Search Results (1,662)

6PPD and its ozonation product 6PPD-quinone (6PPD-Q) are ubiquitous tire-derived pollutants linked to environmental and potential human health risks. This study systematically investigated their mechanisms in lipid-metabolism-related diseases (atherosclerosis, type 2 diabetes, and nonalcoholic fatty liver disease) through network toxicology, transcriptomic validation, molecular docking, and experimental models. Targets of 6PPD and 6PPD-Q were predicted using multiple databases and intersected with disease-associated genes. Protein–protein interaction networks, hub gene screening, GO/KEGG enrichment, and GEO transcriptomic datasets identified key shared core targets, including PTGS2, MMP9, CXCL8 (for 6PPD), MAPK14, and PTGS2 (for 6PPD-Q). Molecular docking suggested potential strong binding affinities. Integrative analysis highlighted convergence on oxidative stress, inflammation, lipid dysregulation, and MAPK signaling. In vivo, 40-day exposure to 6PPD and 6PPD-Q in C57BL/6 mice induced hepatic steatosis, elevated serum TC, LDL-C, and HDL-C, upregulated inflammatory cytokines (TNF-α, IL1B, IL6, and IFNG), and core targets. In vitro, both compounds caused dose-dependent cytotoxicity, ROS accumulation, glutathione redox imbalance, and pro-inflammatory activation. These findings suggest that 6PPD and 6PPD-Q may contribute to lipid-metabolism-related toxic responses through shared and distinct processes involving oxidative stress, inflammatory activation, and lipid dysregulation. These results provide preliminary mechanistic insights into their metabolic toxicity and support further experimental evaluation for environmental health risk assessment. Full article

Diabetic kidney disease (DKD) is characterized by progressive renal dysfunction driven by oxidative stress, inflammation, and hemodynamic alterations. Photobiomodulation (PBM) has emerged as a potential non-invasive therapeutic strategy targeting these pathways. To evaluate the effects of PBM on kidney function, hemodynamics, oxidative stress, and inflammatory profile in a rat model of DKD. Adult male Wistar rats were randomly assigned to four groups: control (Ct), Ct + PBM, DKD, and DKD + PBM. Diabetes was induced by streptozotocin (60 mg/kg, i.v.). PBM (808 nm, 100 mW) was applied transcutaneously (3 J per point; 30.48 J/cm²), bilaterally over the renal region, three times per week for six weeks. Kidney function (inulin clearance, serum creatinine, albuminuria), hemodynamics (mean arterial pressure, renal blood flow, renal vascular resistance), oxidative stress markers (urinary H₂O₂, NOx, thiols, Nrf2), and IL-1β levels were evaluated. DKD animals showed impaired kidney function, increased oxidative stress, and elevated inflammatory markers. PBM treatment significantly improved inulin clearance, reduced albuminuria and serum creatinine, increased renal blood flow, and decreased mean arterial pressure and vascular resistance. Oxidative stress markers and IL-1β levels were attenuated, with partial restoration of antioxidant capacity. No significant histological differences were observed. PBM improves kidney function and modulates redox and inflammatory pathways in experimental DKD, supporting its potential as a non-invasive adjunct therapy. Full article

