International Journal of Molecular Sciences最新文献

Dietary pattern characterized by low intake of vegetables and fruits and high consumption of fat, soft drink and desserts are associated with an increased risk of chronic diseases. To investigate the effects of folate status and fructose intake on adenine-induced chronic kidney disease (CKD), seven-week-old C57BL/6 mice were divided into six groups and fed either a control diet (Ctrl), a 26% (w/w) high-fructose diet (Hfru), Ctrl plus 0.15% adenine (Ctrl+ade), Hfru+ade, Hfru with folate deficiency plus adenine (Hfru-f+ade), or Hfru with tenfold folate supplementation plus adenine (Hfru+f10+ade). After 10 weeks on the assigned diets, adenine was administrated to the +ade groups for 7 weeks. The results showed that all adenine-treated mice exhibited increased fasting blood glucose, urinary glucose, and elevated renal expression of collagen 1a1 (Col1a1), fibronectin (Fn1), and smooth muscle α-actin (Acta2). Compared with Ctrl mice, Hfru-fed mice showed significantly higher serum creatinine, increased urinary protein, and reduced creatinine clearance. Adenine induced kidney injury in all +ade groups, with the most severe damage observed in Hfru-f+ade mice, as indicated by elevated blood urine nitrogen (BUN), urinary protein, neutrophil gelatinase-associated lipocalin (NGAL), and renal fibrosis. In contrast, Hfru+f10+ade mice showed the lowest levels of these renal injury markers. The Hfru+ade diets increased renal Hif1α and iNos gene expression, which was further exacerbated by folate deficiency. Secretion of the anti-inflammatory cytokine interleukin (IL-10) by splenocytes was significantly reduced under folate-deficient conditions. Renal IL-10 levels were suppressed in all +ade groups but were significantly increased by folate supplementation. Renal IL-10 levels were negatively correlated with the inflammatory chemokine monocyte chemoattractant protein (MCP-1) and transforming growth factor (TGF)-β, whereas renal MCP-1 levels showed positive correlations with TGF-β and IL-6. Overall, these findings suggest that high fructose consumption in the absence of adequate folate intake may be of concern for CKD progression.

The recently described genus Candolleomyces (Basidiomycota, Agaricales, Psathyrellaceae) is now recognized as a distinct taxonomic group separate from Psathyrella. Currently, no fully assembled and accurately annotated genomes of Candolleomyces species are available, limiting our understanding of their physiological traits and biotechnological potential. Numerous tools exist for fungal genome assembly and annotation, each using different algorithms, resulting in substantial variation in gene content and distribution within the same genome. In this work, a hybrid assembly and annotation of the genome of strain CMU-8613 were performed using pipelines that combine different assembly and annotation tools. Phylogenetic analysis showed that the analyzed strain CMU-8613 belongs to Candolleomyces candolleanus. The assembled genome size ranged from 46.8 Mb (NECAT + Racon) to 59.3 Mb (Canu + Coprinellus micaceus genome assembly), depending on the assembly and polishing strategy. The analysis identified 15-25 secondary metabolite gene clusters (BGCs), depending on the genome assembly and the tools used for BGC prediction. In strain CMU-8613, CAZyme-encoding genes varied across assemblies: 494 genes were detected in the Flye assembly and 453 in NECAT; in both cases, the AA (Auxiliary Activities) and GH (Glycoside Hydrolases) families were the most represented. The diversity of CAZymes observed among Candolleomyces species suggests differences in their saprophytic capacities. Analysis of the MAT-A/MAT-B loci revealed that C. candolleanus possesses a tetrapolar mating system. This study provides the first annotated genome of C. candolleanus, highlighting its enzymatic potential to degrade plant biomass and its capacity to synthesize diverse secondary metabolites. The combination of assembly and annotation tools employed here offers robust alternative strategies for characterizing non-model fungi or species lacking high-quality reference genomes.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and pathological α-synuclein aggregation. Growing evidence identifies chronic neuroinflammation-particularly NLRP3 inflammasome activation in microglia-as a central driver for PD onset and progression. Misfolded α-synuclein, mitochondrial dysfunction, and environmental toxins act as endogenous danger signals that prime and activate NLRP3 inflammasome, leading to caspase-1-mediated maturation of IL-1β and IL-18 and subsequent pyroptotic cell death. Impaired mitophagy, due to defects in PINK1/Parkin pathways or receptor-mediated mechanisms, permits accumulation of dysfunctional mitochondria and release DAMPs, thereby amplifying NLRP3 activity. Studies demonstrate that promoting mitophagy or directly inhibiting NLRP3 attenuates neuroinflammation and protects dopaminergic neurons in PD models. Autophagy-inducing compounds, along with NLRP3 inhibitors, demonstrate neuroprotective potential, though their clinical translation remains limited due to poor blood-brain barrier penetration, off-target effects, and insufficient clinical data. Additionally, the context-dependent nature of mitophagy underscores the need for precise therapeutic modulation. This review summarizes current understanding of inflammasome-mitophagy crosstalk in PD, highlights major pharmacological strategies under investigation, and outlines its limitations. Future progress requires development of specific modulators, targeted delivery systems, and robust biomarkers of mitochondrial dynamics and inflammasome activity for slowing PD progression.

