生物学最新文献

Background: The most prevalent endocrine disorder affecting women is PCOS. Programmed death of ovarian cells has yet to be elucidated. Ferroptosis is a kind of iron-dependent necrosis featured by significantly Fe⁺²-dependent lipid peroxidation. The ongoing study aimed to reinforce fertility by combining therapy with AgNPs and (Zileuton) in PCOS rats' model.

Methods: The study included 75 adult female rats divided into 5 groups; control, PCOS, PCOS treated with AgNPs, PCOS treated with Zileuton, and PCOS group treated with AgNPs and Zileuton. The study investigated the anti-ferroptotic, anti-inflammatory, antioxidant, antiapoptotic, histopathological and immunohistochemical examinations of COX-2 and VEGF.

Results: The combination of AgNPs and Zileuton showed significant reduction of inflammatory mediators (IL-6, TNF-α, NFk-B) compared with diseased group (P-value < 0.05), regression of ferroptosis marks (Panx1 and TLR4 expression, Fe⁺² levels) compared with diseased group (P-value < 0.05), depression of apoptotic marker caspase 3 level compared with diseased animals (P-value < 0.05), depression of MDA level, elevation of HO-1, GPx4 activity, and reduction of Cox2 and VEGF as compared with the diseased, AgNPs or zileuton-treated groups (P-value < 0.05).

Conclusion: The study showed that the combination of AgNPs and zileuton guards against, inflammation, apoptosis, and ferroptosis in PCO.

Drosophila melanogaster is a highly versatile model organism that has profoundly advanced our understanding of human diseases. With more than 60% of its genes having human homologs, Drosophila provides an invaluable system for modelling a wide range of pathologies, including neurodegenerative disorders, cancer, metabolic diseases, as well as cardiac and muscular conditions. This review highlights key developments in utilizing Drosophila for disease modelling, emphasizing the genetic tools that have transformed research in this field. Technologies such as the GAL4/UAS system, RNA interference (RNAi) and CRISPR-Cas9 have enabled precise genetic manipulation, with CRISPR-Cas9 allowing for the introduction of human disease mutations into orthologous Drosophila genes. These approaches have yielded critical insights into disease mechanisms, identified novel therapeutic targets and facilitated both drug screening and toxicological studies. Articles were selected based on their relevance, impact and contribution to the field, with a particular focus on studies offering innovative perspectives on disease mechanisms or therapeutic strategies. Our findings emphasize the central role of Drosophila in studying complex human diseases, underscoring its genetic similarities to humans and its effectiveness in modelling conditions such as Alzheimer's disease, Parkinson's disease and cancer. This review reaffirms Drosophila's critical role as a model organism, highlighting its potential to drive future research and therapeutic advancements.

Klebsiella pneumoniae is a gram-negative pathogen that can cause multiple diseases including sepsis, urinary tract infections, and pneumonia. The escalating detections of hypervirulent and antibiotic-resistant isolates are giving rise to growing public concerns. Outer membrane vesicles (OMVs) are spherical vesicles containing bioactive substances including lipopolysaccharides, peptidoglycans, periplasmic and cytoplasmic proteins, and nucleic acids. Emerging studies have reported various roles of OMVs in bacterial virulence, antibiotic resistance, stress adaptation, and host interactions, whereas knowledge on their roles in K. pneumoniae is currently unclear. In this review, we summarized recent progress on the biogenesis, components, and biological function of K. pneumoniae OMVs, the impact and action mechanism in virulence, antibiotic resistance, and host immune response. We also deliberated on the potential of K. pneumoniae OMVs in vaccine development, as diagnostic biomarkers, and as drug nanocarriers. In conclusion, K. pneumoniae OMVs hold great promise in the prevention and control of infectious diseases, which merits further investigation.

