Lenacapavir (GS-6207) is a capsid inhibitor approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced people with multidrug-resistant HIV-1. Here, this study provides a comprehensive overview of lenacapavir, with a particular focus on its long-acting properties, pharmacodynamics, pharmacokinetics, clinical efficacy and safety, and resistance profile. Clinical trials have demonstrated that long-acting lenacapavir is highly effective not only for treating HIV-1 infection but also as a pre-exposure prophylactic agent. The future development of fixed-dose, long-acting combination regimens incorporating lenacapavir and other long-acting antiretroviral agents offers significant potential for durable and effective HIV-1 management in clinical settings.

• Klíčová slova
• Drug combination, Drug resistance, HIV-1 therapy, Lenacapavir, Pre-exposure prophylaxis,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Rifampicin is a model ligand of the pregnane X receptor (PXR), the nuclear receptor involved in the regulation of cytochrome P450 3A4 (CYP3A4). Rifampicin forms several degradation products and metabolites of which 25-desacetylrifampicin is the most abundant in vivo. Here, we aimed to study both the stability and metabolism of rifampicin in media and 2D and 3D primary human hepatocytes (PHHs). Additionally, we analyzed interactions of rifampicin derivatives with PXR. We described that rifampicin gradually degrades by more than 50 % in the medium partly into quinone over 72 h. We observed 25-desacetylrifampicin in 2D PHHs but not in 3D PHHs. Contrary, rifampicin was converted into quinone in a one-direction process in media of 3D PHHs. The potency of rifampicin and its derivatives to activate human PXR was arranged as follows: 3-formylrifamycin SV > rifampicin quinone > rifampicin > rifampicin N-oxide > 25-desacetylrifampicin, respectively, but none activates mouse and rat PXR. The binding differences between rifampicin and 25-desacetylrifampicin were modeled in silico. Finally, we showed that overexpressed uptake organic anion transporting polypeptide 1B1 (OATP1B1) potentiated activation of PXR by rifampicin and rifampicin quinone, but overexpressed efflux multidrug resistance protein 1 (MDR1) decreased PXR activation by all derivatives.

• Klíčová slova
• Cytochrome P450, Hepatocyte spheroid, Metabolism, Molecular docking, Pregnane X receptor, Rifampicin,
• MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• hepatocyty * metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši MeSH
• pregnanový X receptor * metabolismus   MeSH
• rifampin * farmakologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP3A MeSH
• pregnanový X receptor * MeSH
• rifampin * MeSH

Citrulline is a non-proteinogenic amino acid that forms as by-product in nitric oxide (NO) synthesis from arginine and may act in concert with NO as an independent signaling molecule that involves in the mechanism of vascular smooth muscle vasodilation. In this study we examined the effects of citrulline on pulmonary artery smooth muscles. Experimental design comprised outward potassium currents measurements in enzymatically isolated rat pulmonary artery smooth muscle (PASMc) cells using whole-cell patch clamp technique, isometric contractile force recordings on rat pulmonary artery rings and method of molecular docking simulation. Citrulline in a concentration 10-9-10-5 M relaxed phenylephrine (PHE)-preactivated SM of rat pulmonary artery in a dose-dependent manner (EC50 0,67 μM). This citrulline-induced relaxation was dependent on an intact endothelium. Bath application of citrulline (10-8-10-5 M) on isolated PASMc induced a significant increase in the amplitude of outward potassium current (Ik). The adenosine antagonist caffeine (10-6 M) effectively blocked both the citrulline-induced relaxation response and Ik increment. Molecular docking modeling suggests that caffeine blocking the potent activity of citrulline results from competitive interactions at the A2 adenosine receptor binding site. In summary, our data suggest that citrulline, released with NO at low concentrations, can effectively interact with adenosine receptors in smooth muscle cells, causing their relaxation, indicating surprising interaction between NO and adenosine pathways.

