Search Results (7,732)

Background and Objectives: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have emerged as potential biomarkers in type 2 diabetes mellitus and its complications. This pilot exploratory study aimed to identify circulating miRNAs with differential expression in plasma from patients with newly diagnosed type 2 diabetes mellitus compared to age- and sex-matched healthy controls. Materials and Methods: Peripheral venous blood samples were collected from diabetic patients (n = 24) and controls (n = 12). Due to the exploratory nature of the study and limited sample material, samples were pooled within each group prior to plasma separation. Total RNA, including miRNAs, was extracted from plasma and analyzed using a high-throughput qPCR panel. Two normalization methods were applied to assess miRNA expression, and overlapping results were used for downstream analysis. Fold regulation was calculated using the 2^(−ΔCt) method. Results: A total of 33 and 42 miRNAs were identified as differentially expressed using the first and second normalization methods, respectively. Fourteen miRNAs were consistently downregulated across both methods. Several of these miRNAs, including hsa-miR-26a-5p, hsa-miR-146a-5p, hsa-miR-186-5p, hsa-miR-19a-3p, and hsa-miR-652-3p, have been previously associated with glucose metabolism, inflammation, and diabetic complications, such as retinopathy, neuropathy, and endothelial dysfunction. The pooling strategy enabled an efficient exploratory assessment of miRNA expression patterns while reducing inter-individual variability. Conclusions: This exploratory pilot study identifies a panel of circulating miRNAs with altered expression in pooled plasma samples from patients with newly diagnosed type 2 diabetes mellitus. These findings provide preliminary insights that warrant further validation in larger, individual-level studies to assess their diagnostic and prognostic potential. Full article

Acute Coronary Syndrome (ACS) is a severe manifestation of Coronary Artery Disease (CAD) caused by the rupture of unstable atherosclerotic plaques, resulting in reduced myocardial blood flow. Smoking is a major risk factor for ACS and has been associated with increased matrix metalloproteinase (MMP) activity, which contributes to the degradation of the plaque fibrous cap. However, the molecular alterations associated with smoking in ACS remain incompletely understood. This study aimed to investigate the expression of α1nAChR, ERK1/2, and c-FOS genes, together with MMP protein levels in atherosclerotic plaque tissues and peripheral blood mononuclear cells (PBMCs) of CAD patients. A total of 41 atherosclerotic plaque samples (26 smokers, 15 non-smokers) and 180 clinical subjects [n = 30 per group: ACS, chronic coronary syndrome (CCS), and controls; smokers and non-smokers] were included. Gene expression of ⍺1nAChR, ERK 1/2, and c-FOS was analyzed by RT-qPCR, while protein levels of MMP-2, MMP-9, and TIMP 3 were measured using ELISA. The expression of ERK 1/2 and c-FOS were significantly higher in plaque tissues of smokers compared with non-smokers (1.671- and 1.327-fold; p < 0.05). In PBMCs, α1nAChR expression was higher in CCS smokers (1.383-fold), while ERK 1/2 expression was higher in ACS smokers (1.355-fold). MMP-9 levels were significantly elevated in ACS and CCS compared with controls (p < 0.001). In conclusion, smoking CAD patients demonstrated increased expression of α1nAChR, ERK and MMP-9, indicating smoking-associated alterations in ⍺1nAChR-ERK signaling-related biomarkers in ACS. Full article

