Search Results (160,594)

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the “first-in-class” small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC₅₀ = 7.72, pCC₅₀ < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure–activity relationship insights. Full article

Sequence-based tools have greatly improved the molecular description of soil bioremediation, but detection alone cannot confirm that a contaminant is being degraded by a defined pathway. In soils, bioavailability limitations, redox microsites, relic DNA, gene mobility, and community restructuring can decouple gene presence from reaction flux. This review synthesizes an operational framework that separates three inferential levels: pathway potential, in situ activity, and verified pathway operation. The framework links inoculant fate, functional gene abundance, gene expression, pathway reconstruction, stable isotope probing, and targeted chemical analysis under explicit quality assurance, quality control, and decision rules. Particular attention is given to distinguishing parent compound loss from mineralization and detoxification and to using isotopic attribution when functional redundancy or inoculant-native overlap obscures agency. Instead of being presented as conceptually new, these principles are organized into a practical workflow for soil systems. This structure clarifies what can be discerned from genes, transcripts, proteins, metabolites, and transformation products at each evidentiary tier and provides a conservative basis for integrating multi-omics with mechanistic and quantitative interpretation. Full article

Objective: The aim of this case series was to investigate the safety and efficacy of vancomycin–gentamicin embedded PMMA beads (VGPB) in the setting of acute pyogenic soft tissue infections (STIs) of the extremities. Materials and Methods: A retrospective study of 19 cases diagnosed with pyogenic STIs of the lower or upper extremity in two academic institutions was conducted between January 2017 and December 2023. All patients underwent surgical debridement, systemic antibiotics and intrawound deposition of vancomycin and gentamicin embedded cement beads (2 g of vancomycin plus 1 g of gentamicin diluted in 40 g of PMMA). Upon second look (4th–7th day post-index surgery) the cement beads were removed, serum samples from the surgical site of infection and from peripheral blood were obtained and the concentration of eluted vancomycin and gentamicin was measured. Furthermore, the white blood cell count (WBC), C reactive protein serum levels (CRP) and erythrocyte sedimentation rate (ESR) were measured before the surgical debridement and after the end of the bead therapy. All patients were reevaluated after discharge with a mean follow-up of 4.4 years (range, 1 to 7.6). Results: Wound vancomycin and gentamicin levels were significantly higher than those measured in the serum (34.01 ± 4.47 μg/mL versus 11.96 ± 2.79 μg/mL, p < 0.001 and 5.75 ± 1.22 μg/mL versus 0.51 ± 0.14 μg/mL, p < 0.001 respectively). Serum vancomycin and gentamicin concentrations were below the level of toxicity and no adverse events related to antibiotic-embedded bead treatment were documented. Serum WBC, ESR and CRP levels before debridement (13,446 ± 935.7 c/μL, 42.3 ± 18.7 mm/h and 113.9 ± 20.26 mg/L respectively) were significantly higher than those after the end of treatment (7889 ± 1203.6 c/μL, p < 0.001; 30.3 ± 9.14 mm/h, p = 0.017; and 22.7 ± 6.68 mg/L, p < 0.001 respectively). Two cases (10.5%) had a local recurrence of their STIs. Both of them relapsed within 4 months after their treatment and both had Gram-negative pathogens. Conclusions: Vancomycin–gentamicin PMMA bead pouch therapy appears to be a safe and effective adjuvant treatment for pyogenic soft tissue infections, offering high local antibiotic availability without systemic adverse effects. Full article

Research based on the similarities between canine and human mammary tumors should extend beyond clinical, pathophysiological, epidemiological, and histopathological characteristics to include applicable molecular markers with prognostic significance. However, despite shared similarities, important differences must also be considered in comparative and translational studies. The nuclear erythroid 2-related factor (NRF2), a nuclear transcription factor that regulates the expression of antioxidant proteins, is pathologically activated during carcinogenesis. The role of NRF2 in human breast cancer is well established, making it a potential prognostic marker. Objectives: This study aimed to evaluate NRF2 tissue expression in mammary neoplasms of female dogs and its association with tumor progression, other prognostic factors, and survival. Methods: A group of 57 female dogs was studied. Tissue samples of mammary glands from 10 healthy dogs and 47 dogs with mammary neoplasms (39 malignant tumors and 8 benign tumors) were examined for NRF2 immunoexpression. Clinicopathological data and immunohistochemical expression, assessed by histochemical score (H-score), were correlated. Results: NRF2 tissue expression showed a predominantly cytoplasmic distribution and a lower H-score in tumors with higher malignancy grading. Dogs with higher NRF2 H-scores had improved survival rates (p = 0.0036). Univariate analysis revealed significant associations between H-scores < 135 and behavior (p = 0.007), tumor size (p = 0.001), and Ki-67 index (p = 0.018). Conclusions: These results suggest that NRF2 also holds prognostic value in the evaluation of canine mammary tumors. Full article