• Klíčová slova
• Adenosine receptors, Caffeine, Citrulline, Endothelium, Nitric oxide, Vascular smooth muscle,
• MeSH
• arteria pulmonalis účinky léků   metabolismus   MeSH
• citrulin * farmakologie   metabolismus   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• purinergní receptory P1 metabolismus   MeSH
• simulace molekulového dockingu * MeSH
• svaly hladké cévní metabolismus   účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• citrulin * MeSH
• purinergní receptory P1 MeSH

GABAB receptors (GBRs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GBRs regulate fast synaptic transmission by gating Ca2+ and K+ channels via the Gβγ subunits of the activated G protein. It has been demonstrated that auxiliary GBR subunits, the KCTD proteins, shorten onset and rise time and increase desensitization of receptor-induced K+ currents. KCTD proteins increase desensitization of K+ currents by scavenging Gβγ from the channel, yet the mechanism responsible for the rapid activation of K+ currents has remained elusive. In this study, we demonstrate that KCTD proteins preassemble Gβγ at GBRs. The preassembly obviates the need for diffusion-limited G protein recruitment to the receptor, thereby accelerating G protein activation and, as a result, K+ channel activation. Preassembly of Gβγ at the receptor relies on the interaction of KCTD proteins with a loop protruding from the seven-bladed propeller of Gβ subunits. The binding site is shared between Gβ1 and Gβ2, limiting the interaction of KCTD proteins to these particular Gβ isoforms. Substituting residues in the KCTD binding site of Gβ1 with those from Gβ3 hinders the preassembly of Gβγ with GBRs, delays onset and prolongs rise time of receptor-activated K+ currents. The KCTD-Gβ interface, therefore, represents a target for pharmacological modulation of channel gating by GBRs.

• Klíčová slova
• G protein, GABA(B), GIRK channel, GPCR, KCTD,
• MeSH
• draslíkové kanály metabolismus   genetika   MeSH
• gating iontového kanálu * fyziologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• proteiny vázající GTP - beta-podjednotky * metabolismus   genetika   MeSH
• proteiny vázající GTP - gama-podjednotky * metabolismus   genetika   MeSH
• receptory GABA-B * metabolismus   genetika   MeSH
• Xenopus laevis MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• draslíkové kanály MeSH
• G-protein Beta gamma MeSH Prohlížeč
• proteiny vázající GTP - beta-podjednotky * MeSH
• proteiny vázající GTP - gama-podjednotky * MeSH
• receptory GABA-B * MeSH

BACKGROUND AND AIM: Osmotic changes represent a burden for the body and their limitation would be beneficial. We hypothesized that ubiquitous natural compounds could guard against cytotoxic effects of osmotic stress. We evaluated the anti-hypertonic mechanism of quercetin and 2,3-dehydrosilybin in H9c2 cells in vitro. EXPERIMENTAL PROCEDURE: Protective effect of both compounds was determined by neutral red assay, cell apoptosis was estimated by measuring caspase-3 activity and verified by western blot and annexin V assay. Phosphorylation level of selected proteins was also detected. Mitochondrial membrane potential was evaluated using dye JC-1. Ca2+ signals were evaluated using genetically encoded fluorescent Ca2+ biosensor GCaMP7f. Formation of reactive oxygen species was measured using an oxidant-sensing probe dihydrofluorescein diacetate. KEY RESULTS: Quercetin protected H9c2 cells against hypertonic stress-induced cell death. We observed a significant increase in intracellular Ca2+ levels ([Ca2+]cyto) when cells originally placed in a hypertonic solution were returned to a normotonic environment. Quercetin was found to prevent this increase in [Ca2+]cyto and also the depolarization of mitochondrial membrane potential. CONCLUSIONS AND IMPLICATIONS: Quercetin, but not 2,3-dehydrosilybin, reduced adverse effects of osmotic stress mainly by dampening the elevation of [Ca2+]cyto and mitochondrial Ca2+ overload. This may consequently prevent MPTP pore opening and activation of apoptosis.

