生物学最新文献

Obesity and its metabolic complications represent a major and growing public health burden, for which effective therapeutic strategies remain limited. Although super-enhancers are recognized as key regulators of cell identity and adipogenesis, the roles of super-enhancer- microRNAs in obesity and adipocyte dysfunction remain insufficiently characterized. Here, we identify miR-1260b as a super-enhancer-associated miRNA that influences human adipogenesis. Analysis of adipose-related datasets from SEdb 2.0 revealed that MIR1260B is consistently linked to a clustered SE region across multiple human adipose tissues. Integrated ATAC-seq and Hi-C analyses demonstrated progressive chromatin opening and dynamic enhancer-promoter interactions between this SE and the MIR1260B promoter during adipogenic differentiation. Functionally, miR-1260b overexpression markedly inhibited adipocyte differentiation of human adipose-derived stem cells. Quantitative proteomic profiling revealed that miR-1260b suppresses adipogenic and lipogenic programmes while activating lipid catabolic pathways. Notably, the MIR1260B-associated SE overlaps with a previously reported diabetes-associated SNP, and external clinical datasets indicate reduced miR-1260b levels in umbilical cord serum from children at increased risk of obesity. Together, these findings suggest that miR-1260b may function as a super-enhancer-associated regulator that inhibits adipogenesis and indicate that SE-informed multi-omics approaches can aid in identifying miRNA regulators relevant to metabolic disorders of obesity.

Clinically prior hyperglycemia may lead to long-lasting adverse cardiovascular effects, a process referred to as 'glycemic memory.' Epigenetic modifications, specifically DNA methylation changes, may play a key role in this phenomenon. This study investigated if prior high glucose delivery to cardiomyocytes, led to worsened cardiovascular effects upon pressure overload and to ascertain the gene expression and corresponding DNA methylation signatures linked to glycemic memory. Using inducible and cardiomyocyte-specific glucose transporter 4 (GLUT4) overexpressing mice. We induced glucose delivery for 2 weeks, then returned to basal uptake for 2 weeks, followed by sham or transverse aortic constriction (TAC) surgery as a secondary stress. Mice were followed for an additional 8 weeks and assessed for contractile function, cellular remodeling, and molecular changes. TAC led to an exacerbated hypertrophic response and cardiac dysfunction in the transgenic mice. Subsequent analysis identified molecular changes akin to heart failure, worsened cardiac fibrosis, and oxidative stress. Using bulk RNA-sequencing and reduced representation bisulfite sequencing, we discovered differential gene expression and DNA methylation signatures that persisted even after cellular glucose levels reverted to normal. Significant changes across both expression and methylation-identified enriched pathways related to adverse cardiac events, supporting a glycemic memory response. Glycemic memory led to cardiac structural and functional exacerbation, mimicking heart failure, when subjected to a secondary stress. Our data identified transcriptome, and preliminary DNA methylome changes which may potentially be molecular signatures of future therapeutic targets associated with this heart failure susceptibility resulting from enhanced glucose delivery.

Mutations in superoxide dismutase 1 (SOD1) cause paralysis in familial amyotrophic lateral sclerosis and promote its misfolding into neurotoxic aggregates. Previous studies have shown that mice expressing the ALS-causing G85R variant of SOD1 develop paralysis much faster after intraspinal injection of spinal homogenates from paralysed G85R SOD1 mice. These findings, and other studies in cell models, established the prionoid templating properties of misfolded mutant SOD1. Previously, however, we noted that the widely used Gur1-G93A SOD1 mice, which express at high levels and develop paralysis by 6 months of age, were resistant to seeding by homogenates from paralysed G93A mice. A line of G93A mice that expresses at very low levels (VLE-G93A) was responsive to seeding but at low efficiency. The poor susceptibility of G93A-SOD1 mice to seeding was not what we expected if prion-like propagation is essential to SOD1 ALS pathogenesis. In our prior studies, seeding homogenates from paralysed G93A-SOD1 mice were injected into the spine of newborn mice, leading us to question whether older G93A SOD1 mice might be more susceptible to seeding. Here, we establish that adult VLE G93A SOD1 mice (up to 12 months of age) injected intrathecally with seeding homogenates containing misfolded G93A or G85R SOD1 developed accelerated motor neuron disease efficiently. Thus, we demonstrate that both the route and age of inoculation can influence the efficiency of SOD1 seeding to induce motor neuron disease in VLE G93A-SOD1 mice. These data, together with our earlier reports, suggest that prion-like templating contributes to disease progression in SOD1-ALS.

