Biomedicines最新文献

Background/Objectives: The meninges, the protective membranes covering the central nervous system, undergo complex developmental processes that are critical for CNS integrity and function. Connexin 37 (Cx37) and 40 (Cx40), members of the connexin family of gap junction proteins, have been implicated in various physiological and pathological processes. They play a critical role in cell-cell communication. The aim of our study was to investigate the expression of connexins Cx37, Cx40, and Panx1 in the meninges of both human and murine models (yotari and wild type) at the 6th week/E13.5 and 8th week/E15.5 of developmental stages. Methods: Human embryonic tissues (6th-8th week, n = 4 for the 6th week and n = 4 for the 8th week) and mouse embryos (yotari Dab1^-/^- and wild type, E13.5-E15.5) were collected and fixed in 4% paraformaldehyde. Paraffin sections were stained for Cx37, Cx40, and Panx1 using immunofluorescence. Images were analyzed in ImageJ, and statistical comparisons were performed using one-way ANOVA with Tukey's post hoc test (p < 0.05). Results: Cx37 was consistently expressed across all developmental stages, with the highest threshold area percentage observed at E13.5 and E15.5 in murine leptomeninges, demonstrating statistically significant differences compared to controls (p < 0.05) and notably from corresponding human stages (p < 0.001). Strong Cx37 staining intensity at E13.5 was noted in both wild-type and yot mice, while human leptomeninges displayed mild staining at the 6th week of development. In contrast, both human and murine pachymeninges exhibited moderate Cx37 expression. Additionally, the expression of Cx37 in wild-type mice surpassed that of human samples at both E13.5 and E15.5 stages (p < 0.01 and p < 0.001, respectively). For the developing dura mater, Cx37 expression peaked at E15.5 in yot mice, significantly different from both wild-type and human dura mater (p < 0.01 and p < 0.05). Cx40 expression was highest in the leptomeninges at E15.5. Panx1 was similarly expressed across stages, with the highest threshold area percent observed in wild-type leptomeninges and pachymeninges at E15.5, showing significant differences compared to yot mice and human samples (p < 0.05). Both leptomeninges and pachymeninges exhibited mild Panx1 staining at E13.5, while stronger staining was observed at E15.5 in murine samples, contrasting with mild intensity in human counterparts. Conclusions: These findings highlight the implications of Dab1 deficiency for the expression of gap junction proteins during meninges development, implicating their importance in intercellular communication that is essential for normal meningeal and neurodevelopmental processes.

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal stem cell disorders in which disrupted post-transcriptional regulation contributes to aberrant hematopoiesis and leukemic transformation. The miRNA biogenesis machinery, which comprises Drosha, DGCR8, Dicer, TARBP2, and AGO1, ensures the precise maturation of miRNAs that control lineage commitment and proliferation. However, the extent to which alterations in this pathway reshape hematopoietic gene networks during myeloid disease evolution remains largely unexplored. Methods: Bone marrow samples from newly diagnosed, untreated MDS and AML patients and matched healthy controls were analyzed for the expression of five key miRNA biogenesis genes using quantitative real-time PCR. Statistical comparisons, correlation matrices, and ROC analyses were performed to characterize gene-expression differences. These results were integrated with multigene logistic modeling, decision-curve analysis, and exploratory random forest/SHAP approaches to evaluate molecular interactions and diagnostic relevance. Results: DROSHA, DICER1, and TARBP2 were significantly downregulated in both MDS and AML, suggesting impaired miRNA maturation and a loss of global post-transcriptional control. DGCR8 expression increased across higher-risk MDS groups, suggesting compensatory activation of the Microprocessor complex, whereas AGO1 levels remained relatively stable, consistent with partial maintenance of RISC function. Correlation analyses revealed a co-regulated DROSHA-TARBP2-AGO1 module. ROC, logistic, and machine learning models identified DGCR8 and DICER1 as the strongest diagnostic discriminators. The integrated five-gene signature achieved high discriminative performance (AUC ≈ 0.98) and showed promise but remains preliminary potential for clinical application. Conclusions: Our findings suggest that defects in miRNA biogenesis disrupt hematopoietic homeostasis, reflecting common mechanisms in MDS and AML. The dysregulation of DICER1, DGCR8, and TARBP2 offers insights into miRNA-driven leukemogenesis and may pave the way for miRNA-based diagnostic and therapeutic strategies, pending validation in larger cohorts. Although transcript-level data are provided, future studies should include functional validation to determine the impact on downstream miRNA processing and hematopoietic pathways.