• Klíčová slova
• 2,3-dehydrosilybin, Calcium, H9c2 cells, Hypertonic stress, Quercetin,
• MeSH
• apoptóza * MeSH
• buněčná smrt MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• oxidační stres MeSH
• quercetin * farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• quercetin * MeSH
• reaktivní formy kyslíku MeSH

Fibroblast growth factor 21 (FGF21) reduces body weight, which was attributed to induced energy expenditure (EE). Conflicting data have been published on the role of uncoupling protein 1 (UCP1) in this effect. Therefore, we aimed to revisit the thermoregulatory effects of FGF21 and their implications for body weight regulation. We found that an 8-day treatment with FGF21 lowers body weight to similar extent in both wildtype (WT) and UCP1-deficient (KO) mice fed high-fat diet. In WT mice, this effect is solely due to increased EE, associated with a strong activation of UCP1 and with excess heat dissipated through the tail. This thermogenesis takes place in the interscapular region and can be attenuated by a β-adrenergic inhibitor propranolol. In KO mice, FGF21-induced weight loss correlates with a modest increase in EE, which is independent of adrenergic signaling, and with a reduced energy intake. Interestingly, the gene expression profile of interscapular brown adipose tissue (but not subcutaneous white adipose tissue) of KO mice is massively affected by FGF21, as shown by increased expression of genes encoding triacylglycerol/free fatty acid cycle enzymes. Thus, FGF21 elicits central thermogenic and pyretic effects followed by a concomitant increase in EE and body temperature, respectively. The associated weight loss is strongly dependent on UCP1-based thermogenesis. However, in the absence of UCP1, alternative mechanisms of energy dissipation may contribute, possibly based on futile triacylglycerol/free fatty acid cycling in brown adipose tissue and reduced food intake.

• Klíčová slova
• Brown adipose tissue, Energy expenditure, Fibroblast growth factor 21, Futile fatty acid cycle, Uncoupling protein 1, Weight loss,
• MeSH
• adrenergní látky MeSH
• energetický metabolismus MeSH
• fibroblastové růstové faktory * MeSH
• hmotnostní úbytek * MeSH
• kyseliny mastné neesterifikované * MeSH
• myši obézní MeSH
• myši MeSH
• tělesná hmotnost MeSH
• triglyceridy MeSH
• uncoupling protein 1 genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adrenergní látky MeSH
• fibroblast growth factor 21 MeSH Prohlížeč
• fibroblastové růstové faktory * MeSH
• kyseliny mastné neesterifikované * MeSH
• triglyceridy MeSH
• uncoupling protein 1 MeSH

Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM2.5 represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.

• Klíčová slova
• Air pollution, Carcinogenesis, Diesel exhaust, Genotoxicity, Inflammation, Occupational exposure, Smoking, Tumor metastasis, Tumor microenvironment, Tumor promotion,
• MeSH
• látky znečišťující vzduch * toxicita   MeSH
• lidé MeSH
• monitorování životního prostředí MeSH
• nádorové mikroprostředí MeSH
• nádory plic * chemicky indukované   genetika   MeSH
• pevné částice toxicita   MeSH
• polycyklické aromatické uhlovodíky * toxicita   MeSH
• receptory aromatických uhlovodíků genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• látky znečišťující vzduch * MeSH
• pevné částice MeSH
• polycyklické aromatické uhlovodíky * MeSH
• receptory aromatických uhlovodíků MeSH

A carbon-carbon linkage is created when a methyl group is implanted on dUMP, thus resulting in the formation of dTMP by thymidylate synthase. The methyl group is deleted by aromatase when androgens are converted to estrogens. The methyl group is rearranged with the help of vitamin B12 in the isomerization of methylmalonyl-CoA to succinyl-CoA. S-adenosylmethionine (SAM) serves as the universal methyl donor involved in the biosynthesis of adrenaline and creatine(phosphate). It also interferes with the 5'-mRNA capping and the degradation of catecholamines (i.e. adrenaline, noradrenaline). Cholesterol could be viewed as a conglomeration of methyl groups. Finally, as part of valine, two methyl functions participate in the origin of one of the most frequent hereditary diseases on earth, sickle cell anemia.

