The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, especially in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and an overall dearth of drug targets against Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for their activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. In vitro resistance selections using wildtype and mutator P. falciparum lines revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

• MeSH
• antimalarika * farmakologie   MeSH
• chinoxaliny * farmakologie   MeSH
• léková rezistence účinky léků   MeSH
• lidé MeSH
• Plasmodium falciparum * účinky léků   MeSH
• protozoální proteiny metabolismus   genetika   MeSH
• Schistosoma účinky léků   MeSH
• schistosomóza farmakoterapie   MeSH
• tropická malárie farmakoterapie   parazitologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimalarika * MeSH
• chinoxaliny * MeSH
• protozoální proteiny MeSH

Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.

• MeSH
• antitumorózní látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• chinoxaliny * chemie   farmakologie   chemická syntéza   MeSH
• fotochemoterapie * MeSH
• fotosenzibilizující látky * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * účinky léků   patologie   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky * MeSH
• chinoxaliny * MeSH
• fotosenzibilizující látky * MeSH
• komplexní sloučeniny * MeSH
• reaktivní formy kyslíku MeSH
• ruthenium * MeSH

Antimicrobial resistance remains a global issue, hindering the control of bacterial infections. This study examined the antimicrobial properties of 2,3-N,N-diphenyl quinoxaline derivatives against Gram-positive, Gram-negative, and Mycobacterium species. Two quinoxaline derivatives (compounds 25 and 31) exhibited significant activity against most strains of Staphylococcus aureus, Enterococcus faecium, and Enterococcus faecalis tested, with MIC values ranging from 0.25 to 1 mg/L. These compounds also showed effective antibacterial activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecium/E. faecalis (VRE) strains. They demonstrated comparable or superior activity to four current antibiotics (vancomycin, teicoplanin, daptomycin, and linezolid) against a wide range of clinically relevant isolates. Additionally, they were more effective in preventing S. aureus and E. faecalis biofilm formation compared to several other antibiotics. In summary, these two quinoxaline derivatives have potential as new antibacterial agents.

• Klíčová slova
• Enterococcus faecalis, Enterococcus faecium, MRSA, Staphylococcus aureus, VRE, biofilm, quinoxaline,
• MeSH
• antibakteriální látky * farmakologie   MeSH
• biofilmy * účinky léků   růst a vývoj   MeSH
• chinoxaliny * farmakologie   MeSH
• Enterococcus faecalis * účinky léků   MeSH
• lidé MeSH
• methicilin rezistentní Staphylococcus aureus * účinky léků   MeSH
• mikrobiální testy citlivosti * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibakteriální látky * MeSH
• chinoxaliny * MeSH

• MeSH
• adjuvancia imunologická terapeutické užití   škodlivé účinky   MeSH
• BCG vakcína * terapeutické užití   škodlivé účinky   MeSH
• chinoxaliny terapeutické užití   MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• nádory močového měchýře neinvadující svalovinu MeSH
• nádory močového měchýře * farmakoterapie   patologie   MeSH
• pyrazoly * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• BCG vakcína * MeSH
• chinoxaliny MeSH
• erdafitinib MeSH Prohlížeč
• pyrazoly * MeSH

Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase IIβ has recently been identified as a plausible target of anthracyclines in cardiomyocytes. We examined the putative topoisomerase IIβ selective agent XK469 as a potential cardioprotective and designed several new analogs. In our experiments, XK469 inhibited both topoisomerase isoforms (α and β) and did not induce topoisomerase II covalent complexes in isolated cardiomyocytes and HL-60, but induced proteasomal degradation of topoisomerase II in these cell types. The cardioprotective potential of XK469 was studied on rat neonatal cardiomyocytes, where dexrazoxane (ICRF-187), the only clinically approved cardioprotective, was effective. Initially, XK469 prevented daunorubicin-induced toxicity and p53 phosphorylation in cardiomyocytes. However, it only partially prevented the phosphorylation of H2AX and did not affect DNA damage measured by Comet Assay. It also did not compromise the daunorubicin antiproliferative effect in HL-60 leukemic cells. When administered to rabbits to evaluate its cardioprotective potential in vivo, XK469 failed to prevent the daunorubicin-induced cardiac toxicity in either acute or chronic settings. In the following in vitro analysis, we found that prolonged and continuous exposure of rat neonatal cardiomyocytes to XK469 led to significant toxicity. In conclusion, this study provides important evidence on the effects of XK469 and its combination with daunorubicin in clinically relevant doses in cardiomyocytes. Despite its promising characteristics, long-term treatments and in vivo experiments have not confirmed its cardioprotective potential.