Background: Chronic kidney disease (CKD) is a major global health burden, affecting more than 850 million people worldwide. Increasing evidence implicates engulfment and cell motility 1 (ELMO1), a cytoplasmic adaptor protein that regulates cytoskeletal remodeling, phagocytosis, and immune responses through the ELMO1–DOCK1–Rac1 signaling axis, in renal injury and disease progression. Methods: This narrative review identified relevant publications through searches of PubMed, Web of Science, and Google Scholar using combinations of the terms “ELMO1,” “kidney disease,” “diabetic kidney disease,” “IgA nephropathy,” “focal segmental glomerulosclerosis,” “acute kidney injury,” and “renal fibrosis.” English-language original research articles, genetic association studies, mechanistic investigations, and selected review articles were preferentially included according to their relevance to ELMO1 in kidney diseases. Results: Genetic association studies have implicated the ELMO1 locus in susceptibility to diabetic kidney disease (DKD), although associated variants and effect sizes differ across populations. Experimental studies suggest that ELMO1 regulates cytoskeletal remodeling, inflammatory responses, oxidative stress, and extracellular matrix deposition through the canonical ELMO1–DOCK1–Rac1 signaling pathway as well as Rac1-independent mechanisms. Available evidence supports a role for ELMO1 in DKD and renal fibrotic remodeling. In focal segmental glomerulosclerosis, the relevance of ELMO1 is primarily inferred from Rac1-associated podocyte injury pathways, whereas evidence in acute kidney injury remains limited and context-dependent. ELMO1 may contribute to inflammatory injury in ischemia–reperfusion settings but may also support efferocytosis and tissue repair in nephrotoxic injury models. In IgA nephropathy, evidence for a direct role of ELMO1 remains limited and is currently based largely on indirect mechanistic observations involving mucosal immunity and glomerular injury responses. Conclusions: ELMO1 is a context-dependent regulator of cytoskeletal, inflammatory, oxidative, and matrix-remodeling processes relevant to kidney disease. The strongest evidence currently supports its involvement in DKD, whereas its roles in other kidney diseases remain to be further defined in disease-specific, cell-type-specific, and stage-specific experimental models. Further studies are required to clarify its potential as a biomarker or therapeutic target in CKD. Full article

Background/Objectives: Protein kinases represent major therapeutic targets because dysregulation of their phosphorylation activity is associated with several diseases, including cancer, diabetes, and inflammatory disorders. Thus, many researchers in the pharmaceutical filed are making significant effort to design potent new protein kinase inhibitors (PKIs) as potential drugs. In this context, we aimed to identify new alternatives by exploiting the chemical space defined by ligands of the nucleotide-binding protein family for the discovery of novel protein kinase inhibitors. Protein kinases bind the nucleotide adenosine triphosphate (ATP) and belong to the nucleotide-binding protein group. Methods: All ligands of the nucleotide-binding protein family, excluding known kinase inhibitors, that were identified in the ChEMBL database were used in a structure-based virtual screening approach. From this set, we aimed to identify novel nucleotide-binding protein inhibitors (NBPIs) as novel kinase inhibitors. A total of 19,709 NBPI compounds that were dissimilar to known PKIs were docked on five protein kinases, and the 200 best scoring docking poses were retained for potential purchase. Results: Only 25 compounds were commercially available in stock and were evaluated experimentally on a panel of 10 diverse protein kinases. Three NBPI compounds, one of which had originally been identified as active against the ATP-binding cassette transporter ABCG2, were identified as Haspin kinase inhibitors with micromolar activity. Conclusions: This study presents an efficient computational approach to identifying novel kinase inhibitors from a database of ligands of the nucleotide-binding protein family, and the protocol could be applied to other protein target families. Full article

Inflammatory and oxidative stress within the pancreatic islet microenvironment can alter insulin-derived peptides and generate neoepitopes that may reshape autoreactive T cell recognition in type 1 diabetes (T1D). One such modification, C19S, represents a cysteine-to-serine substitution at position 19 of the insulin B-chain and has recently been identified among human leukocyte antigen class II (HLA-II)-associated insulin neoepitopes recognized by autoreactive CD4+ T cells. Although the biological relevance of C19S has been determined, the molecular features that may distinguish C19S-specific T cell receptor (TCR) engagement from native insulin recognition remain incompletely defined. Here, we used comparative protein–protein docking, molecular dynamics (MD) simulations, interface-contact analysis, conformational landscape analysis, and binding-energy calculations to examine TCR engagement of human leukocyte antigen DQ8 (HLA-DQ8) presenting either native insulin peptide or the corresponding C19S insulin peptide. Initial modeling indicated that both peptide-HLA-DQ8 complexes were compatible with TCR-bound ternary complex formation. However, the C19S-containing complex was predicted to exhibit altered peptide-centered dynamics, changes in peptide backbone presentation, and reorganization of both TCR-peptide and TCR-HLA-DQ8 contacts. Comparative molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) analyses further suggested a distinct calculated energetic profile under the applied modeling conditions for the C19S-containing complex, with residue-level decomposition localizing energetic differences to selected interface hotspots. Together, these findings provide a molecular framework for generating hypotheses about how C19S may reshape the HLA-DQ8-presented insulin recognition surface, with implications for future experimental studies of autoreactive CD4+ T cell recognition and antigen-specific tolerogenic strategies in T1D. Full article

