Biomolecules & biomedicine最新文献

Neuroendocrine bladder carcinoma (NEBC) is a rare but highly aggressive histologic subtype of bladder cancer with poor prognosis, often driven by delayed diagnosis and limited therapeutic options; despite widespread use of next-generation sequencing, its cellular origin remains unclear and controversial. We aimed to synthesize up-to-date molecular and immune features of NEBC and translate them into practical guidance for diagnosis and treatment. We performed a narrative review of English-language studies indexed in PubMed and Web of Science (January 2000-August 2025) using predefined keywords, integrating genomic, transcriptomic, immunohistochemical, and clinical outcome data. Key findings indicate frequent co-occurrence and probable common clonal origin with urothelial bladder carcinoma, with hallmark TP53 and RB1 alterations, prevalent APOBEC-driven mutagenesis, and recurrent TERT promoter mutations; tumor mutation burden is heterogeneous but can be high. Despite this, NEBC commonly exhibits an immune-cold or immune-excluded microenvironment characterized by low PD-L1 expression and T-cell dysfunction, which may blunt responses to immune checkpoint inhibitor monotherapy. Diagnostic practice still relies on morphology supported by immunohistochemistry (synaptophysin, chromogranin A, CD56, GATA3), with emerging tools such as INSM1 and a decision-tree model using synaptophysin, CD117, and GATA3 that improve accuracy. Therapeutically, neoadjuvant chemotherapy-most commonly EP or IA-followed by radical cystectomy improves outcomes compared with initial cystectomy alone, while metastatic disease is typically managed with EP chemotherapy and radiotherapy with limited durability. Early data support immunotherapy, particularly immune checkpoint inhibitors, and suggest potential benefit from chemoimmunotherapy; a prospective trial of neoadjuvant anti-PD-L1 plus EP is underway, and antibody-drug conjugates and bladder-sparing multimodality strategies are emerging. In conclusion, comprehensive molecular and immune characterization is critical to refine diagnosis, optimize patient selection, and accelerate prospective trials that evaluate neoadjuvant chemotherapy, chemoimmunotherapy, and targeted approaches in NEBC.

Hypertensive disorders of pregnancy are major causes of maternal and perinatal morbidity and mortality, and nutritional factors such as vitamin D and calcium have been proposed as modifiable risks; therefore, we investigated the association between maternal vitamin D and calcium status and pregnancy-induced hypertension (PIH) and pre-eclampsia (PE) and explored the relation with supplementation. In this observational cross-sectional study, 84 third-trimester women were enrolled from two hospitals in Lublin, Poland (41 PIH/PE, 43 controls). Serum total and ionised calcium, 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D₃ were measured using standardised immunoassays, and group differences, correlations, and multivariable logistic regression were applied with adjustment for body mass index (BMI), maternal age, gestational age, calcium fractions, and gestational diabetes. PIH/PE cases had lower 25(OH)D than controls (27.8 vs 35.7 ng/mL; p = 0.012) and higher BMI (33.0 vs 27.5 kg/m²; p < 0.001), while total and ionised calcium and 1,25-dihydroxyvitamin D₃ were similar (all p ≥ 0.40); supplement use was more frequent among controls (84% vs 73%). In adjusted models, higher BMI increased the odds of PIH/PE (OR 1.19 per kg/m²) and higher 25(OH)D was protective (OR 0.92 per ng/mL); discrimination was fair (AUC 0.78). These findings support an association between vitamin D insufficiency and obesity with hypertensive pregnancy disorders and suggest preserved calcium homeostasis, but given the cross-sectional design, third-trimester sampling, small sample size, and non-standardised supplementation, causal inference and preventive recommendations cannot be made; larger prospective studies beginning in early pregnancy are warranted to test whether optimising vitamin D and calcium can reduce hypertensive complications.

