Search Results (8,021)

Background/Objectives: This study aimed to explore potential associations between gut microbiota and the in vivo tissue exposure profiles of bioactive constituents derived from Gastrodia elata in spontaneously hypertensive rats (SHRs). Methods: Fecal microbiota transplantation (FMT), high-performance liquid chromatography (HPLC) tissue quantification, and 16S rRNA gene sequencing were applied in the present work. Results: Distinct tissue exposure patterns of Gastrodia elata-derived gastrodin (GAS) and gastrodigenin (HBA) were observed following gut microbiota remodeling. Noticeable shifts in the relative abundance of specific intestinal bacterial taxa were detected between hypertensive SHRs and normotensive Wistar rats, and these taxonomic alterations showed correlation with tissue levels of the target herbal components. Conclusions: It should be noted that the FMT experimental design in this study cannot fully decouple microbiota-related effects from drug treatment confounders; hence, our findings represent preliminary correlative observations rather than definitive causal evidence. This work provides experimental clues for understanding host–microbe–herb interplay under hypertensive conditions and may offer reference information for optimizing administration strategies of natural hypotensive compounds. Full article

Background/Objectives: Traditional machine learning metrics often fail to capture the clinical consequences of classification errors, particularly in high-stakes screening applications. When applying task-specific AI tools to human lives, clinicians cannot rely on simple, headline metrics and marketing materials. Impressive accuracy figures can hide dangerous algorithmic shortcuts that collapse when encountering actual patients. This study addresses the gap between statistical performance and clinical utility by evaluating classifiers for prescription opioid misuse using a clinically oriented framework. Methods: Three ensemble models, namely, Cost-Sensitive Bagged Trees (CSBT-Untuned and CSBT-Tuned) and Random Undersampling Boosting (RUSBoost), were trained on National Survey on Drug Use and Health data and assessed using composite metrics integrating clinical priorities and asymmetric error costs. Results: The results demonstrate that while CSBT-Untuned achieved the highest raw accuracy of 86.7%, it missed 61.5% of positive cases. Conversely, the threshold-optimized CSBT-Tuned model achieved enhanced minority class detection and numerically higher Clinical Discriminative Performance Scores under sensitivity-priority scenarios, though its performance remained statistically comparable to RUSBoost given overlapping confidence intervals. Learning curve analysis confirmed stable convergence for the cost-sensitive bagging approach. Conclusions: Before accepting AI tools in patient care, physicians must demand an evaluation report similarly detailed to this manuscript, utilizing this framework as guidance for what an evidence report should demonstrate prior to clinical deployment. Full article

Ulcerative colitis remains a major clinical challenge due to limited availability of safe, orally active anti-inflammatory drugs. Although phase II metabolism is traditionally viewed as a detoxification process, certain metabolites retain or exhibit enhanced pharmacological activity, offering an underexplored drug discovery opportunity. Here, we investigated phase II metabolite-inspired tripeptide editing using M13, a glutathione-conjugated metabolite of the anti-inflammatory natural product 6-shogaol, as a lead scaffold. A focused library of 38 analogs was generated by systematic tripeptide editing while preserving the central cysteine-containing 6-shogaol-derived scaffold. Phenotypic nuclear factor-κB (NF-κB) reporter screening identified 29 of 38 analogs with greater inhibitory activity than M13 at the screening concentration. Two selected leads, MLY2 and MLY8, demonstrated enhanced anti-inflammatory activity in Dextran Sulfate Sodium-induced experimental colitis, including restoration of colon length and reductions in fecal lipocalin-2 and pro-inflammatory cytokines. Both compounds also suppressed inflammatory cytokine production more effectively than M13 in ex vivo colonic biopsies from patients with treatment-refractory ulcerative colitis. In parallel, MLY2 and MLY8 showed no detectable mutagenicity under the Ames assay conditions and were well tolerated in a preliminary single-dose maximum tolerated dose study. Collectively, these findings establish phase II metabolite-inspired tripeptide editing as a productive lead-discovery strategy and identify MLY2 and MLY8 as anti-inflammatory leads warranting further preclinical characterization. Full article

