Search Results (6,535)

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

In this study, we investigated the protective effects of CPP-C3M4 against Salmonella-induced hepatic injury in lambs. Thirty 72-day-old Hu sheep were randomly divided into five groups: the control group (CON), the Salmonella-infected group (ST), and three CPP-C3M4 pretreatment groups at low, medium and high doses (CPP-C3M4-L, CPP-C3M4-M, and CPP-C3M4-H). The results showed that administration of CPP-C3M4 via duodenal fistula significantly alleviated liver enlargement and histopathological damage caused by Salmonella infection. CPP-C3M4 improved liver function by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride (TG) levels. It enhanced the liver antioxidant capacity by increasing glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities. It also alleviated inflammatory responses by downregulating the mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), toll-like receptor 2 (TLR2), and toll-like receptor 9 (TLR9). Transcriptomic Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis further confirmed that CPP-C3M4 exerts its protective effects by suppressing multiple inflammatory pathways, with the interleukin-17 (IL-17) signaling axis being a key target of regulation. These results indicate that CPP-C3M4 is a promising alternative antimicrobial substance for preventing and alleviating Salmonella-induced liver injury in lambs. Full article

Collagen, long regarded as the inert structural scaffold of the extracellular matrix, is now recognised as a source of bioactive signaling molecules: enzymatic hydrolysis releases low-molecular-weight bioactive collagen peptides that act systemically. This narrative review synthesises in vitro, animal-model, and veterinary clinical evidence with explicit differentiation of evidence levels; literature was identified through structured searches of PubMed, Web of Science, and Google Scholar, covering peer-reviewed, English-language reports published between 2000 and January 2026, without a formal systematic protocol. Across rodent, porcine, and human pharmacokinetic studies, orally administered collagen hydrolysate is efficiently absorbed, with a fraction reaching the circulation as intact prolyl-hydroxyproline and hydroxyprolyl-glycine through the conserved PEPT1/PEPT2 transporters; reported bioavailability varies with source, dose, and method, so no single value generalises across species. Native collagen and larger collagen fragments engage structure-dependent receptors in vitro (α2β1 integrins, DDR1/DDR2, GPVI, LAIR-1/2) that require triple-helical or Gly-Pro-Hyp presentation, whereas it is not established that the di- and tripeptides that reach the circulation after oral dosing engage them; their systemic actions are partly attributable to intracellular routes, including the Keap1–Nrf2 axis, HDAC/HAT modulation, and glycine-dependent glutathione synthesis. The gut–collagen peptide axis, a model derived from rodent and cell-culture data, links microbial bile acid remodeling and FXR/TGR5 signaling to systemic effects. Current evidence supports validated use in canine and equine osteoarthritis; species-specific bioavailability studies in dogs and cats remain the priority. Full article

Maternal and paternal attachment may relate differently to adolescent depressive symptoms, but the potential contribution of oxytocin receptor (OXTR) gene single nucleotide polymorphisms (SNPs) to these associations remains unclear. This six-month longitudinal study included 746 seventh- and tenth-grade students (50.7% female) from Guangzhou, China. Parent-child attachment and saliva samples for genotyping were collected at baseline, and depressive symptoms were assessed at follow-up using the CES-D-10. Overall, 48.8% of adolescents screened positive for depressive symptoms. Compared with adolescents below the cutoff, those who screened positive reported lower parental trust/communication and higher alienation (all p < 0.01). In adjusted linear regression models, father-child trust/communication was negatively associated with subsequent depressive symptoms (β = −0.26, p < 0.01), whereas mother-child alienation was positively associated with subsequent depressive symptoms (β = 0.15, p = 0.02). Exploratory moderation analyses showed a nominal rs2254295 × mother-child alienation interaction before correction (β = −0.07, p = 0.046), but this effect did not survive FDR correction. Father-child trust/communication and mother-child alienation showed distinct associations with adolescent depressive symptoms. The possible moderating role of OXTR rs2254295 should be regarded as preliminary and requires replication in larger independent samples. Full article

