Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Gestational 25-hydroxyvitamin D (25[OH]D) is important in fetal lung development and may influence offspring respiratory outcomes, making accurate exposure assessment essential to understand clinical associations. Therefore, we used the combined data from two large RCTs investigating prenatal vitamin D supplementation, which included early and late prenatal 25(OH)D measurements, to refine a population pharmacokinetic model of vitamin D-25(OH)D and estimate individual area under the curve (AUC) Z-scores. The primary outcome was physician-diagnosed offspring asthma/wheezing at ages 3 and 6 years, and lung function, as a secondary outcome, was evaluated by spirometry at the ages 6 and 8 years. In total, 1319 mother-child pairs were included. We found that clearance of 25(OH)D increased with gestational age and bodyweight, and decreased with higher baseline 25(OH)D levels. Prenatal 25(OH)D AUC Z-scores were negatively associated with asthma/wheezing at age 3 years (aOR = 0.75, 95 % CI = 0.64-0.88, p < 0.001) and 6 years (aOR = 0.83, 95 % CI = 0.72-0.95, p = 0.008). Longitudinal analysis of lung function from age 6-8 years showed that AUC Z-scores were positively associated with percent-predicted FEV₁ (β = 1.2₁%, 95 % CI = 0.30-2.11; p = 0.009), FVC (β = 0.79 %, 95 % CI = 0.13-1.46; p = 0.021), FEV₁/FVC ratio (β = 0.56 %, 95 % CI = 0.11-1.01; p = 0.015) and FEF_25-75 % (β = 2.18 %, 95 % CI = 0.46-3.91; p = 0.009). These results together indicate an exposure-outcome relationship where higher gestational 25(OH)D exposure, estimated by AUC, is associated with reduced childhood asthma/recurrent wheeze and improved lung function.

Sustained activation of the SIRT3-NLRP3 inflammasome has been associated with worse outcomes after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Following tMCAO, significantly elevated levels of NLRP3, ASC, cleaved caspase 1, IL-1β, and IL-18 were observed in the ischemic subventricular zone. Moreover, tMCAO increased NLRP3 expression while decreasing SIRT3 levels, suggesting a connection between these two processes. Furthermore, we discovered that inflammation induced by the NLRP3 inflammasome impaired post-stroke hippocampal and subventricular neurogenesis, while nestin (a marker for NSPCs) and Sox2 (a marker for stem cell pluripotency) were downregulated after tMCAO. However, systemic administration of MCC950 reduced inflammatory signaling and effectively restored neurogenesis. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.

The human lacrimal gland (LG), located above the outer orbital region within the frontal bone socket, is essential in maintaining eye surface health and lubrication. It is firmly anchored to the orbital periosteum by the connective tissue, and it is vital for protecting and lubricating the eye by secreting lacrimal fluid. Disruption in the production, composition, or secretion of lacrimal fluid can lead to dry eye syndrome, a condition characterized by ocular discomfort and potential eye surface damage. This review explores the recent advancements in LG organoid generation using tissues and stem cells, highlighting cutting-edge techniques in biomaterial-based and scaffold-free technologies. Additionally, we shed light on the complex pathophysiology of LG dysfunction, providing insights into the LG physiological roles while identifying strategies for generating LG organoids and exploring their potential clinical applications. Alterations in LG morphology or secretory function can affect the tear film stability and quality, leading to various ocular pathological conditions. This comprehensive review underlines the critical crosslink of LG organoid development with disease modeling and drug screening, underscoring their potential for advancing therapeutic applications.

There is currently no cure or disease-modifying treatment for post-traumatic osteoarthritis (PTOA). This study aims to assess the efficacy of dimethyl fumarate (DMF), a US-FDA approved drug for multiple sclerosis, as a treatment for PTOA. PTOA was induced in male Lewis rats by medial meniscal transection (MMT) surgery, and DMF was intra-articularly administered once, one week following surgery. PTOA progression was evaluated using histological, molecular, and radiographic analyses, while secondary allodynia was measured longitudinally, and pain-related markers expression were analyzed in dorsal root ganglion (DRG). 3D radiographic imaging by µCT analysis revealed that DMF treatment attenuated cartilage degradation by decreasing cartilage lesions, surface roughness, and osteophyte formation in the proximal tibiae. Histological analysis showed that DMF markedly inhibited cartilage erosion and cartilage surface fibrillation. Gene expression and Luminex analysis indicated that DMF suppressed joint inflammation by inhibiting inflammatory cytokines. DMF mitigated allodynic pain behavior at 6 weeks and repressed pain mediator expression (Calca, Tac1, Trpv1) in lumbar DRGs. Additionally, DMF treatment inhibited inflammatory gene expression and cytokine secretion induced by IL1β stimulation of human articular chondrocytes in vitro. Mechanistically, DMF treatment reduced colony-stimulating factor 2 (CSF2 or GM-CSF) level in the synovial fluid in vivo and inhibited its expression in human OA chondrocytes. Furthermore, siRNA targeting of CSF2 reduced inflammatory gene expression in human chondrocytes. The findings suggest that DMF reduced inflammatory gene expression, inhibited cartilage degeneration, and mitigated PTOA development in rats. It also alleviated pain behavior indicating its potential as a disease-modifying therapy for PTOA.

