Journal of Biomedical Research最新文献

The study aimed to assess the taxonomic diversity and composition of gut microbiota in Arkhangelsk residents, Northwestern Russia, with varying metabolic statuses. A population-based cross-sectional "Know Your Heart" study (2015-2017, participants aged 35-69 years) included a health examination and gut microbiota analysis ( n = 685). Participants were divided into four metabolic phenotypes: metabolically healthy non-obese (MHN), metabolically unhealthy non-obese (MUN), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Analyses were performed using RStudio software (v.4.2.0) with the vegan and phyloseq packages (v.1.42.0) for microbiota analysis. The sample was distributed across phenotypes as follows: MHN (47.6%), MUN (22.1%), MHO (10.4%), and MUO (19.9%). Beta-diversity analysis revealed significant differences in overall microbiome composition between MUO and MHN participants, while alpha-diversity did not differ significantly across phenotypes. The MHN group was characterized by a higher abundance of beneficial commensals such as Christensenellaceae R-7 group, Ruminococcaceae UCG-005, and Eubacterium xylanophilum group, which are taxa previously associated with metabolic health and longevity. In contrast, the MUO group showed an increased abundance of Streptococcus salivarius and Negativibacillus, taxa linked to gut dysbiosis and metabolic disorders. Blautia spp. emerged as a major hub in the microbiota of obese participants, consistent with its reported association with visceral fat. In conclusion, microbial composition was similar in obese participants despite metabolic dysfunction, whereas unidirectional taxonomic shifts were observed in those with metabolic dysfunction alone. The differences in the predominance of microbial taxa across metabolic phenotypes suggest that these taxa have a role in the development of metabolic disorders and obesity.

The highly conserved human leukocyte antigen-A2 (HLA-A2)-restricted epitope NS3-1073 represents a promising candidate for a therapeutic vaccine against hepatitis C virus (HCV). In this study, we engineered a set of fusion proteins based on the artificial peptide SAP, which were expressed in Escherichia coli and spontaneously self-assembled into nanosized particles displaying HCV epitopes, including NS3-1073. To enhance immunogenicity, the T helper epitope PADRE was incorporated into the construct. Alpha-helical linkers were introduced between SAP and the epitopes to facilitate proper protein folding. Notably, a helical linker with a high supercoiling propensity enabled soluble expression of the fusion protein containing both the NS3-1073 and PADRE, allowing purification of the in vivo-formed nanoparticles by metal affinity chromatography. Human dendritic cells derived from peripheral blood monocytes showed robust activation in response to the fusion proteins and preferentially stimulated T lymphocytes toward a Th1-biased immune response. In mice, immunization with nanoparticles carrying NS3-1073 induced splenocyte proliferation in response to in vitro stimulation with a mixture of NS3 peptides. These results demonstrate that recombinant nanoparticle-based carriers presenting the NS3-1073 epitope can be produced in bacterial systems and hold strong potential as a foundation for a therapeutic HCV vaccine.

The genetic landscape of male infertility is highly complex. It is estimated that at least 1000-2000 genes are involved in human and mouse infertility. Although functional analyses have been performed on hundreds of genes, many others still have unknown functions. Generating gene-editing mice is a powerful tool for exploring whether a given gene is essential for male reproduction in vivo. In this study, we investigated the function of six genes, Efcab7, Tekt3, Mlf1, Rp1l1, Agbl2, and Tmsb15a, using the CRISPR/Cas9 system. Mating tests with mutant mice revealed that all six genes are dispensable for male fecundity when individually ablated. Meanwhile, phenotypic analyses of testicular appearance and weight, testis and epididymis morphology, and sperm motility parameters in these six mutant mice also showed no significant differences compared with wild-type mice. In summary, our results suggested that these six genes could be deprioritized for other researchers when they are interested in their roles in male infertility, thereby preventing duplicative research efforts.

