International Journal of Molecular Sciences最新文献

Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, large capacity, and high transduction efficiency, making them widely used as oncolytic vectors and for creating vector-based vaccines. This review also considers the application of adenoviral vectors in oncolytic virotherapy and gene therapy for inherited diseases, analyzing strategies to enhance their efficacy and specificity. However, despite significant progress in this field, the use of adenoviral vectors is limited by their high immunogenicity, low specificity to certain cell types, and limited duration of transgene expression. Various strategies and technologies aimed at improving the characteristics of adenoviral vectors are being developed to overcome these limitations. Significant attention is being paid to the creation of tissue-specific promoters, which allow for the controlled expression of transgenes, as well as capsid modifications that enhance tropism to target cells, which also play a key role in reducing immunogenicity and increasing the efficiency of gene delivery. This review focuses on modern approaches to adenoviral vector modifications made to enhance their effectiveness in gene therapy, analyzing the current achievements, challenges, and prospects for applying these technologies in clinical practice, as well as identifying future research directions necessary for successful clinical implementation.

Amino acids are the main form of nitrogen in plants, and their transport across cell membranes relies on amino acid transporters (AATs). Among the plant AATs, the TaATLa subfamily comprises 18 members, yet the bioinformatics characteristics and functions of TaATLa genes in common wheat remain poorly understood due to their complex genomes. This study performed genomic analyses of TaATLas. These analyses included chromosome distributions, evolutionary relationships, collinearity, gene structures, and expression patterns. An analysis of cis-acting elements and predicted miRNA-TaATLas regulatory networks suggests that TaATLas are regulated by light, hormones, and stress signals. Functional assays revealed that TaATLa6 transports glutamine (Gln), glutamate (Glu), and aspartate (Asp) in yeast. In contrast, TaATLa4 specifically transports Gln and Asp. Furthermore, TaATLas exhibits diverse gene expression patterns, with TaATLa4-7D enhancing yeast heat tolerance in a heterologous expression system, indicating its potential role in adapting to environmental stress by regulating amino acid transport and distribution. This study sheds light on the functional roles of TaATLa genes, with implications for improving nitrogen use in wheat and other crop species.

This study investigates the effect of reduced saliva production on intestinal histological structure and microbiome composition using a sialoadenectomy murine model, evaluating differences in saliva secretion, body weight, intestinal histopathological changes, and microbiome alteration using 16S rRNA gene sequencing across three groups (control, sham, and sialoadenectomy). For statistical analysis, one-way analysis of variance and multiple comparisons using Bonferroni correction were performed. p-values < 0.05 were considered statistically significant. Microbiome analysis was performed using Qiime software. The results show that reduced saliva secretion leads to structural changes in the intestinal tract, including shorter and atrophic villi, deformed Paneth cells, decreased goblet cell density, and immunohistochemical changes in epidermal growth factor and poly(ADP-ribose) polymerase-1, especially at three months after surgery. They also showed significant alterations in the intestinal microbiome, including increased Lactobacillaceae and altered populations of Ruminococcaceae and Peptostreptococcaceae, suggesting potential inflammatory responses and decreased short-chain fatty acid production. However, by 12 months after surgery, these effects appeared to be normalized, indicating potential compensatory mechanisms. Interestingly, sham-operated mice displayed favorable profiles, possibly due to immune activation from minor surgical intervention. This study underscores saliva's essential role in intestinal condition, emphasizing the "oral-gut axis" and highlighting broader implications for the relationship between oral and systemic health.

Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD expression and suppressed muscle regenerative capacity, in the skeletal muscle of aged mice. LncRNA-3 could interact with both the MyoD1 promoter and RbAp46/48, a subunit of Polycomb repressive complex 2 (PRC2). LncRNA-3 could recruit PRC2 to the MyoD1 promoter and enhance the MyoD1 silencing, which, in turn, suppressed the muscle regenerative capacity. Muscle-specific lncRNA-3 knockdown could restore the muscle regenerative capacity in the aged mice. Exogenous RbAp46/48 binding motif (Rb-motif-2) treatment in skeletal muscle could compete for the lncRNA-3 binding, and therefore, enhance the muscle regenerative capacity in the aged mice. Taken together, lncRNA-3 requires PRC2 for MyoD1 silencing to suppress muscle regenerative capacity during aging. These findings provide a novel therapeutic target and a new strategy to elevate the muscle regenerative capacity in the aged population.

Biotechnology continues to drive innovation in the production of pharmaceuticals, biofuels, and other valuable compounds, leveraging the power of microbial systems for enhanced yield and sustainability. Genome-scale metabolic (GSM) modeling has become an essential approach in this field, which enables a guide for targeting genetic modifications and the optimization of metabolic pathways for various industrial applications. While single-species GSM models have traditionally been employed to optimize strains like Escherichia coli and Lactococcus lactis, the integration of these models into community-based approaches is gaining momentum. Herein, we present a pipeline for community metabolic modeling with a user-friendly GUI, applying it to analyze interactions between Methylococcus capsulatus, a biotechnologically important methanotroph, and Escherichia coli W3110 under oxygen- and nitrogen-limited conditions. We constructed models with unmodified and homoserine-producing E. coli strains using the pipeline implemented in the original BioUML platform. The E. coli strain primarily utilized acetate from M. capsulatus under oxygen limitation. However, homoserine produced by E. coli significantly reduced acetate secretion and the community growth rate. This homoserine was taken up by M. capsulatus, converted to threonine, and further exchanged as amino acids. In nitrogen-limited modeling conditions, nitrate and ammonium exchanges supported the nitrogen needs, while carbon metabolism shifted to fumarate and malate, enhancing E. coli TCA cycle activity in both cases, with and without modifications. The presence of homoserine altered cross-feeding dynamics, boosting amino acid exchanges and increasing pyruvate availability for M. capsulatus. These findings suggest that homoserine production by E. coli optimizes resource use and has potential for enhancing microbial consortia productivity.

Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates a large number of proteins including BMAL1, which is involved in the regulation of glucocorticoid synthesis in the adrenal glands and the sensitivity of glucocorticoid receptor target genes. Male mice with a point mutation Q31L in the Disc1 gene were exposed to chronic unpredictable stress (CUS), after which the behavioral and physiological stress response assessed. To assess whether there were any changes in BMAL1 in key brain regions involved in the stress response, immunohistochemistry was applied. It was shown that the Q31L mice had an aberrant behavioral response, especially to the 2 weeks of CUS, which was expressed in unchanged motor activity, increased time of social interaction, and alterations in anxiety and fear-related behavior. Q31L males did not show an increase in blood corticosterone levels after CUS and a decrease in body weight. Immunohistochemical analysis in intact Q31L mice revealed a decrease in BMAL1 immunofluorescence in the CA1 hippocampal area and lateral habenula. Thus, the Q31L mutation of the Disc1 gene disrupts behavioral and physiological stress response and the BMAL1 dysregulation may underlie it, so this protein can act as a molecular target for the treatment of affective disorders.

All cells secrete various types of membrane vesicles, known as extracellular vesicles (EVs), and this process is conserved throughout evolution [...].

Myocardial infarction (MI) remains the leading cause of death globally, imposing a significant burden on healthcare systems and patients. The gut-heart axis, a bidirectional network connecting gut health to cardiovascular outcomes, has recently emerged as a critical factor in MI pathophysiology. Disruptions in this axis, including gut dysbiosis and compromised intestinal barrier integrity, lead to systemic inflammation driven by gut-derived metabolites like lipopolysaccharides (LPSs) and trimethylamine N-oxide (TMAO), both of which exacerbate MI progression. In contrast, metabolites such as short-chain fatty acids (SCFAs) from a balanced microbiota exhibit protective effects against cardiac damage. This review examines the molecular mediators of the gut-heart axis, considering the role of factors like sex-specific hormones, aging, diet, physical activity, and alcohol consumption on gut health and MI outcomes. Additionally, we highlight therapeutic approaches, including dietary interventions, personalized probiotics, and exercise regimens. Addressing the gut-heart axis holds promise for reducing MI risk and improving recovery, positioning it as a novel target in cardiovascular therapy.

Leizhou goats can be classified into tall and short types based on their size and habits. The tall Leizhou goats are well-suited for grazing management due to their robust physique, while the dwarf types are smaller, grow rapidly, and are more appropriate for feeding management systems. In this study, whole-genome resequencing was conducted to identify genomic variants in 15 Tall-legged (TL) and 15 Short-legged (SL) Leizhou goats, yielding 8,641,229 high-quality SNPs in the Leizhou goat genome. Phylogenetic tree and principal component analyses revealed obvious genetic differentiation between the two groups. Fst and θπ analyses identified 420 genes in the TL group and 804 genes in the SL group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the phosphatidylinositol signaling system is associated with growth and development. Additionally, Genome-Wide Association Study (GWAS) analysis identified eight genes linked to leg length, including B4GALT7 and NR1D1. Notably, the NC_030818.1 (g.53666634T > C) variant was significantly associated with leg length traits, where the CC genotype was linked to shorter legs and the TT genotype to longer legs. This study identifies candidate genes and molecular markers, serving as a reference point for breeding and genetic improvement efforts in Leizhou goats and other goat breeds.

Lentinus edodes serves as a significant source of both medicine and food, with its key component, lentinan (LNT), recognized as an effective immunomodulator. However, the mechanisms by which it regulates immune and intestinal functions under conditions of immunosuppression remain unclear. This study aims to investigate the components of lentinan and examine its potential effects on countering cyclophosphamide (CP)-induced immunosuppression, intestinal barrier damage, and dysregulation of gut microbiota. In this study, the effects of LNT were evaluated by serological indicators, histopathological changes in ileum, tight-junction-related protein expression, cytokine expression levels, and gut microbiota 16S rRNA gene sequencing. We found that LNT was effective in mitigating the abnormalities in body weight, immune organ index, and serum levels of IL-6, IL-2, IFN-γ, and IgG in mice induced by CP (p < 0.05). Furthermore, LNT demonstrated the ability to alleviate intestinal barrier damage induced by CP by increasing the mRNA levels of TNF-α, IL-1β, IFN-γ, Occludin, and ZO-1 (p < 0.05). Additionally, 16S rRNA gene sequencing revealed that LNT also normalized the disrupted abundance of Firmicutes, Proteobacteria, and Bacteroidets caused by CP. This restoration brought the gut microbiota back to normal levels and increased the abundance of certain tumor-inhibiting bacteria, such as Alistipes. Overall, lentinan demonstrated the ability to reverse the immunosuppressive effects induced by cyclophosphamide and modulate gut microbiota to restore a healthy microbial balance.