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https://www.readbyqxmd.com/read/30547573/6-phenylpyrimidin-4-ones-as-positive-allosteric-modulators-at-the-m1-machr-the-determinants-of-allosteric-activity
#1
Manuela Jörg, Emma T van der Westhuizen, Elham Khajehali, Wessel A C Burger, Jonathan M White, Kwok H C Choy, Andrew B Tobin, Patrick M Sexton, Celine Valant, Ben Capuano, Arthur Christopoulos, Peter J Scammells
Targeting allosteric sites of the M1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study...
December 14, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/30529302/m1-muscarinic-receptors-facilitate-hippocampus-dependent-cognitive-flexibility-via-modulating-glua2-subunit-of-ampa-receptors
#2
Cai-Hong Xiong, Ming-Gang Liu, Lan-Xue Zhao, Mu-Wen Chen, Ling Tang, Ying-Hui Yan, Hong-Zhuan Chen, Yu Qiu
Cognitive flexibility is an important aspect of executive function. The cholinergic system, an important component of cognition, has been shown to modulate cognitive flexibility mainly through the striatum and prefrontal cortex. The role of M1 muscarinic receptors (M1 mAChRs), an important therapeutic target in the cholinergic system, in hippocampus-dependent cognitive flexibility is unclarified. In the present study, we demonstrated that selective activation of M1 mAChRs promoted extinction of initial learned response and facilitated acquisition of reversal learning in the Morris water maze, a behavior test that is mainly dependent on the hippocampus...
December 6, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/30507034/optimization-and-pharmacological-characterization-of-receptor-mediated-g-i-o-activation-in-postmortem-human-prefrontal-cortex
#3
Yuji Odagaki, Masakazu Kinoshita, Toshio Ota, J Javier Meana, Luis F Callado, Jesús A García-Sevilla
The biochemical abnormalities in transmembrane signal transduction mediated through G protein-coupled receptors (GPCRs) have been postulated as underlying pathophysiology of psychiatric diseases such as schizophrenia and mood disorders. In the present study, the experimental conditions of agonist-induced [35 S]GTPγS binding in postmortem human brain membranes were optimized, and the responses induced by a series of agonists were pharmacologically characterized. The [35 S]GTPγS binding assay was performed in postmortem human prefrontal cortical membranes by means of filtration techniques, and standardized as to GDP concentration, membrane protein content, MgCl2 and NaCl concentrations in assay buffer, incubation period, and effect of white matter contamination...
December 3, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/30501602/role-of-muscarinic-acetylcholine-receptors-in-breast-cancer-design-of-metronomic-chemotherapy
#4
M E Sales, A J Español, A R Salem, P Pulido Martínez, Y Sanchez, F Sanchez
BACKGROUND: Muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies. METHODS: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment...
December 2, 2018: Current Clinical Pharmacology
https://www.readbyqxmd.com/read/30500461/protective-potentials-of-far-infrared-ray-against-neuropsychotoxic-conditions
#5
REVIEW
Naveen Sharma, Eun-Joo Shin, Nam Hun Kim, Eun-Hee Cho, Ji Hoon Jeong, Choon Gon Jang, Seung-Yeol Nah, Toshitaka Nabeshima, Yukio Yoneda, Jean Lud Cadet, Hyoung-Chun Kim
Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the underlying mechanism conveyed by FIR remains unclear. Recently, we demonstrated that exposure to FIR induces antioxidant potentials via up-regulation of glutathione peroxidase (GPx)-1 gene. The antioxidant potentials might be important for the modulation on the neuropsychotoxic conditions. Exposure to FIR protects from methamphetamine (MA)-induced memory impairments via phosphorylation of ERK 1/2 signaling by positive modulation of protein kinase C δ (PKCδ), M1 muscarinic acetylcholine receptor (M1 mAChR), and nuclear factor E2-related factor 2 (Nrf2) transcription factor...