Obesity and type 2 diabetes mellitus (T2DM) are multifactorial disorders characterized by insulin resistance, chronic low-grade inflammation, adipose tissue dysfunction, and multi-organ metabolic impairment. MicroRNAs (miRNAs) act as post-transcriptional gene regulators and play critical roles in metabolic homeostasis, the modulation of insulin signaling, adipogenesis, inflammatory pathways, and energy balance in key insulin-target tissues, including liver, skeletal muscle, and adipose tissue. This review summarizes mechanistic and translational insights into miRNA regulation in obesity, insulin resistance, and T2DM, integrating data from human studies and experimental models on miRNA sequence codes and extracellular vesicle sorting pathways. We focus on the tissue-specific and systemic roles of miRNAs, highlighting their contribution to inter-organ communication and metabolic network regulation. In addition, we emphasize their emerging roles as predictive biomarkers, modulators of treatment response, and promising targets for RNA-based interventions. Advances in sequence-specific miRNA sorting and extracellular vesicle-mediated delivery may provide avenues for therapeutic intervention. However, challenges related to delivery efficiency, tissue specificity, off-target effects, and variability in miRNA quantification remain important barriers to clinical translation. Addressing these limitations may help define the clinical utility of miRNAs as biomarkers and therapeutic targets in metabolic disorders. Full article

Background: Diabetic cardiomyopathy (DCM) is characterized by myocardial inflammation, apoptosis, and fibrosis that contribute to ventricular remodeling and dysfunction. We investigated the effects of 5-methoxytryptophan (5-MTP) on histopathological and molecular markers of myocardial remodeling in a rat model of DCM. Methods: Forty-eight Sprague–Dawley rats with DCM induced by a high-fat high-fructose diet and low-dose streptozotocin (25 mg/kg) were randomized to control or 5-MTP treatment (25, 50, or 100 mg/kg) and evaluated after 8, 16, and 32 days. Histopathological assessment using hematoxylin–eosin and Masson’s trichrome staining, along with immunohistochemical analysis of inflammatory, apoptotic, and fibrotic markers, was performed. Results: Myocardial inflammatory histopathological scores did not differ significantly among groups. Myocardial fibrosis assessed by Masson’s trichrome staining was significantly reduced at day 16 (p = 0.020), with all 5-MTP doses demonstrating lower fibrosis scores than DCM controls. Collagen I expression did not differ significantly. Caspase-3 expression was significantly reduced in all treatment groups at day 16 (p = 0.029), with persistent reduction at day 32 only in the 100 mg/kg group (p = 0.004). Early molecular modulation was observed through reduced TGF-β expression at day 8 in the 25 mg/kg and 50 mg/kg groups, followed by reduced SMAD3 expression at day 16 in the 25 mg/kg and 100 mg/kg groups. At day 16, AKT expression increased in the 25 mg/kg group, while cytoplasmic NF-κB expression decreased in the 25 mg/kg and 100 mg/kg groups. Conclusion: 5-MTP demonstrated time-dependent changes in molecular and histopathological markers associated with myocardial remodeling in experimental DCM. Full article

Cardiovascular disease remains a leading cause of mortality despite major advances in lipid lowering and risk-factor control, highlighting the importance of residual cardiovascular risk. Inflammation is a central driver of atherosclerosis, while obesity promotes chronic low-grade inflammation, adipose tissue dysfunction, ectopic fat accumulation, and vascular injury. This narrative review focuses on obesity-associated inflammation as an upstream contributor to residual atherosclerotic risk and evaluates whether incretin-based therapies modify this pathway through weight loss, metabolic improvement, and additional inflammatory or vascular mechanisms. Data from mechanistic studies, biomarker analyses, vascular imaging studies, and cardiovascular outcome trials are reviewed. Anti-inflammatory trials support inflammation as a modifiable therapeutic pathway, although clinical benefit depends on the therapeutic target, timing, and patient selection. Glucagon-like peptide-1 receptor agonists reduce inflammatory and oxidative stress biomarkers and show anti-atherosclerotic effects in experimental models, but human vascular imaging data remain inconclusive. Cardiovascular outcome trials establish benefit with several GLP-1 receptor agonists, including semaglutide in selected patients with overweight or obesity without diabetes. However, direct human evidence for receptor-mediated anti-inflammatory or anti-atherosclerotic effects remains limited, and the relative contributions of weight loss, metabolic improvement, and additional mechanisms remain uncertain. Full article