Prostate cancer (PC) is a common malignancy driven by interacting genetic, environmental, and lifestyle factors, including hereditary mutations (BRCA1/2, HPC1, AR variants), premalignant lesions [proliferative inflammatory atrophy (PIA), prostatic intraepithelial neoplasia (PIN)], and Western dietary patterns. This narrative review aims to synthesize evidence on the role of microRNAs (miRNAs) in PC pathogenesis and clinical management across diagnosis, prognosis, therapy, and recurrence prediction. We searched PubMed/MEDLINE (2004-present) using predefined terms, screened reference lists, excluded outdated records, and prioritized biomarker studies with AUC ≥ 0.85. Current diagnostic pathways-digital rectal examination, prostate-specific antigen (PSA) testing, multiparametric MRI, and Gleason-based International Society of Urological Pathology (ISUP) grading-are complemented by molecular tools (4Kscore, PHI, SelectMDx, TMPRSS2-ERG, PCA3, ConfirmMDx). MiRNAs, key post-transcriptional regulators, contribute to PC via dysregulated biogenesis and modulation of androgen receptor signaling within an inflamed, remodeled tumor microenvironment. Circulating and exosomal miRNAs (notably miR-21, miR-375, and miR-182-5p) exhibit greater specificity and stability than PSA, enabling non-invasive diagnosis, risk stratification, treatment monitoring, and recurrence prediction. Therapeutic approaches-antagomirs, sponges, miRNA masks, and CRISPR editing-show preclinical promise, while chemical modifications [peptide nucleic acids (PNAs), locked nucleic acids (LNAs), C2' modifications] improve stability and delivery but remain limited by biodistribution, tissue penetration, off-target effects, and immunogenicity. In conclusion, standardized workflows and multicenter validation, integrated with clinical and imaging data, are essential to translate miRNA-based tools into precision PC management.

Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are a clinically attractive regenerative and immunomodulatory platform that combines ethical accessibility, low immunogenicity, rapid expansion, genetic stability, and a potent paracrine secretome. This study aimed to synthesize evidence on safety, efficacy, and translational readiness by conducting a focused PubMed review (2014-2024) restricted to clinical studies and trials, using predefined inclusion and exclusion criteria and structured data extraction. Across indications, UC-MSCs show a consistent safety profile and signals of benefit mediated by tissue repair and immune regulation: in musculoskeletal disease they improve osteoarthritis pain and function and may slow osteonecrosis; in hepatology they sustain gains in decompensated cirrhosis, mitigate acute allograft rejection, and aid recovery from ischemic-type biliary lesions; as induction in renal transplantation they are feasible with early graft benefits; in type 2 diabetes responders improve glycemic control and inflammation, while maternal and obstetric factors can shape intrinsic cell properties; in neurology, studies in cerebral palsy, chronic spinal cord injury, and traumatic optic neuropathy report motor, sensory, and visual improvements; in COVID-19-related acute respiratory distress syndrome (ARDS) trials show better oxygenation, radiological recovery, quality of life, and modulation of the TNF-sTNFR2 axis; in immune-mediated and transplant settings they reduce graft-versus-host disease, with signals in systemic lupus erythematosus, refractory immune thrombocytopenia, Crohn's fistulas, and as cotransplant support in aplastic anemia. The limitations of this study encompass small sample sizes, single-center designs, and short-duration trials. Additionally, there is significant heterogeneity concerning the source, manufacturing processes, dosage, administration routes, and endpoints. Other challenges include adherence to good manufacturing practices (GMP), issues related to potency, biobanking, logistical constraints, cost factors, and regulatory obstacles. Large multicenter randomized trials with standardized protocols and long-term follow-up, and combination strategies with biomaterials, gene engineering, and extracellular vesicle or exosome products, are needed to confirm durable benefit and enable routine clinical integration.

Cerebral ischemic injury, a major cause of mortality and disability, results from reduced or interrupted blood flow to the brain, most commonly in ischemic stroke. Insufficient oxygen and nutrient supply disrupts cellular metabolism, leading to neuronal death, neurological dysfunction, and lasting impairments. Current therapeutic strategies, including thrombolysis, mechanical thrombectomy, and anticoagulation, primarily aim to restore perfusion and provide neuroprotection by preserving the ischemic penumbra. While these interventions can partially rescue viable tissue in the acute phase, their effectiveness is constrained by narrow therapeutic windows, low recanalization rates, and contraindications, leaving significant unmet clinical needs. Consequently, the search for novel, targeted approaches has become a central focus of ischemic stroke research. Recent discoveries have identified lactylation, a newly recognized post-translational modification derived from lactate, as a key regulator of gene expression, protein function, and metabolic reprogramming. Once regarded as a simple glycolytic byproduct, lactate is now known to act as both an alternative energy substrate and a signaling molecule, influencing neuronal metabolism, antioxidant defense, and inflammatory responses. In ischemic brain injury, lactylation modifications of histone and non-histone proteins may either protect neurons-by supporting energy homeostasis, regulating stress-responsive genes, and suppressing apoptosis-or exacerbate injury through neuroinflammation, excitotoxicity, and immune evasion. Evidence indicates that the outcomes of lactylation depend on lactate concentration, timing of accumulation, cell type, and the balance between "writer" and "eraser" enzymes. Therefore, lactylation emerges as a promising yet complex therapeutic target in cerebral ischemia. Modulating lactate metabolism and its downstream modifications offers new opportunities to expand the therapeutic window, attenuate neuronal injury, and improve recovery. This review summarizes the molecular mechanisms linking lactate and lactylation to ischemic injury, highlights current contradictions in experimental findings, and explores the potential of targeting lactylation pathways for innovative treatment strategies.

Delays in intensive care unit (ICU) admissions are prevalent in overcrowded hospitals and can adversely affect patient outcomes. However, the extent of this impact, particularly beyond short-term mortality, remains unclear. We hypothesized that ICU admission delays exceeding 6 hours after consultation would independently increase 90-day mortality and prolong ICU length of stay. We conducted a retrospective analysis of data from 273 adult patients admitted to the ICU of a tertiary university hospital between January and December 2019. Patients were stratified into two groups: early admission (≤6 hours) and delayed admission (>6 hours). Multivariate Cox regression was employed to identify independent predictors of mortality. Delayed ICU admission was observed in 72.8% of patients. Although delayed admission was not independently associated with increased mortality in the multivariate analysis (HR: 0.88; 95% CI: 0.61-1.27), it was significantly correlated with prolonged ICU length of stay and higher 90-day mortality in the univariate analysis (p = 0.039), with no significant difference in vasopressor-free days (p = 0.809). In our assessment of independent mortality predictors, we found that patients with higher APACHE-II and Charlson scores experienced longer delays in ICU transfer. Additionally, respiratory and circulatory failure at admission were independently associated with increased mortality (HR: 2.17; 95% CI: 1.51-3.12). While early ICU admission did not independently predict mortality, it was linked to extended ICU stays, an increased treatment burden, and adverse long-term outcomes. These findings underscore the necessity of refining triage processes and evaluating baseline patient severity when interpreting the impact of ICU admission timing on outcomes.

Nicotine addiction poses a significant public health threat, particularly within the realm of emergency medicine, where it is associated with serious complications, including cardiovascular events and respiratory distress. The limited effectiveness of current pharmacological treatments for nicotine dependence underscores the urgent need for innovative and effective therapeutic approaches. Recent studies have shown that ivermectin, an antiparasitic agent, modulates the GABAergic, glutamatergic, and purinergic systems, which are implicated in the pathophysiology of addiction. This study aimed to examine the effects of ivermectin on the acquisition, extinction, and reinstatement of nicotine dependence in mice, utilizing the conditioned place preference (CPP) test, a widely recognized methodology in drug addiction research. Ivermectin (1 and 5 mg/kg, i.p.) was co-administered with nicotine (0.5 mg/kg, i.p.) over three consecutive days during the acquisition phase of nicotine dependence. In a separate experiment, the influence of ivermectin on the reinstatement of nicotine-induced CPP was assessed following an extinction period, using a single nicotine priming injection (0.1 mg/kg). Results indicated that ivermectin (1 and 5 mg/kg) significantly reduced the development of nicotine dependence (p < 0.05). Furthermore, ivermectin (5 mg/kg) facilitated the extinction of nicotine-induced CPP (p < 0.01) and attenuated the reinstatement of nicotine-induced CPP triggered by a priming dose of nicotine (p < 0.01). In contrast, administration of the lower dose of ivermectin (1 mg/kg) did not yield statistically significant effects on either the extinction or reinstatement phases (p > 0.05). Additionally, nicotine administration, alone or in combination with ivermectin at the tested doses, did not produce significant changes in motor coordination or locomotor activity. These findings suggest that ivermectin may attenuate both the acquisition and reinstatement of nicotine-induced CPP while facilitating the extinction of nicotine dependence. Collectively, the results indicate that ivermectin holds potential as a therapeutic agent in the treatment of nicotine addiction.

Allergic rhinitis (AR) is a prevalent chronic condition in childhood, and its increasing incidence has prompted research into potential associations with modifiable factors such as obesity. This meta-analysis aimed to assess the multivariate-adjusted relationship between childhood obesity and AR. A systematic search was conducted across PubMed, Embase, and Web of Science for observational studies that reported on the association between obesity and AR in children. Only studies that included multivariate adjustments for at least age and sex were considered. Random-effects models were employed to pool odds ratios (ORs) with 95% confidence intervals (CIs), accounting for heterogeneity. Fifteen cross-sectional studies comprising 23 datasets involving a total of 569,856 children were included in the analysis. The overall results indicated that obesity was not significantly associated with AR (adjusted OR: 1.04, 95% CI: 1.00-1.09; p = 0.08; I² = 24%). However, subgroup analyses revealed a significant association in Western countries (OR: 1.12, 95% CI: 1.00-1.24; p = 0.04; I² = 0%), while no significant association was found in Asian countries (OR: 1.04, 95% CI: 0.97-1.12; p = 0.27; I² = 52%). Notable associations were identified in studies utilizing national or international BMI cutoffs (OR: 1.06, 95% CI: 1.01-1.10; p = 0.02) and those with physician-diagnosed AR (OR: 1.07, 95% CI: 1.02-1.13; p = 0.006), but not in studies employing the 95th percentile BMI definition or ISAAC-based AR diagnosis. No significant differences were observed based on age or sex. Meta-regression analysis indicated that age, sex, and study quality score did not significantly influence the results (p all > 0.05). Egger's test revealed no evidence of publication bias (p = 0.43). In conclusion, while no significant overall association between childhood obesity and AR was found, subgroup analyses suggest potential links within specific populations and under particular methodological definitions. These findings should be interpreted with caution, and further longitudinal studies are necessary to determine whether preventive strategies aimed at reducing childhood obesity may also impact allergic outcomes.

Uterine leiomyomas are the most common benign tumors of the female genital tract, and alongside hormonal and genetic factors, emerging evidence implicates vitamin D deficiency in their pathogenesis. We investigated the association between serum 25-hydroxyvitamin D [25(OH)D] and the presence of uterine leiomyomas in women with unexplained infertility. In this retrospective case-control study, 148 women aged 18-45 years presenting to the Infertility Clinic of Ankara Bilkent City Hospital between July 2019 and February 2024 were included: 74 had imaging-confirmed leiomyomas (non-submucosal; FIGO types 4-6) and 74 infertile controls had no leiomyomas. Serum 25(OH)D was measured and demographic/clinical data were analyzed with appropriate parametric and non-parametric tests; correlations used Spearman's rho, and an ANCOVA adjusted for body mass index (BMI) and season assessed group differences. Groups were comparable in age and BMI (e.g., age 35.08 ± 5.79 vs 33.30 ± 5.57 years; p = 0.062). Mean serum 25(OH)D was significantly lower in women with leiomyomas than in controls (41.4 ± 23.7 vs 62.0 ± 34.2 nmol/L; p < 0.001), and this difference remained significant after adjustment for BMI and season (ANCOVA F = 10.7, p = 0.001). Vitamin D levels did not differ by leiomyoma number (single vs multiple: 44.1 ± 21.6 vs 38.5 ± 25.83 nmol/L; p = 0.32) or location (intramural vs subserosal: 40.7 ± 24.9 vs 43.1 ± 21.1 nmol/L; p = 0.69), and were not correlated with leiomyoma size (Spearman r = -0.04; p = 0.70). Among women with unexplained infertility, uterine leiomyomas are thus associated with significantly lower serum 25(OH)D levels, independent of BMI and season, whereas vitamin D status is unrelated to leiomyoma number, size, or location. These findings support a potential role of vitamin D deficiency in leiomyoma pathogenesis and underscore the need for larger, multicenter prospective studies to clarify causality and clinical implications.

Ischemia-reperfusion injury (IRI) presents a complex pathophysiology characterized by oxidative stress and inflammation. Arbutin, widely recognized for its use in skin whitening, also exhibits antioxidant, anti-inflammatory, and anticancer properties. This study aimed to assess the potential protective effects of arbutin at two different doses against IRI in the kidneys. Twenty-four male Wistar albino rats were randomly assigned to four equal groups: Control, IRI, 250 mg/kg arbutin + IRI (AR250+IRI), and 1000 mg/kg arbutin + IRI (AR1000+IRI). Arbutin was administered orally via gavage for 14 days to ensure sub-acute application. Following left kidney nephrectomy, ischemia was induced in the right kidney using a non-traumatic clamp for 45 minutes, succeeded by 60 minutes of reperfusion. Blood and tissue samples were subsequently collected for analysis. In the IRI group, levels of malondialdehyde, myeloperoxidase, interleukin-1 beta, and creatinine were significantly elevated; these levels decreased in the groups receiving arbutin supplementation. Notably, ischemia-modified albumin, urea, superoxide dismutase (inhibition ratio), and tumor necrosis factor alpha levels were reduced in the AR1000+IRI group. Additionally, decreased levels of catalase and glutathione peroxidase were observed in the AR1000+IRI group. Histopathological examination revealed flattening, necrosis, degeneration, dilation, glomerular necrosis, sclerosis, Bowman capsule dilation, and interstitial hemorrhage in the IRI group. The AR250+IRI group exhibited mild cortical-medullary congestion and a slight increase in glomerular size. Conversely, the AR1000+IRI group displayed a histological appearance resembling that of the control group. In conclusion, arbutin demonstrates potential protective effects against IRI. Its use may be recommended prophylactically for individuals at risk of developing IRI.