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Kateřina Melková, Vojtěch Zapletal, Séverine Jansen, Erik Nomilner, Milan Zachrdla, Jozef Hritz, Jiří Nováček, Markus Zweckstetter, Malene R Jensen, Martin Blackledge, Lukas Zidek
Microtubule-associated protein 2c (MAP2c)1 is a 49-kDa intrinsically disordered protein regulating the dynamics of microtubules in developing neurons. MAP2c differs from its sequence homologue Tau in the pattern and kinetics of phosphorylation by cAMP-dependent protein kinase (PKA). Moreover, the mechanisms through which MAP2c interacts with its binding partners and the conformational changes and dynamics associated with these interactions remain unclear. Here, we used NMR relaxation and paramagnetic relaxation enhancement techniques to determine the dynamics and long-range interactions within MAP2c...
June 20, 2018: Journal of Biological Chemistry
Annabelle M Watts, Nicholas P West, Allan W Cripps, Pete K Smith, Amanda J Cox
BACKGROUND: Investigations of gene expression in allergic rhinitis (AR) typically rely on invasive nasal biopsies (site of inflammation) or blood samples (systemic immunity) to obtain sufficient genetic material for analysis. New methodologies to circumvent the need for invasive sample collection offer promise to further the understanding of local immune mechanisms relevant in AR. METHODS: A within-subject design was employed to compare immune gene expression profiles obtained from nasal washing/brushing and whole blood samples collected during peak pollen season...
June 19, 2018: International Archives of Allergy and Immunology
Muhammad Irfan, Da Hye Jeong, Hyuk-Woo Kwon, Jung-Hae Shin, Sang-Joon Park, Dongmi Kwak, Tae-Hwan Kim, Dong-Ha Lee, Hwa-Jin Park, Man Hee Rhee
BACKGROUND & PURPOSE: Ginseng (Panax ginseng C.A. Mayer) contains saponin fractions called ginsenosides, which are thought to be the main components responsible for its various pharmacological activities. Ginsenosides have cardioprotective and antiplatelet effects. In the present study, we evaluated the effects of ginsenoside Rp3 (G-Rp3) on platelet function. METHODS: The in vitro effects of G-Rp3 were evaluated on agonist-induced human and rat platelet aggregation, while [Ca2+ ]i mobilization, granule secretion, integrin αIIb β3 activation, and clot retraction were assessed in rat platelets...
June 8, 2018: Vascular Pharmacology
Vinay Lanke, S T R Moolamalla, Dipanjan Roy, P K Vinod
Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years)...
2018: Frontiers in Aging Neuroscience
Pang-Dian Fan, Giuseppe Narzisi, Anitha D Jayaprakash, Elisa Venturini, Nicolas Robine, Peter Smibert, Soren Germer, Helena A Yu, Emmet J Jordan, Paul K Paik, Yelena Y Janjigian, Jamie E Chaft, Lu Wang, Achim A Jungbluth, Sumit Middha, Lee Spraggon, Huan Qiao, Christine M Lovly, Mark G Kris, Gregory J Riely, Katerina Politi, Harold Varmus, Marc Ladanyi
In ∼30% of patients with EGFR -mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR -mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET , a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1...
June 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yushuang Yang, Jie Yang, Fenghua Sui, Pengfei Huo, Hailing Yang
Objective: This study used bioinformatics to determine genetic factors involved in progression of acute myocardial infarction (MI). Materials and Methods: In this prospective study, gene expression profile GSE59867 was downloaded from the Gene Expression Omnibus database, which contained 46 normal samples obtained from stable coronary artery disease patients (n=46) who were without history of MI (control) and 390 samples from patients (n=111) who had evolving ST-segment elevation myocardial infarction (STEMI) as the MI group...
October 2018: Cell Journal
Erika N Cline, Maíra Assunção Bicca, Kirsten L Viola, William L Klein
The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death. The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor...
May 18, 2018: Journal of Alzheimer's Disease: JAD
Jun Ren, Yi Cheng, Zhen-Hua Ming, Xin-Yan Dong, Yu-Zhong Zhou, Guo-Lian Ding, Hai-Yan Pang, Tanzil Ur Rahman, Rubab Akbar, He-Feng Huang, Jian-Zhong Sheng
BACKGROUND: The existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia...
May 25, 2018: Epigenetics & Chromatin
Yangyang Li, Tengteng Zhu, Huan Yang, Sulayman Dib-Hajj, Stephen Waxman, Ye Yu, Tian-Le Xu, Xiaoyang Cheng
Voltage-gated sodium channel Nav1.7 is a key molecule in nociception, and its dysfunction has been associated with various pain disorders. Here, we investigated the regulation of Nav1.7 biophysical properties by Fyn, a Src family tyrosine kinase. Nav1.7 was coexpressed with either constitutively active (FynCA) or dominant negative (FynDN) variants of Fyn kinase. FynCA elevated protein expression and tyrosine phosphorylation of Nav1.7 channels. Site-directed mutagenesis analysis identified two tyrosine residues (Y1470 and Y1471) located within the Nav1...
January 1, 2018: Molecular Pain
Chuanzhou Li, Jürgen Götz
The protein tyrosine kinase Pyk2 is encoded by PTK2B, a novel Alzheimer's disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit increased tyrosine phosphorylation and accumulation of tau...