Antibiotic resistance is a critical global health threat, already causing over 1.27 million deaths annually and projected to exceed 10 million by 2050. This crisis is compounded by stagnation in novel antibiotic discovery, highlighting the need for mechanism–based innovation. Here, we provide an integrative framework linking antibiotic mechanisms of action, bacterial resistance pathways, and emerging therapeutic strategies. Antibiotics are systematically categorized by their molecular targets, cell wall synthesis, membrane integrity, nucleic acid replication, protein synthesis, and metabolic pathways, while resistance mechanisms are outlined in parallel, including enzymatic degradation, target modification, efflux, and permeability barriers. We further highlight novel approaches such as structure–guided drug design, synergistic combinations, nanoparticle delivery, and artificial intelligence–driven discovery. Precision medicine and microbiome modulation are also emphasized as next–generation interventions. By bridging molecular mechanisms with translational strategies, this review outlines opportunities to guide antibiotic innovation and advance precision therapies against the escalating threat of antimicrobial resistance. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Cardiomyopathies comprise a heterogeneous group of myocardial disorders characterized by structural and/or functional abnormalities in the absence of secondary causes of myocardial dysfunction. Although genetic determinants play a central role in many forms of the disease, incomplete penetrance and the frequent absence of identifiable pathogenic variants suggest that additional mechanisms contribute to disease onset and progression. Growing evidence supports the pathogenic role of autoimmune processes in several cardiomyopathy phenotypes. A spectrum of autoantibodies targeting cardiac self-antigens, including structural proteins, intercalated disc components, intracellular proteins such as calreticulin, and G protein-coupled receptors, has been identified in affected patients. Experimental and clinical data suggest that these autoantibodies may exert functional effects on cardiomyocyte signaling pathways and intercellular coupling, thereby promoting maladaptive remodeling, progressive ventricular dysfunction, and an increased risk of arrhythmias. Accordingly, autoantibody profiling may facilitate the identification of biologically distinct cardiomyopathy subsets with potential diagnostic and prognostic implications. From a therapeutic perspective, pathogenic autoantibodies can be removed from patient serum through plasmapheresis or immunoadsorption strategies, and these approaches have been associated with improvements in hemodynamic parameters and clinical outcomes in selected patients. Full article

Chinese rice-field eels (Monopterus albus) are a commercially farmed freshwater fish species in China. In recent years, the rapid expansion of aquaculture has been accompanied by frequent outbreaks of viral diseases, posing a serious threat to the sustainability of the Chinese rice-field eel farming industry. In this study, a rhabdovirus strain was isolated from diseased Chinese rice-field eels at a farm located in Xiantao, Hubei Province, China. Although the complete genomic sequence of CrERV-XT showed higher identity to the infectious hemorrhagic syndrome virus (IHSV) (96.16%) than to CrERV (94.39%), phylogenetic analysis based on the L protein placed CrERV-XT within the same clade as CrERV, supporting its tentative classification as a novel variant of CrERV. Furthermore, the amino acid sequence of the L protein showed greater similarity to that of CrERV (97.89%) than to IHSV, while the N, P, M and G proteins exhibited higher homology with their counterparts in IHSV. CrERV-XT displayed considerable genetic divergence from known CrERV isolates, which is presumably attributed to its geographic isolation in different locations. Alignment of the G protein sequences from five strains (CrERV-XT, CrERV, CrERV-TYY25, CrERV-XY0907 and IHSV) revealed a total of 39 amino acid mutation sites. These findings provide valuable insights for investigating conserved functional domains within the CrERV G protein for the rational design of vaccine antigens against this emerging virus. Full article

Tumor metastasis is closely associated with coagulation and inflammation, particularly via thrombin–PAR1 signaling. However, the potential of natural polysaccharides such as rhamnan sulfate (RS) to modulate these pathways and suppress metastasis remains unclear. We aimed to investigate the effects of orally administered RS derived from Monostroma nitidum on melanoma metastasis and its underlying mechanisms. Male C57BL/6J mice were orally administered water or RS daily. On day 8, saline or B16 melanoma cells were injected intravenously. Mice were treated for 21 days and divided into four groups (control, RS-only, M + W, and M + RS; n = 5/group). Metastasis and related molecular factors were analyzed in plasma, lung, and aortic tissues. Significant lung and aortic metastases were observed in the M + W group but were markedly suppressed in the M + RS group. RS reduced the expression of inflammatory factors (e.g., IL-6, PAR1), proteases, leukocyte activation markers, complement factors, angiogenic factors, and EMT-related factors. Conversely, thrombin, thrombomodulin, plasmin, TAFIa, and tight junction proteins were increased in RS-treated mice. RS suppresses melanoma metastasis by modulating thrombin–PAR1-mediated inflammation and associated pathways. These findings suggest RS as a potential therapeutic agent, although further mechanistic and clinical studies are required. Full article

