings indicate a potential biological pathway linking mAge-related metabolic dysregulation that may provide insight into breast cancer risk.

Porcine reproductive and respiratory syndrome virus(PRRSV) is an economically important pathogen for global pork industry. As a positive-strand RNA virus, lacking exonuclease-mediated proofreading, its RNA-dependent RNA polymerase (RdRP) domain within the nonstructural protein 9(nsp9) plays a vital role in maintaining replication accuracy. To identify the residues of PRRSV that regulates replication fidelity, its RdRP structure was predicted by using Alpha Fold 2 and aligned with the solved structure of coxsackievirus B3 (CVB3) RdRP. This comparison identified conserved residues in PRRSV RdRP that are potentially involved in fidelity. Using site-directed mutagenesis, nucleoside analog sensitivity tests, and next-generation sequencing(NGS), it was found that the nsp9 K541R mutation enhances fidelity, as increasing viral resistance to mutagens like ribavirin, 5-Fluorouracil(5-FU), and 5-Azacytidine(5-AZC), as well as generating lower rate of non-contiguous junctions. In contrast, mutations at other positions, including A394G, L396S, and R401A, reduced fidelity and elevated frequency of recombination and mutation accumulation. Structural modeling revealed that the highly conserved residue K336 is spatially adjacent to the key fidelity site K541 but situated on the opposite side of the RNA channel. We found that K336R exhibits a dissociated "resistance-high recombination" phenotype. The findings reveal the importance of specific residues in PRRSV RdRP for replication fidelity and provide insights into the potential for improving the stability and safety of live attenuated vaccines through targeted modifications. Furthermore, the study emphasizes the structural conservation of fidelity determinants across RNA viruses, despite low sequence similarity, which can offer a framework for identifying fidelity key sites in other viral RdRPs.

Hypertrophic scars (HS) frequently result from severe burns, surgical procedures and other causes of deep skin damage. The impact of serum/glucocorticoid regulated kinase family member 3 (SGK3) on the formation of HS remains unclear. HS model rats were constructed by the scalding method. In addition, tissue samples from clinical patients were collected to detect the SGK3 levels in normal skin and HS tissues by RT-qPCR and western blotting. Human-derived HS fibroblasts (HSFBs) were isolated and identified using immunofluorescence. Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine staining and scratch assays were applied to test the ability of the HSFBs to proliferate and migrate. The influence of an SGK3 inhibitor on wound healing in rats was assessed using hematoxylin and eosin staining, Masson staining, immunofluorescence and immunohistochemistry. In addition, the levels of collagen and the proteins involved in the mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK) pathway were measured by western blotting. SGK3 was highly expressed in HS tissues. Knockdown of SGK3 resulted in reduced SGK3 levels in HSFBs. Knockdown of SGK3 reduced the proliferation and migration ability of HSFBs and suppressed cellular fibrosis. Injection with an SGK3 inhibitor reduced the burn scar area, decreased epithelial thickness and inhibited collagen deposition in rats. This inhibitor also resulted in the downregulation of collagen and MAPK/ERK pathway-related proteins. In addition, MAPK/ERK pathway agonists attenuated the effect of SGK3 inhibition, promoting HS formation while inhibiting wound healing in rats; however, MAPK inhibitors had the opposite effect. In conclusion, inhibition of SGK3 reduces the proliferation, migration and fibrosis abilities of HSFBs as well as promotes wound healing and inhibits HS formation in rats by downregulating the MAPK/ERK pathway.

Alzheimer's disease and Parkinson's disease are the two most prevalent neurodegenerative disorders worldwide, both characterized by progressive neuronal loss. Despite distinct pathophysiological features, they share cellular dysfunctions such as abnormal protein aggregation, oxidative stress, and neuroinflammation, research into which might be beneficial for developing novel therapeutic strategies that could tackle both conditions. This review highlights the emerging role of the gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide as modulators of adult neurogenesis and neuroprotection in Alzheimer's disease and Parkinson's disease. We have gathered recent evidence demonstrating that these endogenous gases exert anti-inflammatory, antioxidant, and anti-apoptotic effects, and, critically, promote neurogenesis - suggesting a dual neuroprotective and neuroregenerative therapeutic potential. The unique physicochemical features of these gasotransmitters, including their ability to cross the blood-brain barrier and diffuse rapidly throughout the neural tissue, further support their suitability as candidates for innovative neuroregenerative treatments. While clinical translation remains challenging, harnessing the neurogenic and neuroprotective actions of these gasotransmitters may offer transformative avenues for addressing the increasing burden of Alzheimer's disease and Parkinson's disease.

In response to stress, cells undergo gene expression reprogramming to cope with external stimuli. Cells utilize a conserved stress response mechanism called global downregulation of translation, leading to the storage of translationally repressed mRNAs in RNA granules. During oxidative stress induced by H2O2, genes responsible for combating oxidative stress, such as catalases, are strongly induced. However, the post-transcriptional regulatory events affecting these genes during H2O2 stress are not well-explored. Scd6, an RGG-motif-containing protein in yeast, acts as a translational repressor through its interaction with eIF4G1. This study identifies the role of Scd6 in oxidative stress response by regulating cytoplasmic catalase T1 (CTT1). We observe that peroxide stress induces the assembly of Scd6 puncta, which do not colocalize with P-bodies or stress granules. Scd6 overexpression increased sensitivity, while deletion enhanced tolerance to H2O2 treatment. Increased ROS accumulation and decreased Ctt1 protein levels were observed upon Scd6 overexpression due to translation repression of CTT1 mRNA. CTT1 mRNA interacts with Scd6. smFISH analysis and RNA immunoprecipitation studies reveal that localization of Scd6 to puncta upon peroxide stress reduces its interaction with CTT1 mRNA, allowing derepression. The role of Scd6 in peroxide stress response is conserved since the human homolog LSm14A also localizes to puncta upon H2O2 stress, and its overexpression reduces survival in response to peroxide stress. Overall, this study identifies a unique example of translation regulation whereby stress-induced localization of the translation repressor protein to puncta leads to derepression of the target mRNA.