The growth and accumulation of active ingredients of Angelica sinensis were affected by rhizosphere soil microbial communities and soil environmental factors. However, the correlationship between growth and active ingredients and soil biotic and abiotic factors is still unclear. This study explored rhizosphere soil microbial community structures, soil physicochemical properties, enzyme activities, and their effects on the growth and active ingredient contents of A. sinensis in three principal cropping areas. Results indicated that the growth indices, ligustilide, ferulic acid contents, and soil environmental factors varied in cropping areas. Pearson correlation analysis revealed that the growth of A. sinensis was affected by organic matter, total nitrogen, total phosphorus, and available phosphorus; ferulic acid and ligustilide accumulation were related to soil catalase and alkaline phosphatase activities, respectively. Illumina MiSeq sequencing showed that the genera Mortierella and Conocybe were the dominant fungal communities, and Sphingomonas, Pseudomonas, Bryobacter, and Lysobacter were the main bacterial communities associated with the rhizosphere soil. Kruskal-Wallis one-way ANOVA and Spearman correlation conjoint analysis demonstrated a significant positive correlation (p < 0.001) among the composition of the rhizosphere microbial communities at all three sampling sites. The growth and active ingredient accumulation of A. sinensis not only was significantly susceptible to the bacterial communities of Sphingomonas, Epicoccum, Marivita, Muribaculum, and Gemmatimonas but also were significantly influenced by the fungal communities of Inocybe, Septoria, Tetracladium, and Mortierella (p < 0.05). Our findings provide a scientific basis for understanding the relationship between the growth and active ingredients in A. sinensis and their corresponding rhizosphere soil microbial communities, soil physicochemical properties, and enzyme activities.

• MeSH
• Angelica sinensis * růst a vývoj   chemie   mikrobiologie   MeSH
• Bacteria klasifikace   genetika   izolace a purifikace   MeSH
• dusík analýza   MeSH
• fosfor analýza   MeSH
• houby klasifikace   genetika   izolace a purifikace   MeSH
• mikrobiota * MeSH
• půda chemie   MeSH
• půdní mikrobiologie * MeSH
• rhizosféra * MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Čína MeSH

L eishmaniasis is a prevalent disease that impacts 98 countries and territories, mainly in Africa, Asia, and South America. It can cause substantial illness and death, particularly in its visceral manifestation that can be specifically targeted in the development of medications to combat leishmaniasis. This study has found natural compounds with possible inhibitory activity against APX using a reliable and accurate QSAR model. Despite the severe side effects of current treatments and the absence of an effective vaccination, these compounds show promise as a potential treatment for the disease. Nine hit compounds were found, and subsequent molecular docking was performed. Estradiol cypionate showed the lowest binding energy (- 10.5 kcal/mol), thus showing the strongest binding, and also had the strongest binding affinity, with a ΔGTotal of - 26.31 ± 3.01 kcal/mol, second only to the control molecule. Additionally, three hits viz. cloxacillin-sodium (- 16.57 ± 2.89 kcal/mol), cinchonidine (- 16.04 ± 3.27 kcal/mol), and quinine hydrochloride dihydrate (13.38 ± 1.06 kcal/mol) also showed significant binding affinity. Multiple interactions between drugs and active site residues demonstrated a substantial binding affinity with the target protein. The identified compounds exhibited drug-like effects and were orally bioavailable based on their ADME-toxicology features. Overall, estradiol cypionate, cloxacillin sodium, cinchonidine, and quinine hydrochloride dihydrate all exhibited inhibitory effects on the APX enzyme of Leishmania donovani. These results suggest that further investigation is needed to explore the potential of developing novel anti-leishmaniasis drugs using these compounds.

• MeSH
• antiprotozoální látky * farmakologie   chemie   MeSH
• inhibitory enzymů * farmakologie   chemie   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• leishmanióza * farmakoterapie   MeSH
• lidé MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Aim: The study aimed to investigate the level of postpartum anxiety in the research sample of women after childbirth and factors related to increased level of postpartum anxiety. The goal was also to establish the basic psychometric properties of the Postpartum Specific Anxiety Scale (PSAS-SK) in the Slovak language, and explore selected sociodemographic, perinatal, and anamnestic factors related to increased level of postpartum anxiety in a Slovak research sample. Design: Quantitative cross-sectional research study. Methods: The study involved 122 postpartum women (four-eight weeks postpartum, age 29.5; ± 4.8; 19-42). Data were collected using the standardized PSAS-SK questionnaire alongside sociodemographic and anamnestic data. Statistical analyses included nonparametric tests (Kruskal-Wallis test and Mann-Whitney U test) and confirmatory factor analysis (CFA) to assess the results. Results: Clinically significant levels of postpartum anxiety occurred in 25% of research participants. We found a significant relationship between perception of childbirth as traumatic and increased levels of postpartum anxiety. However, no significant relationship was confirmed between level of postpartum anxiety and education parity, type of childbirth, complications during pregnancy, perinatal loss, skin-to-skin contact, or health complications in the child. The PSAS-SK had high internal consistency in a Slovak research sample (Cronbach's alpha 0.96). Results of the CFA focusing on confirmation of the four-factor structure of the PSAS-SK indicated the following results: χ2(df = 405) = 2188.0, p < 0.001, CFI = 0.07, RMSEA = 0.008. Conclusion: The Postpartum Specific Anxiety Scale is a valuable tool for the early detection of postpartum anxiety symptoms and for supporting interventions to manage heightened anxiety during the postpartum period, including recommendation of specialized mental health care when appropriate.

Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.

• MeSH
• antifungální látky * farmakologie   chemie   chemická syntéza   farmakokinetika   MeSH
• Cryptococcus neoformans * účinky léků   enzymologie   MeSH
• inhibitory proteas * farmakologie   chemie   chemická syntéza   farmakokinetika   MeSH
• lidé MeSH
• makrocyklické sloučeniny * farmakologie   chemie   chemická syntéza   farmakokinetika   MeSH
• mikrobiální testy citlivosti MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

PI3K signaling pathway is crucial for a plethora of cellular processes and is extensively linked with tumorigenesis and chemo-/radioresistance. Although a number of small molecule inhibitors have been synthesized to control PI3K-mediated signaling, only a limited clinical success has been reached. Thus, the search for novel promising candidates is still ongoing. Herein, we present a novel series of N-(5-(2-morpholino-4-oxo-3,4-dihydroquinazolin-8-yl)pyridin-2-yl)acylamides designed to simultaneously inhibit PI3K and DNA-PK activity. Compared to a commercial DNA-PK/PI3K inhibitor AZD7648, synthesized compounds generally exhibited markedly lower baseline cytotoxicity in all tested cell lines (MC38, B16F10, 4T1, CT26 and HEK-239). Through an array of biological experiments, we selected two most promising compounds, 2 and 6. While in cell-free conditions, 6 acted as a very efficient pan-PI3K and DNA-PK inhibitor, in physiological conditions, 2 performed better and acted as a potent chemosensitizer able to increase the amount of DNA double strand breaks induced by doxorubicin. This was plausibly due to its improved ability to accumulate in nuclei as evidenced by confocal analyses. Importantly, using P-gp overexpressing CT26 cells, we found that 2 is an efficient inhibitor of multidrug resistance (MDR) able to down-regulate expression of mRNA encoding MDR-driving proteins ABCB1A, ABCB1B and ABCC1. We also demonstrate that 2 can be simply loaded into lipid nanoparticles that retain its chemosensitizing properties. Taken together, the presented study provides a solid basis for a subsequent rational structure optimization towards new generation of multitarget inhibitors able to control crucial signaling pathways involved in tumorigenesis and drug resistance.

• MeSH
• chemorezistence * účinky léků   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy * farmakologie   MeSH
• inhibitory proteinkinas * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mnohočetná léková rezistence * účinky léků   MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• P-glykoprotein * antagonisté a inhibitory   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• proteinkinasa aktivovaná DNA * antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Background and Objectives: Aortic stenosis (AS) is a frequent valvular disease characterized by the obstruction of left ventricular outflow. The resulting hemodynamic and structural changes create an arrhythmogenic substrate, with sudden cardiac death (SCD) often caused by ventricular arrhythmias (VAs) being a feared complication. This review examines the relationship between severe AS and VA, detailing the epidemiology, pathophysiological mechanisms, risk factors, and management approaches prior to aortic valve replacement (AVR). Materials and Methods: We conducted a comprehensive narrative review of the historical and contemporary literature investigating ventricular arrhythmias in severe aortic stenosis. Literature searches were performed in PubMed, MEDLINE, and Scopus databases using keywords, including "aortic stenosis", "ventricular arrhythmia", "sudden cardiac death", and "aortic valve replacement". Both landmark historical studies and modern investigations utilizing advanced monitoring techniques were included to provide a complete evolution of the understanding. Results: The prevalence of ventricular ectopy and non-sustained ventricular tachycardia increases with AS severity and symptom onset. Left ventricular hypertrophy, myocardial fibrosis, altered electrophysiological properties, and ischemia create the arrhythmogenic substrate. Risk factors include the male sex, concomitant aortic regurgitation, elevated filling pressures, and syncope. Diagnostic approaches range from standard electrocardiography to continuous monitoring and advanced imaging. Management centers on timely valve intervention, with medical therapy serving primarily as a bridge to AVR. Conclusions: Ventricular arrhythmias represent a consequence of valvular pathology in severe AS rather than an independent entity. Their presence signals advanced disease and a heightened risk for adverse outcomes. Multidisciplinary management with vigilant monitoring and prompt surgical referral is essential. Understanding this relationship enables clinicians to better identify high-risk patients requiring urgent intervention before life-threatening arrhythmic events occur.