The study presents novel photocrosslinked hydrogels based on methacrylated chitosan and methacrylated gelatin/allyl-modified gelatin and compares their properties as drug delivery systems in wound healing applications. The polymers were selected due to their biocompatible, mucoadhesive, cell-interactive properties and flexibility in adjusting their structure, making them suitable candidates for applications that require tissue repair. A range of hydrogel formulations was obtained by modulating the ratio of modified chitosan to two distinct modified gelatins, with photocrosslinking performed using Irgacure 2959 as the photoinitiator. FT-IR analysis, SEM data, and swelling and mechanical properties confirmed the 3D networking and the compatibility between the hydrogel components. Allylic gelatin-based hydrogels present larger pores and a stronger pH-responsive swelling behaviour compared to methacrylated gelatin-based samples, reflecting the higher flexibility of allylic gelatin networks. The hydrogels release bacitracin during the first six hours, with a release profile that follows a non-Fickian diffusion mechanism. Cytocompatibility and wound healing potential were tested in the presence of human and mouse fibroblasts, cells with a pivotal role in the wound healing process. All formulated hydrogels exhibit antioxidant capacity and protein stabilization properties, which are attributed to the presence of chitosan in their composition. The cytocompatibility, in vitro wound healing, and biological properties of the obtained hydrogels, as well as the drug release results, confirm their suitability in wound healing applications. Full article

Soybean (Glycine max) is relatively recalcitrant to genetic manipulations; hence, it is often interrogated with transient means such as virus-induced gene silencing (VIGS). We earlier modified cowpea severe mosaic virus (CPSMV) to develop a soybean-friendly VIGS system referred to as QUIN-FZ. Here we report additional calibrations of this system. We enhanced the intra-bacterial stability of plasmid QUIN, which contained a CPSMV RNA1 cDNA embedded with four introns, by adding a fifth intron, resulting in PENTIN. We separately upgraded the plasmid FZ, which contained a modified CPSMV RNA2 cDNA with a cloning site in the middle of the viral polyprotein, by creating another cloning site within the 3′ untranslated region, leading to ZY. We next used the new PENTIN-ZY system to investigate a putative soybean protein kinase designated QL18. Virus-mediated overexpression of two allelic, 147-amino-acid (aa) protein fragments, derived from two different QL18 orthologs, elicited drastically different responses in soybeans. While the fragment derived from soybean accession OX20-8 prevented the cognate virus from infecting top young leaves in at least 50% of inoculated seedlings, its allelic counterpart derived from soybean accession PI427105B elicited apical necrosis in 100% of soybean seedlings. By examining progeny viruses as well as viruses encoding chimeras of the two fragments, we identified more than a dozen mutations that abrogated these unique phenotypes. Our findings establish the PENTIN-ZY system as a versatile tool for overexpressing small proteins and protein fragments, accelerating their functional characterization. Full article

Background: Neuronal apoptosis is the core pathological mechanism of cerebral ischemic–reperfusion injury (CIRI); although Astragaloside IV (AS-IV) has demonstrated neuroprotective activity against CIRI, its specific molecular mechanisms underlying the regulation of this apoptosis-related pathway remain to be systematically elucidated. Methods: We establish an in vivo model of middle cerebral artery occlusion/reperfusion (MCAO/R) in rats and an in vitro model of oxygen–glucose deprivation/reperfusion (OGD/R) in PC12 cells. Six core apoptotic proteins, including CytC, Apaf-1, BAX, Bcl-2, Caspase3, and Caspase9, were detected using neurological function scoring, TTC/HE/Nissl staining, TUNEL staining, Western blot, and immunofluorescence techniques. Molecular docking and molecular dynamics simulation were utilized to analyze the binding affinity between AS-IV and the aforementioned apoptotic proteins. Results: Molecular docking and dynamics simulation demonstrated AS-IV stably binds six core apoptotic proteins, and comparative analysis with target-specific reference ligands identified Apaf-1 as its primary target with the most favorable binding properties. In rat MCAO/R models, AS-IV alleviated neurological deficits, reduced cerebral infarct volume and improved brain pathological damage; in PC12 cell OGD/R models, it decreased neuronal apoptosis. Western blot and immunofluorescence confirmed AS-IV downregulated pro-apoptotic proteins (cytoplasmic CytC, Apaf-1, BAX, cleaved-Caspase9/3) and upregulated anti-apoptotic Bcl-2. Conclusions: This study clarifies the anti-apoptotic molecular mechanism of AS-IV, it alleviates CIRI by targeting the CytC/Apaf-1 mitochondrial apoptotic pathway. Full article

