cAMP synthesis
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A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15-5.57 μM) as well as anti-enterococcal (MICs/MBCs 2.34-44.5 μM) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 μM, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 μM). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.
A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different positions of the benzene ring. The method consists of reacting appropriate aniline derivatives with 5,12-(dimethyl)thioquinantrenediinium bis-chloride. A series of new quinobenzothiazine derivatives was obtained with propyl, allyl, propargyl and benzyl substituents in 9, 10 and 11 positions, respectively. The structure of the obtained compounds was analyzed by 1H and 13C NMR (HSQC, HMBC) and X-ray analysis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). In addition, all the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. 9-Benzyloxy-5-methyl-12H-quino [3,4-b][1,4]benzothiazinium chloride (6j), 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6a) and 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6d) demonstrated high activity against the entire tested microbial spectrum. The activities of the compounds were comparable with oxacillin, tetracycline and ciprofloxacinagainst staphylococcal strains and with rifampicin against both mycobacterial strains. Compound 6j had a significant effect on the inhibition of bacterial respiration as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity, but also bactericidal activity. Preliminary in vitro cytotoxicity screening of the compounds performed using normal human dermal fibroblasts (NHDF) proved that the tested compounds showed an insignificant cytotoxic effect on human cells (IC50 > 37 μM), making these compounds interesting for further investigation. Moreover, the intermolecular similarity of novel compounds was analyzed in the multidimensional space (mDS) of the structure/property-related in silico descriptors by means of principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The distance-oriented structure/property distribution was related with the experimental lipophilic data.
Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
- MeSH
- antiflogistika chemie farmakokinetika farmakologie terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie MeSH
- cyklické nukleotidfosfodiesterasy, typ 7 antagonisté a inhibitory MeSH
- imidazoly chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesteras chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesterasy 4 chemie farmakokinetika farmakologie terapeutické užití MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- potkani Wistar MeSH
- pyridiny chemie farmakokinetika farmakologie terapeutické užití MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.
- MeSH
- adrenergní látky metabolismus MeSH
- bílá tuková tkáň metabolismus MeSH
- hnědá tuková tkáň metabolismus MeSH
- hormony štítné žlázy metabolismus MeSH
- lipogeneze fyziologie MeSH
- myši transgenní MeSH
- signální transdukce fyziologie MeSH
- termogeneze genetika MeSH
- tukové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND AND PURPOSE: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. EXPERIMENTAL APPROACH: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M2 receptors was modelled in silico. KEY RESULTS: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. CONCLUSIONS AND IMPLICATIONS: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.
- MeSH
- agonisté muskarinových receptorů * farmakologie MeSH
- antagonisté muskarinových receptorů farmakologie MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- křečci praví MeSH
- krysa rodu rattus MeSH
- receptor muskarinový M2 MeSH
- receptory muskarinové * MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Though bivalve mollusks are keystone species and major species groups in aquaculture production worldwide, gamete biology is still largely unknown. This review aims to provide a synthesis of current knowledge in the field of sperm biology, including spermatozoa motility, flagellar beating, and energy metabolism; and to illustrate cellular signaling controlling spermatozoa motility initiation in bivalves. Serotonin (5-HT) induces hyper-motility in spermatozoa via a 5-HT receptor, suggesting a serotoninergic system in the male reproductive tract that might regulate sperm physiology. Acidic pH and high concentration of K+ are inhibitory factors of spermatozoa motility in the testis. Motility is initiated at spawning by a Na+-dependent alkalization of intracellular pH mediated by a Na+/H+ exchanger. Increase of 5-HT in the testis and decrease of extracellular K+ when sperm is released in seawater induce hyperpolarization of spermatozoa membrane potential mediated by K+ efflux and associated with an increase in intracellular Ca2+ via opening of voltage-dependent Ca2+ channels under alkaline conditions. These events activate dynein ATPases and Ca2+/calmodulin-dependent proteins resulting in flagellar beating. It may be possible that 5-HT is also involved in intracellular cAMP rise controlling cAMP-dependent protein kinase phosphorylation in the flagellum. Once motility is triggered, flagellum beats in asymmetric wave pattern leading to circular trajectories of spermatozoa. Three different flagellar wave characteristics are reported, including "full", "twitching", and "declining" propagation of wave, which are described and illustrated in the present review. Mitochondrial respiration, ATP content, and metabolic pathways producing ATP in bivalve spermatozoa are discussed. Energy metabolism of Pacific oyster spermatozoa differs from previously studied marine species since oxidative phosphorylation synthetizes a stable level of ATP throughout 24-h motility period and the end of movement is not explained by a low intracellular ATP content, revealing different strategy to improve oocyte fertilization success. Finally, our review highlights physiological mechanisms that require further researches and points out some advantages of bivalve spermatozoa to extend knowledge on mechanisms of motility.
- MeSH
- druhová specificita MeSH
- energetický metabolismus MeSH
- flagella fyziologie MeSH
- mlži fyziologie MeSH
- motilita spermií fyziologie MeSH
- spermie cytologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
... Fredrick -- 7 Hearing Impairment, 43 -- Lionel Van Maldergem, Guy Van Camp, and Paul Deltenre -- 8 Vertigo ... ... Cowan, Bryce Mendelsohn, and Seymour Packman -- 38 Inborn Errors of Urea Synthesis, 298 -- Sandesh C.S ...
