QM/MM study reveals novel mechanism of KRAS and KRAS catalyzed GTP hydrolysis.

As a crucial drug target, KRAS can regulate most cellular processes involving guanosine triphosphate (GTP) hydrolysis. However, the mechanism of GTP hydrolysis has remained controversial over the past decades. Here, several different GTP hydrolysis mechanisms catalyzed by wild-type KRAS (WT-KRAS) and KRAS mutants were discussed via four QM/MM calculation models.

Molecular Characterization and Potential Inhibitors Prediction of Protein Arginine Methyltransferase-2 in Carcinoma: An Insight from Molecular Docking, ADMET Profiling and Molecular Dynamics Simulation Studies.

Objectives: To predict and characterize the three-dimensional (3D) structure of protein arginine methyltransferase 2 (PRMT2) using homology modeling, besides, the identification of potent inhibitors for enhanced comprehension of the biological function of this protein arginine methyltransferase (PRMT) family protein in carcinogenesis.

Materials And Methods: An method was employed to predict and characterize the three-dimensional structure. The bulk of PRMTs in the PDB shares just a structurally conserved catalytic core domain.

Characterization of extracellular vesicles by capillary zone electrophoresis: A novel concept for characterization of a next-generation drug delivery platform.

Extracellular vesicles (EVs) are a part of a cell-to-cell communication system of prokaryotic and eukaryotic organisms. Their ability to penetrate biological barriers and to transfer molecules between cells shows their potential as a novel class of drug delivery platform. However, because of the great heterogeneity of EVs and the complexity of biological matrices from which they are typically isolated, reliable quality control procedures need to be established to ensure their safety for medical use.

Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry.

Background And Aims: Overweight and obesity are modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD) in the general population, but their prevalence in individuals with heterozygous familial hypercholesterolaemia (HeFH) and whether they confer additional risk of ASCVD independent of LDL cholesterol (LDL-C) remains unclear.

Methods: Cross-sectional analysis was conducted in 35 540 patients with HeFH across 50 countries, in the EAS FH Studies Collaboration registry. Prevalence of World Health Organization-defined body mass index categories was investigated in adults (n = 29 265) and children/adolescents (n = 6275); and their association with prevalent ASCVD.

The impact of combination of zofenopril and different diuretics on regression of myocardial reperfusion injury and oxidative status in spontaneously hypertensive rats.

As several decades of research have shown the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors alone or in combination with diuretics, we were interested in investigating the effects of subchronic therapy of these drugs on ischemia-reperfusion (I/R) damage to the heart, as well as their influence on oxidative status. The research was conducted on 40 spontaneously hypertensive male Wistar Kyoto rats, divided into 4 groups. Animals were treated for four weeks with 10 mg/kg/day zofenopril alone or in combination with hydrochlorothiazide, indapamide and spironolactone per os.

Life stage impact on the human skin ecosystem: lipids and the microbial community.

Sebaceous free fatty acids are metabolized by multiple skin microbes into bioactive lipid mediators termed oxylipins. This study investigated correlations between skin oxylipins and microbes on the superficial skin of pre-pubescent children (N = 36) and adults (N = 100), including pre- (N = 25) and post-menopausal females (N = 25). Lipidomics and metagenomics revealed that Malassezia restricta positively correlated with the oxylipin 9,10-DiHOME on adult skin and negatively correlated with its precursor, 9,10-EpOME, on pre-pubescent skin.

Inclination of antidepressant medication continuation during pregnancy between 2012 and 2023 in Japan: A cohort study.

Background: As multiple Japanese academic societies have recently issued treatment guidelines for perinatal antidepressant treatments, it is considered worthwhile to evaluate the latest trends and continuation of antidepressant medication during pregnancy to optimize antenatal prescriptions.

Methods: The prevalence, trend, and continuation of antidepressant use during pregnancy in Japan from 2012 to 2023 were evaluated, using a large administrative claims database, in women whose pregnancies ended in live births. Annual changes were evaluated using a multivariate logistic regression model adjusted for maternal age at delivery.

Analysis of Chemical Components of Penicillium chrysogenum Crude Extract Using Liquid Chromatography Coupled With Q-Exactive Orbitrap Mass Spectrometry Combined With GNPS Molecular Networking.

