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methylation histamine

Joanna Sniecikowska, Monika Głuch-Lutwin, Adam Bucki, Anna Więckowska, Agata Siwek, Magdalena Jastrzębska-Więsek, Anna Partyka, Daria Wilczyńska, Karolina Pytka, Krzysztof Pociecha, Agnieszka Cios, Elżbieta Wyska, Anna Wesołowska, Maciej H Pawłowski, Mark Varney, Adrian Newman-Tancredi, Marcin Kołaczkowski
Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as 'biased agonists' of serotonin 5-HT1A receptors. Compounds were tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. The novel series showed high 5 HT1A receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, 5-HT2A, histamine H1 and muscarinic M1 receptors, and favorable drug-likeness properties (CNS-MPO, Fsp3, LELP)...
February 5, 2019: Journal of Medicinal Chemistry
Silvia Bua, Susanna Haapanen, Marianne Kuuslahti, Seppo Parkkila, Claudiu T Supuran
The β-carbonic anhydrase (CA, EC from the pathogenic protozoan Entamoeba histolytica , EhiCA, was investigated for its activation with a panel of natural and non-natural amino acids and amines. EhiCA was potently activated by D-His, D-Phe, D-DOPA, L- and D-Trp, L- and D-Tyr, 4-amino-L-Tyr, histamine and serotonin, with KA s ranging between 1.07 and 10.1 M. The best activator was D-Tyr (KA of 1.07 µM). L-Phe, L-DOPA, L-adrenaline, L-Asn, L-Asp, L-Glu and L-Gln showed medium potency activation, with KA s of 16...
February 1, 2019: Metabolites
Caroline Louis, Karine Llopis, Laurence Danober, Fany Panayi, Pierre Lestage, Daniel Beracochea
This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2-3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer's disease. The object recognition task allows the study of natural forgetting and is classically used in assessing drug effects on memory. Here, we show that mice exhibit significant object recognition at short (15 min) but not long (24 h) retention intervals separating the familiarization and recognition phases...
November 26, 2018: Behavioural Pharmacology
Wataru Ichinose, Tsukasa Sawato, Haruna Kitano, Yasuhiro Shinozaki, Mieko Arisawa, Nozomi Saito, Takeo Yoshikawa, Masahiko Yamaguchi
Optically active helicene derivatives inhibit the activity on histamine N-methyl transferase (HNMT). Specifically, methyl (P)-1,12-dimethylbenzo[c]phenanthrene-8-carboxylate with 6-iodo and 5-trifluoromethanesulfonyloxy groups inhibits HNMT activity on the μM order of IC50 . Chirality is important, and (M)-isomers exhibits substantially reduced activity. The 6-iodo group is also essential, which suggests the involvement of halogen bonds in protein binding. Substituents on the sulfonate moiety also affect the inhibitory activity...
November 20, 2018: Journal of Antibiotics
Daniel Röth, Abby J Chiang, Weidong Hu, Gabriel B Gugiu, Christina N Morra, James Versalovic, Markus Kalkum
Colonization of the gut by certain probiotic Lactobacillus reuteri strains has been associated with reduced risk of inflammatory diseases and colorectal cancer. Previous studies pointed to a functional link between immunomodulation, histamine production, and folate metabolism, the central 1-carbon pathway for the transfer of methyl groups. Using mass spectrometry and NMR spectroscopy, we analyzed folate metabolites of L. reuteri strain 6475 and discovered that the bacterium produces a 2-carbon-transporting folate in the form of 5,10-ethenyl-tetrahydrofolyl polyglutamate...
November 19, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ebru Aydin, Alexander Hallner, Hanna Grauers Wiktorin, Anna Staffas, Kristoffer Hellstrand, Anna Martner
Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-KrasG12D  × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-KrasG12D ) were treated with Nα -methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H2 receptors...
October 15, 2018: Oncogene
Tatyana S Khlebnicova, Yuri A Piven, Alexander V Baranovsky, Fedor A Lakhvich, Iryna V Sorokina, Tatyana G Tolstikova
A series of novel fluorine-containing lupane triterpenoid acid derivatives with fluoroaromatic amide moieties at the C-28 position (1-8) or with 2-(fluoroacyl)cyclopentane-1,3-dione fragments at the C-3 position (9-18) of lupane skeleton was synthesized. A simple synthesis of novel lupane triterpenoid hybrids with 2-(fluoroacyl)-2-cyclopenten-1-one moieties was developed. An interaction of 2-acyl-3-chlorocyclopent-2-en-1-ones, obtained from corresponding cyclic β-triketones, with methyl 3-amino-3-deoxybetulinate gave 3β-isomers (9-13) and 3α-isomers (14-18) of target hybrids, which were isolated as individual compounds...