• Klíčová slova
• XK469, anthracyclines, cardiotoxicity, dexrazoxane, topoisomerase II,
• MeSH
• antibiotika antitumorózní toxicita   MeSH
• antracykliny * toxicita   terapeutické užití   MeSH
• chinoxaliny * MeSH
• daunomycin toxicita   terapeutické užití   MeSH
• DNA-topoisomerasy typu II metabolismus   terapeutické užití   MeSH
• doxorubicin toxicita   MeSH
• inhibitory topoisomerasy II * toxicita   terapeutické užití   MeSH
• kardiotoxicita MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• poškození DNA MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• antracykliny * MeSH
• chinoxaliny * MeSH
• daunomycin MeSH
• DNA-topoisomerasy typu II MeSH
• doxorubicin MeSH
• inhibitory topoisomerasy II * MeSH
• XK 469 MeSH Prohlížeč

Pentamethinium indolium salts are promising fluorescence probes and anticancer agents with high mitochondrial selectivity. We synthesized two indolium pentamethinium salts: a cyclic form with quinoxaline directly incorporated in the pentamethinium chain (cPMS) and an open form with quinoxaline substitution in the γ-position (oPMS). To better understand their properties, we studied their interaction with mitochondrial phospholipids (cardiolipin and phosphatidylcholine) by spectroscopic methods (UV-Vis, fluorescence, and NMR spectroscopy). Both compounds displayed significant affinity for cardiolipin and phosphatidylcholine, which was associated with a strong change in their UV-Vis spectra. Nevertheless, we surprisingly observed that fluorescence properties of cPMS changed in complex with both cardiolipin and phosphatidylcholine, whereas those of oPMS only changed in complex with cardiolipin. Both salts, especially cPMS, display high usability in mitochondrial imaging and are cytotoxic for cancer cells. The above clearly indicates that conjugates of pentamethinium and quinoxaline group, especially cPMS, represent promising structural motifs for designing mitochondrial-specific agents.

• Klíčová slova
• Fluorescence mitochondrial probe, Pentamethinium salt, Quinoxaline,
• MeSH
• antitumorózní látky * farmakologie   chemie   MeSH
• chinoxaliny farmakologie   MeSH
• fosfatidylcholiny MeSH
• kardiolipiny * MeSH
• soli MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 4-chlorophenyl methyl sulfide MeSH Prohlížeč
• antitumorózní látky * MeSH
• chinoxaliny MeSH
• fosfatidylcholiny MeSH
• kardiolipiny * MeSH
• soli MeSH

OBJECTIVE: Pharmacological manipulations of glutamatergic ionotropic receptors have been suggested as a promising target for addiction treatment. Antagonists of AMPA/kainate receptors were shown to reduce alcohol intake or alcohol-seeking in various animal models. In this study, we evaluated the effect of NBQX, an AMPA/kainate receptor antagonist, on methamphetamine (METH) and nicotine self-administration in rats. METHODS: Male Wistar rats were trained to self-administer METH (0.08 mg/kg per infusion, session of 90 min) and nicotine (0.03 mg/kg per infusion, session of 60 min) under the fixed ratio 1 schedule of reinforcement. The maintenance training was 2 weeks. During the second week, NBQX was injected subcutaneously at doses of 5 or 10 mg/kg 20 min before the session or intravenously (IV) at doses of 1 and 5 mg/kg 10 min before the session. Following the maintenance training, rats were subjected to forced abstinence for 2 weeks and 1 day of the drug-free relapse-like session with IV NBQX treatment performed as before. RESULTS: Although NBQX did not affect nicotine maintenance, it significantly suppressed the drug-paired responding in the relapse session. Regarding METH, NBQX did not exert a significant effect at either phase of the study. CONCLUSIONS: These findings suggest selective involvement of AMPA/kainate receptors in the relapse of nicotine seeking after a period of forced abstinence.

• Klíčová slova
• AMPA/kainate receptor, methamphetamine, nicotine, relapse, self-administration,
• MeSH
• autoaplikace MeSH
• chinoxaliny MeSH
• krysa rodu Rattus MeSH
• methamfetamin * farmakologie   MeSH
• nikotin MeSH
• potkani Wistar MeSH
• recidiva 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
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline MeSH Prohlížeč
• chinoxaliny MeSH
• methamfetamin * MeSH
• nikotin MeSH