• Klíčová slova
• Adrenaline, Aromatase, Capping of mRNA, Catecholamines, Cholesterol biosynthesis, Creatine(phosphate), Isomerization, Methylmalonyl-CoA -> succinyl-CoA, S-adenosylmethionine (SAM), Sickle cell anemia, Thymidylate synthase, Vitamin B(12),
• MeSH
• adrenalin MeSH
• cholesterol * MeSH
• vitamin B 12 * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adrenalin MeSH
• cholesterol * MeSH
• vitamin B 12 * MeSH

Both aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) belong among key regulators of xenobiotic metabolism in the intestinal tissue. AhR in particular is activated by a wide range of environmental and dietary carcinogens. The data accumulated over the last two decades suggest that both of these transcriptional regulators play a much wider role in the maintenance of gut homeostasis, and that both transcription factors may affect processes linked with intestinal tumorigenesis. Intestinal epithelium is continuously exposed to a wide range of AhR, PXR and dual AhR/PXR ligands formed by intestinal microbiota or originating from diet. Current evidence suggests that specific ligands of both AhR and PXR can protect intestinal epithelium against inflammation and assist in the maintenance of epithelial barrier integrity. AhR, and to a lesser extent also PXR, have been shown to play a protective role against inflammation-induced colon cancer, or, in mouse models employing overactivation of Wnt/β-catenin signaling. In contrast, other evidence suggests that both receptors may contribute to modulation of transformed colon cell behavior, with a potential to promote cancer progression and/or chemoresistance. The review focuses on both overlapping and separate roles of the two receptors in these processes, and on possible implications of their activity within the context of intestinal tissue.

• Klíčová slova
• Aryl hydrocarbon receptor, Colon cancer, Dietary contaminants, Epithelial barrier, Inflammation, Intestine, Microbial agonists, Pregnane X receptor,
• MeSH
• karcinogeneze genetika   metabolismus   MeSH
• kolon metabolismus   MeSH
• myši MeSH
• pregnanový X receptor metabolismus   MeSH
• receptory aromatických uhlovodíků * genetika   metabolismus   MeSH
• steroidní receptory * metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků * MeSH
• steroidní receptory * MeSH

ATP-binding cassette (ABC) drug efflux transporters and drug metabolizing enzymes play crucial roles in pharmacokinetic drug-drug interactions and multidrug tumor resistance (MDR). Tazemetostat (EPZ-6438, Tazverik) is a novel epigenetic drug that has been recently approved for the therapy of advanced epithelioid sarcoma and follicular lymphoma. Additionally, this medication is currently being clinically tested to treat several other cancers such as non-small cell lung cancer (NSCLC). This study aimed to investigate the inhibitory effects of tazemetostat on selected ABC transporters/cytochrome P450 3A4 (CYP3A4) enzyme to comprehensively explore its role in MDR. First, our accumulation and molecular docking studies showed that tazemetostat is a unique triple inhibitor of ABCB1, ABCC1, and ABCG2 transporters. In contrast, tazemetostat exhibited only low level of interaction with the CYP3A4 isozyme. Drug combination assays confirmed that tazemetostat is a multipotent MDR modulator able to synergize with various conventional chemotherapeutics in vitro. Subsequent caspase activity assays and microscopic staining of apoptotic nuclei proved that the effective induction of apoptosis is behind the observed synergies. Notably, a potent MDR-modulatory capacity of tazemetostat was recorded in primary ex vivo NSCLC explants generated from patients' biopsies. On the contrary, its possible position of pharmacokinetic MDR's victim was excluded in comparative proliferation assays. Finally, tested drug has not been identified as an inducer of resistant phenotype in NSCLC cell lines. In conclusion, we demonstrated that tazemetostat is a unique multispecific chemosensitizer, which has strong potential to overcome limitations seen in the era of traditional MDR modulators.

• Klíčová slova
• ABC transporter, Cytochrome P450, Drug-drug interaction, Multidrug resistance, Non-small cell lung cancer, Tazemetostat,
• Publikační typ
• časopisecké články MeSH