Background/Objectives: Type 2 diabetes is increasingly recognized as a systemic disorder driven not only by chronic hyperglycemia and insulin resistance, but also by dysregulated interorgan communication. Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as biologically active carriers of proteins, lipids, and microRNAs capable of modulating gene expression in recipient cells. This narrative review integrates clinical, experimental, and translational evidence on EV-associated microRNAs as candidate biomarkers and potential mediators of diabetic complications, with emphasis on diabetic neuropathy, diabetic kidney disease, diabetic retinopathy, and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This review was aligned with the SANRA framework and focused on biological plausibility, evidence from tissue and biofluids, biomarker potential, therapeutic implications, and barriers to clinical translation. Studies were additionally interpreted according to biological matrix, EV-carrier specificity, analytical platform, study design, and level of functional validation. Results: Across complications, EV-associated microRNAs appear to participate in shared pathogenic processes, including oxidative stress, inflammation, endothelial dysfunction, fibrosis, angiogenesis, neurodegeneration, and metabolic memory. In diabetic neuropathy, microRNAs such as miR-146a, miR-155, miR-21-5p, and miR-148a-3p have been linked to neuroinflammation, Schwann-cell dysfunction, axonal injury, and neuropathic pain. In diabetic kidney disease, miR-21, miR-29, miR-30, and miR-126 are implicated in podocyte injury, tubulointerstitial fibrosis, albuminuria, and microvascular dysfunction. In diabetic retinopathy, microRNAs including miR-146a, miR-155, miR-21, miR-126, and miR-200b contribute to neurovascular injury, inflammation, barrier disruption, and angiogenesis. In MASLD associated with diabetes, hepatocyte-derived EVs carrying microRNAs such as miR-1 and miR-126a-3p may link hepatic lipotoxicity to endothelial inflammatory and β-cell dysfunction. Conclusions: Although EV-associated microRNAs offer promising opportunities for biomarker discovery, risk stratification, and targeted therapies, clinical translation remains limited by heterogeneity in EV isolation, microRNA quantification, biological matrices, and outcome definitions. Distinguishing EV-associated miRNAs from total circulating extracellular miRNAs remains essential for biological interpretation. Standardized, longitudinal, and externally validated studies are required before these signals can be implemented as actionable tools in precision diabetes care. Full article

Background/Objectives: Diabetes mellitus is a multifactorial metabolic disorder characterized by chronic hyperglycemia, oxidative stress, and lipid metabolism dysregulation, leading to severe systemic complications. Increasing interest has been directed toward plant-derived bioactive compounds as potential therapeutic alternatives. The present study aimed to comparatively evaluate the phytochemical profile and biological effects of Acanthus balcanicus and Vaccinium myrtillus in a streptozotocin-induced experimental model of diabetes mellitus. Methods: Aqueous extracts of both plant species were prepared and characterized using high-performance liquid chromatography and spectrophotometric assays to determine phenolic and flavonoid content. Antioxidant activity was assessed using the DPPH radical scavenging method. In vivo experiments were conducted on streptozotocin-induced diabetic mice over a five-week period, evaluating glycemic levels, lipid profile, body weight, food and water intake, and oxidative stress markers, including SOD, GPx, GR, and lipid peroxidation. Results: Both extracts exhibited antioxidant activity and contained measurable amounts of phenolic compounds and flavonoids. Acanthus balcanicus demonstrated higher radical scavenging capacity, whereas Vaccinium myrtillus showed higher total flavonoid content. In vivo, administration of the plant extracts was associated with improvements in selected metabolic parameters compared with untreated diabetic animals. In particular, Acanthus balcanicus produced a marked reduction in blood glucose levels and improved lipid profile and oxidative stress markers under the present experimental conditions. Both extracts reduced hyperglycemia, hyperlipidemia, and oxidative stress markers compared with the diabetic control group. Conclusions: The findings provide preliminary evidence that aqueous extracts of Acanthus balcanicus and Vaccinium myrtillus may exert glucose-lowering and antioxidant effects in a streptozotocin-induced experimental model of diabetes. Under the present experimental conditions, administration of Acanthus balcanicus was associated with greater improvement in selected metabolic and oxidative stress parameters than the botanical comparator Vaccinium myrtillus. However, these findings remain preliminary and require confirmation in dose–response studies including a standard pharmacological control. However, these results should be interpreted cautiously because the study was conducted in a short-term animal model and did not include a positive pharmacological control or direct mechanistic validation. Further studies including standard antidiabetic drugs, insulin measurements, extended biochemical and histological evaluation, and mechanistic assays are required before any therapeutic relevance for diabetes management can be established. Full article

