Search Results (11,824)

Background: The active ingredients of essential plant oils appear as potentially effective antinematodal drugs or substances that can potentiate the action of already-existing anthelmintics. So far, we have verified that, aside from the direct effect on the neuromuscular system of nematodes, some of them can potentiate the effects of drugs that are agonists or antagonists of nematode cholinergic receptors. Methods: In this study, the antinematodal effects of geraniol and carvacrol were compared, as well as their interaction in the experimental model Caenorhabditis elegans, on the contractile properties of Ascaris suum neuromuscular preparations and on the ACR-16 nicotinic acetylcholine receptor (nAChR) of A. suum expressed in Xenopus leavis oocytes. Results: The combination of geraniol and carvacrol showed a synergistic nematocidal effect in the tests on C. elegans, reducing the value of individual LC₅₀ by almost 10-times. This combination also exerted a synergistic inhibitory effect on the contractions of A. suum, significantly increased the EC₅₀ of ACh and reduced the maximal contractile effect. The synergistic interaction of these two monoterpenes on Asu-ACR-16 nAChR expressed in Xenopus oocytes resulted in a significant decrease in the maximum current, while the ACh EC₅₀ value remained unchanged. Conclusions: Our findings provide a better understanding of the mode of action of monoterpene plant compounds. The possible antiparasitic application of active ingredients of essential plant oils that exhibit a synergistic anthelmintic effect represents an important basis for the development of new drugs and new therapeutic procedures. Full article

This study systematically explored the interaction mechanisms between two KRAS G12C inhibitors (Sotorasib and Adagrasib) and human serum albumin (HSA) via UV-vis spectroscopy, fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, and molecular docking methods. The experimental findings demonstrated that both drugs caused static quenching of HSA fluorescence, with binding constants of 13.64 × 10³ M⁻¹ (Sotorasib) and 63.67 × 10³ M⁻¹ (Adagrasib), demonstrating significant selectivity differences in their binding affinities. UV spectral analysis demonstrated distinct microenvironmental perturbations: Sotorasib and Adagrasib induced a shift (∆λ = 7 nm and ∆λ = 8 nm, respectively) at 211 nm, consistent with altered polarity in HSA’s binding pockets. Fluorescence spectroscopy confirmed a 1:1 binding stoichiometry, with Stern-Volmer analysis validating static quenching as the dominant mechanism. Three-dimensional fluorescence spectra further highlighted Adagrasib’s stronger conformational impact, reducing tyrosine and tryptophan residue fluorescence intensities by 16% (Peak 1) and 10% (Peak 2), respectively, compared to Sotorasib. Molecular docking revealed divergent binding modes: Sotorasib occupied Sudlow Site I via three hydrogen bonds and hydrophobic interactions (∆G = −24.60 kJ·mol⁻¹), whereas Adagrasib bound through one hydrogen bond and hydrophobic forces (∆G = −30.92 kJ·mol⁻¹), with stability differences attributed to structural characteristics. This study uses multispectral technology and molecular docking to reveal the binding mechanism of Sotorasib and Adagrasib with HSA, providing a theoretical basis for designing highly targeted albumin nanocarriers. The strong binding properties of Adagrasib and HSA may reduce the toxicity of free drugs, providing direction for the development of long-acting formulations. Full article

Background/Objective: Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool for predicting pharmacokinetics (PK) to support drug development and precision medicine. However, it has not been established for non-renal clearance pathways in patients with end-stage renal disease (ESRD), a population that bears heavy medication burden and is thereby at high risk for drug–drug–disease interactions (DDDIs). Furthermore, the pronounced inter-individual variability in PK observed in ESRD patients highlights the urgent need for individualized PBPK models. Methods: In this study, we developed a PBPK population model for ESRD patients, incorporating functional changes in key drug-metabolizing enzymes and transporters (DMETs), including CYP3A4, OATP1B1/3, P-gp, and BCRP. The model was initially constructed using the recalibrated demographic and physiological parameters of ESRD patients. Then, we used five well-validated substrates (midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin) and their corresponding PK profiles from ESRD patients taking a microdose cocktail regimen to simultaneously estimate the abundance of all these DMETs. Lastly, machine learning was employed to identify potential factors influencing individual clearance. Results: Our study suggested a significant reduction in hepatic OATP1B1/3 (75%) and intestinal P-gp abundance (34%) in ESRD patients. Ileum BCRP abundance was estimated to increase by 100%, while change in hepatic CYP3A4 abundance is minimal. Notably, simulations of drug combinations revealed potential DDDI risks that were not observed in healthy volunteers. Machine learning further identified Clostridium XVIII and Escherichia genus abundances as significant factors influencing dabigatran clearance. For rosuvastatin, aspartate aminotransferase, total bilirubin, Bacteroides, and Megamonas genus abundances were key influencers. No significant factors were identified for midazolam, pitavastatin, or atorvastatin. Conclusions: Our study proposes a feasible strategy for individualized PK prediction by integrating PBPK modeling with machine learning to support the development and precise use of the aforementioned DMET substrates in ESRD patients. Full article

