Search Results (2,147)

Iridoids are compounds recognized for their neuroprotective properties and their potential application in the treatment of neurodegenerative diseases. Geniposide (GP) and asperuloside (ASP) are iridoids that have demonstrated some biological activities. In this study, the potential neuroprotective effects of these iridoids were evaluated through in silico and in vivo assays, using Caenorhabditis elegans (C. elegans) strains CF1553 (sod-3::GFP), GA800 (cat::GFP), and CL2166 (gst-4::GFP). The results suggested that neither compound appears to have good passive permeability through the blood–brain barrier (BBB). However, an active transport mechanism involving the glucose transporter GLUT-1 may be present, as both compounds contain glucose in their molecular structure. In addition, they can inhibit the activity of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). GP at 1 and 2 mM reversed the H₂O₂-induced increase in sod-3 expression, while ASP at 1 and 2 mM reversed the increase in gst-4 expression. Worm survival was more adversely affected by higher concentrations of GP than ASP, although both similarly reduced acetylcholinesterase activity. These findings suggest that GP and ASP exhibit very low toxicity both in silico and in vivo in C. elegans, and positively modulate key enzymes involved in antioxidant pathways, highlighting their potential for neuroprotective applications. Full article

Background: Salmonella infections pose a serious threat to both animal and human health worldwide. Notably, there is an increasing trend in the resistance of Salmonella to fluoroquinolones, the first-line drugs for clinical treatment. Methods: Utilizing Salmonella Typhimurium CICC 10420 as the test strain, ciprofloxacin was used for in vitro induction to develop the drug-resistant strain H1. Changes in the minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined using the broth microdilution method. Transcriptomic and metabolomic analyses were conducted to investigate alterations in gene and metabolite expression. A combined drug susceptibility test was performed to evaluate the potential of exogenous metabolites to restore antibiotic susceptibility. Results: The MICs of strain H1 for ofloxacin and enrofloxacin increased by 128- and 256-fold, respectively, and the strain also exhibited resistance to ceftriaxone, ampicillin, and tetracycline. A single-point mutation of Glu469Asp in the GyrB was detected in strain H1. Integrated multi-omics analysis showed significant differences in gene and metabolite expression across multiple pathways, including two-component systems, ABC transporters, pentose phosphate pathway, purine metabolism, glyoxylate and dicarboxylate metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A biosynthesis, pyrimidine metabolism, arginine and proline biosynthesis, and glutathione metabolism. Notably, the addition of exogenous glutamine, in combination with tetracycline, significantly reduced the resistance of strain H1 to tetracycline. Conclusion: Ciprofloxacin-induced Salmonella resistance involves both target site mutations and extensive reprogramming of the metabolic network. Exogenous metabolite supplementation presents a promising strategy for reversing resistance and enhancing antibiotic efficacy. Full article

Background: Spectrin proteins are critical cytoskeleton components that maintain cellular structure and mediate intracellular transport. Pathogenic variants in SPTBN1, encoding βII-spectrin, have been associated with various neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy. Here we report a Korean infant with infantile epileptic spasms syndrome (IESS) and an SPTBN1 mutation and provide a review of this mutation. Methods: The genomic data of the patient were analyzed by whole exome sequencing. A comprehensive literature review was conducted to identify and analyze all reported SPTBN1 variants, resulting in a dataset of 60 unique mutations associated with neurodevelopmental phenotypes. Case Presentation: A 10-month-old Korean female presented with IESS associated with a de novo heterozygous SPTBN1 mutation (c.785A>T; p.Asp262Val). The patient exhibited global developmental delay, microcephaly, hypotonia, spasticity, and MRI findings of diffuse cerebral atrophy and corpus callosum hypoplasia. Electroencephalography revealed hypsarrhythmia, confirming the diagnosis of IESS. Seizures persisted despite initial treatment with vigabatrin and steroids. Genetic analysis identified a likely pathogenic variant within the calponin homology 2 (CH2) domain of SPTBN1. Conclusions: This is the first report of an association between IESS and an SPTBN1 CH2 domain mutation in a Korean infant. This finding expands the clinical spectrum of SPTBN1-related disorders and suggests domain-specific effects may critically influence phenotypic severity. Further functional studies are warranted to elucidate the pathogenic mechanisms of domain-specific variants. Full article