A Chinese isolate of the fungus Penicillium chrysogenum was analyzed using liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry combined with Global Natural Products Social Networking (GNPS) on culture condition leading to the rapid identification of 20 secondary metabolites. Among them are eight polyketones, two phthalides, six diketopiperazine alkaloids, and others. A meleagrine network was examined and proposed as a promising candidate for new natural products.

Molecular evidence for the efficacy of PBM therapy in the treatment of Oral lichen planus.

Purpose: Oral lichen planus (OLP) is a chronic inflammatory disease, in which T-Lymphocytes induce apoptosis of basal keratinocytes, leading to the formation of symptomatic lesions. It is assumed that blocking the cell death program and enhancing cell proliferation would be crucial to the healing process. The aim of the study was to verify the efficacy of Photobiomodulation (PBM) in OLP management, by evaluating the effects of laser irradiation on the processes of apoptosis and cell proliferation.

Association between underlying health conditions and long COVID among non-hospitalized and hospitalized individuals as modified by health literacy: A multi-center study.

Objectives: We investigated the effect modification of health literacy (HL) in ameliorating the negative impact of underlying health conditions (UHC) on long COVID among non-hospitalized and hospitalized survivors.

Study Design: An online cross-sectional study was conducted in Vietnam from December 2021 to October 2022.

Methods: A sample of 4507 participants recruited from 18 hospitals and health centers were those aged 18 or older, had contracted COVID-19 for at least 28 days, and were not in the acute phase of reinfection.

Effectiveness for remission maintenance rate and safety of different rituximab regimens for treating anti-neutrophil cytoplasmic antibody-associated vasculitis in Japan: a J-CANVAS study.

Rituximab (RTX) has been reported to effectively maintain remission in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In this multicenter study involving 57 patients who achieved remission after 24 weeks, we evaluated the effectiveness of RTX in maintaining remission in patients with AAV. Patients were divided into three groups based on RTX administration: continuous, induction phase-only, and maintenance phase-only groups.

Nutritional Status, Frailty, Oral Health, and Oral Motor Functions in Long-Term Care Residents with Swallowing Dysfunction.

: Swallowing dysfunction is a prevalent but often overlooked problem in long-term care facilities. This study investigated the relationships between nutritional deficits, frailty, oral health, and swallowing dysfunction. Additionally, we explored the associations between oral muscle weakness, frailty markers, and swallowing dysfunction.

Metabolomics in Atrial Fibrillation: Unlocking Novel Biomarkers and Pathways for Diagnosis, Prognosis, and Personalized Treatment.

Atrial fibrillation (AF) is the most frequent arrhythmia in the adult population associated with a high rate of severe consequences leading to significant morbidity and mortality worldwide. Therefore, its prompt recognition is of high clinical importance. AF detection often remains challenging due to unspecific symptoms and a lack of reliable biomarkers for its prediction.

Biomarkers for the Molecular Diagnosis of IgE-Mediated Hymenoptera Venom Allergy in Clinical Practice.

Hymenoptera venom allergy (HVA) is a potentially life-threatening condition, making accurate diagnosis crucial for identifying significant IgE sensitizations and enabling effective venom immunotherapy. In this review, we provide a detailed overview of biomarkers for the molecular diagnosis of IgE-mediated hypersensitivity to Hymenoptera insect venoms in clinical practice, and we present, in a structured manner, their importance in differentiating genuine sensitizations versus cross-sensitizations using different diagnostic procedures. Updated algorithms are provided, along with the advantages and limitations of molecular diagnosis approaches.

The Potential Metalloestrogenic Effect of Aluminum on Breast Cancer Risk for Antiperspirant Users.

The etiopathogenesis of breast cancer depends on genetic conditions, but recently more attention has been paid to the dependence of BC on certain environmental factors, for example, metalloestrogens, which include aluminum (Al) contained in antiperspirants used daily. The use of Al derivatives in antiperspirants in concentrations specified by the FDA, as well as European regulations (SCCS, 2020), do not classify Al as a hazardous and carcinogenic substance for humans. However, Al used to treat excessive sweating raises concerns, as many in vitro studies indicate that it can cause gene instability, change gene expression or increase oxidative stress, and also affect the body's hormonal balance as a metalloestrogen.

Alpinetin Exhibits Antioxidant and Anti-Inflammatory Effects in C57BL/6 Mice with Alcoholic Liver Disease Induced by the Lieber-DeCarli Ethanol Liquid Diet.