Backgroud: The growing prevalence of diabetes mellitus necessitates the development of safe and effective inhibitors of carbohydrate-metabolizing enzymes, particularly α-amylase and α-glucosidase. Methods: In this study, a series of pyrimidine–oxadiazole derivatives (1–10) was synthesized and structurally characterized using elemental analysis, HREI-MS, and ¹H/¹³C NMR spectroscopy. The compounds were evaluated for in vitro inhibitory activity against both enzymes, with acarbose as the reference drug. Results: IC₅₀ values ranged from 6.70 ± 0.20 to 21.10 ± 0.10 μM for α-amylase and 7.10 ± 0.20 to 21.80 ± 0.40 μM for α-glucosidase. Compounds 2, 3, and 6 displayed superior dual inhibitory activity compared to acarbose (IC₅₀ = 10.10 ± 0.20 and 10.50 ± 0.10 μM, respectively). Structure–activity relationship analysis revealed that electronic effects of aromatic substitutions significantly influenced enzyme inhibition. Molecular docking supported the experimental findings by demonstrating stable binding interactions within the enzyme active sites. Preliminary safety profiling in male Wistar rats showed no observable behavioral changes, hematological abnormalities, or hepatic and renal dysfunction following repeated administration of the lead compound. Conclusions: These results highlight pyrimidine–oxadiazole derivatives as promising and well-tolerated dual enzyme inhibitors for further antidiabetic drug development. Full article

Background/Objectives: Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus characterized by progressive nerve degeneration and chronic neuropathic pain. Current therapies, including pregabalin, primarily provide symptomatic pain relief and have limited effects on preventing structural nerve damage. Therefore, the development of disease-modifying therapies remains an important unmet clinical need. This study investigated the neuroprotective effects of choline alfoscerate (CA) and its ability to attenuate mechanical hypersensitivity in a streptozotocin (STZ)-induced rat model of DPN. Methods: Diabetes was induced in rats using STZ, and administration protocols were optimized to establish sustained hyperglycemia while minimizing mortality. CA treatment was initiated immediately after STZ administration and continued throughout the study period. Mechanical sensitivity was assessed using the von Frey test. Histopathological examination of sciatic nerves was performed to evaluate structural alterations, and serum biochemical and lipid parameters were analyzed to assess systemic metabolic changes. Results: STZ-treated diabetic rats developed persistent hyperglycemia, mechanical allodynia, elevated serum triglyceride levels, and marked structural deterioration of sciatic nerve fascicles. CA treatment significantly increased paw withdrawal thresholds despite sustained hyperglycemia, indicating attenuation of mechanical hypersensitivity independent of glycemic control. Histopathological evaluation demonstrated reduced nerve fiber degeneration, attenuation of edema-like changes, and preservation of sciatic nerve architecture in CA-treated animals. In addition, CA significantly reduced serum triglyceride levels compared with diabetic controls. Conclusions: CA attenuated mechanical hypersensitivity and exerted neuroprotective effects in STZ-induced diabetic rats. These benefits occurred independently of glucose lowering and were accompanied by improvements in nerve morphology and lipid metabolism. The findings suggest that CA may represent a promising therapeutic candidate for preserving peripheral nerve integrity and attenuating neuropathic progression in diabetic peripheral neuropathy. Full article