Honduras is progressing toward malaria elimination as part of the Mesoamerican goal for 2030. As transmission declines, malaria increasingly occurs in focal outbreaks, particularly in geographically confined settings such as islands. Following an increase in cases beginning in 2024, the Bay Islands Department experienced continued outbreak transmission during 2025. This study characterized the genetic diversity and multilocus haplotype patterns of Plasmodium falciparum and P. vivax lineages circulating during this outbreak. Cases were confirmed by photo-induced electron transfer PCR (PET-PCR). Genetic diversity was assessed by Sanger sequencing of pfmsp1 for P. falciparum, and pvcsp and pvmsp3α for P. vivax; pfmdr1 was analysed separately as a drug-resistance marker. Diversity indices and multilocus profiles were analysed using DnaSP. Forty-nine samples were analysed: 18 P. falciparum and 31 P. vivax infections from three municipalities. All P. falciparum isolates carried a single pfmsp1 haplotype of the K1 allelic family. In P. vivax, two concordant multilocus haplotypes were detected: A/A predominated, whereas B/B was observed in five samples, mainly early in the outbreak. The outbreak showed marked P. falciparum homogeneity and restricted P. vivax multilocus diversity, consistent with focal amplification of limited parasite lineages. However, multiple introductions of genetically similar parasites cannot be excluded. Full article

Background: Osteoarthritis (OA) is a prevalent degenerative joint disease lacking effective disease-modifying therapies, which necessitates the discovery of key genes for mechanistic exploration and therapeutic development. Methods: We integrated three large-scale cis-protein quantitative trait locus datasets and two OA genome-wide association study summary statistics to screen candidate proteins by two-stage proteome-wide Mendelian randomization (MR). Causal association reliability was validated via summary-data-based Mendelian randomization (SMR) and Bayesian colocalization analyses. A phenome-wide association study (PheWAS) was performed to evaluate potential pleiotropic effects of the candidates. Subsequently, transcriptomic and single-cell RNA sequencing datasets were employed to evaluate the candidate genes’ expression stability, classification efficacy in the in vitro models of OA, cell-specific enrichment, and pseudotime expression dynamics in cartilage. Finally, drug repurposing potential was explored by integrating drug–gene interaction database searches and molecular docking. Results: Two-stage cis-pQTL MR combined with cis-eQTL-based SMR analysis identified 14 plasma proteins with consistent effects at the protein and transcript levels. RNA-seq revealed that adrenomedullin (ADM) and complement factor H (CFH) were upregulated in two in vitro models of OA, and both genes exhibited favorable classification efficacy in these models. Bayesian colocalization analysis provided evidence of shared causal variants for ADM, and PheWAS did not detect significant pleiotropic associations for ADM or CFH across the tested phenotypes. Single-cell analysis indicated that ADM was enriched in pre-fibrocartilage chondrocytes with biphasic pseudotime expression, whereas CFH was widely expressed across chondrocyte subsets. Database screening identified 15 potential drugs for ADM and 6 for CFH. Conclusions: Combining MR, multi-omics and pharmacological evidence, we prioritized ADM and CFH as OA candidate genes. Full article

Metal–organic frameworks (MOFs) possess remarkable physicochemical properties, making them highly attractive candidates for advanced drug delivery, catalysis, water purification, gas separation, and biomedical application. Thus, it is important to understand its toxic effect on the environment and human health prior to wide practical application. In this study, UiO-66 nanoparticles (Zr₆O₄(OH)₄—octahedral clusters with benzene-1,4-dicarboxylate linkers) were synthesized and characterized by XRD, SEM, and TEM techniques. The genotoxicity and accumulation of UiO-66 were investigated towards freshwater fish, Nothobranchius rachovii, for the first time. To gain a better understanding of the effects of UiO-66 nanoparticles towards N. rachovii, fish were exposed to UiO-66, the linker, and zirconium salts. The genotoxic risk caused by UiO-66 was detected by analyzing the Chromosome Aberrations (CAs), frequencies of Sister Chromatid Exchanges (SCEs), mitotic index, and accumulations of Zr in tissues of fish treated with UiO-66 samples, linker, zirconium salt, and non-exposed control subjects. Full article

