Search Results (268)

Icariin (ICA) is widely recognized for its health benefits. In this work, we examined the intermolecular interactions between ICA and proteinase K (PK) via multi-spectroscopic techniques and molecular simulations. The experimental findings revealed that ICA quenched the fluorescence emission of PK by forming a noncovalent complex. Both hydrogen bonding and van der Waals interactions are essential for the complex’s formation. Then Förster resonance energy transfer (FRET), competitive experiments, and synchronous fluorescence spectroscopy were adopted to verify the formation of the complex. Molecular docking studies demonstrated that ICA could spontaneously bind to PK by hydrogen bonding and hydrophobic interactions, which is consistent with the spectroscopic results. The PK-ICA complex’s dynamic stability was evaluated using a 50 ns molecular dynamics (MD) simulation. The simulation results revealed no significant structural deformation or positional changes throughout the entire simulation period. The complex appears to be rather stable, as seen by the average root-mean-square deviation (RMSD) fluctuations for the host protein in the PK-ICA complex of 1.08 Å and 3.09 Å. These outcomes of molecular simulations suggest that ICA interacts spontaneously and tightly with PK, consistent with the spectroscopic findings. The approach employed in this research presents a pragmatic and advantageous method for examining protein–ligand interactions, as evidenced by the concordance between empirical and theoretical findings. Full article

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Ochroma lagopus, a fast-growing tropical tree species, faces fertilization challenges due to slope heterogeneity in plantations. This study examined 3-year-old Ochroma lagopus at upper and lower slope positions under five treatments: CK (no fertilizer), F1 (600 g/plant), F2 (800 g/plant), F3 (1000 g/plant), and F4 (1200 g/plant) of secondary macronutrient water-soluble fertilizer. Growth parameters and N-P-K stoichiometry were analyzed. Key results: (1) Height increased continuously with fertilizer dosage at both slopes, while DBH peaked and then declined. (2) At upper slopes (nutrient-poor soil), fertilization elevated leaf P but reduced branch N/K and increased root P/K. At lower slopes (nutrient-rich soil), late-stage leaf N increased significantly, with roots accumulating P/K via a “storage strategy”. Stoichiometric thresholds indicated N-K co-limitation (early-mid stage) shifting to P limitation (late stage) on upper slopes and persistent N-K co-limitation on lower slopes. (3) PCA identified F4 (1200 g/plant) and F1 (600 g/plant) as optimal for upper and lower slopes, respectively. This research provides a theoretical basis for precision fertilization in Ochroma lagopus plantations, emphasizing slope-specific nutrient status and element interactions for dosage optimization. Full article

In order to mitigate the reduction in soybean yield caused by soil salinization, a soybean gene, GmSNF4, which promotes plant tolerance to salt–alkali stress, was identified in this study. The STRING database was used to predict the interaction between GmSNF4 and GmPKS4. The GmPKS4 gene was experimentally shown to be involved in salt–alkali stress tolerance. Firstly, the yeast two-hybrid technique and bimolecular fluorescence complementation (BiFC) technique were used to confirm the interaction between GmSNF4 and GmPKS4: the AMPK-CBM-CBS1 conserved domain was thereby determined to be the region of the GmSNF4 protein involved in the interaction. Secondly, the GmSNF4 gene was induced by salt–alkali stress according to qRT-PCR analysis, and the GmSNF4 protein was localized in the nucleus and cytoplasm. Finally, analysis of GmSNF4’s role in resistance to salt–alkali stress in transgenic soybean plants showed that transgenic lines had better phenotypic, physiological, and stress-related gene expression than non-transgenic soybeans. Thus, GmSNF4 may play a significant role in plant salt–alkali stress tolerance. Full article