Sixth edition xxvi, 1403 stran : ilustrace ; 28 cm
- MeSH
- dítě MeSH
- epilepsie MeSH
- nádory nervového systému MeSH
- nemoci nervového systému MeSH
- neurologie MeSH
- novorozenec MeSH
- pediatrie MeSH
- Check Tag
- dítě MeSH
- novorozenec MeSH
- Publikační typ
- monografie MeSH
- Konspekt
- Lékařské vědy. Lékařství
- NLK Obory
- pediatrie
- neurologie
BACKGROUND: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood. METHODS & RESULTS: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT. Consistent with induction of adipose sympathetic nerve activity, iAdFASNKO mice displayed markedly increased neuronal tyrosine hydroxylase (TH) and neuropeptide Y (NPY) content in iWAT. In contrast, brown adipose tissue (BAT) of iAdFASNKO mice showed no increase in TH or NPY, nor did FASN deletion selectively in brown adipocytes (UCP1-FASNKO mice) cause these effects in iWAT. CONCLUSIONS: These results demonstrate that downregulation of fatty acid synthesis via FASN depletion in white adipocytes of mature mice can stimulate neuronal signaling to control thermogenic programming in iWAT.
- MeSH
- AMP cyklický metabolismus MeSH
- krevní glukóza metabolismus MeSH
- kultivované buňky MeSH
- lipogeneze * MeSH
- mastné kyseliny biosyntéza MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neurony metabolismus fyziologie MeSH
- neuropeptid Y metabolismus MeSH
- sympatický nervový systém cytologie fyziologie MeSH
- syntázy mastných kyselin metabolismus MeSH
- termogeneze * MeSH
- tukové buňky metabolismus MeSH
- tyrosin-3-monooxygenasa metabolismus MeSH
- uncoupling protein 1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces CSR2 transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.
- MeSH
- arrestin genetika metabolismus MeSH
- časové faktory MeSH
- endocytóza * MeSH
- genetická transkripce MeSH
- glukosa nedostatek MeSH
- jaderné proteiny genetika metabolismus MeSH
- mutace MeSH
- protein-serin-threoninkinasy metabolismus MeSH
- proteinfosfatasa 1 metabolismus MeSH
- proteinkinasy závislé na cyklickém AMP metabolismus MeSH
- proteiny 14-3-3 metabolismus MeSH
- proteiny přenášející monosacharidy genetika metabolismus MeSH
- regulace genové exprese u hub MeSH
- represorové proteiny metabolismus MeSH
- Saccharomyces cerevisiae - proteiny genetika metabolismus MeSH
- Saccharomyces cerevisiae genetika metabolismus MeSH
- ubikvitinace MeSH
- Publikační typ
- časopisecké články MeSH
Apremilast je nový cíleně působící syntetický přípravek schválený pro léčbu psoriatické artritidy. Jeho účinnost a bezpečnost byla hodnocena ve čtyřech studiích fáze III rozsáhlého klinického programu PALACE (Psoriatic Arthritis Longterm Assessment of Clinical Efficacy). Apremilast působí jako selektivní inhibitor fosfodiesterázy 4 (PDE4), vede ke zvýšenému množství cAMP a přispívá tak ke snížené tvorbě prozánětlivých cytokinů (TNFα, IL 23 nebo IL 17) a naopak vede ke zvýšené tvorbě protizánětlivých cytokinů (např. IL 10) – důležitých faktorů patogeneze psoriatické artritidy. V tomto přehledném sdělení bude diskutován účinek a bezpečnost apremilastu u pacientů s psoriatickou artritidou. Jedná se o nový a nadějný lék pro psoriatickou artritidu, který je účinný, má příznivý bezpečnostní profil a nevyžaduje laboratorní či jiný monitoring pacientů.
Apremilast is a novel targeted synthetic drug approved for the treatment of psoriatic arthritis. Its effectiveness and safety have been evaluated in four phase III trials within a large clinical program PALACE (Psoriatic Arthritis Longterm Assessment of Clinical Efficacy). Apremilast is a selective phosphodiesterase 4 inhibitor (PDE4), increases the amount of cAMP, reduces the synthesis of proinflammatory cytokines (TNFa, IL-23 or IL-17), and promotes the synthesis of antiinflammatory cytokines (e.g. IL-10) – important factors in the pathogenesis of psoriatic arthritis. In this review, effectiveness and safety of apremilast in patients with psoriatic arthritis are discussed. It is a new and hope-inspiring drug that is effective, has a favorable safety profile and does not require laboratory or any other patient monitoring.
- Klíčová slova
- apremilast, studie PALACE,
- MeSH
- antiflogistika nesteroidní farmakokinetika farmakologie škodlivé účinky terapeutické užití MeSH
- inhibitory fosfodiesterasy 4 MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- psoriatická artritida farmakoterapie MeSH
- randomizované kontrolované studie jako téma MeSH
- thalidomid * analogy a deriváty farmakokinetika farmakologie škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