Alzheimer's disease (AD) is a typical neurodegenerative disorder, characterized by the deposition of β-amyloid (Aβ) plaques. β- and γ-secretases generate Aβ by cleaving amyloid precursor protein. The imbalance between its production and clearance leads to Aβ accumulation, causing neuronal damage through mechanisms such as inducing oxidative stress and inflammatory responses. Long non-coding RNAs (LncRNAs), composed of more than 200 nucleotides, usually do not encode proteins and are involved in processes such as gene expression regulation, chromatin remodelling, and cell cycle control. Studies have shown that LncRNAs play a key role in brain development and the maintenance of neuronal function, especially by influencing Aβ deposition to affect the progression of AD. This review summarizes the pathways by which LncRNAs affect Aβ deposition, classifies them according to their modes of action, discusses the existing problems in current research, and summarizes and prospects their role in the treatment of AD.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that act as essential post-transcriptional regulators in various biological processes. Many studies suggest that miRNAs may modulate the host's immune response or even viral replication during infection. We have identified hsa-miR-203a-3p as a key regulatory candidate influencing innate immune responses, based on a comprehensive analysis of publicly available transcriptomic datasets involving H7N9, HCV, or DENV2 infection. Pathway enrichment analysis of microRNA-targeted genes reveals that hsa-miR-203a-3p targets several components of type I interferon signalling and JAK-STAT pathway. In this study, we report a novel role of hsa-miR-203a-3p as it is elevated in response to polyinosinic-polycytidylic acid [poly(I:C)] transfection and infection with RNA viruses Newcastle Disease Virus (NDV) and A/PR8/H1N1 influenza virus. We found that hsa-miR-203a-3p promotes the A/PR8/H1N1 virus replication by suppressing the host's type-I interferons and interferon-stimulated genes. Our investigation demonstrated that overexpression of hsa-miR-203a-3p led to reduced expression of interferon stimulated genes (ISGs). This regulation is likely mediated through the direct binding of hsa-miR-203a-3p to the 3' UTRs of Janus-activated kinase 1 (JAK1), STAT1 and several IFN-α transcripts. Collectively, these findings highlight the pivotal role of hsa-miR-203a-3p in immune homoeostasis; it regulates type I IFN signalling and downstream antiviral responses, thereby facilitating A/PR8/H1N1 and NDV infection.

The epitranscriptome comprises chemical modifications found on RNA molecules that play essential roles in co- and post-transcriptional gene regulation. Dysregulation of these modifications has been implicated in various diseases, fuelling interest in evaluating them as emerging biomarkers and therapeutic targets. Nanopore direct RNA sequencing provides a powerful platform for profiling diverse RNA modifications at single-molecule resolution, but the complexity of the signals requires advanced computational approaches for interpretation. Artificial intelligence, particularly deep learning (DL), has become central to this effort. While classical DL architectures such as convolutional and recurrent neural networks have been widely applied, more recent approaches employ specialized learning frameworks and ensemble strategies to address challenges of data scarcity, noise, and biological variability while providing higher resolution output. In this review, we summarize these developments and highlight future multidisciplinary opportunities at the intersection of artificial intelligence and biology for characterizing the epitranscriptome obtained with direct RNA nanopore sequencing.

Aspergillus section Flavi encompasses multiple species, with A. flavus being significant for human health because of its dual role as a major aflatoxin producer and opportunist. However, the mechanisms underlying its virulence remain incompletely understood. This study evaluates the pathogenic potential of A. flavus and its relatives using the Galleria mellonella infection model. Twenty-six A. flavus isolates (clinical and environmental) and 17 relatives/domesticated species were tested in G. mellonella, with larval survival monitored over 7 d. Histology, direct microscopy, and culture were used to validate the infection. Growth kinetics and spore sizes were measured to evaluate correlations with pathogenicity. All A. flavus isolates demonstrated high virulence, causing 90%, and 100% mortality of G. mellonella larvae within 3 and 7 d, respectively, with no significant differences between sources. Aflatoxin-producers exhibited higher virulence, resulting in 100% mortality of Galleria larvae within 5 d (p < 0.05). Related species exhibited lower virulence; larval mortalities ranging from 20% to 70% within 3 d, ranked as A. flavus > A. pseudonomiae > A. parasiticus > A. nomiae > A. tamarii > A. pseudocaelatus. Growth kinetics and spore size were correlated with virulence, as rapid growth and smaller spores were associated with increased pathogenicity. Aspergillus flavus exhibits higher virulence than its relatives, with growth rate, and spore size influencing pathogenicity. The G. mellonella model proves effective for comparative virulence studies. These findings highlight the potential health risks of A. flavus, including its domesticated relatives used in food fermentations, necessitating further investigations into their pathogenic potential.