Neutrophils, macrophages, CD3 ⁺, CD4 ⁺, and CD8 ⁺ T-lymphocytes express µ-, δ-, and κ-opioid receptors (ORs) with both high and low affinities for opioids. Mast cells express the atypical OR mas-related G-protein-coupled receptor X2 (MRGPRX2), which has a low affinity for morphine. Neutrophils and macrophages synthesize and release opioid peptides. The activation of ORs increases the synthesis of proinflammatory cytokines and the production of reactive oxygen species (ROS) in unstimulated leukocytes. Conversely, the activation of ORs reduces proinflammatory cytokine synthesis in stimulated neutrophils and macrophages. Morphine inhibits Toll-like receptor 4 (TLR4) expression in macrophages, thereby reducing inflammation. Methadone induces ROS production in mast cells through the activation of TLR4. Stimulation of TLR4 induces β-endorphin synthesis in macrophages. The production of pro-inflammatory cytokines and ROS contributes to cardiac reperfusion injury. The activation of κ ₁- and µ-ORs reduces pro-inflammatory cytokine production by leukocytes and suppresses inflammatory injury to the heart and other organs.

Pulmonary fibrosis (PF) is a progressive lung disorder characterized by excessive deposition of extracellular matrix (ECM) in the alveoli, with irreversible fibrotic remodeling and destruction of alveolar structures. Clinically, PF is manifested by progressive dyspnea and a decline in lung function. These manifestations contribute to a poor prognosis and significantly diminish the quality of life of affected individuals. Current therapeutic options for PF remain limited, highlighting the urgent need to elucidate its molecular mechanisms in order to develop novel treatment strategies. Recent studies have revealed that autophagy and ferroptosis, two critical cell death pathways, engage in intricate crosstalk mechanisms that regulate the pathogenesis of PF. Autophagy maintains cellular homeostasis by mediating lysosome-dependent degradation, whereas ferroptosis is characterized by iron-dependent lipid peroxidation. The interplay between autophagy and ferroptosis plays a pivotal role in modulating fibrosis progression. However, the mechanistic interactions between autophagy and ferroptosis in PF remain poorly understood, particularly regarding their bidirectional crosstalk and their unique role in PF progression. This review aims to systematically synthesize the current understanding of autophagy-ferroptosis interactions in PF, thereby identifying potential therapeutic strategies and drug targets for PF treatment.

Non-obstructive azoospermia (NOA), characterized by impaired spermatogenesis and the complete absence of sperm in the ejaculate, represents one of the most severe forms of male infertility. Current diagnostic strategies rely on invasive procedures such as testicular sperm extraction, underscoring the urgent need for reliable, non-invasive alternatives. In the present study, we performed untargeted metabolomic profiling of human seminal plasma to identify biomarker panels capable of stratifying azoospermia subtypes through a stepwise approach. We identified distinct metabolite biomarker panels comparing NOA vs. obstructive azoospermia (OA), Sertoli cell-only syndrome vs. other NOA subtypes, and hypospermatogenesis vs. maturation arrest. Additionally, cross-species comparative analysis with high-resolution metabolomic data from purified mouse testicular cell populations implicated these biomarkers in specific germ cell stages and metabolic transitions during spermatogenesis. These findings establish a molecular framework for the non-invasive classification of azoospermia subtypes and provide novel insights into the metabolic disruptions underlying male infertility.

While a healthy lifestyle is known to reduce the risk of stroke, the extent to which blood pressure (BP) mediates this association remains unclear. The present study aimed to quantify the mediating role of BP in the association between combined lifestyle factors and stroke incidence. Using data from 51929 participants free of major cardiovascular diseases or cancer at baseline, we employed structural equation modeling to assess the mediating effects of systolic (SBP) and diastolic (DBP) blood pressure. During the follow-up, 2811 incident stroke cases were identified. A healthy lifestyle was significantly associated with a reduced risk of stroke, with SBP mediating 44.70% ( β = -0.0014, 95% confidence interval [CI]: -0.0016 to -0.0012) and DBP mediating 37.81% ( β = -0.0012, 95% CI: -0.0015 to -0.0009) of this association. The mediating effects were attenuated but remained significant for ischemic stroke (SBP: 33.21%; DBP: 27.24%). In conclusion, approximately two-fifths of the protective association between a healthy lifestyle and stroke may be mediated by BP. These findings suggest that BP control may serve as an important early indicator for evaluating the effectiveness of lifestyle interventions in reducing stroke risk.