May 16, 2018: Journal of Alzheimer's Disease: JAD
Young Hwan Park, Do Kyun Kim, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Keun Young Min, Jimo Koo, Su Jeong Kim, Changhee Kang, Young Mi Kim, Hyung Sik Kim, Wahn Soo Choi
Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC50 , ∼ 27.9 nM) and BMMCs (IC50 , ∼ 99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activated T cells (LAT), phospholipase (PL) Cγ1, Akt, and mitogen-activated protein (MAP) kinases (Erk1 / 2, p38, and JNK) in mast cells...
May 16, 2018: Biochemical Pharmacology
Kamel Laribi, Mustapha Alani, Catherine Truong, Alix Baugier de Materre
OBJECTIVE: Mature T-cell lymphomas are a heterogeneous group of T-cell malignancies with a poor outcome. The discovery of new molecular biomarkers has led to the emergence of new drugs in recent years that target various signaling pathways. METHOD: We examined all pertinent published patents through 2015 that analyzed novel methods for the diagnosis and treatment of T cell lymphoma, as well as related published and unpublished studies. Selection criteria were established before data collection...
May 16, 2018: Recent Patents on Anti-cancer Drug Discovery
Nicholas J Bernard
No abstract text is available yet for this article.
May 14, 2018: Nature Reviews. Rheumatology
Dawei Wu, Sarina K Mueller, Angela L Nocera, Kristen Finn, Towia A Libermann, Benjamin S Bleier
Background Dysfunctional innervation might contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), but the state of the axonal outgrowth signaling in CRSwNP is unknown. The purpose of this study was to explore the axonal outgrowth pathway-related protein expression in CRSwNP. Methods Institutional review board approved study in which tissue proteomes were compared between control and CRSwNP patients (n = 10/group) using an aptamer-based proteomic array and confirmed by whole transcriptomic analysis...
January 1, 2018: American Journal of Rhinology & Allergy
Dmitri Samovski, Pallavi Dhule, Terri Pietka, Miriam Jacome-Sosa, Eric Penrose, Ni-Huiping Son, Robert C Flynn, Kooresh I Shoghi, Krzysztof L Hyrc, Ira J Goldberg, Eric R Gamazon, Nada A Abumrad
During reduced energy intake, skeletal muscle maintains homeostasis by rapidly suppressing insulin-stimulated glucose utilization. Loss of this adaptation is observed with deficiency of the fatty acid transporter CD36. A similar loss is also characteristic of the insulin resistant state where CD36 is dysfunctional. To elucidate what links CD36 to muscle glucose utilization we examined whether CD36 signaling might influence insulin action. First, we show that CD36 deletion specific to skeletal muscle reduces expression of insulin signaling and glucose metabolism genes...
May 10, 2018: Diabetes
Giulio Poli, Margherita Lapillo, Carlotta Granchi, Jessica Caciolla, Nayla Mouawad, Isabella Caligiuri, Flavio Rizzolio, Thierry Langer, Filippo Minutolo, Tiziano Tuccinardi
Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC50  = 4.8 μM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Shahid Muhammad Iqbal, Mohammed Aufy, Waheed Shabbir, Rosa Lemmens-Gruber
Cardiac sodium channel NaV 1.5 is the predominant form of sodium channels in cardiomyocytes, which exists as a macromolecular complex and interacts with multiple protein partners. Fyn kinase is one of the interacting proteins which co-localize, phosphorylate and modulate the NaV 1.5 channel. To elaborate this interaction we created expression vectors for the N-terminal, intracellular loop and C-terminal regions of the NaV 1.5 channel, to express in HEK-293 cells. By co-immunoprecipitation and anti-phosphotyrosine blotting, we identified proline-rich binding sites for Fyn kinase in the N-terminal, IC-loopi-ii and C-terminal...
May 7, 2018: FEBS Journal
Lei Zhao, Chang Zhang, Xiaoxiao Luo, Pei Wang, Wei Zhou, Shan Zhong, Yunxia Xie, Yibo Jiang, Ping Yang, Renkuang Tang, Qin Pan, Andrew R Hall, Tu Vinh Luong, Jiangao Fan, Zac Varghese, John F Moorhead, Massimo Pinzani, Yaxi Chen, Xiong Z Ruan
BACKGROUND AND AIMS: Fatty acid translocase CD36 (CD36) is a membrane protein with multiple immuno-metabolic functions. Palmitoylation has been suggested to regulate the distribution and functions of CD36, but little is known about its significance in non-alcoholic steatohepatitis (NASH). METHODS: Human liver tissue samples were obtained from patients undergoing liver biopsy for diagnostic purposes. CD36 knockout mice were injected with lentiviral vectors expressing wild-type CD36 or CD36 with mutated palmitoylation sites...
April 27, 2018: Journal of Hepatology
Md Izhar Ashraf, Seng-Kai Ong, Shama Mujawar, Shrikant Pawar, Pallavi More, Somnath Paul, Chandrajit Lahiri
Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets...
April 27, 2018: Scientific Reports
Hao Jiang, Li Dong, Fangyan Gong, Yuping Gu, Henghun Zhang, Dong Fan, Zhiguo Sun
Inflammatory genes serve a crucial role in the pathogenesis of inflammation‑associated tumors. However, as recent studies have mainly focused on the effects of single inflammatory genes on colorectal cancer (CRC), but not on the global interactions between genes, the underlying mechanisms between inflammatory genes and CRC remain unclear. In the current study, two inflammation‑associated networks were constructed based on inflammatory genes, differentially expressed genes (DEGs) in CRC vs. normal samples, and protein‑protein interactions (PPIs)...
July 2018: International Journal of Molecular Medicine
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