Experimental Biology and Medicine最新文献

The antiretroviral (ARV) drug combination of abacavir sulfate, dolutegravir, and lamivudine [ABC/DTG/3TC; Tri combination Anti-retroviral therapy (TC-ART)] has revolutionized HIV treatment by effectively targeting different stages of viral replication. Despite its therapeutic efficiency for maintaining low viremia in the mother during pregnancy, there are concerns for long-term liabilities in offspring that are indirectly exposed during vulnerable periods of development. The commensal microbiota plays a crucial role in maintaining overall gut health, and disruption of the microbiome is often linked to various extraintestinal effects such as immune dysregulation and inflammation. We recently reported the effects of this drug combination in altering fecal microbiome composition of aged rats perinatally exposed to ABC/DTG/3TC-ART. The fecal microbiome can provide only a snapshot of the composition of microbial community at the end of the digestive tract, which may not reflect the microbial population interacting with ileal mucosa. Thus, the current work reports the effects of this drug combination in the gut mucosa-associated microbiome of the same animals, which showed significant microbial diversity and species richness in high dose exposed female adult offspring, along with dose-dependent changes in Firmicutes/Bacteroidetes ratio. The high dose exposure also showed an increase in opportunistic bacterial species in male animals. Overall, we found that, similar to the fecal microbiome, perinatal exposure to TC-ART led to sex- and dose-dependent alterations in the gut mucosa-associated microbial population in aged rats, suggesting that early life exposure to these drugs may influence gut mucosa-associated immune responses and intestinal permeability.

Advanced glycation end products (AGEs) have been associated with vascular pathologies including abdominal aortic aneurysms (AAAs), although their causal role remains unclear. In this study, we observed significant accumulation of AGEs in human AAAs, particularly in cases associated with intraluminal thrombus (ILT). In vitro, AGE exposure induced vascular smooth muscle cell (VSMC) migration and suppressed contractility, accompanied by reduced expression of contractile markers (α-SMA and MYH11) and elevated MMP-2. This phenotypic transformation was linked to the activation of the NLRP3 inflammasome and RAGE/RhoA/ROCK signaling, and was reversible upon inhibition of RAGE, RhoA, or ROCK. In macrophages, AGE pretreatment had minimal effects on basal cytokine secretion but attenuated LPS-induced IL-6 and IL-1β release and NF-κB activation. Co-culture experiments further revealed that AGE-pretreated macrophages reduced LPS-driven pro-migratory effects on VSMCs. Spatial transcriptomics demonstrated enriched AGE-RAGE signaling in αSMA+ VSMCs and CD68+αSMA+ macrophage-like VSMCs in ILT-containing AAAs. Overall, these associative findings implicate AGE-RAGE signaling in AAA pathogenesis and warrant further investigation to establish causality.

Cataract is the leading cause of blindness globally, imposing a significant socioeconomic burden. While diet is associated with various eye diseases, the causal relationship between dietary-related characteristics (DRCs) and cataract remains unclear. This study investigates the causal associations between DRCs and cataract using Mendelian randomization (MR) to provide insights into potential dietary interventions for cataract prevention. We conducted a two-sample MR analysis using data from the open GWAS database, focusing on individuals of European descent. Instrumental variables were selected based on stringent criteria, and multiple MR methods were applied to estimate causal effects. Sensitivity analyses assessed the robustness of the findings. Significant causal associations were found between oily fish intake (OR = 0.86) and variation in diet (OR = 1.26) with cataract. Sensitivity analyses supported the robustness of these findings. Mediation effect analysis suggested that the intake of oily fish might indirectly influence cataract risk through metabolites. This study provides evidence for causal relationships between specific DRCs and cataract, highlighting the potential role of dietary interventions in cataract prevention.

The focus of this study was to evaluate motor unit number and size across the upper extremity in older adults (aged 60+ years) versus young healthy adults (aged 20-30 years). We hypothesized that older adults would have: fewer motor units and increased motor unit size as compared to young healthy adults (H1), that motor unit size would differ across the upper extremity muscles as compared to young healthy adults (H2), and higher body mass index (BMI) would be associated with lower motor unit numbers (H3). Compound muscle action potential (CMAP), motor unit number index (MUNIX), and motor unit size index (MUSIX) were evaluated in five muscles of the upper extremity. Group differences in CMAP due to aging were accounted for by increased body mass index (BMI); group differences in MUSIX were not impacted by BMI. No difference in MUNIX was found; however, an influence of BMI was found across groups. While this data provides supporting evidence of age-related motor unit changes, body composition changes with age may confound these conclusions when surface electromyography is utilized as the measurement modality. Adiposity estimation should be considered in future EMG studies, particularly in populations with higher BMI values.