Actinobacillus pleuropneumoniae (APP) is a significant pathogen in the swine industry, leading to substantial economic losses and highlighting the need for effective vaccines. This study evaluates the potential of APP-derived extracellular vesicles (APP-EVs) as a vaccine candidate compared to the commercial Coglapix vaccine. APP-EVs, isolated using tangential flow filtration (TFF) and cushioned ultracentrifugation, exhibited an average size of 105 nm and a zeta potential of -17.4 mV. These EVs demonstrated stability under external stressors, such as pH changes and enzymatic exposure and were found to contain 86 major metabolites. Additionally, APP-EVs induced dendritic cell (DC) maturation in a Toll-like receptor 4 (TLR4)-dependent manner without cytotoxicity. APP-EVs predominantly elicited Th1-mediated IgG responses in immunized mice without significant liver and kidney toxicity. Contrarily, unlike Coglapix, which induced stronger Th2-mediated responses and notable toxicity. In addition, APP-EVs triggered APP-specific Th1, Th17, and cytotoxic T lymphocyte (CTL) responses and promoted the activation of multifunctional T-cells. Notably, APP-EV immunization enhanced macrophage phagocytosis and improved survival rates in mice challenged with APP infection compared to those treated with Coglapix. These findings suggest that APP-EVs are promising vaccine candidates, capable of inducing potent APP-specific T-cell responses, particularly Th1, Th17, CTL, and multifunctional T-cells, thereby enhancing the protective immune response against APP infection.

Perceived discrimination, recognized as a chronic psychosocial stressor, has adverse consequences on health. DNA methylation (DNAm) may be a potential mechanism by which stressors get embedded into the human body at the molecular level and subsequently affect health outcomes. However, relatively little is known about the effects of perceived discrimination on DNAm. To identify the DNAm sites across the epigenome that are associated with discrimination, we conducted epigenome-wide association analyses (EWAS) of three discrimination measures (everyday discrimination, race-related major discrimination, and non-race-related major discrimination) in 1,151 participants, including 565 non-Hispanic White, 221 African American, and 365 Hispanic individuals, from the Multi-Ethnic Study of Atherosclerosis (MESA). We conducted both race/ethnicity-stratified analyses as well as trans-ancestry meta-analyses. At false discovery rate of 10%, 7 CpGs and 4 differentially methylated regions (DMRs) containing 11 CpGs were associated with perceived discrimination exposures in at least one racial/ethnic group or in meta-analysis. Identified CpGs and/or nearby genes have been implicated in cellular development pathways, transcription factor binding, cancer and multiple autoimmune and/or inflammatory diseases. Of the identified CpGs (7 individual CpGs and 11 within DMRs), two CpGs and one CpG within a DMR were associated with expression of cis genes NDUFS5, AK1RIN1, NCF4 and ADSSL1. Our study demonstrated the potential influence of discrimination on DNAm and subsequent gene expression.

The resistance of commonly used clinical antibiotics, such as daptomycin (DAP), has become increasingly serious in the fight against Staphylococcus aureus (S. aureus) infection. It is essential to explore key pathogenicity-driven genes/proteins in bacterial infection and antibiotics resistance, which contributes to develop novel therapeutic strategies against S. aureus infections. The nt5 gene of S. aureus, encoding 5'-nucleotidase (NT5), is nearly unknown for its function in drug resistance and bacterial infection. Herein, to reveal nt5 gene role in drug resistance and infection ability of S. aureus, we performed nt5^C166T gene mutation using a clustered regulatory interspaced short palindromic repeat ribonucleic acid (RNA)-guided base editing system to investigate the lose-of-function of NT5 protein. Subsequent transcriptome sequencing of the mutant strain revealed that nt5 inactivation caused changes in cell membrane integrity and inhibited nucleotide metabolism, suggesting the nt5 gene may be involved in bacterial drug resistance and virulence. The mutant strain exhibited enhanced tolerance to DAP treatment by attenuating cell membrane potential dissipation and slowing deoxyribonucleic acid release. Moreover, the nt5 mutation alleviated abscess degree of mouse kidneys caused by S. aureus infection byreducing the expression of IL-1β, IL-6, and IL-18. The nt5 mutant strain was easily swallowed by host immune cells, resulting in weak bacterial toxicity of the S. aureus mutant in the bacterial infection process. In summary, nt5 gene mutation confers tolerance to DAP and a lower bacterial capacity to form kidney abscesses through phagocytosis of host immune cells, which indicates the targeted inhibition of NT5 protein would offer a potential new therapeutic strategy against S. aureus infection.