Zearalenone is a common mycotoxin that impairs reproductive function, particularly by damaging ovarian granulosa cells. This study investigated the protective effect and underlying mechanism of scutellarin against zearalenone-induced injury in porcine ovarian granulosa cells. Cells were isolated and identified by follicle-stimulating hormone receptor immunofluorescence. Cell viability, cell-cycle distribution, and related molecular changes were evaluated using the MTT assay, flow cytometry, qRT-PCR, and Western blot. Scutellarin showed no obvious cytotoxicity within the tested range and attenuated the zearalenone-induced reduction in cell viability. Flow cytometry analysis demonstrated that scutellarin alleviated zearalenone-induced cell-cycle disturbance. At the molecular level, scutellarin upregulated the expression of cell-cycle-related factors, including CDK1, CDK2, CDK4, and PCNA, and increased the expression of Wnt/β-catenin signaling-related proteins, including WNT5A, β-catenin, c-MYC, and CCND1. WNT5A knockdown further indicated that scutellarin-mediated regulation of PCNA, CDK1, and CDK4 is WNT5A-dependent, whereas its effect on CDK2 may involve a WNT5A-independent mechanism. These findings indicate that scutellarin alleviates zearalenone-induced granulosa cell injury partly through WNT5A-associated modulation of cell-cycle-related proteins, providing mechanistic insights for its protective effects. Full article

Modulating the immune microenvironment has become an emerging strategy for promoting functional bone regeneration, identifying key therapeutic targets remains challenging. Our previous work showed that Nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing protein 5 (NLRC5) is involved in bone destruction associated with periodontitis, but its potential and mechanism in regulating bone tissue repair and regeneration have not been fully elucidated. A monocortical bone defect model was established in the mouse femur to assess the impact of NLRC5 on in situ bone healing and regeneration. Mouse bone marrow-derived mesenchymal stem cells (BMSCs) were isolated to evaluate the effects of NLRC5 on osteogenic differentiation, proliferation, and migration. RNA sequencing was used to explore the direct regulatory mechanism of NLRC5 on osteogenic differentiation of mouse BMSCs. Mass cytometry was employed to examine the effect of NLRC5 on the bone marrow immune microenvironment, followed by in vitro validation experiments. Loss of NLRC5 impaired the healing and regeneration of femoral bone defects in mice, and led to a high inflammatory state in the early stage of healing. The absence of NLRC5 inhibited the osteogenic differentiation ability of BMSCs, and could be restored by NLRC5 overexpression, which was achieved through activation of the phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT) signaling pathway. Mass cytometry data revealed that NLRC5 may serve as an important factor in maintaining the differentiation and maturation of regulatory T cells (Tregs). By modulating the levels of inflammatory cytokines, NLRC5 further influences the osteogenic differentiation of BMSCs. NLRC5 serves as a key regulator and promising candidate for bone repair. NLRC5 contributes to bone regeneration through a dual mechanism: it promotes BMSCs osteogenic differentiation, at least in part via the PI3K/AKT/β-catenin signaling pathway, and indirectly modulates the local immune microenvironment to facilitate bone repair. Full article

Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic β-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid metabolic turnover. Emerging data confirm that ARF6 acts as a master rheostat of glucose-stimulated insulin secretion (GSIS) in β-cells through downstream cell division control protein 42/Ras-related C3 botulinum toxin substrate 1 (Cdc42/Rac1) cascades. Pathogenic ARF6 hyperactivation triggers a cascade of β-cell lesions: mitochondrial impairment, autophagic suppression and exacerbated inflammatory signaling, accelerating the progression of obesity and T2DM. First-line therapeutics ranging from GLP-1 (Glucagon-like peptide-1) receptor agonists and metformin to SGLT2 (Sodium-Glucose Cotransporter 2) inhibitors partially restore metabolic homeostasis by rectifying aberrant ARF6-dependent signaling axes. This review comprehensively delineates ARF6’s canonical cellular roles, mechanistic bridges connecting ARF6 to β-cell failure and metabolic deterioration, and functional crosstalk between ARF6 and established anti-metabolic pharmacotherapies. We further address unresolved research gaps and prospective translational avenues, offering actionable perspectives to advance ARF6 as a tractable therapeutic target for obesity and T2DM management. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes mellitus and obesity, have recently attracted attention for their potential effects on periodontal tissues. This systematic review aimed to evaluate the current evidence regarding the relationship between GLP-1-based therapies and periodontal health, with particular emphasis on anti-inflammatory, osteogenic, and regenerative mechanisms. A comprehensive literature search of PubMed, Web of Science, and Embase databases identified 22 eligible studies, including in vitro, animal, and human investigations. The available evidence suggests that GLP-1RAs such as liraglutide and exendin-4 may attenuate periodontal inflammation, reduce alveolar bone loss, and enhance osteogenic differentiation of periodontal ligament and dental pulp stem cells through modulation of pathways including MAPK/ERK, Wnt/β-catenin, NF-κB, and PKCβ2. Clinical observations additionally indicate a bidirectional relationship between periodontitis and incretin signalling, with periodontal therapy associated with increased systemic GLP-1 levels. However, the current evidence remains heterogeneous and is largely limited to preclinical and observational studies. Randomised clinical trials are required to determine the clinical efficacy and therapeutic relevance of GLP-1-based therapies in periodontitis management. Full article

Auger-electron-emitting radionuclides offer a distinctive route toward molecular-scale radiotherapy because their biological effects depend primarily on the nanoscale location of the decay event rather than on long-range tissue penetration. This review examines Auger-emitting radionuclides from a radiopharmaceutical perspective, integrating decay-associated physicochemical processes, cellular dosimetry, subcellular targeting, and translational relevance. We first discuss the physical determinants of Auger radiotoxicity, including Auger and Coster–Kronig electrons, internal-conversion electrons, local ionization density, and possible molecular consequences of highly localized Auger cascades. Cellular S values are used to illustrate how the same radionuclide can produce markedly different absorbed doses depending on whether activity is localized in the nucleus, cytoplasm, cell membrane, or neighboring cells. Iodine-125 incorporated into DNA as [¹²⁵I]iododeoxyuridine ([¹²⁵I]IUdR) remains the classical reference model for maximal Auger-mediated radiotoxicity. However, this direct DNA-incorporation model should not be generalized to receptor-targeted radiopharmaceuticals, which usually achieve indirect nuclear, chromatin-associated, perinuclear, membrane-associated, or vesicular localization rather than incorporation into DNA. These alternative source–target geometries may also produce biologically relevant effects, but they are mechanistically distinct from DNA-proximal [¹²⁵I]IUdR decay. Particular attention is given to iodine-123 versus iodine-125, the influence of physical half-life and specific activity, the interpretation of terbium-161 as a hybrid β⁻/internal-conversion/Auger emitter, and the overlooked radiobiological relevance of diagnostic Auger emitters such as technetium-99m, indium-111, and gallium-67. We conclude that Auger-emitter radiopharmaceuticals cannot be ranked by electron yield or decay scheme alone. Their therapeutic or toxicological relevance emerges from the integration of decay-associated physicochemical processes, cellular source–target dosimetry, intracellular trafficking, retention, and the temporal realization of dose delivery. Full article

Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac remodelling in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by metabolic and hypertensive stress (MHS). Methods: Male and female C57BL/6J mice were exposed to MHS (angiotensin II + high-fat diet) for 28 days, with or without mirabegron treatment (2 mg/kg/day). Cardiac structure and function were assessed by echocardiography, and molecular and histological analyses were performed on cardiac and BATs. Results: Mirabegron attenuated several features of cardiac remodelling in males, including cardiac hypertrophy, left atrial enlargement, and left ventricular dilation. These effects were associated with reduced expression of genes related to hypertrophy and fibrosis. In contrast, it was shown that females exhibited a less pronounced response pattern. BAT mass and thermogenic gene expression (Ucp1) increased more markedly in males than in females, suggesting differential BAT responsiveness between sexes. Conclusions: β3-AR activation is associated with sex-dependent cardiac responses in this HFpEF model, with more pronounced protective effects in males. These findings are consistent with a potential contribution of BAT activation to cardiac remodelling, although causality was not directly demonstrated in the present study. Full article