October 5, 2018: Steroids
Carolyn D Keagy
The topic of interstitial cystitis (IC), also known as painful bladder syndrome (PBS), and folate/one carbon metabolism has previously been unaddressed in research. This narrative review highlights a potential connection for those with mast cell-related IC and histamine-mediated pain that is explored through four conceptual sections. The first section focuses on the nature of mast cell involvement and histamine-mediated pain in some interstitial cystitis patients. The second section reviews the literature on folate status in wider allergic conditions...
October 6, 2018: International Urogynecology Journal
Klaus J Wirth
BACKGROUND: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer's disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. OBJECTIVE: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase (atipamezole) or decrease (xylazine) NE in the brain...
2018: Journal of Alzheimer's Disease: JAD
Steffen Pockes, David Wifling, Max Keller, Armin Buschauer, Sigurd Elz
On the basis of the long-known prototypic pharmacophore 3-(1 H -imidazol-4-yl)propylguanidine (SK&F 91486, 2 ), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2 R) agonists with various alkyl spacers were synthesized. Aiming at increased H2 R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h / gp / r H2 R...
March 31, 2018: ACS Omega
Gwan Ui Hong, Jin Whan Cho, Soo Youl Kim, Joo Ho Shin, Jai Youl Ro
This study aimed to investigate the role of transglutaminase 2 (TG2) expressed in mast cells in substantia nigra (SN) in Parkinson's disease (PD) model or human PD patients. C57BL/6 mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by ip injection to induce PD. Bone marrow-derived mast cells (BMMCs) were adoptively transferred to TG2 knockout (KO or TG2-/- ) mice by iv injection 1 day before MPTP injection or stimulated by 1 methyl-4-phenylpyridinium (MMP+ ). KO-MPTP mice showed reduced expression of tyrosine hydroxylase (TH) and dopamine (DA) transporter (DAT) and loss of TH+ DA neurons, and expression of markers (c-kit, tryptase, FcεRI), mediators' release (histamine, leukotrienes, cytokines), and TG2 related to mast cells, and co-localization of DA neuronal cells and mast cells in SN tissues or release of mediators and TG2 activity in SN tissues and sera versus those in WT (wild type)-MPTP or BM + KO-MPTP mice...
November 1, 2018: Toxicology and Applied Pharmacology
Masanori Fujii, Kaori Takeuchi, Yuna Umehara, Masafumi Takeuchi, Takanori Nakayama, Sayaka Ohgami, Erika Asano, Takeshi Nabe, Susumu Ohya
In chronic pruritic diseases such as atopic dermatitis, pruritus is exacerbated during nocturnal sleep; however, the underlying mechanism remains unclear. We previously demonstrated that acute administration of the sedative-hypnotics ethanol markedly enhanced itch-associated spontaneous scratching in a diet-induced mouse model of atopic dermatitis. In the present study, to expand our previous finding and provide a general mechanism for the central modulation of chronic itch, we examined whether other hypnotic drugs, such as barbiturates and benzodiazepines, also enhance scratching, and further investigated the underlying mechanism...
October 5, 2018: European Journal of Pharmacology
Tomoya Hirano, Takashi Fujiwara, Hideaki Niwa, Michitake Hirano, Kasumi Ohira, Yusuke Okazaki, Shin Sato, Takashi Umehara, Yuki Maemoto, Akihiro Ito, Minoru Yoshida, Hiroyuki Kagechika
The histone methyltransferase SET7/9 methylates not only histone but also non-histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups...
August 10, 2018: ChemMedChem
Lin da Jia, Tan Tan Gao, Qi Peng, Jing Lv, Jie Zhang, Min Chen, Fu Ping Song
yhcZ and yhcY genes constitute a two-component system in Bacillus subtilis and B. cereus that regulates bacterial growth. However, the exact biological function of yhcZ gene in B. thuringiensis has not been fully elucidated. In this study, we proved that HD73_5824 is an yhcZ gene in B. thuringiensis subsp. kurstaki HD73 strain by combining gene functional annotation, analysis of upstream and downstream genes arrangement, and amino acid sequence alignment. This yhcZ gene may co-regulate bacterial growth with HD73_5825 gene (yhcY gene) by constituting a two-component system...
