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Biological & Pharmaceutical Bulletin 2024Ensitrelvir is a noncovalent inhibitor of the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2. Acquisition of drug resistance in virus-derived...
Ensitrelvir is a noncovalent inhibitor of the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2. Acquisition of drug resistance in virus-derived proteins is a serious therapeutic concern, and drug resistance occurs due to amino acid mutations. In this study, we computationally constructed 24 mutants, in which one residue around the active site was replaced with alanine and performed molecular dynamics simulations to the complex of Mpro and ensitrelvir to predict the residues involved in drug resistance. We evaluated the changes in the entire protein structure and ligand configuration in each of these mutants and estimated which residues were involved in ensitrelvir recognition. This method is called a virtual alanine scan. In nine mutants (S1A, T26A, H41A, M49A, L141A, H163A, E166A, V186A, and R188A), although the entire protein structure and catalytic dyad (cysteine (Cys)145 and histidine (His)41) were not significantly moved, the ensitrelvir configuration changed. Thus, it is considered that these mutants did not recognize ensitrelvir while maintaining Mpro enzymatic activities, and Ser1, Thr26, His41, Met49, Leu141, His163, Glu166, Val186, and Arg188 may be related to ensitrelvir resistance. The ligand shift noted in M49A was similar to that observed in M49I, which has been shown to be experimentally ensitrelvir resistant. These findings suggest that our research approach can predict mutations that incite drug resistance.
Topics: Coronavirus 3C Proteases; Catalytic Domain; Molecular Dynamics Simulation; SARS-CoV-2; Alanine; Drug Resistance, Viral; Humans; Mutation; COVID-19 Drug Treatment; Protease Inhibitors; Indazoles; Triazines; Triazoles
PubMed: 38763751
DOI: 10.1248/bpb.b24-00031 -
Scientific Reports May 2024Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world...
Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.
Topics: Humans; Male; Female; United States; Middle Aged; Aged; United States Food and Drug Administration; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Benzamides; Adult; Triazines; Carcinoma, Non-Small-Cell Lung; Aged, 80 and over; Young Adult; Lung Neoplasms; Adolescent; Imidazoles
PubMed: 38762672
DOI: 10.1038/s41598-024-62356-w -
RSC Advances May 2024A synthetic approach to ten metabolites of iodosulfuron-methyl sodium and metsulfuron-methyl was performed and reported in this study. The compounds of interest were...
A synthetic approach to ten metabolites of iodosulfuron-methyl sodium and metsulfuron-methyl was performed and reported in this study. The compounds of interest were prepared by controlled hydrolytic degradation of active substances or by synthesis from commercially available triazine precursor 10. Obtained compounds were characterized by IR, NMR, and elemental analysis techniques. Metabolites and active substances were utilized during the development of a separation and quantification method using reversed-phase high-performance liquid chromatography coupled with tandem mass spectrometry. The validated method was applied for the analysis of all studied compounds in the extracts from water samples collected from the Vistula river (Toruń, Poland).
PubMed: 38756849
DOI: 10.1039/d4ra01725k -
Journal of Dairy Science May 2024Excessive concentrations of free fatty acids (FFA) are the main factors causing immune dysfunction and inflammation in dairy cows with ketosis. Polarization of...
Fatty acids promote M1 polarization of monocyte-derived macrophages in healthy or ketotic dairy cows and a bovine macrophage cell line via impairing mTOR-mediated autophagy.
Excessive concentrations of free fatty acids (FFA) are the main factors causing immune dysfunction and inflammation in dairy cows with ketosis. Polarization of macrophages (the process of macrophages freely switching from one phenotype to another) into M1 or M2 phenotypes is an important event during inflammation induced by environmental stimuli. In non-ruminants, mammalian target of rapamycin (mTOR)-mediated autophagy (a major waste degradation process) regulates macrophage polarization. Thus, the objective was to unravel the role of mTOR-mediated autophagy on macrophage polarization in ketotic dairy cows. Four experiments were performed as follows: (1) In vitro differentiated monocyte-derived macrophages from healthy dairy cows or dairy cows with clinical ketosis (CK) were treated with 100 ng/mL lipopolysaccharide (LPS) and 100 ng/mL interferon-γ (IFN-γ) or 10 ng/mL interleukin-4 (IL4) and 10 ng/mL interleukin-10 (IL10) for 24 h; (2) Immortalized bovine macrophages were treated with 0, 0.3, 0.6, 1.2 mM FFA and LPS and IFN-γ or IL4 and IL10 for 24 h; (3) Macrophages were pretreated with 2 μM 4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine (MHY1485) for 30 min before treatment with LPS and IFN-γ or IL4 and IL10; (4) Macrophages were pretreated with 100 nM rapamycin (RAPA) for 2 h before treatment with LPS and IFN-γ or IL4 and IL10. Compared with healthy cows, cows with CK had a greater mean fluorescence intensity (MFI) of CD86, but lower MFI of CD206 and lower number of autophagosomes and autolysosomes in macrophages. Exogenous FFA treatment upregulated protein abundance of inducible nitric oxide synthase (iNOS) and mean fluorescence intensity of CD86, whereas it downregulated the protein abundance of arginase 1 (ARG1) and mean fluorescence intensity of CD206. In addition, FFA increased the p-p65/p65 protein abundance and tumor necrosis factor α (TNFA), interleukin-1B (IL1B), and interleukin-6 (IL6) mRNA abundance, but decreased LC3-phosphatidylethanolamine conjugate (LC3-II) protein abundance and autophagosomes and autolysosomes number. Pretreatment with MHY1485 promoted macrophage M1 polarization and inhibited macrophage M2 polarization via decreased mTOR-mediated autophagy. Activation of mTOR-mediated autophagy by pretreatment with RAPA attenuated the upregulation of inflammation in M1 macrophages that was induced by FFA. These data revealed that high concentrations of FFA promote macrophage M1 polarization in ketotic dairy cows via impairing mTOR-mediated autophagy.
PubMed: 38754818
DOI: 10.3168/jds.2023-24357 -
BMC Cancer May 2024This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment...
OBJECTIVE
This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment and prediction for stage IVA NPC. Furthermore, it endeavors to pinpoint specific subgroups that may derive significant benefits from S-1 adjuvant chemotherapy.
METHODS
A total of 834 patients diagnosed with stage IVA NPC were enrolled in this study and randomly allocated into training and validation cohorts. Multivariate Cox analyses were conducted to identify independent prognostic factors for constructing the nomogram. The predictive and clinical utility of the nomogram was assessed through measures including the AUC, calibration curve, DCA, and C-indexes. IPTW was employed to balance baseline characteristics across the population. Kaplan-Meier analysis and log-rank tests were utilized to evaluate the prognostic value.
RESULTS
In our study, we examined the clinical features of 557 individuals from the training cohort and 277 from the validation cohort. The median follow-up period was 50.1 and 49.7 months, respectively. For the overall cohort, the median follow-up duration was 53.8 months. The training and validation sets showed 3-year OS rates of 87.7% and 82.5%, respectively. Meanwhile, the 3-year DMFS rates were 95.9% and 84.3%, respectively. We created a nomogram that combined PNI, NRI, and EBV DNA, resulting in high prediction accuracy. Risk stratification demonstrated substantial variations in DMFS and OS between the high and low risk groups. Patients in the high-risk group benefited significantly from the IC + CCRT + S-1 treatment. In contrast, IC + CCRT demonstrated non-inferior 3-year DMFS and OS compared to IC + CCRT + S-1 in the low-risk population, indicating the possibility of reducing treatment intensity.
CONCLUSIONS
In conclusion, our nomogram integrating NLR, PNI, and EBV DNA offers precise prognostication for stage IVA NPC. S-1 adjuvant chemotherapy provides notable benefits for high-risk patients, while treatment intensity reduction may be feasible for low-risk individuals.
Topics: Humans; Nomograms; Male; Female; Middle Aged; Nasopharyngeal Carcinoma; Chemotherapy, Adjuvant; Prognosis; Neoplasm Staging; Nasopharyngeal Neoplasms; Inflammation; Adult; Nutrition Assessment; Herpesvirus 4, Human; Tegafur; DNA, Viral; Drug Combinations; Oxonic Acid; Aged; Kaplan-Meier Estimate
PubMed: 38734620
DOI: 10.1186/s12885-024-12330-6 -
International Journal of Molecular... Apr 2024This study presents the initial attempt at introducing a magnetic molecularly imprinted polymer (MIP) designed specifically for lamotrigine with the purpose of...