Alcohol-associated liver disease (ALD) is a common non-communicable chronic liver disease characterized by a spectrum of conditions ranging from steatosis and alcohol-associated steatohepatitis (AH) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of ALD involves a complex interplay of various molecular, biochemical, genetic, epigenetic, and environmental factors. While the mechanisms are well studied, therapeutic options remain limited.

Current Strategies in Developing Antibacterial Surfaces for Joint Arthroplasty Implant Applications.

Prosthetic joint infections (PJIs) remain a significant challenge, occurring in 1% to 2% of joint arthroplasties and potentially leading to a 20% to 30% mortality rate within 5 years. The primary pathogens responsible for PJIs include Staphylococcus aureus, coagulase-negative staphylococci, and Gram-negative bacteria, typically treated with intravenous antibiotic drugs. However, this conventional approach fails to effectively eradicate biofilms or the microbial burden in affected tissues.

Potential Clinical Application of Analysis of Bisphenols in Pericardial Fluid from Patients with Coronary Artery Disease with the Use of Liquid Chromatography Combined with Fluorescence Detection and Triple Quadrupole Mass Spectrometry.

Bisphenols may negatively impact human health. In this study, we propose the use of HPLC-FLD for the simultaneous determination of bisphenols in pericardial fluid samples collected from patients with coronary artery disease undergoing coronary artery bypass surgery. For sample preparation, a fast, simple, and "green" DLLME method was used, achieving mean recovery values in the range of 62%-98% with relative standard deviations between 2% and 6% for all analytes.

Thiosemicarbazone-Based Compounds: A Promising Scaffold for Developing Antibacterial, Antioxidant, and Anticancer Therapeutics.

This paper presents the synthesis and characterization of new thiosemicarbazone derivatives with potential applications as antibacterial, antioxidant and anticancer agents. Six thiosemicarbazone derivatives (L-L5) were synthesized by reacting an appropriate thiosemicarbazide derivative with 2-pyridinecarboxaldehyde. The structures of the obtained compounds were confirmed using mass spectrometry, infrared spectroscopy, and NMR spectroscopy.

Synthesis of Novel Benzothiazole-Profen Hybrid Amides as Potential NSAID Candidates.

Herein, we report the synthesis of a series of new compounds by combining 2-aminobenzothiazole with various profens. The compounds were characterized using techniques such as H- and C-NMR, FT-IR spectrometry, and high-resolution mass spectrometry (HRMS), with detailed HRMS analysis conducted for each molecule. Their biological activities were tested in vitro, revealing significant anti-inflammatory and antioxidant effects, comparable to those of standard reference compounds.

The Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying -Substituents.

It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR.

Brain distribution study of [C]-Riluzole following intranasal administration in mice.

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined.

Mitochondrial disorder diagnosis and management- what the pediatric neurologist wants to know.

Childhood-onset mitochondrial disorders are rare genetic diseases that often manifest with neurological impairment due to altered mitochondrial structure or function. To date, pathogenic variants in 373 genes across the nuclear and mitochondrial genomes have been linked to mitochondrial disease, but the ensuing genetic and clinical complexity of these disorders poses considerable challenges to their diagnosis and management. Nevertheless, despite the current lack of curative treatment, recent advances in next generation sequencing and -omics technologies have laid the foundation for precision mitochondrial medicine through enhanced diagnostic accuracy and greater insight into pathomechanisms.

Risk factors of short-term poor functional outcomes and long-term durability of ruptured large or giant intracranial aneurysms.

Objective: Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality rates. In particular, functional outcomes of SAH caused by large or giant (≥ 10 mm) ruptured intracranial aneurysms are worsened by high procedure-related complication rates. However, studies describing the risk factors for poor functional outcomes specific to ruptured large/giant aneurysms are sparse.

Hepatocellular Carcinoma Cells in Humans Exhibit Resistance to Suberoylanilide Hydroxamic Acid (SAHA) Owing to the Diminished Level of Hsa-miR-125a-5p.

Hepatocellular carcinoma (HCC) presents an escalating public health challenge globally. However, drug resistance has emerged as a major impediment to successful HCC treatment, limiting the efficacy of curative interventions. Despite numerous investigations into the diverse impacts of hsa-miR-125a-5p on tumor growth across different cancer types, its specific involvement in chemotherapy resistance in HCC remains elusive.