Candida albicans is the most prevalent opportunistic pathogenic fungus in humans, and its extracellular vesicles (EVs) play crucial roles in its growth and pathogenesis. Previously, we found that C. albicans EVs at low levels could promote its growth. However, the effects of EVs when accumulated at high concentrations in C. albicans remain unclear. This study revealed that a high concentration of EVs inhibited hyphal development in C. albicans in a time-dependent manner. Transcriptome and RT-qPCR analyses showed that EVs significantly upregulated the transcription repressor NRG1 and downregulated hyphal-specific genes in a laboratory strain and five clinical isolates, while EVs failed to repress nrg1Δ/Δ hyphae. Further experiments confirmed that EVs upregulated the upstream transcription factor SKO1 (but downregulated BRG1) to increase NRG1 expression, thereby inhibiting hyphal formation. Cargo proteins in EVs were key components that inhibited C. albicans hyphal growth. Additionally, EV-treated C. albicans showed improved mouse survival and reduced organ fungal burden in candidemia, but EVs did not attenuate virulence in nrg1Δ/Δ-infected mice. These results reveal that C. albicans EVs at high levels play an important role in its pathogenicity and highlight the potential for novel therapeutic strategies.

The essential bacterial type II topoisomerases gyrase and topoisomerase IV have been exploited as the therapeutic targets of fluoroquinolone antibacterials for over four decades. Despite their broad utility, the effectiveness of fluoroquinolones has been increasingly undermined by the widespread emergence of target-mediated resistance, highlighting the need for alternative therapeutic strategies. Recent advances have produced two mechanistically distinct classes of gyrase/topoisomerase IV-targeted antibacterials: the triazaacenaphthylenes and the spiropyrimidinetriones. The first-in-class agents gepotidacin and zoliflodacin, respectively, were approved for human use in 2025, representing the first new antibacterial classes targeting these enzymes in decades. This commentary examines the mechanisms of action of these agents, contrasts their interactions with gyrase and topoisomerase IV relative to fluoroquinolones, and considers their potential to address resistance while preserving the long-term clinical viability of therapy directed against the bacterial type II topoisomerases.

Alternative splicing (AS) is a fundamental mechanism governing transcriptomic diversity and cellular identity. Although 293T (human embryonic kidney) and A549 (human lung adenocarcinoma) cell lines are widely used, cell-type-specific splicing dynamics-including responses to receptor overexpression-remain incompletely characterized. To address this, we integrated Oxford Nanopore long-read sequencing with BGI short-read data to profile transcriptomes under both basal and GPCR-overexpressing conditions (ADORA3 in 293T; P2RY12 in A549). Full-length isoform analysis using FLAIR and SQANTI3 revealed extensive transcriptomic complexity, including 18.02% novel isoforms in 293T and 19.52% in A549 cells. We found that 293T cells exhibited a stable transcriptome architecture enriched in splicing-related pathways, whereas A549 cells underwent broader transcriptional remodeling linked to tumorigenic processes. These findings suggest that 293T cells may be a suitable model for investigating splicing regulation, while A549 cells could serve as a relevant system for exploring tumor-related transcriptome dynamics. Our work elucidates context-dependent AS regulation and underscores the value of integrating long-read sequencing with FLAIR/SQANTI3 for dissecting cell-state-specific transcriptome dynamics.