Designing optimal heritage tourism routes in secondary cities involves complex trade-offs between cultural richness, travel time, carbon emissions, spatial coherence, and group satisfaction. This study addresses the Personalized Group Trip Design Problem (PGTDP) under real-world constraints by proposing DRL–IMVO–GAN—a hybrid multi-objective optimization framework that integrates Deep Reinforcement Learning (DRL) for policy-guided initialization, an Improved Multiverse Optimizer (IMVO) for global search, and a Generative Adversarial Network (GAN) for local refinement and solution diversity. The model operates within a digital twin of Warin Chamrap’s old town, leveraging 92 POIs, congestion heatmaps, and behaviorally clustered tourist profiles. The proposed method was benchmarked against seven state-of-the-art techniques, including PSO + DRL, Genetic Algorithm with Multi-Neighborhood Search (Genetic + MNS), Dual-ACO, ALNS-ASP, and others. Results demonstrate that DRL–IMVO–GAN consistently dominates across key metrics. Under equal-objective weighting, it attained the highest heritage score (74.2), shortest travel time (21.3 min), and top satisfaction score (17.5 out of 18), along with the highest hypervolume (0.85) and Pareto Coverage Ratio (0.95). Beyond performance, the framework exhibits strong generalization in zero- and few-shot scenarios, adapting to unseen POIs, modified constraints, and new user profiles without retraining. These findings underscore the method’s robustness, behavioral coherence, and interpretability—positioning it as a scalable, intelligent decision-support tool for sustainable and user-centered cultural tourism planning in secondary cities. Full article

Biostimulants, particularly single amino acids, can increase plant growth and crop quality, gaining significant attention. This study investigates the effects of 10 amino acids via root/foliar application on the growth, quality, taste, and volatile flavor of mini-watermelons and compares the differences between the application methods. Here, we employed electronic noses, electronic tongues, and gas chromatography–ion mobility spectrometry to investigate these effects. Root application excels in fruit growth and pectin accumulation, while foliar application boosts soluble protein and specific nutrients. Specifically, root application (except for Val) significantly increases fruit weight, with Gly being most effective for longitudinal diameter, while most amino acids (except Val/Lys) promote transverse diameter. Pectin content shows bidirectional regulation: root application of Glu/Gly/Lys/Pro/Trp/Val enhances pectin, whereas foliar application inhibits it. For taste indices, most treatments improve soluble solids (except Glu root/Arg-Leu foliar), and Ala/Asp/Glu/Gly reduce titratable acids, optimizing the sugar–acid ratio. Foliar application is more efficient for soluble protein accumulation (Ala/Glu/Gly/Pro/Leu). For nutritional quality, except for Lys, all treatments increase vitamin C and widely promote total phenolics and lycopene, with only minor exceptions, and only Arg foliar application enhances ORAC. Additionally, the results revealed that root-applied lysine and valine greatly raised the levels of hexanal and 2-nonenal, whereas foliar-applied valine significantly increased n-nonanal and (Z)-6-nonenal. Overall, we found that amino acids can considerably improve mini-watermelon production, quality, taste, and antioxidant capacity, providing theoretical and practical references for their widespread use in agriculture. Full article