Municipal wastewater catchments are significant sources of symbiotic, opportunistic, and drug-resistant bacteria that can acquire or enhance their resistance. This “re-emergence of threats” presents a serious public health issue, especially during crisis conditions (COVID-19). The aim of this study was to propose a sampling algorithm, identify strategically important sites within the wastewater catchment, expand the range of bacterial indicators, and rapidly confirm potential threats using in vitro diagnostics in both raw and treated sewage. A parallel objective was to evaluate the effectiveness of sequencing methods in pre-epidemic studies. The research was conducted as part of a long-term surveillance program at transportation hubs, healthcare facilities, residential complexes, and wastewater treatment plants in Warsaw, Poland. Total nucleic acid (TNA) was isolated from samples, amplified using qPCR kits, and selected samples underwent next-generation sequencing. In raw sewage, the most frequently detected regions included sequences complementary to the bacterial vanB gene, the Integron Verona-encoded metallo-β-lactamase (VIM) gene, and markers for Mycobacterium tuberculosis. Treated environmental effluents primarily contained DNA fragments complementary to the bacterial vanB sequence, along with genes related to resistance against oxacillin and imipenem, as well as the VIM gene and Legionella sp. 16S rRNA sequencing of the sewage samples revealed the presence of 12 promising bacterial indicators relevant to public health and environmental hygiene. The proposed algorithm aligns with the provisions of EU Directive 2024/3019 and in vitro diagnostic tests demonstrated the potential and utility of rapid screening analyses of wastewater during disruptions or crises, as well as in situations involving equipment shortages and logistical challenges in healthcare. The proposed expanded range of bioindicators could expedite decision-making regarding preventive measures and medical support for various counties, hospitals, and transportation hubs in large urban areas. The sequencing results further emphasized the need to broaden the scope of the bacterial indicators for environmental surveillance. Full article

Aging and cancer form a biological continuum influenced by epigenomic changes, metabolic dysfunction, inflammation, cellular senescence, and loss of tissue homeostasis. Age-related epigenetic alterations can promote cancer, which exploits plasticity for evolution, immune evasion, metastasis, and resistance. Nutrition and metabolism affect this process through one-carbon metabolism, methyl-donor availability, acetyl-CoA and NAD⁺ balance, redox status, microbiome metabolites, and chromatin enzyme activity. Circulating biomarkers such as cell-free DNA methylation, mutation-based ctDNA, fragmentomic features, and non-coding RNAs can detect tumor and host changes linked to aging, inflammation, nutrition, and treatment with minimal invasiveness. This review explores the epigenetic aging–cancer link, how nutrition and metabolism modify pathways, and the potential of circulating biomarkers for diagnosis, prognosis, prediction, and monitoring. The focus is on epigenetic plasticity, drug-tolerant states, resistance, epigenetic drugs, metabolic targeting, and nutritional interventions. New technologies, including single-cell and spatial epigenomics, long-read sequencing, and multimodal computational approaches, aid biomarker discovery and clinical use. Challenges include variability, misclassification, heterogeneity, confounding, reverse causality, overfitting, and limited validation. Clinical applications need standard workflows, representative cohorts, transparent models, and proof that biomarker-guided strategies improve outcomes. Full article

Rhythm control therapy has an important role in atrial fibrillation (AF) management, and antiarrhythmic drugs (AADs) remain essential for pharmacological cardioversion, maintenance of sinus rhythm, reduction in AF burden, and treatment before or after catheter ablation. However, their efficacy varies substantially among patients, while proarrhythmia, organ toxicity, drug interactions, and treatment discontinuation frequently limit their use. Current drug selection therefore relies mainly on safety-based exclusion based on structural heart disease, ventricular function, coronary disease, renal or hepatic function, and baseline conduction and repolarization characteristics, rather than on individualized prediction of comparative therapeutic benefit. This narrative review examines the potential role of artificial intelligence (AI), machine learning (ML), computational electrophysiology, and cardiac digital twins across the AAD treatment pathway. Particular attention is given to patient selection, comparative drug choice, prediction of cardioversion success and sinus-rhythm maintenance, dose optimization, proarrhythmia assessment, extracardiac toxicity, and longitudinal safety surveillance. AI can potentially integrate clinical, electrocardiographic (ECG), imaging, wearable, genomic, and pharmacological data to estimate patient-specific efficacy and toxicity. ML models have already demonstrated the feasibility of predicting drug-induced QT prolongation from electronic health records and detecting ECG signatures associated with drug-induced arrhythmic risk. Moreover, patient-specific AF digital twins have been used to simulate electrophysiological responses to amiodarone and identify patients with different subsequent rhythm outcomes. Nevertheless, most available applications remain retrospective, single-center, non-comparative, or proof-of-concept, and few directly support selection among alternative AADs. Most are prognostic, estimate outcomes under observed care, or predict drug-specific toxicity; models that estimate outcomes under alternative AADs remain the essential missing element. AI-supported antiarrhythmic therapy represents a promising transition from population-based prescribing toward individualized estimation of efficacy, toxicity, and monitoring requirements. Its clinical adoption will require multicenter external validation, causal treatment-effect modeling, prospective workflow evaluation, randomized impact trials, transparent uncertainty reporting, and continued clinician oversight. Full article

Magnetoelectric materials couple magnetic and electrical order parameters and can convert remotely applied magnetic fields into localized electrical responses. At the nanoscale, this functionality is commonly pursued through core–shell architectures in which a magnetostrictive or magnetic core is mechanically coupled to a piezoelectric or ferroelectric shell. The resulting strain-mediated transduction is attractive for biomedical and bioelectronic applications because magnetic fields penetrate biological tissue with comparatively low attenuation, whereas the generated electrical signals can interact directly with charged biomolecules, cell membranes, ion channels, and electroactive tissues. This review critically evaluates magnetoelectric core–shell nanoparticles from a broad biomedical and bioelectronic perspective. The physical basis of direct and converse magnetoelectric coupling is first discussed, with emphasis on nanoscale boundary conditions, magnetic-domain state, ferroelectric polarization, interfacial strain transfer, ionic screening, and nonlinear field dependence. Representative magnetic-core/piezoelectric-shell material families, including ferrite-based, multiferroic-oxide, lead-free piezoelectric, PZT-containing, and polymer-integrated architectures, are compared in terms of magnetic response, piezoelectric activity, chemical stability, biocompatibility, toxicity, and processability. Particular attention is given to CoFe₂O₄–BaTiO₃ (CFO-BTO) as a benchmark magnetoelectric core–shell system, while alternative material combinations are comparatively discussed to reflect the broader diversity of the field. Synthesis and processing strategies, structural and physicochemical characterization, surface engineering, and local or macroscopic magnetoelectric measurement methods are examined together with the artifacts that can complicate quantitative interpretation. Particular attention is paid to particle size, shell thickness, crystallinity, aggregation, colloidal stability, surface chemistry, biomolecular functionalization, and their influence on magnetoelectric performance and biological interactions. The available literature demonstrates substantial progress in magnetically triggered drug delivery and cancer therapy, wireless neural and cardiac stimulation, tissue engineering, immunomodulation, wound healing, multimodal imaging, and related bioelectronic applications. Biosensing is also considered an important emerging direction; however, direct quantitative detection of proteins, nucleic acids, pathogens, and cancer biomarkers using isolated core–shell magnetoelectric nanoparticles remains comparatively underdeveloped. The review therefore distinguishes experimentally established biomedical and bioelectronic functionalities from less mature biosensing concepts and identifies the measurement, safety, clinically relevant magnetic-field exposure, scalable manufacturing, device-integration, and regulatory challenges that must be addressed for translation. A practical roadmap is proposed for developing reproducible, lead-free, biologically stable, and quantitatively characterized magnetoelectric nanoparticle platforms for next-generation wireless biomedical and bioelectronic technologies. Full article

With the continuous escalation of antimicrobial resistance, drug repurposing based on approved drugs has emerged as a promising strategy for the development of novel anti-infective agents. This study aimed to evaluate the antibacterial effect of the FDA-approved drug Ponatinib hydrochloride against multidrug-resistant S. aureus. Broth microdilution assay showed that ponatinib hydrochloride exhibited potent activity against Gram-positive bacteria, while the MICs against Gram-negative bacteria were all >100 μM. In addition, the MICs against 15 clinical multidrug-resistant S. aureus isolates ranged from 6.25 to 25 μM. Time-kill assay further revealed a pronounced concentration- and time-dependent bactericidal effect, with bacterial viability reduced to nearly the detection limit within 24 h at 4 × MIC. Anti-biofilm assays showed that ponatinib hydrochloride significantly inhibited S. aureus biofilm formation and disrupted mature biofilms. Moreover, serial passaging for 30 days did not induce an obvious increase in resistance. Mechanistic investigations demonstrated that ponatinib hydrochloride increased membrane permeability, induced intracellular reactive oxygen species (ROS) accumulation, and markedly reduced ATP levels. Finally, in a mouse infection model, ponatinib hydrochloride significantly improved the survival of infected mice, with a survival rate of 70% observed in the 15 mg/kg treatment group, while also reducing bacterial burdens and pro-inflammatory cytokine levels in tissues. Collectively, ponatinib hydrochloride exhibits potent antibacterial activity against multidrug-resistant S. aureus both in vitro and in vivo and represents a promising candidate for anti-MRSA therapy. Full article

Current all-optical chiral sorting approaches are ineffective for nanoscale drug molecules with weak chirality, as their faint optical response cannot maintain the chiral sorting mechanism. To overcome this physical limitation, the theoretical study proposes a core–shell composite chiral sensing microsphere, in which a drug crystal core is encapsulated by a nematic liquid crystal shell, acting as a chirality-amplifying carrier for optofluidic detection. Using a sodium ibuprofen nanocrystal as a representative weakly chiral drug, the optimal core–shell sensing structure was determined to consist of a nematic liquid crystal E7 shell with a radius of 19 μm and a sodium ibuprofen crystal core with a radius of 9.5 μm. This optimized configuration amplifies the molecular chirality parameter from 10⁻⁶ to 6.5 × 10⁻³ and yields the maximum transverse separation velocity of 1.19 μm/s. Hydrodynamic calculations demonstrate that when the optimized composite sensing microsphere accumulates an absolute transverse displacement greater than 19 μm within a microfluidic channel, the maximum longitudinal flow velocity of the system reaches 2.4 μm/s, satisfying the geometric threshold required for continuous sensing and sorting. This study provides a design strategy to advance optofluidic sensing and sorting systems for nanoscale chiral drugs. Full article

Acute myeloid leukemia (AML) is cytogenetically and phenotypically heterogeneous, and this diversity contributes to differences in how patients respond to therapies that target apoptosis. Venetoclax, a selective BCL-2 inhibitor, has been demonstrated to improve outcomes when combined with hypomethylating drugs (HMAs) such as azacitidine or decitabine; nonetheless, clinical trials have indicated that resistance and recurrence are prevalent. This review examines the current evidence linking chromosomal abnormalities and cellular differentiation state to mitochondrial apoptotic pathways, with an emphasis on how these factors influence dependence on certain anti-apoptotic BCL-2 family proteins. We summarize how specific cytogenetic subtypes and high-risk groups (including monosomy 7/del(7q) and complex karyotype/TP53-altered AML) frequently show stress-adaptive signaling and reliance on multiple anti-apoptotic pathways, which can limit the durability of response to BCL-2 inhibition. Lineage-associated dependencies are also examined, such as monocytic differentiation (which leads to increased MCL-1 reliance) and erythroid/megakaryocytic differentiation, which has been associated with increased BCL-XL dependence and venetoclax resistance. Finally, we discuss the therapeutic implications of dependence mapping, including venetoclax combinations and direct MCL-1/BCL-XL targeting, and propose promising biomarker strategies that can detect dependence shifts early and guide appropriate treatment selection. Full article

Liposomal drug-delivery systems can improve the formulation performance of poorly soluble compounds by enhancing aqueous dispersion, protecting encapsulated agents, and modifying release behavior. Co-encapsulation of pharmacologically distinct compounds may provide a formulation strategy for comparing combined delivery with a single agent nanoliposomal system. This study aimed to develop and characterize atorvastatin–rutin co-loaded nanoliposomes and to compare their antioxidant, anti-inflammatory, and SRB-based cytotoxic activity with the corresponding free-drug and single-loaded nanoliposomal formulations. Nanoliposomes were prepared by thin-film hydration and characterized by particle size, polydispersity index, zeta potential, encapsulation efficiency, lyophilization-associated retention of encapsulation efficiency, morphology, and in vitro release. A reverse-phase HPLC method was validated for simultaneous atorvastatin and rutin quantification, and lyophilized formulations were evaluated for retention of encapsulation efficiency. In vitro assays included DPPH radical scavenging, nitrite inhibition in LPS-stimulated RAW 264.7 macrophages, and SRB-based cytotoxicity screening across human cancer cell lines and normal periodontal ligament fibroblasts. The co-loaded nanoliposomes achieved encapsulation efficiencies of 88.46% for atorvastatin and 81.74% for rutin; after lyophilization, encapsulation efficiency decreased to 72.31% for atorvastatin and 76.63% for rutin. The nanoliposomal formulations showed measurable DPPH radical-scavenging activity, nitrite-inhibition activity in LPS-stimulated macrophages, and SRB-based antiproliferative activity in several cancer cell lines, while showing no detectable cytotoxicity toward PDL fibroblasts within the tested concentration range. With exquisite similarity to apoptogenic Anti-VEGF antiangiogenesis chemotherapeutic efficacies ofcisplatin; nanoliposomal atorvastatin and co-loaded atorvastatin with rutin were remarkable comparable (in descending order of human VEGF mitigations) in mammary T47D> uterine cervix HeLa> lung A549 adherent monolayers post 72 h incubations. These findings support further investigation of atorvastatin–rutin co-loaded nanoliposomes as an in vitro formulation platform; however, formal synergy analysis, cellular uptake studies, mechanistic assays, pharmacokinetic evaluation, and in vivo safety testing remain necessary. Further in vivo studies are required to determine pharmacokinetic behavior, tissue distribution, therapeutic relevance, and systemic safety. Full article

Background/Objectives: Oral solid dosage (OSD) forms are historically categorized as low-risk vectors for leachables under the assumption that solid-state matrices impose severe kinetic barriers against migrant migration and reactivity. This study investigates an unexpected unknown impurity, detected as part of a routine ICH Q3B testing program to control drug product impurities in a blister-packed tablet. Since the impurity exceeded the ICH Q3B identification threshold applicable for this drug product (1.0% w/w relative to API or 5 µg total daily intake (TDI), whichever is lower), a forensic investigation into the origins and identity of the impurity was performed. Methods: Placebo and packaging line studies were performed to isolate the origin of the impurity. Systematic structure elucidation was carried out using high-resolution mass spectrometry (HRMS), isotopic fine structure analysis, and de novo chemical synthesis. To enable definitive characterization, preparative HPLC was utilized to isolate the compound for high-field 2D-NMR spectroscopy (801 MHz). Results: The impurity was proven to be independent of active pharmaceutical ingredient degradation, forming only when tablet excipients were stored in sealed PVC blister packaging. Co-incubation of the PVC heat stabilizer derivative dimethyltin bis(2-ethylhexyl mercaptoacetate) (DMTE) with pyrrolidin-2-one (a povidone excipient degradation product) generated an identical chromatographic and MS/MS spectral profile. NMR spectroscopy unambiguously identified the structure as 2-ethylhexyl 2-((5-oxopyrrolidin-2-yl)thio)acetate. Conclusions: This study provides the first direct evidence of an organotin-catalyzed solid-state reaction between a packaging leachable and a tablet excipient under 25 °C/60% RH storage conditions. While this implies that the impurity should not be evaluated under the ICH Q3B guidelines, the findings directly challenge the assumed “low-risk” status of OSD packaging regarding leachables and highlight the necessity for interaction-focused, chemistry-based risk assessments, as outlined in emerging ICH Q3E guidelines. Full article