Therapeutic resistance remains a critical barrier in effective cancer treatment, contributing to disease recurrence, progression, and reduced patient survival. In recent years, natural bioactive compounds have emerged as promising adjuncts in oncology due to their ability to modulate multiple biological processes involved in resistance. This review explores current evidence on the role of natural compounds in influencing cancer cell behavior and their interactions with the tumor microenvironment. By organizing these compounds into chemical families, we provide a structured overview of their potential to enhance the efficacy of standard chemotherapy and reduce resistance-related mechanisms. We also highlight innovative strategies, including combination therapies and advanced drug delivery systems, that aim to improve their clinical applicability. Overall, this work underscores the relevance of integrating natural bioactives into modern cancer therapy and calls for further translational research to bridge preclinical findings with clinical implementation. Full article

This study investigates the use of food supplements (FS) among polymedicated elderly individuals and assesses potential FS–drug interaction risks. A total of 98 community-dwelling older adults were surveyed and 18.4% reported FS use. FS were mostly used for musculoskeletal and cognitive support, with 71% having potential metabolic interactions via CYP enzymes or P-glycoprotein. Monthly costs reached €55. The findings reveal a complex interaction landscape and financial burden, underscoring the need for medication reviews and health literacy efforts to ensure safer FS use in older adults. This study aligns with One Health principles by linking clinical, social, and economic aspects of aging. Full article

Background: Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS) are two common autoimmune disorders for which the choice of drug regimen is clinically crucial. However, due to drug-drug interactions and individual differences, the therapeutic process faces greater risks. Methods: In this study, we propose a drug recommendation model that combines drug combination frequency, risk assessment, and genetic interaction information with the aim of providing personalized, low-risk treatment options for patients with lupus erythematosus and antiphospholipid syndrome. We extracted drug combination frequencies and drug-gene interaction information from data sources, such as the MIMIC-III clinical database, Drug Bank, and Gene Expression Omnibus. The model comprehensively evaluates the frequency of drug combinations, the risk level, and the gene interaction information through a greedy algorithm to recommend the optimal drug alternatives. Results: The experimental results show that the model is able to effectively reduce the potential risk between drugs while ensuring the drug treatment effect. In addition, the performance evaluation of the drug recommendation model shows that the model performs well under different drug combinations and clinical scenarios, and can provide clinicians with effective drug substitution suggestions. Conclusions: This study provides an important theoretical basis and technical support for advancing the realization of personalized therapy and precision medicine. Full article

Polymers and polymer composites offer versatile possibilities for engineering the physico-chemical properties of materials on micro- and macroscopic scales. This review provides an overview of polymeric and polymer-decorated particles that can serve as drug-delivery vectors: linear polymers, star polymers, diblock-copolymer micelles, polymer-grafted nanoparticles, polymersomes, stealth liposomes, microgels, and biomolecular condensates. The physico-chemical interactions between the delivery vectors and biological cells range from chemical interactions on the molecular scale to deformation energies on the particle scale. The focus of this review is on the structure and elastic properties of these particles, as well as their circulation in blood and cellular uptake. Furthermore, the effects of polymer decoration in vivo (e.g., of glycosylated plasma membranes, cortical cytoskeletal networks, and naturally occurring condensates) on drug delivery are discussed. Full article

Cucurbitacin B (CuB), a tetracyclic triterpenoid compound isolated from Cucurbitaceae plants, exhibits inhibitory effects on various tumor cells (e.g., liver, gastric, and colorectal cancer cells). Since the 1970s–1980s, cucurbitacin tablets containing CuB have been used as an adjuvant therapy for chronic hepatitis and primary liver cancer. CuB exerts anticancer effects through multiple mechanisms: inducing apoptosis, cell cycle arrest (G2/M or S phase), autophagy, and cytoskeleton disruption; inhibiting migration, invasion, and angiogenesis (via VEGF/FAK/MMP-9 and Wnt/β-catenin pathways); regulating metabolic reprogramming and immune responses; inducing pyroptosis, ferroptosis, and epigenetic changes; and reversing tumor drug resistance. These effects are associated with signaling pathways like JAK/STAT, PI3K/Akt/mTOR, and FOXM1-KIF20A. To improve its application potential, strategies such as structural modification (e.g., NO donor conjugation), combination therapy (with gemcitabine or cisplatin), and nanomaterial-based delivery (e.g., liposomes and exosome-mimicking nanoparticles) have been developed to enhance efficacy, reduce toxicity, and improve bioavailability. CuB shows broad-spectrum anticancer activity, but further research is needed to clarify the mechanisms underlying its cell-specific sensitivity and interactions with the immune system. This review systematically summarizes the physicochemical properties, anticancer mechanisms, and strategies for applying CuB and suggests future research directions, providing references for scientific research and clinical translation. Full article

Since the start of the COVID-19 pandemic, increasing evidence has shown that SARS-CoV-2 infection can cause long-term symptoms, collectively known as long COVID, and that patients with mild COVID-19 can also be affected by persistent fatigue, cognitive impairment, dyspnea, muscle pain, etc. Recent research has also found multiple organ systems, including the liver, to be significant sites of ongoing injury. This narrative review summarizes current knowledge on organ involvement during and after COVID-19, with particular focus on early and delayed hepatic manifestations and associated risk factors. Pathogenesis appears to be multifactorial, involving direct virus action, the body’s immune-mediated inflammatory response, microvascular damage, drug-induced hepatotoxicity, and, in some cases, reactivation or exacerbation of pre-existing liver conditions. The hepatic clinical manifestations range from asymptomatic elevations of transaminases to cholangiopathy and even fibrosis. These can persist or progress for months after the initial infection with SARS-CoV-2 is resolved, requiring prolonged monitoring and interdisciplinary care, especially in the presence of metabolic disorders, obesity, or hepatitis. Neurological, cardiovascular, and other sequelae are discussed in parallel, with attention paid to common inflammatory and thrombotic pathways. This review concludes that liver dysfunction is of particular interest in long-COVID due to the liver’s central role in metabolism and inflammation. While further research is being conducted into organ-specific and systemic interactions, the available evidence makes a compelling case for extended monitoring and integrated management strategies post infection. Full article

Despite the widespread use of vaccines against SARS-CoV-2, COVID-19 continues to pose global health challenges, requiring efficient drug screening and repurposing strategies. This study presents a novel hybrid framework that integrates deep learning (DL) with molecular docking to accelerate the identification of potential therapeutics. The framework comprises three crucial steps: (1) a previously developed DL model is employed to rapidly screen candidate compounds, selecting those with predicted interaction scores above a cut-off value of 0.8; (2) AutoDock Vina version 1.5.6 and LeDock version 1.0 are used to evaluate binding affinities, with a threshold of <−7.0 kcal·mol⁻¹; and (3) predicted drug–protein binding sites are evaluated to determine their overlap with known active residues of the target protein. We first validated the framework using four experimentally confirmed COVID-19 drug–target pairs and then applied it to identify potential inhibitors of the SARS-CoV-2 main protease (M^Pro). Among 29 drug candidates selected based on antiviral, anti-inflammatory, or anti-cancer properties, only Enasidenib met all three selection criteria, showing promise as an M^Pro inhibitor. However, further experimental and clinical studies are required to confirm its efficacy against SARS-CoV-2. This work provides an interpretable strategy for virtual screening and drug repurposing, which can be readily adapted to other DL models and docking tools. Full article

Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath tumors that are rarely curable. There are two recently FDA-approved drugs, selumetinib and mirdametinib, for pNF1 patients who have symptomatic and inoperable plexiform neurofibromas; however, these treatments achieve only approximately 30% tumor shrinkage. Fibroblasts, the most abundant cell types within the pNF1 tumor microenvironment, are implicated in pNF1 growth and invasion; however, how fibroblasts affect a drug response of pNF1 remains poorly understood. In the present study, we focused on contributions of fibroblasts to the drug resistance in pNF1 via their secretome. We employed our established three-dimensional (3D) culture system incorporating human pNF1 tumor cells (Nf1^−/−) and primary fibroblasts (Nf1^+/−) grown in our patented microfluidic culture chips for monocultures and parallel cocultures in which 3D pNF1 structures and fibroblasts share their secretome without direct cell-to-cell contact. Three-dimensional pNF1 structures in 3D parallel cocultures with fibroblasts exhibited greater drug resistance than ones in monocultures. We found that pNF1 tumor cells showed increased P-glycoprotein expression when incubated with fibroblast-derived conditioned media or parallel cocultured with fibroblasts, compared to control conditions. Pharmacological inhibition of P-glycoprotein partially restored drug sensitivity. Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes. Full article

The escalating crisis of multidrug resistance, together with the persistence of antibiotic residues in clinical and environmental matrices, demands integrated strategies that couple sensitive detection, efficient decontamination, and controlled delivery. However, current techniques for quantifying avibactam (AVI)—a broad-spectrum β-lactamase inhibitor—such as HPLC-UV lack the sensitivity and specificity required for both therapeutic drug monitoring and environmental surveillance. Encapsulation of AVI within cyclodextrins (CDs) may simultaneously enhance its stability, bioavailability, and detectability, while the high binding affinities of CDs position them as molecular traps capable of scavenging residual AVI. In this study, the inclusion complexation of AVI with various CDs was examined through molecular dynamics (MD) simulations, experimental isothermal titration calorimetry (ITC), and non-covalent interaction (NCI) analysis. Stable 1:1 inclusion complexes were observed between AVI and β-cyclodextrin (β-CD), 2,6-dimethyl-β-cyclodextrin (DM-β-CD), and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), with standard Gibbs free energies of binding (ΔG°) of –3.64, –3.24, and –3.11 kcal/mol, respectively. In contrast, γ-cyclodextrin (γ-CD) exhibited significantly weaker binding (ΔG° = –2.25 kcal/mol). DFT-based NCI analysis revealed that cooperative interaction topology and cavity complementarity, rather than the sheer number of localized contacts, govern complex stability. Combined computational and experimental data establish β-CD derivatives as effective supramolecular hosts for AVI, despite an entropic penalty in the DM-β-CD/AVI complex. These CD–AVI affinities support the development of improved analytical methodologies and pharmaceutical formulations, and they also open avenues for decontamination strategies based on molecular trapping of AVI. Full article

Proteolysis-targeting chimera (PROTAC) technology has demonstrated remarkable progress in tumor therapy, attributed to its unique capability of catalytically degrading “undruggable” targets. In the context of the ongoing global health threat posed by the Coronavirus Disease 2019 (COVID-19) pandemic, the application scope of PROTAC technology has been gradually extended to the field of antiviral research. Unlike traditional small molecule inhibitors, PROTAC employs an “event-driven” mechanism to achieve ubiquitination-mediated degradation of target proteins. This approach holds great promise in addressing challenges such as drug resistance, targeting host-dependent factors, and high-mutagenic viral proteins. This article provides a comprehensive review of the application progress of PROTAC technology in antiviral therapy, with a particular emphasis on successful cases across a range of viral pathogens, including Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), influenza virus, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Additionally, it delves into the challenges encountered in this field and ponders future development directions. Through the integration of the latest research findings, this article proposes a dual-target degradation strategy based on the host–pathogen interaction interface. These proposals aim to offer theoretical support for the clinical translation of antiviral PROTACs. Full article

This study explores the clinical, behavioural, and environmental risks of chronic proton pump inhibitor (PPI) use in older adults through a One Health perspective. Among 246 participants, 32.5% were receiving PPI therapy, with 91.3% on long-term treatment, frequently lacking clear clinical justification. Polypharmacy, drug interactions, and risky lifestyle behaviours were common. Environmental review highlighted the potential persistence of PPI transformation products in water systems, raising concerns about ecological impact and antimicrobial resistance. These findings underscore the urgency of implementing deprescribing strategies, enhancing patient education, and adopting sustainable prescribing practices that align human and environmental health. Full article

Cellular senescence is a fundamental contributor to numerous dysfunctions and degenerative diseases, including osteoporosis. In genetically modified and preclinical animal models, therapeutic strategies targeting persistent senescent cells have been shown to delay and prevent osteoporosis. Senolytics are a class of drugs or compounds designed to selectively eliminate senescent cells without adversely affecting normal cells. In this review, we focus on the role of senolytic agents in regulating bone metabolism and their potential in the treatment of osteoporosis. We discussed major types of senolytics, such as natural compounds, kinase inhibitors, Bcl-2 family inhibitors, inhibitors of the mouse double minute 2/p53 interaction, heat shock protein 90 inhibitors, p53-binding inhibitors, and histone deacetylase inhibitors. This review also highlights the progress of senolytics in clinical trials. However, clinical results diverge from preclinical evidence. Therefore, senolytics should be critically evaluated as a potential therapeutic strategy for osteoporosis, with further validation required. Full article