Background/Objectives: Vernal keratoconjunctivitis (VKC) is a chronic, recurrent allergic disease with the risk of permanent injury or visual disabilities. Tacrolimus (FK506) is a potent immunosuppressant with insoluble ability and a high molecular weight. Methods: To address this disease, we successfully prepared FK506-loaded polymeric micelles (0.01%, FK506-MS) by a simple, organic solvent-free method. The physicochemical properties of FK506-MS were characterized. Corneal permeability, biocompatibility, and bioavailability were evaluated in vitro and in vivo in comparison with a commercially available FK506 suspension (0.1%, FK506-Susp). Therapeutic efficacy was also assessed in a murine model of VKC. Results: FK506-MS exhibited a small, homogeneous particle size with near-neutral surface charge. FK506-MS displayed a rapid and sustained release, along with excellent biocompatibility and stability. Ocular pharmacokinetic studies in rabbits revealed that FK506-MS, despite being only one-tenth the concentration of FK506-Susp, could achieve sufficient concentration in the conjunctiva with a prolonged half-life (T1/2) while systemic exposure in blood was markedly reduced. FK506-MS elicited comparable therapeutic responses across evaluated parameters: clinical symptoms, molecular biomarkers of inflammation, and histopathological findings. Conclusions: The dose-sparing advantage of FK506-MS suggests that the conventional paradigm of concentration-dependent therapeutic efficacy may require further refinement. The nanomicellar delivery system not only overcomes the solubility limitation of FK506 but also exhibits a potential therapeutic paradigm: achieving comparable clinical efficacy with a lower dose and reduced systemic exposure. These results provide a promising preclinical basis for the potential development of a topical tacrolimus therapy that may offer improved safety, cost-effectiveness, and patient adherence. Full article

Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10⁻¹⁷] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10⁻⁸]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients. Full article

Background/Objectives: This study evaluates the prognostic value of baseline inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in advanced cutaneous melanoma treated with first-line immunotherapy. Methods: This multicenter retrospective study included 162 patients with unresectable stage III/IV cutaneous melanoma treated with first-line pembrolizumab, nivolumab, or nivolumab plus ipilimumab. Biomarkers were calculated from complete blood counts obtained within 30 days before treatment start. Cut-offs were defined by ROC analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Response was assessed by RECIST v1.1. Results: Higher baseline NLR, PLR, MLR, SII, and PIV were more common in patients with adverse baseline features, including liver metastases, elevated LDH, and poorer ECOG performance status. Patients with biomarker values below the cut-offs had significantly longer PFS and OS. In biomarker-specific multivariable models adjusted for selected clinical covariates, PIV retained the most consistent association with PFS and OS, while MLR was associated with PFS, and PLR with OS. Conclusions: Baseline inflammatory biomarkers from routine blood counts provide useful prognostic information in advanced melanoma treated with first-line ICIs. PIV showed the most consistent association with survival outcomes and may support initial risk stratification alongside LDH, ECOG, and metastasis pattern. However, prospective validation in independent cohorts is needed before routine clinical implementation. Full article

Background: Residential lifestyle medicine programs have documented immediate and long-term improvements in cardiometabolic risk factors. Despite this, adherence among participants varies in such programs, limiting the positive outcomes that can be achieved. This study aimed to assess how adherence to positive lifestyle behaviors correlates with cardiometabolic risk factors at the end of a residential lifestyle medicine program and at three or more months of follow-up. Methods: Patients enrolled in a NEWSTART^® lifestyle medicine program were invited to participate in this prospective chart review. Outcomes included changes in BMI, blood pressure, medication and supplement use, cardiometabolic disease biomarkers, Mediterranean eating pattern, meat intake, and other lifestyle behaviors. Results: Among 109 adults (78% female; 62% overweight or obese) enrolled in a 6- to 39-day (mean 14.5-day) residential intervention, meat intake reduced by 3.2 servings/week, MEPA III scores increased by 2.3, water intake increased by 2.1 glasses/day, and exercise increased by 193 min/week (all p < 0.01). From baseline to end of program, reductions were noted in blood glucose (−5.3 mg/dL, p = 0.01), total cholesterol (−16.0 mg/dL, p < 0.01), LDL cholesterol (−11.0 mg/dL, p < 0.01), HDL cholesterol (−2.0 mg/dL, p < 0.01), triglycerides (−13 mg/dL, p < 0.01), serum creatinine (0.03 mg/dL, p = 0.049), systolic blood pressure (−6.0 mmHg, p < 0.01), diastolic blood pressure (−3.0 mmHg, p = 0.01), weight (−3.2 kg, p < 0.01). At a mean of 8.6 months follow-up, reductions in triglycerides (14.9 mg/dL, p = 0.03), and weight (2.8 kg, p < 0.01), from baseline were sustained, and water intake increased 20% from baseline (1.1 glasses/day, p = 0.01). Improved adherence to a Mediterranean eating pattern score, increase in water intake and reductions in meat intake and BMI predicted favorable health outcomes. Conclusions: Participation in the lifestyle medicine program was associated with improvements in cardiometabolic risk factors during intervention and at follow-up. These outcomes correlated with adherence to positive lifestyle behaviors. Sustained weight reduction as well as dietary and cardiometabolic improvements in our participants suggest the NEWSTART^® intervention may hold promise for maintaining cardiometabolic health. Full article

Food-induced anaphylaxis (FIA) is a life-threatening allergic reaction, while wheat-dependent exercise-induced anaphylaxis (WDEIA) is triggered by wheat ingestion plus cofactors. To elucidate their differences, we profiled serum extracellular vesicle (EV) proteomes from 240 participants, including WDEIA, FIA, oral allergy syndrome (OAS), and healthy controls. All blood samples were obtained at least one month after the most recent acute allergic reaction, using TMT-based LC-MS/MS with ELISA validation. A total of 583 EV proteins were confidently identified, revealing distinct immune features. Compared with controls, EV-derived C1-inhibitor (C1-INH) significantly decreased in both WDEIA and FIA, showing diagnostic potential for systemic anaphylaxis. Seventy-six proteins differed between WDEIA and FIA, with reduced apolipoprotein E (APOE) in FIA and elevated eosinophil cationic protein (ECP) in WDEIA, both exhibiting good discriminatory power. These findings indicate that serum EV proteomics can reveal unique immune signatures and identify C1-INH, APOE, and ECP as potential biomarkers distinguishing food-related anaphylaxis subtypes. Full article

Introduction: The NF-κB signaling pathway is a key regulator of oncogenic processes; however, its systemic role in meningiomas remains poorly understood. The aim of this pilot study was to evaluate the expression of genes encoding NF-κB isoforms and IKK complex subunits in peripheral blood mononuclear cells (PBMCs) of patients with meningiomas prior to tumor resection. Methods: The study included 31 patients with meningiomas (WHO grades G1-G3) and 18 healthy volunteers. PBMCs were isolated using density gradient centrifugation, and total RNA was extracted. mRNA expression levels of NFKB1, NFKB2, RELA, RELB, c-REL, CHUK, IKBKB, and IKBKG were quantified by real-time PCR, with GAPDH used as the reference gene. Results: In patients with meningiomas, significantly lower expression of NFKB1 and higher expression of RELA, CHUK, and IKBKB were observed compared with the control group. NFKB1 expression was significantly higher in patients with higher tumor grades (WHO G2/G3) than in those with grade G1 tumors. Moreover, male patients exhibited higher expression levels of c-REL, CHUK, and IKBKB than female patients. Strong positive correlations were observed between components of the canonical NF-κB pathway. Discussion: The results may indicate systemic dysregulation of the NF-κB pathway in immune cells of patients with meningiomas, potentially characterized by activation of the canonical pathway and a shift toward p65/p65 homodimer formation. These alterations could reflect mechanisms associated with immunosuppression. NFKB1 expression may warrant further investigation as a candidate peripheral biomarker of tumor aggressiveness, while the observed sexual dimorphism in gene expression might suggest that sex could represent a relevant factor, requiring confirmation in prospective studies. Full article