Pediatric kidney transplantation (KTx) offers the best outcomes for children with end-stage renal disease (ESRD), offering dramatic improvements in survival, quality of life, growth, and developmental outcomes compared to dialysis. Modern regimens centered on tacrolimus, mycophenolate mofetil, and risk-adapted induction have substantially reduced acute rejection and improved graft survival. This viewpoint summarizes the evolution of pediatric immunosuppression, current practice trends, and emerging strategies aimed at minimizing toxicity while preserving long-term graft function. Recent data show increasing use of T-cell-depleting induction, selective application of IL-2 receptor antagonists, and gradual adoption of steroid-sparing and mTOR-based protocols. Nevertheless, progress is limited by a scarcity of pediatric randomized trials, continued reliance on extrapolated adult evidence, infection risk, long-term metabolic complications, and adherence challenges during adolescence. Insights from recent trials including steroid minimization, everolimus-based regimens, and selective Belatacept use highlight opportunities for more individualized, risk-adapted therapy. Future efforts must prioritize precision approaches supported by biomarkers, multicenter collaboration, and long-term follow-up. Overall, contemporary trends support a shift toward tailored immunosuppression that balances efficacy with safety to optimize outcomes in pediatric KTx recipients.

Objective: This study aims to analyze relationships between body composition, biochemical parameters, and cardiac function in young adults to identify mechanisms of cardiac dysfunction in obesity. Methods: This is a cross-sectional study of 60 young adults (mean age 20.4 years) divided into healthy (n = 29) and overweight/obese (n = 31) groups. Body composition was assessed using bioelectrical impedance analysis. We calculated the SMM-to-Fat ratio (skeletal muscle mass %/body fat %) as a continuous composite metric. Cardiac function was evaluated using 3D speckle-tracking echocardiography, with a 3D global circumferential strain pre-specified as the primary endpoint. Results: The obese group showed unfavorable body composition with lower SMM% (38.0 ± 10.8 vs. 47.1 ± 5.6%), higher body fat% (28.3 ± 12.6 vs. 16.0 ± 8.3%), and lower SMM-to-Fat ratio (2.1 ± 2.3 vs. 4.8 ± 5.1; all p < 0.001). C-peptide was 75% higher (p < 0.001), indicating compensatory hyperinsulinemia. The primary endpoint showed impairment in the obese group (-19.8 ± 4.7 vs. -22.2 ± 2.9%; p = 0.023, d = 0.61), while longitudinal strain was preserved, indicating selective mid-wall dysfunction. The SMM-to-Fat ratio demonstrated a stronger association with circumferential strain (r = -0.467, p = 0.008) than SMM% alone (r = -0.414, p = 0.021) and remained an independent predictor in multivariable analysis (β = -0.88, p = 0.019), whereas SMM% did not achieve significance (p = 0.159). Comprehensive analysis revealed correlation reversal across all body composition parameters between groups, with minerals% and total body water% emerging as additional independent predictors. Conclusions: Young obese adults exhibit selective mid-wall cardiac dysfunction. The SMM-to-Fat ratio, representing muscle-adiposity balance, is superior to SMM% alone for predicting cardiac dysfunction. Our findings suggest that the relative balance, rather than absolute muscle mass, determines cardiac health in obesity, with implications for body composition assessment and intervention strategies.

Obesity remains a major global health challenge, with glucagon-like peptide-1 receptor agonists (GLP-1RAs) providing substantial yet sensitive benefits in weight reduction, glycemic control, and cardiovascular protection. Despite robust trial data, real-world persistence is limited by cost, tolerability, and hedonic adaptation. Intermittent fasting and time-restricted eating offer physiologically complementary, low-cost strategies that enhance fat oxidation, insulin sensitivity, and metabolic flexibility while engaging behavioral mechanisms of self-control and dietary regularity. This narrative review synthesizes current evidence and proposes a pragmatic, phased framework integrating GLP-1RA therapy with structured intermittent fasting and protein-optimized nutrition. The model emphasizes sequential initiation, transition, and maintenance phases designed to align pharmacologic appetite suppression with lifestyle-driven metabolic remodeling. Mechanistically, GLP-1RAs target vascular and neuroendocrine pathways, whereas fasting activates nutrient-sensing networks (AMPK, mTOR, sirtuins) associated with autophagy and longevity. Combined application may preserve lean mass, improve psychological autonomy, and reduce healthcare costs. Future research should validate this hybrid strategy in randomized trials assessing long-term weight durability, functional outcomes, and cost-effectiveness. By uniting pharmacologic potency with behavioral sustainability, phased GLP-1-fasting integration may represent an effective, affordable, and longevity-oriented paradigm for metabolic health.