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

• Klíčová slova
• DMB, cellular respiration, early cardiac remodeling, glucagon-like peptide-1 receptor agonists, metabolism, mitochondrion, proteomics,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• chinoxaliny aplikace a dávkování   farmakologie   MeSH
• glykolýza MeSH
• mapy interakcí proteinů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• oxidativní fosforylace MeSH
• proteomika metody   MeSH
• remodelace komor účinky léků   MeSH
• sarkoplazmatická Ca2+-ATPáza metabolismus   MeSH
• srdeční komory metabolismus   MeSH
• srdeční mitochondrie metabolismus   MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• Atp2a2 protein, mouse MeSH Prohlížeč
• chinoxaliny MeSH
• sarkoplazmatická Ca2+-ATPáza MeSH

AIMS: To compare success rates and characteristics of smokers treated a second time by a smokers' clinic with success rates of their first treatment. DESIGN: Retrospective cohort study. SETTING: Tobacco Dependence Treatment clinic in Prague, Czech Republic, between 2005 and 2017. PARTICIPANTS: A total of 5225 smokers treated either once (n = 5006, single treatment sample, SS) or also second time (n = 219, re-treated sample, RS), on average 4.47 years after the first visit. INTERVENTION: Smokers received intensive treatment of tobacco dependence with pharmacotherapy options. Outcomes were evaluated after 1 year. In case of failure or relapse, participants could undergo re-treatment in the same setting at least 1 year after the start of the first treatment. MEASUREMENTS: Twelve-month self-reported continuous abstinence; CO-validated (≤ 6 parts per million); number of visits; type of pharmacotherapy; mental health history; Fagerström Test for Cigarette Dependence; time between first and second treatment. RESULTS: The abstinence rate in the SS was 34.8% [95% confidence interval (CI) = 33.4%, 36.1%] and in the RS was 37% (95% CI = 30.6%, 43.8%) and 39.7% (95% CI = 33.2%, 45.5%) for their first and second treatments, respectively. The samples were comparable on smoking and socio-demographic characteristics and pharmacotherapy used, but the RS in the second treatment had a higher prevalence of diagnosed mental health disorder at 39.3% (95% CI = 32.8%; 46.1%) compared with 23.7% (95% CI = 22.5%; 24.9%) in the SS. Participants who initiated their second quit attempt 1 to 2 years after the first one were less successful than those who initiated their second quit attempt later (25 versus 43%; P < 0.05). The results of the first treatment cycle were not found to be a reliable predictor for outcomes of the second cycle of treatment in univariate or multivariate logistic regression (odds ratio = 1.35, 95% CI = 0.70-2.63, P = 0.373). CONCLUSION: In Prague, Czech Republic, smokers re-attending stop-smoking treatment more than 2 years after their previous quit attempt appear to achieve similar success rates to those being treated for the first time.

• Klíčová slova
• Mental health, nicotine, pharmacotherapy, re-treatment, tobacco, tobacco dependence, tobacco use disorder, varenicline,
• MeSH
• ambulantní zařízení MeSH
• kohortové studie MeSH
• kouření epidemiologie   MeSH
• kuřáci statistika a číselné údaje   MeSH
• látky pro odvykání kouření terapeutické užití   MeSH
• lidé MeSH
• odvykání kouření metody   MeSH
• poruchy vyvolané užíváním tabáku terapie   MeSH
• prostředky pro ukončení závislosti na tabáku statistika a číselné údaje   MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• vareniklin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• látky pro odvykání kouření MeSH
• vareniklin MeSH

PURPOSE OF REVIEW: Fibroblast growth factor receptor (FGFR) signalling, especially induced by FGFR3, is a crucial factor in the pathogenesis of urothelial carcinoma and was therefore extensively studied over the last decades. In this review, we summarize the most relevant findings of the past two years. RECENT FINDINGS: Recent studies support the concept that FGFR3 mediates a pathway of urothelial carcinogenesis associated with low malignant potential. FGFR3 may represent a highly accurate biomarker for diagnosis and prediction of recurrence, progression or therapy response. The pan FGFR-inhibitor erdafitinib was recently approved for urothelial carcinoma, whereas several other FGFR-targeted drugs are currently undergoing clinical trials. SUMMARY: Numerous recent studies focus on the role of FGFR3 in different urothelial carcinoma subtypes and its potential clinical application as noninvasive biomarker, as well as therapeutic target.

• MeSH
• antitumorózní látky terapeutické užití   MeSH
• chinoxaliny terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   patologie   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• nádory močového měchýře farmakoterapie   patologie   MeSH
• pyrazoly terapeutické užití   MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• receptory fibroblastových růstových faktorů antagonisté a inhibitory   terapeutické užití   MeSH
• urologické nádory farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• chinoxaliny MeSH
• erdafitinib MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• pyrazoly MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• receptory fibroblastových růstových faktorů MeSH