Background: “CFTR modulators” (also named “caftor”) have been developed and introduced into clinical practice to improve the functionality of defective CFTR protein. Therapeutic drug monitoring (TDM) is not currently used for CFTR modulators in routine clinical practice and there is still much to learn about the pharmacokinetic/pharmacodynamic (PK/PD) and the safety profiles of these drugs in a real-world setting. Moreover, therapeutic ranges are not yet available for both pediatric and adult cystic fibrosis (CF) patients. Methods: A new and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for contemporary quantification of ivacaftor (IVA), tezacaftor (TEZ) and elexacaftor (ELX) in plasma samples has been developed and validated. The clinical performance of our method has been tested on samples collected during the routine clinical practice from n = 25 pediatric patients (aged between 7 and 17 years) affected by cystic fibrosis. This LC-MS/MS method has been validated according to ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines for the validation of bioanalytical methods. Results: Our method fulfilled ICH guidelines in terms of accuracy, precision, selectivity, specificity and carry-over. Intra- and inter-day accuracy and precision were ≤15%. The 9-day autosampler stability was 90–100% for TEZ and ELX; meanwhile, it fell to 76% for IVA. An injection volume of 1 µL and a wider quantification range (0.1–20 µg/mL) represent a novelty of our method in terms of sensitivity and fields of application. Finally, the evaluation of PK exposure parameters for IVA revealed strong agreement with previously published reports and with results from the summary of product characteristics (SmPCs). Conclusions: This method could be adopted to contemporarily measure ELX/TEZ/IVA plasma levels for both PK studies and monitor therapy compliance, especially in case of poor or partial responses to treatment, or to evaluate drug–drug interactions when multiple concomitant medications are required. Considering also the high cost burden of these medications to the health system, a TDM-based approach could facilitate more cost-effective patient management. Full article

Background/Objective: Cerivastatin (Cer), a cholesterol-lowering statin, was withdrawn from the market due to fatal cases of rhabdomyolysis, particularly when co-administered with gemfibrozil (Gem), a strong CYP2C8 inhibitor. However, the pharmacokinetic (PK) mechanisms underlying these adverse events remain unclear. This study investigates the impact of drug–drug interactions (DDIs) involving Gem and itraconazole (Itr), a potent CYP3A4 inhibitor, on plasma concentrations of Cer and its major metabolites—M23, M1, and cerivastatin lactone (Cer-L)—with a focus on the risk of excessive Cer-L accumulation. Methods: We applied a newly developed Metabolite-Linked Model that simultaneously characterizes parent drug and metabolite kinetics by estimating metabolite formation fractions (f_M) and elimination rate constants (K_eM). The model was calibrated using observed DDI data from Cer + Gem and Cer + Itr scenarios and then used to predict outcomes in an untested Cer + Gem + Itr combination. Results: The model accurately reproduced observed metabolite profiles in single-inhibitor DDIs. Predicted AUCR values for Cer-L were 4.2 (Cer + Gem) and 2.1 (Cer + Itr), with reduced K_eM indicating CYP2C8 and CYP3A4 as primary elimination pathways. In the dual-inhibitor scenario, Cer-L AUCR reached ~70—far exceeding that of the parent drug—suggesting severe clearance impairment and toxic accumulation. Conclusions: Dual inhibition of CYP2C8 and CYP3A4 may cause dangerously elevated Cer-L levels, contributing to Cer-associated rhabdomyolysis. This modeling approach offers a powerful framework for evaluating DDI risks involving active or toxic metabolites, supporting safer drug development and regulatory assessment. Full article

The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular dynamics (MD) simulations to investigate the balance between pharmacodynamic (PD) and pharmacokinetic (PK) properties in Mpro inhibitor design. We developed ML models to classify Mpro inhibitors based on experimental IC₅₀ data, combining molecular descriptors with structural insights from MD simulations. Our Support Vector Machine (SVM) model achieved strong performance (training accuracy = 0.84, ROC AUC = 0.91; test accuracy = 0.79, ROC AUC = 0.86), while our Logistic Regression model (training accuracy = 0.78, ROC AUC = 0.85; test accuracy = 0.76, ROC AUC = 0.83). Notably, PK descriptors often exhibited opposing trends to binding affinity: hydrophilic features enhanced binding affinity but compromised PK properties, whereas hydrogen bonding, hydrophobic, and π–π interactions in Mpro subsites S2 and S3/S4 are fundamental for binding affinity. Our findings highlight the need for a balanced approach in Mpro inhibitor design, strategically targeting these subsites may balance PD and PK properties. For the first time, we demonstrate antagonistic trends between pharmacokinetic (PK) and pharmacodynamic (PD) features through the integrated application of ML/MD. This study provides a computational framework for rational Mpro inhibitors, combining ML and MD to investigate the complex interplay between enzyme inhibition and drug likeness. These insights may guide the hit-to-lead optimization of the novel next-generation Mpro inhibitors of SARS-CoV-2 with preclinical and clinical potential. Full article