Background/Objectives: Neuroinflammation is a leading factor in secondary brain damage following a traumatic brain injury (TBI). Existing therapeutic approaches have limited efficacy against neuroinflammation. The bone marrow, the primary hematopoietic organ, is also a source of inflammatory cells. We propose that targeting the sympathetic regulation of inflammatory cell mobilization could reduce neuroinflammation after TBI. Methods: In ICR mice, we investigated the immune cell response in the blood, bone marrow, motor cortex, and the subventricular zone after TBI modeling and treatment with the sympatholytic agent reserpine. Results: TBI induced neutrophilia and lymphocytosis in the peripheral blood, activated hematopoiesis in the bone marrow, and triggered neuroinflammation and degenerative changes in the cerebral cortex (CC) and the subventricular zone (SVZ) of mice. Reserpine reduced leukocytosis in the blood and hematopoietic activity in the bone marrow of mice with TBI compared to untreated TBI mice. Furthermore, reserpine decreased neutrophilic and lymphocytic infiltration, as well as the number of Iba1⁺ microglial cells, including M1-polarized microglia, Caspase-3⁺ cells, and cells expressing myeloperoxidase (MPO) in the CC and SVZ of treated mice. The activity of degenerative processes was also reduced. Additionally, reserpine reduced the number of M2-polarized microglial cells in the SVZ. Conclusions: The sympatholytic drug reserpine may hold promise for the development of a novel approach to treating neuroinflammation and degeneration following a TBI. This is based on its ability to reduce hematopoiesis and mobilize inflammatory cells from the bone marrow into the bloodstream.

Crohn's disease (CD) remains a highly complex disorder, and the progress of preclinical gene therapy for CD has been constrained by several significant challenges. These include the identification of optimal therapeutic gene targets, the difficulty of targeting therapy-resistant cells within a chronic inflammatory microenvironment, particularly in the enteric nervous system (ENS), and the lack of robust animal models that faithfully recapitulate human pathology, as classical models largely rely on toxin-induced colitis. This review synthesizes major preclinical studies on gene therapy for CD and related inflammatory bowel diseases (IBD). We critically assess the rationale and biodistribution data for different vector platforms, considering vector type, promoter, and route of administration, in the ileum and colon of both rodent and non-human primate models. Special attention is given to strategies targeting the ENS. Finally, we explore the putative therapeutic aims of these approaches, including direct attenuation of intestinal inflammation and prevention of postoperative recurrence of CD via local intraoperative gene delivery. Although most data derive from chemical colitis models, this review establishes a foundational framework to inform translational research in gene therapy for CD and other IBDs.

Gynecological endocrine disorders, including polycystic ovary syndrome (PCOS), endometriosis as well as primary ovarian insufficiency (POI)/premature ovarian failure (POF), significantly impact women's reproductive health and overall well-being. While these conditions are primarily driven by disturbances of the hypothalamic-pituitary-gonadal axis, yet growing evidence indicates that oxidative stress plays a crucial role in their development and progression. The combined impact of hormonal imbalance and impaired redox homeostasis contributes to infertility, metabolic dysfunction, and other co-morbidities, such as increased cardiovascular risk. Given that women may live for many years with these chronic conditions, investigating their pathophysiology and associated complications is of particular importance. This narrative review summarizes current knowledge on PCOS, endometriosis, and POI/PMF, emphasizing the contribution of oxidative stress and also highlights the association between these disorders and cardiovascular risk. Furthermore, the utility of rat models is presented to support the advancement of preventive and therapeutic research.

Purpose: This study investigates the association between obstructive sleep apnea (OSA), dry eye disease (DED), and glaucoma, focusing on the impact of positive airway pressure (PAP) usage and air leakage. Methods: This retrospective cross-sectional study included 57 adults with polysomnography-confirmed OSA between 2010 and 2023. Participants were grouped into PAP users (PAP+, n = 40) and non-users (PAP-, n = 17). Ocular assessments included tear film break-up time, Schirmer's test, Oxford staining, meibomian gland evaluation, intraocular pressure, cup-to-disc (C/D) ratio, and retinal nerve fiber layer thickness. PAP device data (usage duration and air leak rate) and OSA severity metrics were recorded. Group comparisons used chi-square and Student's t-test, and regression analyses identified associations between PAP leakage and ocular parameters. Results: Among the 57 OSA patients, PAP users showed a trend toward a higher risk of glaucoma (OR = 0.83) and DED (OR = 0.69) compared to non-users, but neither trend was statistically significant. PAP users had significantly more severe OSA, including longer N1 sleep stage (p = 0.0005), higher apnea-hypopnea index (AHI, p = 0.0001), and poorer oxygenation. PAP leakage: 95% (mean = 25.84 L/min) exceeded the 24 L/min threshold specified in ResMed's clinical guidelines, suggesting suboptimal therapy. Higher PAP leak was significantly associated with a lower Schirmer's test value (p = 0.031) and a higher C/D ratio (p = 0.040) on regression analysis. However, no significant differences were found in ophthalmic parameters between PAP+ and PAP- groups. Conclusions: Suboptimal PAP therapy as mask leakage or nocturnal hemodynamic changes may worsen evaporative dry eye and affect intraocular pressure. Our findings highlight the association between PAP mask leakage and reduced tear production, and suggest that OSA-related optic nerve stress may persist unless both hypoxia and nocturnal IOP fluctuations are properly managed. However, due to the relatively small sample size and retrospective cross-sectional design, future prospective studies with larger cohorts are needed to confirm these associations.

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