Cancer stem cells (CSCs) represent a highly specialized intratumoral compartment responsible for tumor initiation, metastatic dissemination, therapeutic resistance, and disease recurrence. A central conceptual challenge in CSC biology is their capacity to oscillate between a quiescent G₀ state and a proliferative, stem-like phenotype, reflecting a high degree of phenotypic plasticity. Although dysregulation of the G1/S checkpoint is a hallmark of malignant transformation, its mechanistic contribution to CSC identity and plastic behavior remains poorly defined.This review outlines a conceptual model that integrates aberrant G1/S control with CSC state transitions. We propose that defective checkpoint regulation accelerates CSC proliferation, leading to the progressive intracellular accumulation of Cyclin D, which in turn drives a self-reinforcing, rapid G1 progression through phosphorylation-dependent pathways that operate independently of the slower, transcription-driven Cyclin D-Rb-E2F regulatory axis. With continued cycling, depletion of key E2F-regulated DNA replication factors ensues, eventually forcing CSCs into a quiescent, biosynthetic restoration phase. During this interval, essential genomic replication and cell cycle machinery are replenished until microenvironmental or intracellular cues trigger reentry into the proliferative cycle, giving rise to another burst of accelerated division.Through these cyclical perturbations in the Cyclin D/E2F balance, CSCs undergo temporally governed shifts between quiescent and proliferative states, thereby sustaining plasticity, intratumoral heterogeneity, and treatment-resistant phenotypes. This model also identifies potential therapeutic strategies, such as leveraging stimuli-responsive delivery systems that exploit cyclic CSC vulnerabilities.

Background: Colorectal cancer (CRC) represents a significant global health burden, requiring a deeper understanding of the molecular mechanisms that drive its progression. Circular RNAs (circRNAs) have appeared as crucial regulators in cancer, with circ_0050102 as a potential functional molecule in CRC. The present study aimed to determine the diagnostic and functional implications of circ_0050102 in CRC pathogenesis.

Methods: The GSE172229, GSE205094, and GSE134834 datasets were used for the comprehensive analyses of circRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in CRC tumor samples. Functional experiments, including fluorescence in situ hybridization, knockdown assays, flow cytometric analysis, and luciferase reporter assay, were conducted to investigate the effect of circ_0050102 on CRC cell behavior. CircRNA - miRNA - mRNA interaction analysis provided information about the regulatory network that involved circ_0050102, miR-3622a-3p, and baculoviral IAP repeat-containing 5 (BIRC5). Furthermore, the functional impact of circ_0050102 on CRC tumor growth was investigated using in vivo xenograft models.

Results: Our analysis determined circ_0050102 as a significantly differentially expressed circRNA in CRC, with a high area under the receiver operating characteristic curve value, indicating its diagnostic potential. Functional experiments revealed that circ_0050102 is predominantly localized in the cytoplasm of CRC tumor cells, and its knockdown significantly attenuates various CRC cell behavior aspects, including viability, invasion, and migration (p < 0.05). The interaction analysis revealed a potential regulatory axis that involves circ_0050102, miR-3622a-3p, and BIRC5. In vivo experiments demonstrated that circ_0050102 knockdown significantly attenuated CRC tumor development.

Conclusion: Our results revealed that circ_0050102 promotes CRC progression through miR-3622a-3p and BIRC5. The circ_0050102-mediated regulatory network provides valuable information about the intricate mechanisms contributing to CRC pathogenesis.

Objectives: Urolithin A (UA) is a natural polyphenolic compound produced by gut bacteria. Vascular remodeling contributes to hypertension, and vascular smooth muscle cells (VSMCs) proliferation and migration are important processes in vascular remodeling.

Methods: VSMCs were obtained from the thoracic aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Intraperitoneal injections of UA (50 mg/kg, every 2 days for 4 weeks) were performed in SHR.

Results: UA attenuated proliferation and migration, reduced mitochondrial reactive oxygen species (mitoROS) levels, and increased SOD2 activity in VSMCs of SHR, which were prevented by SOD2 knockdown. UA promoted mitochondrial short-length SIRT3 (SL-SIRT3) production and SOD2 deacetylation. SIRT3 inhibitor 3-TYP abolished the effects of UA on SOD2 deacetylation, mitoROS levels and VSMCs proliferation and migration. Repeated intraperitoneal injection of UA every 2 days for 4 weeks attenuated vascular remodeling and hypertension, increased SL-SIRT3 levels and SOD2 activity, and reduced SOD2 acetylation and mitoROS levels in aorta and mesenteric arteries of SHR.

Conclusion: UA attenuates VSMCs proliferation and migration in SHR by increasing mitochondrial SL-SIRT3 level, and subsequent SOD2 deacetylation and mitoROS reduction in SHR. Long-term administration of UA attenuates vascular remodeling, hypertension and oxidative stress in SHR.