Background: The profile of germline genetic variants among colorectal cancer patients in Panama has not yet been explored. Methods: We recruited 95 patients with colorectal cancer in an Oncology Reference Hospital Unit in the Azuero region of central Panama, which exhibited the highest prevalence of colorectal cancer in Panama. DNA analysis was performed with a panel of 113 genes with germline mutations for cancer (TruSight^® Cancer Sequencing Panel from Illumina, San Diego, CA, USA). Results: Among the 95 cases, 10 pathogenic/likely pathogenic variants (P/LP) were identified in the MUTYH, TP53, CHEK2, PALB2, ATM, and BARD1 genes, representing 10% of the total. The variant 1103G>A (p.Gly368Asp) in MUTYH was the most prevalent. The variant at c.1675_1676delCAinsTG (p.Gln559Ter) in PALB2 is new and is reported for the first time in this study. Variants were most frequently detected in the MUTYH and CHEK2 genes, affecting four and two patients, respectively. Notably, none of the 95 Panamanian patients in the initial colorectal cancer cohort had mutations in mismatch repair (MMR) genes. These genes are among the most frequently mutated in other cohorts around the world. Conclusions: The atypical profile of germline genetic variants in this population may be related to the unique characteristics of the Azuero population in Panama’s central region. This profile may partly explain the high prevalence of colorectal cancer among its inhabitants. Full article

Experimental and theoretical studies were applied to investigate the adsorption properties of testagen (KEDG) peptide on copper surfaces in sodium chloride solution and, implicitly, its inhibition efficiency (IE) on metal corrosion. The tetrapeptide synthesized from the amino acids lysine (Lys), glutamic acid (Glu), aspartic acid (Asp), and glycine (Gly), named as H-Lys-Glu-Asp-Gly-OH, achieved an inhibition efficiency of around 86% calculated from electrochemical measurements, making KEDG a promising new copper corrosion inhibitor. The experimental data were best fitted to the Freundlich adsorption isotherm. The standard free energy of adsorption ($\mathsf{\Delta }{\mathrm{G}}_{\mathrm{a}\mathrm{d}\mathrm{s}}^{\mathrm{o}}$) reached the value of −30.86 kJ mol⁻¹, which revealed a mixed action mechanism of tetrapeptide, namely, chemical and physical spontaneous adsorption. The copper surface characterization was performed using optical microscopy and SEM/EDS analysis. In the KEDG presence, post-corrosion, SEM images showed a network surface morphology including microdeposits with an acicular appearance, and EDS analysis highlighted an upper surface layer consisting of KEDG, sodium chloride, and copper corrosion compounds. The computational study based on DFT and Monte Carlo simulation confirmed the experimental results and concluded that the spontaneous adsorption equilibrium establishment was the consequence of the contribution of noncovalent (electrostatic, van der Waals) interactions and covalent bonds. Full article

Background/Objectives: Single-dose pre-operative antibiotic prophylaxis for cardiac-device implantation is recommended but extending antibiotic prophylaxis is common. Locally, 50–60% of patients had extended prophylaxis after pacemaker insertion or generator change. Our antimicrobial stewardship programme (ASP) incorporated behavioural change strategies in implementing a multi-pronged intervention bundle to address this and evaluated its effectiveness and safety. Methods: This single-centre, retrospective cohort study included patients aged 21 years old or older, undergoing uncomplicated pacemaker insertion or generator change at Singapore General Hospital (SGH) from October 2022 to March 2025. To improve antibiotic use, ASP interventions incorporating behaviour change strategies were implemented, namely (1) data-driven feedback, (2) targeted education, (3) identification and engagement of ASP champion, and (4) clinical pathway revision. Results: There were 779 patients evaluated; 380 (48.8%) received standard prophylaxis while 399 (51.2%) received extended prophylaxis with oral antibiotics (mean duration, 3.3 ± 0.8 days). Following ASP interventions, the practice of extended prophylaxis declined significantly from 43.8% to 24.0% (p < 0.01). The incidence of surgical site infections was low and similar in both groups (0.8%, p = 1.000); all infections were superficial. There was also significant reduction in the proportion of patients on all antibiotics from 20.7% to 16.3% (p < 0.01). Identification and engagement of ASP champion proved pivotal in changing prescribing behaviour through peer influence and credibility. Conclusions: The bundled ASP interventions, incorporating behavioural change strategies, have effectively and safely reduced the use of extended prophylaxis post-cardiac device implantation. Behavioural change interventions are essential to achieve sustained stewardship success. Full article