Background: Modern intensive care paradigms prioritize optimal analgesia over heavy sedation. While morphine, fentanyl, and remifentanil are widely used, sufentanil is relatively unknown in several countries. Aimed primarily at intensive care physicians, this narrative review evaluates the utilization of sufentanil in critically ill adult patients across four fundamental dimensions: (1) translational pharmacology (chemical structure, pharmacokinetics, pharmacodynamics, and pharmacogenomics); (2) indications and safety precautions; (3) clinical evidence in ICU patients; and (4) therapeutic positioning in contemporary ICU analgosedation and future research directions. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE focusing on the translational pharmacology, safety parameters, and clinical studies of sufentanil critically ill adults. The synthesis was structured according to SANRA principles for high-quality narrative reviews and includes articles published up to February 2026. Results: Sufentanil exhibits an exceptionally high affinity for the µ-opioid receptor, providing a potency 10-fold greater than fentanyl and 1000-fold greater than morphine. It has an experimental therapeutic index (LD50/ED50) nearly two orders of magnitude wider than that of fentanyl, enabling safe, highly granular bedside titration. Unlike morphine, hepatic CYP3A4 biotransformation yields completely inactive metabolites, preventing toxic accumulation during acute kidney injury. Furthermore, receptor-binding dynamics suggest a lower propensity for recruiting β-arrestins and activating NMDA pathways, potentially reducing opioid-induced hyperalgesia (OIH). Clinically, pilot trials in neurocritical cohorts demonstrate that sufentanil maintains reliable cerebral hemodynamic stability. In postoperative cardiac surgery and large ICU registries, sufentanil may reduce the mechanical ventilation duration, accelerate extubation, and shorten ICU length of stay. Conclusions: For critically ill adults, sufentanil is an excellent alternative to traditional opioids because it offers high-precision titratability, potent analgesia, and a safer metabolic profile. Full article

Decoy receptor 3 (DcR3) is a pleiotropic soluble factor that modulates cellular functions through both decoy and non-decoy mechanisms. DcR3 has been reported to exert anti-apoptotic and anti-inflammatory effects in humans, particularly in cancers and inflammatory diseases. In the present study, we investigated the role of DcR3 in TLR4-mediated innate immune responses in macrophages. Because the DcR3 gene is absent in the mouse genome, we generated myeloid-specific DcR3 knock-in mice and isolated bone marrow-derived macrophages (BMDMs) for functional analyses. Our results showed that DcR3 did not significantly affect LPS-induced expression of COX-2, iNOS, NLRP3, or pro-IL-1β. Aggresome-like induced structures (ALIS), which consist of aggregates of ubiquitinated proteins, are stress-induced cytoplasmic compartments implicated in MHC class I antigen presentation. We found that DcR3 suppressed LPS-induced ALIS formation by attenuating cellular reactive oxygen species production and p38 MAPK activation. In addition to LPS stimulation, DcR3 also reduced the accumulation of ubiquitinated proteins induced by HO-1 inhibitor ZnPP, lysosomal inhibitor bafilomycin A1, and proteasomal inhibitor MG132. Consistent with a role for autophagy in ALIS regulation, rapamycin reduced LPS-induced ALIS formation, whereas bafilomycin A1 induced comparable LC3-II accumulation in both wild-type and DcR3-expressing macrophages. Furthermore, DcR3 expression did not significantly alter LPS-induced p62 or HO-1 expression. Collectively, although DcR3 does not markedly influence LPS-induced inflammatory responses in BMDMs, our findings reveal a previously unrecognized role for DcR3 in suppressing ALIS formation and the accumulation of ubiquitinated proteins in macrophages, thereby suggesting a novel function for DcR3 in maintaining intracellular protein homeostasis under stress conditions. Full article