Renal tubular epithelial cells (RTECs) are increasingly recognized as key players in kidney diseases. They integrate metabolic, inflammatory, and fibrotic signals. This article reviews new data suggesting that RTECs could function as central integrators within diagnostic networks, linking cellular stress responses to detectable blood and urine biomarkers. We discuss the latest advances in multi-omics, extracellular vesicles, and single-cell technologies that enable precise identification of RTEC states. Finally, we discuss the potential of RTEC-centric diagnostics and highlight current limitations in early disease recognition, stratification, and the development of personalized therapeutic interventions. Full article

Background: Head trauma is a major public health concern. Computed tomography (CT) is frequently used to evaluate these patients but may expose them to unnecessary radiation exposure. Various biomarkers have been investigated to predict prognosis and reduce the need for unnecessary imaging. Red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) have been proposed as inflammatory markers; however, their diagnostic value in head trauma remains controversial. This study aimed to determine the value of complete blood count parameters in identifying intracranial injury in patients with mild head trauma. Methods: This prospective, single-center study enrolled 100 adults with mild head trauma. Demographic data, vital signs, neurological assessments, complete blood counts, CT results, and clinical outcomes were also recorded. Patients were categorized as intracranial injury positive (Group 1) or intracranial injury negative (Group 2). We statistically compared the laboratory and demographic data of the groups. Statistical significance was set at p < 0.05. Results: The study included 100 patients with mild head trauma who presented to the emergency department, of whom 11 were in Group 1. The median PLR and lymphocyte levels differed significantly between the groups (p < 0.05). Conclusions: The PLR may serve as a preliminary supportive marker to aid clinical assessment; however, its modest discriminatory performance suggests that it should not be used as a standalone diagnostic tool. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder defined not only by amyloid-β plaques and tau pathology but also by several interacting processes that drive disease progression. These include neuroinflammation, neuronal cell death, synaptic dysfunction, blood–brain barrier (BBB) breakdown, and myelin and axonal damage. Together, they lead to neuronal loss and cognitive decline. In this review, we present a cell-centered framework linking these processes with key molecular markers. Neuroinflammation is driven by activated microglia and astrocytes and is associated with markers such as Iba1, CD68, GFAP, and C3, along with cytokines including IL-1β and TNF-α. Neuronal cell death occurs through apoptosis, ferroptosis, pyroptosis, and necroptosis, with markers such as caspase-3, GPX4, GSDMD, and MLKL. Synaptic dysfunction is reflected by reduced synaptic proteins, including synaptophysin and PSD-95. BBB breakdown increases permeability and reduces clearance of toxic molecules. Myelin and axonal damage, associated with MBP and NfL, disrupt neural connectivity. These processes are dynamically interconnected and may contribute differently across disease stages. This integrated cell-centered and systems-level framework provides insight into AD progression while highlighting potential biomarkers and therapeutic targets for diagnosis, disease monitoring, and therapeutic intervention. Full article

Background: The contribution of oral inflammatory conditions to systemic disease burden remains underexplored within multimorbidity frameworks. Emerging evidence suggests that periodontal inflammation may play a role in the clustering of chronic diseases, yet few studies have evaluated this at a population level using robust datasets. The aims of this study were to investigate whether periodontal diseases are associated with Multiple long-term conditions (MLTCs) burden and severity in two population-based cohorts and to examine whether systemic inflammatory biomarkers mediate these associations. Materials and Methods: We analyzed two population-based cohorts: the UK Biobank (UKB; n = 500,612) and the US National Health and Nutrition Examination Survey (NHANES; n = 10,714). MLTCs were defined as the coexistence of ≥2 chronic diseases. Associations between periodontal diseases and MLTCs were assessed using multivariable logistic and multinomial logistic regression. Causal mediation analyses examined the contribution of systemic inflammatory markers. Results: Approximately half of all participants had MLTCs. The prevalence of periodontal diseases was 17.8% in UKB (self-reported symptoms), and 42.3% in NHANES (clinically assessed). Periodontal diseases were independently associated with greater odds of MLTCs in both UKB (OR 1.12; 95% CI 1.10–1.14) and NHANES (OR 1.22; 95% CI 1.09–1.37). Associations were stronger among adults aged ≤ 60 years. A consistent dose-response relationship was observed between periodontal status and the number and severity of chronic conditions, as well as inflammatory-related MLTCs. Mediation analyses suggested partial effects through white blood cell count, neutrophils, and C-reactive protein. Conclusions: Periodontal inflammation is independently associated with greater multimorbidity burden, particularly in younger adults. Systemic inflammation may offer a plausible biological link, and these findings position oral health as an underrecognized and modifiable target in multimorbidity prevention and management frameworks, warranting prospective investigation. Full article