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article

Topically applied TH1579 alleviated the psoriatic phenotype in the imiquimod-induced psoriasis mouse model by decreasing CD45⁺, Ly6b⁺, and CD3⁺ cell infiltration and downregulating the expression of the proliferation marker PCNA. Moreover, TH1579 strongly suppressed IL-17 expression in mouse skin, accompanied by reduced infiltration of IL-17-producing γδ-T cells. Furthermore, TH1579 decreased keratinocyte viability and proliferation. Mass spectrometry data analysis revealed the enrichment of proteins associated with nucleotide excision repair and cell cycle regulation. The key cell cycle regulatory protein F-box protein S-phase kinase-associated protein 2 (SKP2) was significantly downregulated, along with the psoriasis-associated proliferation marker WNT5a, identified as a SKP2 downstream target. The downregulation of SKP2 and WNT5a was confirmed in MTH1i-treated mouse skin. Our findings support the topical administration of MTH1i TH1579 as a psoriasis treatment. The therapeutic effects depended on the SKP2/WNT5a pathway, which mediates psoriatic hyperproliferation. This study introduces a conceptually innovative topical treatment for psoriasis patients with mild-to-moderate disease who have limited therapeutic options. Full article

Background: Infectious complications are common after percutaneous nephrolithotomy (PCNL). Clinical guidelines recommend, previous to surgery, prolonged antibiotic regimens in patients with preoperative positive urine cultures to reduce infectious risk. However, such strategies may increase selective pressure and promote antimicrobial resistance. Evidence supporting the use of a single antibiotic dose tailored to culture sensitivity in these cases is limited but emerging. Methods: We conducted a retrospective observational study including 187 PCNL procedures performed between 2021 and 2023 under an individualized antibiotic prophylaxis protocol. Patients with negative or contaminated urine cultures received a single empirical dose, while those with recent positive cultures received a single dose based on antimicrobial susceptibility testing. Postoperative complications—including fever, sepsis, and a composite outcome—were analyzed through multivariable logistic regression, comparing high- and low-risk patients. Results: A total of 67.9% of procedures were performed in patients meeting at least one high-risk criterion, including a positive preoperative urine culture in 32.1%. The overall incidence of infectious complications was 11.9% (fever 8.7%, sepsis 3.2%), with no significant differences between risk groups. A low concordance was observed between preoperative and intraoperative urine cultures (Spearman = 0.3954). Conclusions: A single preoperative antibiotic dose adjusted to the antibiogram, even in patients with a positive urine culture, was not associated with increased infectious complications. This approach is an initial step that supports a rational and individualized prophylactic strategy aligned with the goals of antimicrobial stewardship programs (ASPs). Full article

The global impact of the COVID-19 crisis has underscored the need for novel therapeutic candidates capable of efficiently targeting essential viral proteins. Existing therapeutic strategies continue to encounter limitations such as reduced efficacy against emerging variants, safety concerns, and suboptimal pharmacodynamics, which emphasize the potential of natural-origin compounds as supportive agents with immunomodulatory, anti-inflammatory, and antioxidant benefits. The present study significantly advances prior molecular docking research through comprehensive virtual screening of structurally related analogs derived from antiviral phytochemicals. These compounds were evaluated specifically against the SARS-CoV-2 main protease (3CLpro) and papain-like protease (PLpro). Utilizing chemical similarity algorithms via the ChEMBL database, over 600 candidate molecules were retrieved and subjected to automated docking, interaction pattern analysis, and comprehensive ADMET profiling. Several analogs showed enhanced binding scores relative to their parent scaffolds, with CHEMBL1720210 (a shogaol-derived analog) demonstrating strong interaction with PLpro (−9.34 kcal/mol), and CHEMBL1495225 (a 6-gingerol derivative) showing high affinity for 3CLpro (−8.04 kcal/mol). Molecular interaction analysis revealed that CHEMBL1720210 forms hydrogen bonds with key PLpro residues including GLY163, LEU162, GLN269, TYR265, and TYR273, complemented by hydrophobic interactions with TYR268 and PRO248. CHEMBL1495225 establishes multiple hydrogen bonds with the 3CLpro residues ASP197, ARG131, TYR239, LEU272, and GLY195, along with hydrophobic contacts with LEU287. Gene expression predictions via DIGEP-Pred indicated that the top-ranked compounds could influence biological pathways linked to inflammation and oxidative stress, processes implicated in COVID-19’s pathology. Notably, CHEMBL4069090 emerged as a lead compound with favorable drug-likeness and predicted binding to PLpro. Overall, the applied in silico framework facilitated the rational prioritization of bioactive analogs with promising pharmacological profiles, supporting their advancement toward experimental validation and therapeutic exploration against SARS-CoV-2. Full article