Pasteurella multocida toxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogen P. multocida. The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we showed that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca²⁺ inflow, leading to an imbalance of cellular Ca²⁺ homoeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signalling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca²⁺ channel Ca_V3.1 was found to participate in PMT-induced cytoplasmic Ca²⁺ inflow. Knocking out Ca_V3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca²⁺ inflow stimulated by PMT. These findings suggest Ca_V3.1 contributes to PMT-induced respiratory epithelial barrier disruption.

Poly-epigenetic scores (PEGS) are surrogate measures that help capture individual-level risk. Understanding how the associations between PEGS and cardiometabolic risk factors vary by demographics and health behaviors is crucial for lowering the burden of cardiometabolic diseases. We used results from established epigenome-wide association studies to construct trait-specific PEGS from whole blood DNA methylation for systolic and diastolic blood pressure (SBP, DBP), body mass index (BMI), C-reactive protein (CRP), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), and fasting glucose. Overall and race-stratified associations between PEGS and corresponding traits were examined in adults >50 years from the Health and Retirement Study (n = 3,996, mean age = 79.5 years). We investigated how demographics (age, sex, educational attainment) and health behaviors (smoking, alcohol consumption, physical activity) modified these associations. All PEGS were positively associated with their corresponding cardiometabolic traits (p < 0.05), and most associations persisted across all racial/ethnic groups. Associations for BMI, HDL-C, and TG were stronger in younger participants, and BMI and HDL-C associations were stronger in females. The CRP association was stronger among those with a high school degree. Finally, the HDL-C association was stronger among current smokers. These findings support PEGS as robust surrogate measures and suggest the associations may differ among subgroups.

Streptococcus suis, a zoonotic pathogen, is commonly found as a commensal bacterium in the respiratory tracts of pigs. Under specific conditions, it becomes invasive and enters the blood, causing severe systemic infections. For S. suis, effective acquisition of carbon sources in different host niches is necessary for its survival. However, as of now, our understanding of the metabolism of S. suis within the host is highly restricted. Pyruvate formate lyase (PFL) plays a crucial role in bacterial survival of in glucose-limited and hypoxic host tissues. Here, we investigated the physiological and metabolic functions of PFL PflB in S. suis and elucidated its pivotal role in regulating virulence within the mucosal and blood niches. We demonstrate that PflB is a key enzyme for S. suis to support mixed-acid fermentation under glucose-limited and hypoxic conditions. Additionally, PflB is involved in regulating S. suis morphology and stress tolerance, and its regulation of capsular polysaccharide content depends on dynamic carbon availability. We also found that PflB is associated with the capacity of S. suis to cause bacteremia and persist in the upper respiratory tract to induce persistent infection. Our results provide highly persuasive evidence for the relationship between metabolic regulation and the virulence of S. suis.

Lung carcinogenesis is causally linked to cigarette smoking, in part by epigenetic changes. We tested whether accumulated epigenetic change in smokers is apparent in bronchial basal cells as cells of origin of squamous cell carcinoma. Using an EM-seq platform covering 53.8 million CpGs (96% of the entire genome) at an average of 7.5 sequencing reads per CpG site at a single base resolution, we evaluated cytology-normal basal cells bronchoscopically brushed from the in situ tobacco smoke-exposed 'bronchial epithelial field' and isolated by short-term primary culture from 54 human subjects. We found that mean methylation was globally lower in ever (former and current) smokers versus never smokers (p = 0.0013) across promoters, CpG shores, exons, introns, 3'-UTRs, and intergenic regions, but not in CpG islands. Among 6mers with dinucleotides flanking CpG, those containing CGCG showed no effect from smoking, while those flanked with TT and AA displayed the strongest effects. At the gene level, smoking-related differences in methylation level were observed in CDKL1, ARTN, EDC3, CYP1B1, FAM131A, and MAGI2. Among candidate cancer genes, smoking reduced the methylation level in KRAS, ROS1, CDKN1A, CHRNB4, and CADM1. We conclude that smoking reduces long-term epigenome-wide methylation in bronchial stem cells, is impacted by the flanking sequence, and persists indefinitely beyond smoking cessation.