November 27, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/30480808/cholinergic-activity-regulates-the-secretome-of-epicardial-adipose-tissue-association-with-atrial-fibrillation
#6
Marinela Couselo-Seijas, Jose N López-Canoa, Rosa M Agra-Bermejo, Esther Díaz-Rodriguez, Angel L Fernandez, Jose M Martinez-Cereijo, Dario Durán-Muñoz, Susana B Bravo, Alba Velo, Laila González-Melchor, Xesus A Fernández-López, Jose L Martínez-Sande, Javier García-Seara, Jose R González-Juanatey, Moises Rodriguez-Mañero, Sonia Eiras
Botulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real-time polymerase chain reaction or western blot showed their expression in EAT...
November 27, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/30480428/striatal-hippocampal-and-cortical-networks-are-differentially-responsive-to-the-m4-and-m1-muscarinic-acetylcholine-receptor-mediated-effects-of-xanomeline
#7
Catherine A Thorn, Joshua Moon, Clinton A Bourbonais, John Harms, Jeremy R Edgerton, Eda Stark, Stefanus J Steyn, Christopher R Butler, John T Lazzaro, Rebecca E O'Connor, Michael Popiolek
Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, whose efficacy is thought to be mediated through co-activation of the M1and the M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5'-cyclic adenosine monophosphate-response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation, in striatum, hippocampus and prefrontal cortex...
November 27, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/30478974/invasiveness-triggered-state-transition-in-malignant-melanoma-cells
#8
Huan Wang, Yan-Guo Zhang, Jing Ma, Jun-Chang Li, Jian Zhang, Yao-Qing Yu
Cancer cells are considered to have high morphological heterogeneity in human melanoma tissue. Here, we report that epithelial cancer cells are dominant in different development stages of human melanoma tissues. The cellular and molecular mechanisms that maintain melanoma cells in the epithelial state are further investigated in the A2058 cell line. We find that micropore (8 µm) transwell invasion, but not superficial migration in the scratch assay, can induce remarkable morphological changes between epithelial and mesenchymal melanoma cells within 4 days...
November 27, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/30478410/blockade-of-muscarinic-acetylcholine-receptors-facilitates-motivated-behaviour-and-rescues-a-model-of-antipsychotic-induced-amotivation
#9
Jonathan M Hailwood, Christopher J Heath, Benjamin U Phillips, Trevor W Robbins, Lisa M Saksida, Timothy J Bussey
Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4)...
November 27, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/30450304/effect-of-green-flickering-light-on-myopia-development-and-expression-of-m1-muscarinic-acetylcholine-receptor-in-guinea-pigs
#10
Yuan Tao, Xiao-Li Li, Li-Yuan Sun, Yu-Hua Wei, Xiao-Ting Yu, Hong Wang
AIM: To investigate the effects of green flickering light on refractive development and expression of muscarinic acetylcholine receptor (mAChR) M1 in the eyes of guinea pigs. METHODS: Thirty guinea pigs (15-20 days old) were randomly divided into three groups ( n =10/group). Animals in group I were raised in a completely closed carton with green flickering light illumination. Those in group II were kept in the open top closed carton under normal natural light. Guinea pigs were raised in a sight-widen cage under normal natural light in group III...