Periodontitis is a multifactorial disease linked to host immune response and genetic predisposition. The TLR4 Asp299Gly single-nucleotide polymorphism (SNP, rs4986790) has been associated with altered responses to bacterial lipopolysaccharide (LPS) and may influence susceptibility to inflammatory diseases. Given the central role of TLR4 in innate immune recognition of periodontal pathogens, this study investigates the role of rs4986790 in modulating susceptibility to periodontal inflammatory destruction. A total of 1410 individuals from four populations were genotyped, with findings indicating a significant protective effect of the polymorphic allele. Functional assays demonstrated enhanced IL-8 secretion and increased sensitivity to CD14 inhibition in cells expressing the variant receptor. These results suggest that rs4986790 modifies the LPS response via TLR4, potentially offering protection against periodontal breakdown. Full article

Background: Medullary thyroid carcinoma (MTC) has a high rate of local and distant metastases. In particular, the RET protooncogene appears to be the predominant driver mutation for oncogenesis. The German S3 thyroid carcinoma guidelines recommend molecular genetic analysis of the tumour without specifying the site of the tissue sampling. Whether there is difference in RET protooncogene between the primary tumour, lymph node, and distant metastasis has not yet been investigated. However, differences could be important with regard to biopsy localization, and also, thus, the choice of single- or multi-tyrosine-kinase-inhibitor therapy. Methods: In a case of sporadic MTC, Cancer Hotspot panel diagnostics were performed on the primary tumour, lymph node metastasis, and distant metastasis. Mutations were classified using different gene databases, and the different stages of metastasis were compared. Results: RET protooncogene (chr10:43609933, c.1886_1891delTGTGCG, p.Leu629_Asp631delinsHis) was found to be present in the MTC tissue of the primary tumour, lymph node, and distant metastasis in the Cancer Hotspot Panel diagnostic, while the other investigated therapy-relevant mutational profiles were not consistently found. Conclusions: Further longitudinal studies in larger patient cohorts are required to elucidate the role of the RET protooncogene in the metastatic progression of MTC and to determine its impact on the selection of biopsy sites and the subsequent decision-making regarding single- versus multi-tyrosine kinase inhibitor therapy. Full article

Thermosets are plastic composite materials widely used in many industrial sectors of modern society with an increasing presence in the environment. The adverse effects of this material on environmental compartments and biota of thermosets are still unknown. In this work, we studied the potential effects of two thermoset polyester resin-derived microplastics (R930A-SP and R930A-DVE1) on the survival, behavior, morphological changes and subcellular damage of earthworms Eisenia fetida. The proposed experimental conditions simulated environmentally relevant concentrations, taking as a reference other related microplastics present in the environment. Thus, E. fetida specimens were exposed to five concentrations (100, 500, 1000, 1500 and 2000 mg resin per kg soil) of these two resins for 14 days. At concentrations and exposure times studied, no significant effects on growth, measured as weight loss, or on the enzyme biomarkers (cholinesterase, carboxylesterase and glutathione S-transferase) were observed. Similarly, no behavioral changes were detected in earthworms, and the survival rate was 100%. Likewise, no differences were observed between the different formulations of the polyester resins studied. However, this study could serve as a starting point for further studies with higher concentrations and/or exposure times, as well as in combination with other pollutants. Full article