Diabetes mellitus is a major chronic disease that requires continuous monitoring and timely risk assessment to reduce the likelihood of severe long−term complications. Recent advances in mobile health technologies and machine learning (ML) provide new opportunities for developing intelligent systems that support diabetes self−management and early risk screening. This paper presents an end−to−end mobile health platform that integrates diabetes monitoring functionalities with an ML−based prediction service within a modular client−server architecture. The proposed system enables users to record glucose measurements, insulin injections, physical activity, and other health−related information while providing historical data visualization, automated reminder notifications, and real−time diabetes risk prediction. The prediction module was trained using the publicly available PIMA Indians Diabetes Dataset and evaluated using Decision Tree (DT), Random Forest (RF), and XGBoost classifiers. Model performance was assessed using accuracy, precision, recall, specificity, F1−score, calibration analysis, and the area under the receiver operating characteristic curve (AUC). Experimental results showed that the RF classifier achieved the highest AUC (0.925), demonstrating superior discrimination capability among the evaluated models and making it the most suitable candidate for deployment within the proposed platform. Although the current prediction model was trained on a benchmark public dataset, the proposed framework provides a practical foundation for integrating ML-driven decision support into mobile health applications and can be further extended through external clinical validation and personalized prediction models. Full article

Autoimmune diseases arise from a breakdown of immune tolerance and complex interplay of genetic susceptibility, environmental triggers, tissue-specific immune responses, microbiota, and regulatory pathways. Mouse models remain essential for dissecting these mechanisms, but no single model fully reproduces the heterogeneity, chronicity, and immune complexity of autoimmune disease in humans. This review summarizes classical murine and humanized mouse models used to study inflammatory bowel disease (IBD), multiple sclerosis (MS), type-1 diabetes (T1D), and rheumatoid arthritis (RA). We also highlight disease-specific scoring systems, including clinical indices, histopathology, imaging, cytokine profiling, autoantibody assessment, and human immune-cell readouts, as essential tools for standardized interpretation. Conventional murine models provide experimental control and mechanistic clarity, whereas humanized models improve assessment of human immune responses, patient-specific biology, and therapeutic translation. However, humanized systems remain limited by incomplete immune reconstitution, graft-versus-host disease, donor variability, cost, and incomplete tissue architecture. By providing a comparative framework spanning both conventional and humanized models, this review aims to guide informed model selection tailored to specific research questions in autoimmune disease biology and translational therapeutic development. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss, yet its systemic proteomic mediators remain largely elusive. This study aimed to identify causal plasma proteins, map their cell-type-specific localization in the retina, and experimentally validate their expression under disease-relevant stress. We conducted a proteome-wide association study (PWAS) integrating UK Biobank plasma pQTL data (N = 53,022) with DR GWAS summary statistics. Causal relationships were inferred utilizing summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Prioritized candidates were mapped to the Human and Mouse Retina Cell Atlases via single-nucleus RNA sequencing (snRNA-seq). Finally, to substantiate the computational findings, in vitro validation of COL4A1 was performed in ARPE-19 cells cultured under hyperglycemic conditions utilizing quantitative real-time PCR (qPCR) and transcriptomic dataset re-analysis. The PWAS identified 26 proteins significantly associated with DR. Subsequent causal inference prioritized 12 high-confidence candidates, including GSTT2B, COL4A1, PAM, and GALNT3. Notably, GSTT2B emerged as a Tier-1 protective causal protein (Z = −3.609; P_SMR = 1.22 × 10⁻⁴). snRNA-seq mapping revealed that GSTT2B is robustly expressed in Müller glia and the retinal pigment epithelium (RPE), whereas COL4A1 is prominently enriched in vascular compartments. These specific expression signatures exhibited partial conservation across species with notable cell-type specific variations. Crucially, in vitro validation confirmed that COL4A1 mRNA expression is significantly upregulated under high-glucose stress. Furthermore, druggability analysis highlighted actionable targets, identifying GSTT2B as a highly probable causal mediator and COL4A1 as a prioritized candidate for structural intervention. This study provides robust genetic, single-cell, and experimental evidence implicating specific plasma proteins in DR pathogenesis. The identification of GSTT2B-mediated protective pathways and the hyperglycemia-induced upregulation of COL4A1 offer a high-resolution molecular atlas to guide drug repositioning and precision therapeutic strategies. Full article