Osteoarthritis (OA) is a complex, degenerative, multi-factorial joint disease. Because of the difficulty in treating OA, developing new targeting strategies that can be used to understand its molecular mechanisms is critical. Protaetia brevitarsis seulensis larvae offer much therapeutic value; however, the presence of various active compounds and the multi-factorial risk factors for OA render the precise mechanisms of action unclear. A systematic transcriptome analysis was used to investigate the key mechanisms of action of P. brevitarsis seulensis larvae aqueous extract (PBSL) and its compounds on OA. Major mechanisms and transcription factors of PBSL were analyzed by profiling gene expression changes in interleukin (IL)-1β-induced human chondrosarcoma cell (SW1353) treated with PBSL. An in vitro assay was performed to validate the efficacy of the novel mechanism and targets of PBSL. PBSL exerted anti-inflammatory effects on SW1353 cells by regulating many molecular pathways. The IL-6/JAK/STAT3 pathway was significantly downregulated by PBSL, and STAT3 was identified as a major transcription factor regulating PBSL-induced target gene expression. Of the six PBSL compounds, the major compound was regulated by the IL-6/JAK/STAT3 pathway. This study provided potential novel mechanisms and transcription factors for PBSL and its active compounds against OA and indicated that inhibiting the IL-6/JAK/STAT3 pathway is a therapeutic target for treating OA.

As the number of infections and deaths attributable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to rise, it is now becoming apparent that the health impacts of the Coronavirus disease (COVID-19) may not be limited to infection and the subsequent resolution of symptoms. Reports have shown that patients with SARS-CoV-2 infection may experience multiple symptoms across different organ systems that are associated with adverse health outcomes and develop new cardiac, renal, respiratory, musculoskeletal, and nervous conditions, a condition known as Long COVID or the post-acute sequelae of COVID-19 (PASC). This review provides insights into distinct subphenotypes of Long COVID and identifies microbiota dysbiosis as a common theme and crucial target for future therapies. Another important finding is that Long COVID is associated with prolonged and increased inflammation, potentially attributable to immune system dysfunction. A promising solution lies in the potential of probiotics to mitigate Long COVID symptoms by restoring gut microbiota balance and modulating the immune response. By evaluating the current clinical development landscape of the use of probiotics to treat Long COVID symptoms, this paper provides recommendations for future research by stressing the need to understand the modulation of bacterium strains followed by probiotic therapy to understand the association of microbiota dysbiosis with Long COVID symptoms. This will facilitate the development of effective probiotic formulations that could serve as reliable therapies against Long COVID.

An understanding of intracellular mechanisms by which fentanyl and other synthetic opioids exert adverse effects on breathing is needed. Using freely moving adult male guinea pigs, we administered the nitric oxide synthase (NOS) inhibitor, L-NAME (N^G-nitro-L-arginine methyl ester), to determine whether nitrosyl factors, such as nitric oxide and S-nitrosothiols, play a role in fentanyl-induced respiratory depression. Ventilatory parameters were recorded by whole body plethysmography to determine the effects of fentanyl (75 μg/kg, IV) in guinea pigs that had received a prior injection of vehicle (saline), L-NAME or the inactive D-isomer, D-NAME (both at 50 μmol/kg, IV), 15 min beforehand. L- and D-NAME elicited minor effects on most parameters, including frequency of breathing, tidal volume and minute ventilation, although L-NAME did decrease end expiratory pause and non-eupneic breathing index (NEBI). Subsequent injection of fentanyl in guinea pigs pre-treated with vehicle produced profound and sustained reductions in frequency, tidal volume, minute ventilation, peak inspiratory flow, and inspiratory and expiratory drives, while increasing inspiratory time, expiratory time, end inspiratory pause, and NEBI. These ventilatory depressant effects of fentanyl seen in guinea pigs pre-treated with vehicle were markedly diminished in guinea pigs pre-treated with L-NAME. Moreover, the adverse effects of fentanyl on many recorded breathing parameters were converted to stimulatory effects. In contrast, D-NAME did not alter any of the effects of fentanyl on breathing. This study is the first to characterize the role nitrosyl factors play in the intracellular mechanisms involved in fentanyl-induced respiratory depression in guinea pigs.