• MeSH
• aortální stenóza * komplikace   chirurgie   patofyziologie   MeSH
• chirurgická náhrada chlopně * metody   MeSH
• komorová tachykardie etiologie   MeSH
• lidé MeSH
• náhlá srdeční smrt etiologie   MeSH
• rizikové faktory MeSH
• srdeční arytmie * etiologie   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Myocardial remodelling involves structural and functional changes in the heart, potentially leading to heart failure. The deoxycorticosterone acetate (DOCA)/salt model is a widely used experimental approach to study hypertension-induced cardiac remodelling. It allows to investigate the mechanisms underlying myocardial fibrosis and hypertrophy, which are key contributors to impaired cardiac function. In this study, myocardial remodelling in rat deoxycorticosterone acetate/salt model was examined over a three-week period. The experiment involved 11 male Sprague-Dawley rats, divided into two groups: fibrosis (n=6) and control (n=5). Myocardial remodelling was induced in the fibrosis group through unilateral nephrectomy, deoxyco-rticosterone acetate administration, and increased salt intake. The results revealed significant structural changes, including increased left ventricular wall thickness, myocardial fractional volume, and development of myocardial fibrosis. Despite these changes, left ventricular ejection fraction was preserved and even increased. ECG analysis showed significant prolongation of the PR interval and widening of the QRS complex in the fibrosis group, indicating disrupted atrioventricular and ventricular conduction, likely due to fibrosis and hypertrophy. Correlation analysis suggested a potential relationship between QRS duration and myocardial hypertrophy, although no significant correlations were found among other ECG parameters and structural changes detected by MRI. The study highlights the advantage of the DOCA/salt model in exploring the impact of myocardial remodelling on electrophysiological properties. Notably, this study is among the first to show that early myocardial remodelling in this model is accompanied by distinct electrophysiological changes, suggesting that advanced methods combined with established animal models can open new opportunities for research in this field. Key words Myocardial fibrosis, Remodelling, Animal model, DOCA-salt, Magnetic resonance imaging.

• MeSH
• deoxykortikosteron-21-acetát * MeSH
• elektrokardiografie * MeSH
• fibróza MeSH
• krysa rodu rattus MeSH
• kuchyňská sůl škodlivé účinky   MeSH
• modely nemocí na zvířatech MeSH
• myokard patologie   MeSH
• potkani Sprague-Dawley * MeSH
• remodelace komor * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Building reliable and robust quantitative structure-property relationship (QSPR) models is a challenging task. First, the experimental data needs to be obtained, analyzed and curated. Second, the number of available methods is continuously growing and evaluating different algorithms and methodologies can be arduous. Finally, the last hurdle that researchers face is to ensure the reproducibility of their models and facilitate their transferability into practice. In this work, we introduce QSPRpred, a toolkit for analysis of bioactivity data sets and QSPR modelling, which attempts to address the aforementioned challenges. QSPRpred's modular Python API enables users to intuitively describe different parts of a modelling workflow using a plethora of pre-implemented components, but also integrates customized implementations in a "plug-and-play" manner. QSPRpred data sets and models are directly serializable, which means they can be readily reproduced and put into operation after training as the models are saved with all required data pre-processing steps to make predictions on new compounds directly from SMILES strings. The general-purpose character of QSPRpred is also demonstrated by inclusion of support for multi-task and proteochemometric modelling. The package is extensively documented and comes with a large collection of tutorials to help new users. In this paper, we describe all of QSPRpred's functionalities and also conduct a small benchmarking case study to illustrate how different components can be leveraged to compare a diverse set of models. QSPRpred is fully open-source and available at https://github.com/CDDLeiden/QSPRpred .Scientific ContributionQSPRpred aims to provide a complex, but comprehensive Python API to conduct all tasks encountered in QSPR modelling from data preparation and analysis to model creation and model deployment. In contrast to similar packages, QSPRpred offers a wider and more exhaustive range of capabilities and integrations with many popular packages that also go beyond QSPR modelling. A significant contribution of QSPRpred is also in its automated and highly standardized serialization scheme, which significantly improves reproducibility and transferability of models.

• Publikační typ
• časopisecké články MeSH

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.

• MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• halogenace MeSH
• indoly * chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• receptory aromatických uhlovodíků * metabolismus   chemie   MeSH
• simulace molekulového dockingu * MeSH
• transkripční faktory bHLH MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.

• MeSH
• alosterická regulace MeSH
• elektronová kryomikroskopie metody   MeSH
• kationtové kanály TRP metabolismus   chemie   fyziologie   MeSH
• kationtový kanál TRPA1 * metabolismus   chemie   fyziologie   MeSH
• lidé MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH