OBJECTIVE: Insulin-sensitizing drugs, despite their broad use against type 2 diabetes, can adversely affect bone health, and the mechanisms underlying these side effects remain largely unclear. Here, we investigated the different metabolic effects of a series of thiazolidinediones, including rosiglitazone, pioglitazone, and the second-generation compound MSDC-0602K, on human mesenchymal stem cells (MSCs). METHODS: We developed 13C subcellular metabolomic tracer analysis measuring separate mitochondrial and cytosolic metabolite pools, lipidomic network-based isotopologue models, and bioorthogonal click chemistry, to demonstrate that MSDC-0602K differentially affected bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AT-MSCs). In BM-MSCs, MSDC-0602K promoted osteoblastic differentiation and suppressed adipogenesis. This effect was clearly distinct from that of the earlier drugs and that on AT-MSCs. RESULTS: Fluxomic data reveal unexpected differences between this drug's effect on MSCs and provide mechanistic insight into the pharmacologic inhibition of mitochondrial pyruvate carrier 1 (MPC). Our study demonstrates that MSDC-0602K retains the capacity to inhibit MPC, akin to rosiglitazone but unlike pioglitazone, enabling the utilization of alternative metabolic pathways. Notably, MSDC-0602K exhibits a limited lipogenic potential compared to both rosiglitazone and pioglitazone, each of which employs a distinct lipogenic strategy. CONCLUSIONS: These findings indicate that the new-generation drugs do not compromise bone structure, offering a safer alternative for treating insulin resistance. Moreover, these results highlight the ability of cell compartment-specific metabolite labeling by click reactions and tracer metabolomics analysis of complex lipids to discover molecular mechanisms within the intersection of carbohydrate and lipid metabolism.

• Klíčová slova
• Adipocyte, Bone marrow, Lipid flux analysis, Mitochondrial pyruvate carrier, Tracer metabolomics,
• MeSH
• adipogeneze * účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• hypoglykemika farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• metabolomika MeSH
• mezenchymální kmenové buňky * účinky léků   metabolismus   MeSH
• osteogeneze * účinky léků   MeSH
• pioglitazon farmakologie   MeSH
• rosiglitazon farmakologie   MeSH
• thiazolidindiony * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hypoglykemika MeSH
• pioglitazon MeSH
• rosiglitazon MeSH
• thiazolidindiony * MeSH

Local nonequilibrium approach has been used for many purposes when dealing with biological systems. Not only for unraveling important features of cancer development, a disease that affects the lives of many people worldwide, but also to understand drug-target interactions in a more real scenario, which can help to combat this disease. Therefore, aiming to contribute to new strategies against cancer, the present work used this approach to investigate the spectroscopy of 2-(2'-hydroxy-4'-aminophenyl)benzothiazole (HABT) when interacting with the PI3K enzyme, a widely associated target for the mentioned illness. The study consisted of evaluating the Excited State Intramolecular Proton Transfer (ESIPT) performance of HABT, in spectroscopic terms, when interacting with the PI3K enzyme in a local nonequilibrium regime. This scenario could be considered by investigating the metastable states of HABT in this system. From this, it was possible to observe that the ESIPT performance of HABT considerably differs when comparing the solution and protein environments, where 63% have appropriate geometry in the protein environment, against 97% in the aqueous environment. Thus, from an entirely theoretical methodology, the present work provides insights when modeling biological systems and contributes significantly to a better comprehension of promising probes for cancer diagnosis.

• Klíčová slova
• ESIPT, biased MD simulations, cancer, fluorescent sensors, spectroscopic probes,
• MeSH
• benzothiazoly * chemie   MeSH
• fosfatidylinositol-3-kinasy * metabolismus   chemie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádory * enzymologie   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzothiazoly * MeSH
• fosfatidylinositol-3-kinasy * MeSH

AIM: This work explores the synthesis of new bi-heterocyclic hybrid compounds based on quinoline ring and investigates their potential as anticancer agents. MATERIALS & METHODS: The novel fused quinoline-thiazolo[3,2-a] benzimidazole-3(2 h)one hybrids were prepared by regioselective nucleophilic ring opening of the corresponding quinolinyl-oxiranes. In vitro cytotoxic activity was evaluated against human lung (A549) and gastric (AGS) cancer cell lines. RESULTS: Global results showed that all tested compounds have promising inhibitory properties. Compounds 17 and 18 bearing two methoxy groups on the quinoline ring have exhibited remarkable and interesting activities. The investigation of the cell death process showed that these compounds activated a caspase-dependent apoptosis pathway. Results were further supported by molecular docking studies. CONCLUSION: Both compounds exhibited good drug-like characteristics, which make them promising drug candidates.

• Klíčová slova
• Caspase-3, Quinoline, Thiazolobenzimidazole, cytotoxic activity, epoxide ring opening, hybrid compounds, molecular docking,
• MeSH
• apoptóza * účinky léků   MeSH
• benzimidazoly * farmakologie   chemie   chemická syntéza   MeSH
• chinoliny * chemie   farmakologie   chemická syntéza   MeSH
• kaspasy * metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu * MeSH
• thiazoly chemie   farmakologie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzimidazolone MeSH Prohlížeč
• benzimidazoly * MeSH
• chinoliny * MeSH
• kaspasy * MeSH
• protinádorové látky * MeSH
• quinoline MeSH Prohlížeč
• thiazoly MeSH

BACKGROUND: Randomized clinical trials demonstrated similar efficacy and improved safety of direct oral anticoagulants versus warfarin in patients with atrial fibrillation (AF). Long-term data in routine clinical practice are needed. HYPOTHESIS: Patients with AF receiving edoxaban at baseline continue to have low annualized effectiveness and safety event rates in the second year of follow-up, with regional variations observed. METHODS: The Global ETNA-AF program is a prospective, noninterventional study of patients with AF receiving edoxaban. Patient characteristics and annualized clinical event rates were assessed overall and by region across the 2-year follow-up. Annualized event rates of bleeding and thromboembolic events were assessed within the first year and conditionally in patients who were event-free up to 12 months in the second year. RESULTS: This analysis comprised 26 805 patients from Europe (n = 13 164), Japan (n = 10 342), and non-Japanese Asian regions (n = 3299). Patients from Europe had the highest burden of comorbidities. The annualized event rates for major bleeding, any stroke, all-cause death, and cardiovascular death varied by region. The global annualized event rates in the first and second year were 1.31%/year and 0.86%/year for major bleeding, 1.06%/year and 0.65%/year for any stroke, 0.84%/year and 0.73%/year for cardiovascular death, and 3.05%/year and 3.18%/year for all-cause death. CONCLUSION: Annualized event rates for any stroke and major bleeding remained low through 2-year follow-up for patients with AF receiving edoxaban at baseline. Differences in annualized event rates for all-cause and cardiovascular mortality between Europe, Japan, and non-Japanese Asian regions may reflect variations in baseline characteristics. TRIAL REGISTRATION: Europe, NCT02944019; Japan, UMIN000017011; Korea/Taiwan, NCT02951039; Hong Kong, NCT03247582; and Thailand, NCT03247569.

• Klíčová slova
• anticoagulation, atrial fibrillation, direct oral anticoagulant (DOAC), edoxaban, major bleeding, oral anticoagulants, stroke prevention,
• MeSH
• časové faktory MeSH
• cévní mozková příhoda prevence a kontrola   epidemiologie   etiologie   MeSH
• fibrilace síní * farmakoterapie   komplikace   MeSH
• incidence MeSH
• inhibitory faktoru Xa * terapeutické užití   škodlivé účinky   MeSH
• krvácení * chemicky indukované   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• prospektivní studie MeSH
• pyridiny * terapeutické užití   škodlivé účinky   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• thiazoly * terapeutické užití   škodlivé účinky   MeSH
• tromboembolie prevence a kontrola   epidemiologie   etiologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• edoxaban MeSH Prohlížeč
• inhibitory faktoru Xa * MeSH
• pyridiny * MeSH
• thiazoly * MeSH

Wood of broad-leaf tree species is a valued source of renewable biomass for biorefinery and a target for genetic improvement efforts to reduce its recalcitrance. Glucuronoxylan (GX) plays a key role in recalcitrance through its interactions with cellulose and lignin. To reduce recalcitrance, we modified wood GX by expressing GH10 and GH11 endoxylanases from Aspergillus nidulans in hybrid aspen (Populus tremula L. × tremuloides Michx.) and targeting the enzymes to cell wall. The xylanases reduced tree height, modified cambial activity by increasing phloem and reducing xylem production, and reduced secondary wall deposition. Xylan molecular weight was decreased, and the spacing between acetyl and MeGlcA side chains was reduced in transgenic lines. The transgenic trees produced hypolignified xylem having thin secondary walls and deformed vessels. Glucose yields of enzymatic saccharification without pretreatment almost doubled indicating decreased recalcitrance. The transcriptomics, hormonomics and metabolomics data provided evidence for activation of cytokinin and ethylene signalling pathways, decrease in ABA levels, transcriptional suppression of lignification and a subset of secondary wall biosynthetic program, including xylan glucuronidation and acetylation machinery. Several candidate genes for perception of impairment in xylan integrity were detected. These candidates could provide a new target for uncoupling negative growth effects from reduced recalcitrance. In conclusion, our study supports the hypothesis that xylan modification generates intrinsic signals and evokes novel pathways regulating tree growth and secondary wall biosynthesis.

• Klíčová slova
• Glucuronoxylan, fungal xylanases, lignocellulose, secondary cell wall, transgenic aspen, wood development,
• MeSH
• Aspergillus nidulans * genetika   fyziologie   MeSH
• buněčná stěna * chemie   metabolismus   MeSH
• dřevo * MeSH
• endo-1,4-beta-xylanasy metabolismus   MeSH
• Populus * mikrobiologie   fyziologie   MeSH
• rostlinné buňky MeSH
• sacharin MeSH
• stromy fyziologie   MeSH
• xylany * biosyntéza   genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endo-1,4-beta-xylanasy MeSH
• sacharin MeSH
• xylany * MeSH

Free radical polymerization technique was used to formulate Poloxamer-188 based hydrogels for controlled delivery. A total of seven formulations were formulated with varying concentrations of polymer, monomer ad cross linker. In order to assess the structural properties of the formulated hydrogels, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), Scanning electron microscopy (SEM), and X-ray diffraction (XRD) were carried out. To assess the effect of pH on the release of the drug from the polymeric system, drug release studies were carried in pH 1.2 and 7.4 and it was found that release of the drug was significant in pH 7.4 as compared to that of pH 1.2 which confirmed the pH responsiveness of the system. Different kinetic models were also applied to the drug release to evaluate the mechanism of the drug release from the system. To determine the safety and biocompatibility of the system, toxicity study was also carried out for which healthy rabbits were selected and formulated hydrogels were orally administered to the rabbits. The results obtained suggested that the formulated poloxamer-188 hydrogels are biocompatible with biological system and have the potential to serve as controlled drug delivery vehicles.

• MeSH
• akrylové pryskyřice * chemie   MeSH
• diferenciální skenovací kalorimetrie MeSH
• difrakce rentgenového záření MeSH
• hydrogely * chemie   MeSH
• koncentrace vodíkových iontů MeSH
• králíci MeSH
• lékové transportní systémy MeSH
• léky s prodlouženým účinkem chemie   farmakokinetika   MeSH
• mikroskopie elektronová rastrovací MeSH
• nosiče léků chemie   MeSH
• poloxamer * chemie   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• termogravimetrie MeSH
• timolol * aplikace a dávkování   farmakokinetika   chemie   MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• akrylové pryskyřice * MeSH
• carbopol 940 MeSH Prohlížeč
• hydrogely * MeSH
• léky s prodlouženým účinkem MeSH
• nosiče léků MeSH
• poloxamer * MeSH
• timolol * MeSH

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

• Klíčová slova
• 1,3,4-thiadiazole, AML, FLT3-ITD inhibitors, furo[2,3-d]pyrimidine, urea,
• MeSH
• akutní myeloidní leukemie farmakoterapie   patologie   metabolismus   MeSH
• inhibitory proteinkinas * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• pyrimidiny chemie   farmakologie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• simulace molekulového dockingu * MeSH
• thiadiazoly * chemie   farmakologie   chemická syntéza   MeSH
• tyrosinkinasa 3 podobná fms * antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,3,4-thiadiazole MeSH Prohlížeč
• FLT3 protein, human MeSH Prohlížeč
• inhibitory proteinkinas * MeSH
• protinádorové látky * MeSH
• pyrimidiny MeSH
• thiadiazoly * MeSH
• tyrosinkinasa 3 podobná fms * MeSH