This study presents the initial attempt at introducing a magnetic molecularly imprinted polymer (MIP) designed specifically for lamotrigine with the purpose of functioning as a drug carrier. First, the composition of the magnetic polymer underwent optimization based on bulk polymer adsorption studies and theoretical analyses. The magnetic MIP was synthesized from itaconic acid and ethylene glycol dimethacrylate exhibiting a drug loading capacity of 3.4 ± 0.9 μg g. Structural characterization was performed using powder X-ray diffraction analysis, vibrating sample magnetometry, and Fourier transform infrared spectroscopy. The resulting MIP demonstrated controlled drug released characteristics without a burst effect in the phospahe buffer saline at pH 5 and 8. These findings hold promise for the potential nasal administration of lamotrigine in future applications.
Topics: Lamotrigine; Drug Carriers; Molecularly Imprinted Polymers; Molecular Imprinting; Spectroscopy, Fourier Transform Infrared; Drug Liberation; X-Ray Diffraction; Adsorption; Hydrogen-Ion Concentration
PubMed: 38731823
DOI: 10.3390/ijms25094605 -
Molecules (Basel, Switzerland) Apr 2024The recovery of Au(III) from solution using adsorbents in the form of granules or powders is challenging due to issues such as instability during the recovery process or...
The recovery of Au(III) from solution using adsorbents in the form of granules or powders is challenging due to issues such as instability during the recovery process or mass loss caused by small particle size. This study introduces a PEI-TCT/PVDF composite membrane designed to intercept and capture Au(III) in wastewater. Experimental results demonstrated that the PEI-TCT/PVDF membrane exhibits a broad pH range (1-8) and a high retention efficiency for Au(III) of 97.8%, with a maximum adsorption capacity of 294.5 mg/g. The mechanism of Au(III) adsorption on the PEI-TCT/PVDF membrane was mainly through electrostatic adsorption, which caused AuCl to aggregate on the surface of the membrane and gradually reduced to Au and Au. Furthermore, the membrane can be entirely regenerated within 20 min and maintains its performance in subsequent adsorption cycles. This study highlights the potential of PEI-TCT/PVDF membranes for the recovery of precious Au(III).
PubMed: 38731541
DOI: 10.3390/molecules29092051 -
Molecules (Basel, Switzerland) Apr 2024Organic room temperature phosphorescent (ORTP) materials with stimuli-responsive, multicomponent emissive behaviour are extremely desirable for various applications. The...
3-Ethynyltriimidazo[1,2-:1',2'-:1″,2″-][1,3,5]triazine Dual Short- and Long-Lived Emissions with Crystallization-Enhanced Feature: Role of Hydrogen Bonds and π-π Interactions.
Organic room temperature phosphorescent (ORTP) materials with stimuli-responsive, multicomponent emissive behaviour are extremely desirable for various applications. The derivative of cyclic triimidazole () functionalized with an ethynyl group, , is isolated and investigated. The compound possesses crystallization-enhanced emission (CEE) comprising dual fluorescence and dual phosphorescence of both molecular and supramolecular origin with aggregation-induced components highly sensitive to grinding. The mechanisms involved in the emissions have been disclosed thanks to combined structural, spectroscopic and computational investigations. In particular, strong CH⋯N hydrogen bonds are deemed responsible, for the first time in the family, together with frequently observed π⋯π stacking interactions, for the aggregated fluorescence and phosphorescence.
PubMed: 38731457
DOI: 10.3390/molecules29091967 -
Nanomaterials (Basel, Switzerland) Apr 2024The catalytic oxidation of alcohols is an important transformation in the chemical industry. Carbon materials with a large surface area and N doping show great promise...
The catalytic oxidation of alcohols is an important transformation in the chemical industry. Carbon materials with a large surface area and N doping show great promise as metal-free catalysts for the reaction. In this study, a rich N-containing covalent triazine framework polymerized by cyanuric chloride and p-phenylenediamine was used to synthesize N-doped porous carbon with the assistance of a pore-forming agent-NaCl. First, the mass ratio of the polymer/NaCl was optimized to 1:9. Then, the influence of the pyrolysis temperatures (700-1000 °C) on the materials was studied in detail. It was found that the carbon materials were gradually exfoliated by molten salt at high temperatures. XRD and Raman characterizations showed them with a certain graphitization. The optimal doped carbon CNN-1-9-900 achieved the highest surface area of 199.03 mg with the largest pore volume of 0.29 cmg. Furthermore, it had a high N content of 9.9 at% with the highest relative proportion of pyridinic/graphitic N. Due to the synergistic effect between the surface area and pyridinic/graphitic N, CNN-1-9-900 showed the best performance for benzyl alcohol oxidation with TBHP at moderate conditions, and the process also worked for its derivatives.
PubMed: 38727338
DOI: 10.3390/nano14090744 -
BMC Infectious Diseases May 2024Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This...
BACKGROUND AND OBJECTIVES
Amidst limited influenza treatment options, evaluating the safety of Oseltamivir and Baloxavir Marboxil is crucial, particularly given their comparable efficacy. This study investigates post-market safety profiles, exploring adverse events (AEs) and their drug associations to provide essential clinical references.
METHODS
A meticulous analysis of FDA Adverse Event Reporting System (FAERS) data spanning the first quarter of 2004 to the fourth quarter of 2022 was conducted. Using data mining techniques like reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Propagation Neural Network, and Multiple Gamma Poisson Shrinkage, AEs related to Oseltamivir and Baloxavir Marboxil were examined. Venn analysis compared and selected specific AEs associated with each drug.
RESULTS
Incorporating 15,104 Oseltamivir cases and 1,594 Baloxavir Marboxil cases, Wain analysis unveiled 21 common AEs across neurological, psychiatric, gastrointestinal, dermatological, respiratory, and infectious domains. Oseltamivir exhibited 221 significantly specific AEs, including appendicolith [ROR (95% CI), 459.53 (340.88 ∼ 619.47)], acne infantile [ROR (95% CI, 368.65 (118.89 ∼ 1143.09)], acute macular neuroretinopathy [ROR (95% CI), 294.92 (97.88 ∼ 888.64)], proctitis [ROR (95% CI), 245.74 (101.47 ∼ 595.31)], and Purpura senile [ROR (95% CI), 154.02 (81.96 ∼ 289.43)]. designated adverse events (DMEs) associated with Oseltamivir included fulminant hepatitis [ROR (95% CI), 12.12 (8.30-17.72), n=27], ventricular fibrillation [ROR (95% CI), 7.68 (6.01-9.83), n=64], toxic epidermal necrolysis [ROR (95% CI), 7.21 (5.74-9.05), n=75]. Baloxavir Marboxil exhibited 34 specific AEs, including Melaena [ROR (95% CI), 21.34 (14.15-32.18), n = 23], cystitis haemorrhagic [ROR (95% CI), 20.22 (7.57-54.00), n = 4], ileus paralytic [ROR (95% CI), 18.57 (5.98-57.71), n = 3], and haemorrhagic diathesis [ROR (95% CI), 16.86 (5.43-52.40)), n = 3]. DMEs associated with Baloxavir Marboxil included rhabdomyolysis [ROR (95% CI), 15.50 (10.53 ∼ 22.80), n = 26].
CONCLUSION
Monitoring fulminant hepatitis during Oseltamivir treatment, especially in patients with liver-related diseases, is crucial. Oseltamivir's potential to induce abnormal behavior, especially in adolescents, necessitates special attention. Baloxavir Marboxil, with lower hepatic toxicity, emerges as a potential alternative for patients with liver diseases. During Baloxavir Marboxil treatment, focused attention on the occurrence of rhabdomyolysis is advised, necessitating timely monitoring of relevant indicators for those with clinical manifestations. The comprehensive data aims to provide valuable insights for clinicians and healthcare practitioners, facilitating an understanding of the safety profiles of these influenza treatments in real-world scenarios.
Topics: Humans; Dibenzothiepins; Triazines; United States; Oseltamivir; Antiviral Agents; United States Food and Drug Administration; Female; Male; Morpholines; Adult; Middle Aged; Pharmacovigilance; Adverse Drug Reaction Reporting Systems; Adolescent; Pyridones; Young Adult; Aged; Influenza, Human; Child; Triazoles; Thiepins; Pyrazines; Pyridines; Child, Preschool; Oxazines
PubMed: 38724914
DOI: 10.1186/s12879-024-09339-4