Background/Objectives: The need for dual-targeted enzyme inhibitors is critical in addressing complex diseases like Alzheimer’s and glaucoma. Imidazothiadiazole and chalcone moieties are known for diverse bioactivities. This study aimed to develop novel imidazothiadiazole–chalcone hybrids as potential inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase isoforms (hCAs), specifically hCA I and hCA II. Methods: Four hybrid molecules (8a–8d) were synthesized and structurally confirmed via ¹H NMR, ¹³C NMR, FT-IR, MS, and elemental analysis techniques. Their enzyme inhibitory activities were assessed using Ellman’s and Verpoorte’s methods. Molecular docking and 100 ns molecular dynamics (MD) simulations were conducted to examine binding interactions. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted using the pkCSM platform. Results: All compounds showed strong enzyme inhibition: AChE (K_i: 3.86–11.35 nM), BChE (K_i: 1.01–1.78 nM), hCA I (K_i: 45.13–81.24 nM), and hCA II (K_i: 36.08–52.45 nM). Docking analyses confirmed favorable binding, particularly with active-site residues. MD simulations demonstrated stable interactions throughout 100 ns. Compound 8a exhibited the highest cholinesterase inhibition, while compounds 8d and 8c were the most potent against hCA I and hCA II, respectively. The ADMET results showed high absorption and acceptable safety, with mild mutagenicity or cardiotoxicity concerns in select compounds. Conclusions: These findings suggest that imidazothiadiazole–chalcone hybrids are promising multi-target enzyme inhibitors. Their potent activity, structural stability, and pharmacokinetic potential support their further development for therapeutic use in neurodegenerative and ocular diseases. Full article

This study explores the viral dynamics of SARS-CoV-2 infection within host cells by incorporating the pharmacological effects of andrographolide—a bioactive compound extracted from Andrographis paniculata, renowned for its antiviral, anti-inflammatory, and immunomodulatory properties. Through the application of mathematical modeling, the interactions among the virus, host cells, and immune responses are simulated to provide a comprehensive analysis of viral behavior over time. Two distinct models were employed to assess the impact of varying andrographolide dosages on viral load, target cell populations, and immune responses. One model revealed a clear dose–response relationship, whereas the other indicated that additional biological or pharmacological factors may modulate drug efficacy. Both models demonstrated stability, with basic reproductive numbers (R₀) suggesting the potential for viral propagation in the absence of effective therapeutic interventions. This study emphasizes the significance of understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of andrographolide to optimize its therapeutic potential. The findings also underscore the necessity for further investigation into the compound’s absorption, distribution, metabolism, and excretion (ADME) characteristics, as well as its prospective applications in the treatment of not only COVID-19 but also other viral infections. Overall, the results lay a foundational framework for future experimental research and clinical trials aimed at refining andrographolide dosing regimens and improving patient outcomes. Full article

Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. Methods: Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. Results: The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in ${\mathrm{A}\mathrm{U}\mathrm{C}}_{0\to t}$ of dorzagliatin by 41.65% and 20.25%, and in C_max by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. Conclusions: Our findings indicate that the drug–drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation. Full article

Withanolides are a class of naturally occurring C-28 ergostane steroidal lactones with an abundance of biological activities, and their members are promising candidates for antineoplastic drug development. The ADMET properties of withanolides are still largely unknown, and in silico predictions can play a crucial role highlighting these characteristics for drug development, shortening time and resources spent on the development of a drug lead. In this work, ADMET properties of promising antitumoral withanolides were assessed. Each chemical structure was submitted to the prediction tools: SwissADME, pkCSM–pharmacokinetics, admetSAR v2.0, and Molinspiration Cheminformatics. The results indicate a good gastrointestinal absorption rate, inability to cross the blood–brain barrier, CYP3A4 metabolization, without inhibition of other P450 cytochromes, high interaction with nuclear receptors, and a low toxicity. It was also predicted for the inhibition of pharmacokinetics transporters and some ecotoxicity. This demonstrates a viability for oral drug development, with low probabilities of side effects. Full article

The appropriate use of antibiotics is crucial and involves selecting an optimal dosing regimen based on pharmacokinetic (PK) and pharmacodynamic (PD) indicators. Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool that integrates drugs’ physicochemical properties with anatomical and physiological data to predict PK behavior. In pediatric populations, PBPK modeling accounts for developmental changes in organ function, making it particularly useful for optimizing antibiotic dosing across different age groups, from neonates to adolescents. In recent decades, PBPK modeling has been widely applied to predict antibiotic disposition in pediatric patients for various clinical and research purposes. Model-informed precision dosing (MIPD) is an evolving approach that enhances traditional therapeutic drug monitoring by integrating multiple information sources into a mathematical framework. By incorporating PBPK modeling, MIPD could offer a more optimized antibiotic dosing that accounts for PK/PD parameters at the site of infection, improving therapeutic outcomes while minimizing toxicity. This review summarizes currently published pediatric PBPK modeling studies on antibiotics, covering various objectives such as evaluating drug–drug interactions, PK/PD analyses in targeted tissues, predicting PK in specific populations (e.g., maternal/fetal, renal impairment, obesity), and PK predictions for preterm neonates. Based on these reports, the review discusses the implications of PBPK modeling for MIPD in pediatric antibiotic therapy. Full article