Extracellular polymeric substances (EPSs) produced by actinomycetes of the genus Rhodococcus play crucial roles in their ecological success, metabolic versatility, and biotechnological value. This review summarizes existing studies of Rhodococcus EPSs, emphasizing the biochemical composition, functional attributes, and practical significance of EPSs, as well as their importance in biomedicine, bioremediation, and other applications (food industry, biomineralization) with respect to the EPS chemical composition and biological roles. Rhodococcus species synthesize complex EPSs composed primarily of polysaccharides, proteins and lipids that, like in other bacteria, support cell adhesion, aggregation, biofilm formation, and horizontal gene transfer (and can prevent exogenous DNA binding) and are highly important for resistance against toxicants and dissolution/assimilation of hydrophobic compounds. EPSs produced by different species of Rhodococcus exhibit diverse structures (soluble EPSs, loosely bound and tightly bound fractions, capsules, linear and branched chains, amorphous coils, rigid helices, mushroom-like structures, extracellular matrix, and a fibrillar structure with a sheet-like texture), leading to variations in their properties (rheological features, viscosity, flocculation, sorption abilities, compression, DNA binding, and interaction with hydrophobic substrates). Notably, the EPSs exhibit marked emulsifying and flocculating properties, contributing to their recognized role in bioremediation. Furthermore, EPSs possess antiviral, antibiofilm, anti-inflammatory, and anti-proliferating activities and high viscosity, which are valuable in terms of biomedical and food applications. Despite extensive industrial and environmental interest, the molecular regulation, biosynthetic pathways, and structural diversity of Rhodococcus EPSs remain insufficiently characterized. Advancing our understanding of these biopolymers could expand new applications in biomedicine, bioremediation, and biotechnology.

Although there have been advancements in stroke treatment (reperfusion) therapy, and it has been shown that many individuals continue to suffer from partial recoveries and continuing decline in their neurological status as a result of suffering a stroke, a primary barrier to providing precise care to patients with stroke continues to be the inability to capture changes in molecular and cellular programs over time and in biological compartments. This review synthesizes evidence that represents the entire continuum of ischemia, beginning with acute metabolic failure and excitotoxicity, and ending with immune response in the nervous system, reprogramming of glial cells, remodeling of vessels, and plasticity at the level of networks, and organizes this evidence in a temporal framework that includes three biological compartments:central nervous system tissue, cerebrospinal fluid, and peripheral blood. Additionally, this review discusses new technologies which enable researchers to discover biomarkers at an extremely high resolution, including single-cell and spatial multi-omics, profiling of extracellular vesicles, proteoform-resolved proteomics, and glymphatic imaging, as well as new computational methods and machine-learning algorithms to integrate data from multiple modalities and predict trajectories of disease progression. The final section of this review will provide an overview of translationally relevant and ethically relevant issues regarding the deployment of predictive biomarkers, such as privacy, access, equity, and fairness, and emphasize the importance of global coordination of research efforts in order to ensure the clinical applicability and global equity of biomarker-based diagnostics and treatments.

2-Hydroxy-4-Methoxybenzaldehyde (2H4MB) is a valuable aromatic compound with applications in flavour, fragrance, and pharmaceuticals. Because of its endangered status and root-specific accumulation, its production in native plants is restricted. In order to increase 2H4MB yield, this study emphasises recent developments in metabolic engineering, synthetic biology, in vitro culture methods, and AI-assisted route prediction. This review discussed about how CRISPR-based genome editing can be used to modify important biosynthetic genes and regulatory components, as well as how predictive machine learning techniques can be used to improve production conditions. Inadequate genetic resources, poorly understood biosynthetic pathways, and a dearth of reliable transformation systems are among the present constraints. The work highlights the importance of using integrative plant biotechnology techniques to fully realise the industrial and medicinal potential of this underutilised chemical.

In recent decades, anthropogenic activities have substantially increased the release of chemical contaminants in the environment and continuous exposure to chemical stressors has become a pervasive condition for living organisms [...].