Heat stress is a major constraint to productivity and physiological homeostasis in laying hens. This study investigated integrated responses to acute heat stress using a multi-omics approach, including performance traits, serum biochemical parameters, histology, hepatic transcriptomics, cecal metagenomics, and metabolomics. Acute heat stress impaired productive performance, as reflected by changes in egg production and reduced eggshell strength, and induced systemic physiological disturbances, including increased stress- and injury-related blood indicators and disrupted metabolic and electrolyte balance. Histological analysis confirmed liver and intestinal tissue damage. Hepatic transcriptomics revealed inflammatory activation and suppression of metabolic pathways, particularly those involved in lipid metabolism, energy production, and redox homeostasis. Cecal metagenomic and metabolomic analyses showed altered microbial composition and functional potential, along with disruptions in amino acid, lipid, and energy metabolism. Collectively, these findings suggest that acute heat stress is associated with coordinated inflammatory responses and metabolic reprogramming, together with liver and intestinal injury and gut microbiota–metabolite alterations. The study provides a framework for understanding early heat stress responses and highlights potential targets for nutritional and microbiota-based interventions in poultry production. Importantly, serum biochemical indicators such as D-lactic acid and aspartate aminotransferase may serve as potential early biomarkers for monitoring heat-stress-induced physiological disturbances. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Background/Objectives: Psychotic relapse affects over 80% of individuals with schizophrenia-spectrum disorders, driving long-term disability and hospitalization. Clinical relapse management relies on symptomatic monitoring without objective neurobiological tools to guide individualized antipsychotic decisions. Methods: This systematic review synthesizes evidence on neurophysiological, blood-based, molecular, neuroimaging, and digital biomarkers for relapse prediction in schizophrenia-spectrum disorders. Results: Following the PRISMA 2020 guidelines, five databases were searched through March 2026 for longitudinal biomarker studies. Quality was assessed using the Newcastle-Ottawa Scale and PROBAST; findings were synthesized narratively due to substantial heterogeneity. From the 6812 citations screened, 21 studies were included across clinical high-risk, first-episode, and established illness populations. Conclusions: Mismatch negativity and P300 event-related potential (P300) showed the most consistent associations with relapse vulnerability, with mismatch negativity demonstrating relative independence from antipsychotic effects. Inflammatory and neuroendocrine markers—interleukin-6, C-reactive protein, and cortisol awakening response—predicted poor treatment response in multiple longitudinal investigations. Peripheral blood gene expression profiling identified TCF4 network dysregulation as a candidate molecular marker of impending relapse. Neuroimaging models did not outperform standard clinical variables. Digital phenotyping showed ecological promise but remains methodologically nascent. No single biomarker achieves sufficient accuracy for clinical implementation. Neurophysiological and inflammatory markers are the most tractable candidates for monitoring protocols. Future research should prioritize multimodal longitudinal designs, external validation, and systematic antipsychotic confounding control. Among the biomarkers reviewed, mismatch negativity and the interleukin-6/cortisol awakening response combination represent the most tractable candidates for pilot clinical implementation, particularly in specialized early psychosis services and antipsychotic dose-reduction research contexts; no biomarker currently achieves sufficient accuracy for routine use in maintenance treatment decisions. Full article