The Oropouche virus (OROV), an arbovirus transmitted primarily by the Culicoides paraensis midge, has caused significant outbreaks in the Americas, especially in the Amazon region. The virus's spread is closely linked to a combination of environmental, climatic, and ecological factors. These include deforestation, urbanization, and changes in rainfall patterns, which influence the proliferation of vectors, and, consequently, increase the chances of mutations and reassortment events to occur. In 2024 and 2025, the number of OROV cases increased significantly, with outbreaks extending beyond the traditionally endemic Amazon region, highlighting the growing geographic expansion of the disease throughout Brazil. Despite its growing dispersion, diagnostic and therapeutic tools for OROV remain limited. Current diagnostic strategies rely almost exclusively on molecular detection methods, and there are no vaccines for effective prevention. Additionally, immunological responses to OROV infection are not fully understood, and further studies are needed. The ecological dynamics influencing OROV transmission, particularly the role of environmental changes in shaping vector populations, highlight the need for more integrated surveillance and control strategies. The ongoing expansion of OROV outside its traditional hotspots may be indicative of broader environmental shifts that facilitate viral spread. Therefore, continuous monitoring of both environmental and epidemiological data is crucial to understanding and mitigating the impact of OROV in the future. Collaborative efforts among researchers, policymakers, and local communities will be essential to prevent further outbreaks and minimize the health burden caused by OROV. This review summarizes important and up-to-date data information to the ongoing epidemic of Oropouche fever, focusing on topics that are particularly important to Public Health.

Our objective was to study the effect of vitamin D₃ (VD) on hepatocellular oxidative-nitrosative stress and pro/anti-inflammatory cytokines in relation to nitric oxide (NO) formation and NO synthase (NOS) levels in type 2 diabetes mellitus (T2DM). After T2DM induction by high-fat diet and a single streptozotocin injection (25 mg/kg b. w.), male Wistar rats were treated with/without VD (1,000 IU/kg b. w., 30 days). Oxidative stress/inflammation and NOS/NO were assessed by flow cytometry, RT-qPCR, western blotting, and ELISA. A 3.3-fold decrease in serum 25(OH)D₃ was established in diabetic rats, suggesting their VD deficient status. T2DM was associated with excess reactive oxygen species (ROS; 2.4-fold) and NO (2.5-fold) production in hepatocytes paralleled by elevated levels of myeloperoxidase (1.7-fold), carbonylated (2.8-fold) and nitrotyrosylated (1.7-fold) proteins in liver tissue vs. control, indicative of oxidative-nitrosative stress. Low-grade inflammation in diabetic liver was confirmed by increased NF-κB transcriptional activity (1.24-fold) and mRNA expression of proinflammatory cytokines TNF-α (3.5-fold) and IL-1β (2.2-fold) with alleviating mRNAs of anti-inflammatory cytokines IL-4 (1.7-fold) and IL-10 (2.6-fold), while TGF-β1 expression raised 1.4-fold vs. control. Higher iNOS and eNOS mRNAs (2.7- and 3.3-fold, respectively) and protein (2.1- and 3.2-fold, respectively) levels, as well as NOS activity (1.6-fold) were found in diabetic liver. VD supplementation restored 25(OH)D₃, partially normalized NF-κB transcriptional activity and pro/anti-inflammatory cytokines, lowered hepatocellular ROS/NO, and oxidative protein modifications. However, VD had no effect on eNOS, IL-10 and TGF-β1 mRNAs. It also led to a further increase in myeloperoxidase, eNOS and iNOS proteins and NOS activity compared to diabetes. In conclusion, abnormal oxidative metabolism in T2DM is associated with enhanced NF-κB/NOS/NO response, which can be partially attenuated by VD treatment via normalization of pro-oxidative/pro-inflammatory processes. The paradoxical sustained increase in NOS expression in the presence of VD antioxidant activity likely improves hepatocellular NO bioavailability, ultimately reducing T2DM-associated liver injury.

[This corrects the article DOI: 10.3389/ebm.2025.10559.].

COVID-19 booster vaccinations are needed to enhance waning immunity and the emergence of new variants. In Africa, where COVID-19 vaccine coverage is low, there is a paucity of data on COVID-19 vaccine-induced immunity, particularly in the post-omicron era. This study examined the functional activity of vaccine-induced antibody responses against different variants before and after booster vaccinations in adults in Ghana, between November 2022 and February 2023. SARS-CoV-2 nucleocapsid protein and spike receptor binding domain (RBD) antigen-specific IgG levels against different viral variants were determined in plasma. Plasma was tested for the ability to inhibit ACE-2 binding to RBD variants. N antigen-specific antibody levels were comparable between vaccinated and previously infected, but unvaccinated individuals. However, RBD IgG levels before booster vaccinations were significantly higher in vaccinated participants than in exposed, unvaccinated individuals, except for Omicron. RBD IgG levels remained unchanged after the booster in participants with three prior vaccine doses but were significantly higher than in those with only primary vaccinations (Wild type p = 0.0315, Alpha p = 0.0090, Beta p = 0.0020, Delta p = 0.0040) except Omicron (p = 0.09). Participants who received the Pfizer-BioNTech vaccine showed a significant increase (p < 0.05) in RBD IgG levels against all tested variants from baseline to 3 months. In contrast, participants who received the J&J vaccine only showed a significant increase in RBD IgG to Wildtype (p = 0.04), Alpha (p < 0.0001), and Beta (p < 0.0001), but not Delta and Omicron. The inhibition of ACE-2 binding and live virus neutralization titers were significantly higher in vaccinated individuals than in unvaccinated individuals before the booster (p < 0.001). Virus neutralization titers against Wildtype were significantly high 3 months after booster (p < 0.001), but neutralization titers against Omicron remained stable from baseline to 3 months after booster. Extended interval between vaccinations may enhance vaccine-induced antibody responses.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%-90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.