In November 2024, a highly mutated descendant of the Omicron BA.3 subvariant, designated BA.3.2, emerged in South Africa carrying 39 spike mutations, two large N-terminal domain (NTD) deletions and a novel four-amino acid insertion. A key feature of BA.3.2 is extensive NTD remodeling, including a major deletion spanning residues 135–148 affecting the β-hairpin region and contributing to the loss of most of the N1 loop. This study compares the evolutionary dynamics and structural features of BA.3.2 with BA.3. Phylodynamic analyses show that BA.3 underwent early demographic stability followed by a decline in genetic diversity, consistent with limited circulation, whereas BA.3.2 displays recent emergence and a progressive reduction in effective population size without rapid expansion. Selection analyses indicate BA.3 evolution is mainly driven by changes in the receptor-binding domain, while BA.3.2 shows dispersed signals across spike regions, including codon 1162. Structural and molecular dynamic analyses reveal increased flexibility and a broader conformational landscape in the BA.3.2 NTD, driven by the deletion and resulting loss of stabilizing interactions. Overall, BA.3.2 follows a distinct evolutionary trajectory characterized by antigenic remodeling of the spike NTD, underlining the need for continued surveillance of emerging SARS-CoV-2 descendant lineages. Full article

Lifespan is increasing throughout the world leading to a rise in non-communicable diseases in the global population that impacts over 800 million individuals with metabolic disorders, such as diabetes mellitus. Metabolic disease presents a significant challenge for clinical care since multi-organ disease progression ensues despite a broad array of treatment protocols. The pursuit of innovative strategies with mammalian forkhead transcription factors of the “O” class (FoxOs) and intimately related pathways of aging, cellular senescence, telomere integrity, oxidative stress, programmed cell death with apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis, Wnt/β-catenin signaling, Wnt1 inducible signaling pathway protein 1, and the gut microbiome becomes vital to address the clinical hurdles of metabolic disorders. Platforms incorporating novel diagnostics with artificial intelligence and machine learning can further address the underlying mechanisms tied to FoxOs that include the mechanistic target of rapamycin, AMP activated protein kinase, silent mating type information regulation 2 homolog 1 (S. cerevisiae), and glucagon-like peptide-1 receptor agonists that can markedly influence biological outcomes. Given the premise that it is essential to comprehend the intimate relationship that FoxO signaling pathways hold, FoxOs offer an exciting and promising approach to address the clinical aspects of disease onset, progression, and treatment with metabolic disorders. Full article

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), represents a major global health challenge, driven by the increasing prevalence of obesity and sedentary lifestyles. T2DM is characterized by insulin resistance and progressive β-cell dysfunction, leading to chronic hyperglycemia and multiple complications. Among the molecular targets investigated for therapeutic intervention, protein tyrosine phosphatase 1B (PTP1B) has emerged as a key negative regulator of insulin signaling. By dephosphorylating the insulin receptor and its downstream substrates, PTP1B attenuates insulin action and contributes to metabolic dysfunction. In addition to its role in glucose homeostasis, PTP1B is implicated in obesity, diabetic complications, neurodegenerative disorders, and cancer, highlighting its relevance as a multifunctional therapeutic target. However, the development of PTP1B inhibitors remains challenging due to the highly conserved and polar nature of its catalytic site, which limits selectivity and cell permeability. Recent research has focused on alternative strategies, including allosteric modulation and multi-site inhibition, to overcome these limitations. This review provides a comprehensive overview of PTP1B inhibitors from both synthetic (2019–2025) and natural sources, with particular emphasis on natural products reported from 2022 onwards, while including selected earlier studies to provide historical context and illustrate representative structural classes and inhibition mechanisms. Although PTP1B remains an attractive therapeutic target, its clinical validation for diabetes treatment has yet to be achieved. Continued advances in medicinal chemistry and allosteric modulation may help overcome the current translational barriers. Full article