May 20, 2018: Yi Chuan, Hereditas
Jianbo Li, Yang Yang, Didi Wan, Youmei Peng, Jinjie Zhang
Asthma is one of the most prevalent chronic inflammatory diseases of lung. Current asthma therapy using inhaled corticosteroid often results in undesired treatment outcome due to poor compliance and drugs' lack of tissue specificity. N,N,N'-trimethyl-N'-(2-hydroxyl-3-methyl-5-123 Iiodobenzyl)-1,3-propanediamine (HIPD), a phenolic propanediamine derivative, has been used as an imaging agent for localized pulmonary diseases. Inspired by this, N,N,N'-trimethyl-N'-(4-hydroxyl-benzyl)-1,3-propanediamine (TPD), a new HIPD analog, was proposed as a lung-targeting ligand and covalently conjugated to an anti-inflammatory compound Rhein for asthma therapy...
November 2018: Drug Delivery
Iuliia Golovynska, Tatiana V Beregova, Tatiana M Falalyeyeva, Ludmila I Stepanova, Sergii Golovynskyi, Junle Qu, Tymish Y Ohulchanskyy
The enteric nervous system (ENS) and a glutamate receptor (GluR), N-methyl-D-aspartate receptor (NMDAR), participate in gastric acid secretion (GAS) regulation. NMDARs are localized in different stomach cells; however, knowledge of NMDAR expression and function in the ENS is limited. In the present study, we clarified the types of stomach cells that express the NMDARs that are involved in GAS regulation. The pharmacological method of isolated stomach perfusion by Ghosh and Shild combined with direct mapping of NMDARs by fluorescence microscopy in the rat stomach was employed...
May 10, 2018: Scientific Reports
A V Markov, A V Sen'kova, M A Zenkova, E B Logashenko
Due to wide spreading of inflammatory disease and imperfection of available anti-inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12-dioxo-18βH-olean-9(ll),l(2)-dien-30-oate...
March 2018: Molekuliarnaia Biologiia
Beata Olszewska, Anna Stasiak, Daniel McNaught Flores, Wiesława Agnieszka Fogel, Rob Leurs, Krzysztof Walczyński
Presynaptic histamine H₃ receptors (H₃R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H₃R antagonists, and there is a great interest for potent, brain-penetrating H₃ receptor antagonists/inverse agonists to compensate for the neurotransmitter deficits present in various neurological disorders. We have shown that 1-[(benzylfuran-2-yl)methyl]piperidinyl-4-oxyl- and benzyl- derivatives of N -propylpentan-1-amines exhibit high in vitro potencies toward the guinea pig H₃ receptor (jejunum), with pA₂ = 8...
April 19, 2018: International Journal of Molecular Sciences
Gustavo Nieto-Alamilla, Juan Escamilla-Sánchez, María-Cristina López-Méndez, Anayansi Molina-Hernández, Agustín Guerrero-Hernández, José-Antonio Arias-Montaño
In stably-transfected human neuroblastoma SH-SY5Y cells, we have compared the effect of activating two isoforms of 445 and 365 amino acids of the human histamine H3 receptor (hH3 R445 and hH3 R365 ) on [35 S]-GTPγS binding, forskolin-induced cAMP formation, depolarization-induced increase in the intracellular concentration of Ca2+ ions ([Ca2+ ]i) and depolarization-evoked [3  H]-dopamine release. Maximal specific binding (Bmax ) of [3  H]-N-methyl-histamine to cell membranes was 953 ± 204 and 555 ± 140 fmol/mg protein for SH-SY5Y-hH3 R445 and SH-SY5Y-hH3 R365 cells, respectively, with similar dissociation constants (Kd , 0...
April 2018: Journal of Receptor and Signal Transduction Research
Hlaing H Maw, Xingzhong Zeng, Scot Campbell, Mitchell E Taub, Aaron M Teitelbaum
BI 187004, an 11 β -hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N -methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N -methylbenzimidazole metabolite [ N -methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N -methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors...
June 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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