Rhodotorula mucilaginosa plays a key role in developing the taste of dry-cured ham, while the mechanism of Rhodotorula mucilaginosa proteases on myofibrillar protein (MP) hydrolysis and the evolution of taste substances has not been studied. The enzymatic characteristics, hydrolysis capacities for MPs, free amino acid contents, metabolite compositions, and taste attributes were investigated during the interactions of MPs and proteases. The proteases of R. mucilaginosa EIODSF019 (RE) and R. mucilaginosa XZY63-3 (RX) showed high hydrolytic activities at the conditions of pH 5.0~7.0 and 30~40 °C. Compared with RX, RE showed a lower Michaelis constant (Km) value and a better affinity for protein substrates. RE showed a higher capability to degrade myosin and actin compared with RX and P. kudriavzevii XS-5 proteases (PK). The microtopography of enzyme-treated MPs in RE presented a smoother surface and lower root mean square roughness than that in RX and PK. The total content of free amino acids significantly increased from 0.34 mg/100 mL of CK to 17.10 mg/100 mL of RE after 4 h of hydrolysis of MPs. Sixty-two metabolites were identified by LC-MS/MS, and γ-glutamyl peptides were the main components of MP hydrolysates. Sensory scores of umami, richness, and aftertaste showed the largest values in RE among these groups. Partial least squares discriminant analysis and correlation network demonstrated that γ-Glu-Lys, γ-Glu-Tyr, γ-Glu-Glu, γ-Glu-His, γ-Glu-Leu, γ-Glu-Cys, γ-Glu-Ala, and γ-Glu-Gln were positively correlated with the improvements of umami, richness, and aftertaste in RE. Full article

The key objectives of contemporary agriculture are restoring biodiversity, preserving ecosystem health, reducing the effects of climate change, and producing safe and healthy foods. Maintaining high soil fertility while reducing greenhouse gas emissions requires a precise assessment of how fertilization and crop rotation affect carbon and nutrient cycles in agroecosystems. Fertilization affects soil conditions, which alters the environment for soil microbial development and influences the number and composition of soil microbial communities, leading to changes in nutrient and carbon cycling. There is a lack of long-term experimental data on the impact of fertilizer treatments on soil CO₂ emissions, soil microbial communities, and their interactions. The novelty of this study is that it identified the fertilization effects on soil carbon sequestration, soil properties, and microbial communities in the context of a long-term fertilizer experiment in Luvic Chernozem. The fertilization treatments that were continuously pplied for 64 years under a four-crop (wheat, barley, corn, and bean) rotation were nitrogen (N), phosphorus (P), potassium (K), NP, NK, PK, NPK, and control. The chemical and microbiological soil properties and soil CO₂ emissions were monitored. The highest organic carbon content was observed under the NPK (1.42%) and NP (1.43%) treatments. N fertilizer application most significantly affected soil properties, including pH, electrical conductivity, and soil organic carbon content, altering the environment for soil microbial development and influencing the number and composition of soil microbial communities. On average, the field-measured soil C-CO₂ emissions were the most intensive under NP (2.76 kg ha⁻¹ h⁻¹), NPK (2.83 kg ha⁻¹ h⁻¹), and PK (2.51 kg ha⁻¹ day⁻¹) treatments. Full article

Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant HCC827. Model-based simulations were performed to predict and assess therapeutic effects across different treatment groups. Results: The PK/PD model confirmed HAD-B1 enhances the potency of AFT by 1.45-fold. Model-based simulations predicted that combination treatment maintains a lower tumor size compared to AFT monotherapy. Conclusions: This study quantitatively demonstrated the synergistic interaction between HAD-B1 and AFT. The developed PK/PD model provides insights into potential dosing strategies to treat NSCLC resistant to EGFR-TKIs. Further clinical trials are warranted to validate these findings and refine dosing strategies to improve therapeutic outcomes. Full article