2018: International Journal of Ophthalmology
https://www.readbyqxmd.com/read/30450012/m3-muscarinic-acetylcholine-receptors-regulate-epithelial-mesenchymal-transition-perineural-invasion-and-migration-metastasis-in-cholangiocarcinoma-through-the-akt-pathway
#11
Yujie Feng, Xiao Hu, Guangwei Liu, Lianfang Lu, Wei Zhao, Fangzhen Shen, Kai Ma, Chuandong Sun, Chengzhan Zhu, Bingyuan Zhang
Background: Cholangiocarcinoma is a highly malignant tumor type that is not sensitive to radiotherapy or chemotherapy due to aggressive perineural invasion and metastasis. Unfortunately, the mechanisms underlying these processes and the signaling factors involved are largely unknown. In this study, we analyzed the role of M3 muscarinic acetylcholine receptors (M3-mAChR) in cell migration, perineural invasion, and metastasis during cholangiocarcinoma. Methods: We assessed 60 human cholangiocarcinoma tissue samples and 30 normal biliary tissues...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/30423942/effects-of-a-pasty-bone-cement-containing-brain-derived-neurotrophic-factor-functionalized-mesoporous-bioactive-glass-particles-on-metaphyseal-healing-in-a-new-murine-osteoporotic-fracture-model
#12
Vivien Kauschke, Maike Schneider, Annika Jauch, Matthias Schumacher, Marian Kampschulte, Marcus Rohnke, Anja Henss, Coralie Bamberg, Katja Trinkaus, Michael Gelinsky, Christian Heiss, Katrin Susanne Lips
The development of new and better implant materials adapted to osteoporotic bone is still urgently required. Therefore, osteoporotic muscarinic acetylcholine receptor M3 (M3 mAChR) knockout (KO) and corresponding wild type (WT) mice underwent osteotomy in the distal femoral metaphysis. Fracture gaps were filled with a pasty α-tricalcium phosphate (α-TCP)-based hydroxyapatite (HA)-forming bone cement containing mesoporous bioactive CaP-SiO₂ glass particles (cement/MBG composite) with or without Brain-Derived Neurotrophic Factor (BDNF) and healing analyzed after 35 days...
November 9, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30409608/antihypertensive-effects-of-orally-administered-eggplant-solanum-melongena-rich-in-acetylcholine-on-spontaneously-hypertensive-rats
#13
Shohei Yamaguchi, Kento Matsumoto, Masahiro Koyama, Su Tian, Masanori Watanabe, Akihiko Takahashi, Koji Miyatake, Kozo Nakamura
Our previous results (Nakamura et al., 2013, 2016) indicated that acetylcholine (ACh) in orally administered foods exerts antihypertensive effects. Eggplants (Solanum melongena) contain abundant ACh (Horiuchi et al., 2003), and their food functionality was discovered, using spontaneously hypertensive rats, by measuring blood pressure after oral administration of a suspension of lyophilized eggplant powder. We found that lyophilized eggplant powder induced significantly lowered acute and chronic blood pressure levels at very low doses of 0...
March 15, 2019: Food Chemistry
https://www.readbyqxmd.com/read/30407877/direct-sumoylation-of-m1-muscarinic-acetylcholine-receptor-increases-its-ligand-binding-affinity-and-signal-transduction
#14
Jianrong Xu, Panpan Tan, Hui Li, Yongyao Cui, Yu Qiu, Hao Wang, Xuan Zhang, Juan Li, Liang Zhu, Wei Zhou, Hongzhuan Chen
SUMOylation is a significant post-translational modification (PTM) by the small ubiquitin-related modifier (SUMO). Increasing evidence shows SUMOylation regulates GPCR signaling; however, very few GPCRs have been shown to be SUMOylation targets to date. In this study, we identified M1 muscarinic acetylcholine receptor (M1 mAChR), a member of the GPCRs, as a new SUMO substrate. When the mAChR was activated by the agonist carbachol, the colocalization of the M1 mAChR and SUMO-1 protein markedly decreased in immunoprecipitation and immunofluorescence assays...
November 8, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/30387811/spicatoside-a-in-red-liriope-platyphylla-displays-a-laxative-effect-in-a-constipation-rat-model-via-regulating-machrs-and-er-stress-signaling
#15
Ji Eun Kim, Jun Go, Hee Seob Lee, Jin Tae Hong, Dae Youn Hwang
Red Liriope platyphylla extract (EtRLP) has been used as an oriental medicine for treatment of several chronic conditions, such as neurodegenerative disorders, diabetes, and obesity. To investigate the laxative activity of EtRLP, the levels of key constipation markers and their molecular regulators were examined following administration of EtRLP in constipation Sprague Dawley (SD) rats treated with loperamide (Lop). Compared with the Lop+Vehicle‑treated group, the excretion levels of urine and stool were significantly enhanced in the Lop+EtRLP‑treated group, even though feeding levels were kept constant...
January 2019: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/30387129/parasympathectomy-increases-resting-secretion-of-the-submandibular-gland-in-minipigs-in-the-long-term
#16
Xue-Ming Zhang, Yan Huang, Xin Cong, Ling-Han Qu, Kuo Zhang, Li-Ling Wu, Yan Zhang, Guang-Yan Yu
Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long-term effect is unclear. Excessive secretion is observed in half of the patients 4-6 months after SMG transplantation, which completely denervates the gland. Here, we investigated the long-term effect of parasympathectomy on the secretion of SMGs in minipigs. The results showed that the resting salivary secretion of SMGs decreased by 82.9% of that in control at 2 months after denervation, but increased by 156% at 6 months...
November 1, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/30360392/the-anti-inflammatory-effects-of-fermented-herbal-roots-of-asparagus-cochinchinensis-in-an-ovalbumin-induced-asthma-model
#17
Jun Young Choi, Ji Eun Kim, Jin Ju Park, Mi Rim Lee, Bo Ram Song, Ji Won Park, Mi Ju Kang, Hee Seob Lee, Hong Joo Son, Jin Tae Hong, Dae Youn Hwang
Introduction: Roots of Asparagus cochinchinensis , which have pharmacologically active ingredients, have received great attention because they show good therapeutic effects for various inflammatory diseases without specific toxicity. This study investigated the anti-asthmatic effects of a butanol extract of Asparagus cochinchinensis roots that had been fermented with Weissella cibaria (BAW) and its possible underlying cholinergic regulation. Methods: Alterations of the anti-asthmatic markers and the molecular response factors were measured in an ovalbumin (OVA)-induced asthma model after treatment with BAW...
October 22, 2018: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/30327427/re1-silencing-transcription-factor-controls-the-acute-to-chronic-neuropathic-pain-transition-and-chrm2-receptor-gene-expression-in-primary-sensory-neurons
#18
Jixiang Zhang, Shao-Rui Chen, Hong Chen, Hui-Lin Pan
Neuropathic pain is associated with persistent changes in gene expression in primary sensory neurons, but the underlying epigenetic mechanisms that cause these changes remain unclear. The muscarinic cholinergic receptors (mAChRs), particularly the M2 subtype (encoded by the cholinergic receptor muscarinic 2 [Chrm2] gene), are critically involved in the regulation of spinal nociceptive transmission. However, little is known about how Chrm2 expression is transcriptionally regulated. Here we show that nerve injury persistently increased the expression of RE1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor [NRSF]), a gene-silencing transcription factor, in the dorsal root ganglion (DRG)...
October 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/30280567/the-muscarinic-acetylcholine-receptor-m-5-therapeutic-implications-and-allosteric-modulation
#19
Aaron M Bender, Aaron T Garrison, Craig W Lindsley
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5 ) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor's role in physiological processes related to Alzheimer's disease, schizophrenia, and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small-molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology...
October 17, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/30270332/hippocampal-cholinergic-neurostimulating-peptide-suppresses-acetylcholine-synthesis-in-t-lymphocytes
#20
Yuka Saito, Masato Mashimo, Akari Nobeyama, Kana Murakami, Takeshi Fujii
Lymphocytic cholinergic system has important roles in T cell functions, including immune responses and proliferation and differentiation of immune cells. T lymphocytes exclusively produces acetylcholine (ACh) via choline acetyltransferase (ChAT), activating their muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) in an autocrine and paracrine manners. Hippocampal cholinergic neurostimulating peptide (HCNP) is an undecapeptide cleaved from N-terminal of phosphatidylethanolamine-binding protein 1 (PEBP1)...
2018: Biological & Pharmaceutical Bulletin
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