Hydrogels and nanocomposite−enhanced hydrogels, owing to their high−water content, excellent biocompatibility, and mechanical flexibility, have demonstrated broad application prospects in tissue engineering, drug delivery, and flexible electronics. With the continuous advancement of computational power, molecular dynamics (MD) simulations have increasingly become an important tool for characterizing nanocomposite materials and hydrogel systems. This approach enables the capture of structural evolution at the atomic/molecular scale and provides mechanistic insights into deformation behaviors and interaction mechanisms under external stimuli such as mechanical force, temperature, and electric fields. This review is organized around the central framework of “structural construction–interfacial regulation−responsive behavior–dynamic evolution”, and systematically summarizes the recent progress in the application of molecular dynamics and multiscale simulation methods to hydrogels and nanocomposite hydrogels. The systems discussed mainly include synthetic polymer-based hydrogels, natural polymer−based hydrogels, peptide/protein−based hydrogels, and nanocomposite hydrogels. Particular emphasis is placed on modeling strategies and force−field selection principles for describing atomic interactions in various nanocomposite hydrogel systems. In addition, the important applications of multiscale simulation strategies in elucidating the interfacial behavior of hydrogels and the mechanisms underlying their dynamic responses under nonequilibrium conditions are also discussed. Finally, future development trends are outlined, including multiscale coupled simulations, closed−loop correction between experiments and simulations, and data−driven modeling strategies for the precise design and performance prediction of complex hydrogel systems. Full article

Acinetobacter baumannii (A. baumannii) represents a major threat because of its multidrug resistance, achieved through its ability to control virulence, and its mechanisms of drug efflux resistance. In this study, we used a combined experimental–computational approach to create and evaluate antimicrobial peptides that targeted the two essential pathogenic proteins, BfmR and AbaQ. The genomic analysis of a clinical isolate showed an extensive resistome and virulence profile, which matched high-risk global lineages. This study conducted molecular docking of an experimental AMP (cathelicidin KR-12 screened from the literature) and a rationally designed synthetic AMP (modified KR-12 analog) with pathogenic proteins, followed by 200 ns molecular dynamics simulations to evaluate both the binding stability and inhibitory potential of the compounds. The disk diffusion assay and microdilution assay were performed against A. baumannii. The study used comparative trajectory analyses, including RMSD, RMSF, radius of gyration, solvent-accessible surface area, principal component analysis, and MM-PBSA free energy calculations, to show that the synthetic AMP created stable electrostatic and hydrogen-bond networks, which caused conformational locking, and reached lower energy states than the experimental peptide. The synthetic AMP showed significant inhibition in validation in vitro. Contrastingly, the experimental AMP had transient interactions and no specificity. The study demonstrates that rationally designed AMPs have therapeutic potential, while the results create a reliable in silico framework to combat multidrug-resistant A. baumannii. Full article

Atherosclerosis is a complex, multifactorial disease that progresses through distinct stages: initiation, progression, and complication, ultimately leading to acute coronary syndromes (ACS). Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages are central players in this process, influencing plaque stability and vulnerability. Insulin-Like Growth Factor 1 (IGF-1), soluble-Klotho (S-Klotho), and the Growth Hormone Receptor exon 3 deletion polymorphism (GHRd3) have emerged as key modulators of vascular health, impacting these cellular components through various mechanisms. IGF-1 supports endothelial function, enhances VSMC survival and migration, and mitigates inflammation by inhibiting macrophage recruitment and activation, ultimately reducing the risk of plaque destabilization. S-Klotho, an anti-aging protein with potent anti-inflammatory and antioxidant properties, has been linked to vascular protection, with its deficiency associated with endothelial dysfunction, vascular calcification, and impaired VSMC survival. Evidence suggests that IGF-1 may enhance Klotho shedding, indicating a potential synergistic role in maintaining vascular integrity. This narrative review aims to outline the fundamental stages of atherosclerosis progression, consolidate current evidence on the roles of IGF-1 and S-Klotho in modulating key cellular components of atherosclerosis, and shed light on their potential involvement in plaque healing—an area that remains largely unexplored. By integrating established molecular mechanisms, we explore how these factors may contribute to endothelial integrity, VSMC survival, and macrophage activation and polarization, potentially shaping a more stable plaque phenotype and influencing future therapeutic strategies in cardiovascular disease. Full article