BACKGROUND: This research article delves into the battle against the COVID-19 pandemic, focusing on the efficacy and, particularly, the safety of the combination of nirmatrelvir with ritonavir, which is found in the pharmaceutical product Paxlovid®. This study aims to analyze the potential interactions of commonly prescribed medicinal products with Paxlovid®, shedding light on its utilization in specific medical fields. METHODS: Prescription data from the Czech Republic's Institute of Health Information and Statistics (IHIS CR) was analyzed, covering 4 million COVID-19 patients and 87.5 million medication records from September 2019 to February 2022. This study focused on potential drug interactions with Paxlovid among the 50 most frequently prescribed medications, with particular attention to four specialties: general medicine, internal medicine, infectious diseases, and diabetology. RESULTS: In this study of the 50 most commonly prescribed drugs, 56% showed no interaction with Paxlovid, 30% had a potential for interaction, and 14% were not specifically mentioned in relation to Paxlovid, with no drugs found to be contraindicated overall. However, in specific medical fields, including diabetology, infectious diseases, internal medicine, and general medicine, certain drugs had potential interactions when co-administered with Paxlovid. CONCLUSIONS: Paxlovid remains a valuable option for early COVID-19 treatment but requires a careful consideration of potential drug interactions, especially in high-risk specialties. A thorough assessment of concurrent medications is essential to optimize safety and efficacy in patients receiving Paxlovid.

• Klíčová slova
• COVID-19, Paxlovid, drug interactions, nirmatrelvir, ritonavir,
• MeSH
• antivirové látky škodlivé účinky   terapeutické užití   MeSH
• COVID-19 epidemiologie   MeSH
• farmakoterapie COVID-19 * MeSH
• fixní kombinace léků * MeSH
• lékové interakce * MeSH
• lidé MeSH
• ritonavir * terapeutické užití   škodlivé účinky   MeSH
• SARS-CoV-2 účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• antivirové látky MeSH
• fixní kombinace léků * MeSH
• ritonavir * MeSH

The quantification of cellular metabolic activity via MTT assay has become a widespread practice in eukaryotic cell studies and is progressively extending to bacterial cell investigations. This study pioneers the application of MTT assay to evaluate the metabolic activity of biofilm-forming cells within bacterial biofilms on nanofibrous materials. The biofilm formation of Staphylococcus aureus and Escherichia coli on nanomaterials electrospun from polycaprolactone (PCL), polylactic acid (PLA), and polyamide (PA) was examined. Various parameters of the MTT assay were systematically investigated, including (i) the dissolution time of the formed formazan, (ii) the addition of glucose, and (iii) the optimal wavelength for spectrophotometric determination. Based on interim findings, a refined protocol suitable for application to nanofibrous materials was devised. We recommend 2 h of the dissolution, the application of glucose, and spectrophotometric measurement at 595 nm to obtain reliable data. Comparative analysis with the reference CFU counting protocol revealed similar trends for both tested bacteria and all tested nanomaterials. The proposed MTT protocol emerges as a suitable method for assessing the metabolic activity of bacterial biofilms on PCL, PLA, and PA nanofibrous materials.

• Klíčová slova
• Biofilm, MTT, Metabolic activity, Nanofibers, Nanomaterials,
• MeSH
• biofilmy * růst a vývoj   MeSH
• Escherichia coli * fyziologie   MeSH
• glukosa metabolismus   MeSH
• nanovlákna * chemie   MeSH
• nylony chemie   MeSH
• polyestery * chemie   MeSH
• spektrofotometrie metody   MeSH
• Staphylococcus aureus * fyziologie   MeSH
• tetrazoliové soli * metabolismus   chemie   MeSH
• thiazoly metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glukosa MeSH
• nylony MeSH
• poly(lactide) MeSH Prohlížeč
• polycaprolactone MeSH Prohlížeč
• polyestery * MeSH
• tetrazoliové soli * MeSH
• thiazoly MeSH
• thiazolyl blue MeSH Prohlížeč

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

• MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• chemorezistence * MeSH
• isochinoliny MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein bcl-X * metabolismus   antagonisté a inhibitory   MeSH
• protein BCL2L11 * metabolismus   genetika   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   antagonisté a inhibitory   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• synergismus léků MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• A-1155463 MeSH Prohlížeč
• BCL2L1 protein, human MeSH Prohlížeč
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• isochinoliny MeSH
• protein bcl-X * MeSH
• protein BCL2L11 * MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč