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https://www.readbyqxmd.com/read/29342447/design-synthesis-and-anticancer-studies-of-novel-aminobenzazolyl-pyrimidines-as-tyrosine-kinase-inhibitors
#1
Rupesh Chikhale, Sonali Thorat, Rajan Kumar Choudhary, Nikhil Gadewal, Pramod Khedekar
Abnormal signalling from the Protein tyrosine kinases (PTKs) like receptor tyrosine kinases and intracellular tyrosine kinases can lead to diseases such as cancer especially non-small cell lung cancer, chronic myeloid leukaemia and gastrointestinal stromal tumours. Various Protein tyrosine kinase inhibitors are available but face poor bioavailability, severe toxicities and recent cases of drug-resistant cancers prompts for development of better drug molecules. In this study we report the design and development of a novel Protein Tyrosine Kinase (PTK) inhibitor on the basis of pharmacophore modelling...
January 4, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29342258/insulin-and-estrogen-independently-and-differentially-reduce-macronutrient-intake-in-healthy-men
#2
Rosemarie Krug, Linda Mohwinkel, Bernhard Drotleff, Jan Born, Manfred Hallschmid
Context: Insulin administration to the central nervous system inhibits food intake, but this effect has been found to be less pronounced in female compared to male organisms. This sex-specific pattern has been suggested to arise from a modulating influence of estrogen signaling on the insulin effect. Objective: We assessed in healthy young men whether pre-treatment with transdermal estradiol interacts with the hypophagic effect of central nervous insulin administration via the intranasal pathway...
January 12, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29342181/optimization-of-mneongreen-for-homo-sapiens-increases-its-fluorescent-intensity-in-mammalian-cells
#3
Emiko Tanida-Miyake, Masato Koike, Yasuo Uchiyama, Isei Tanida
Green fluorescent protein (GFP) is tremendously useful for investigating many cellular and intracellular events. The monomeric GFP mNeonGreen is about 3- to 5-times brighter than GFP and monomeric enhanced GFP and shows high photostability. The maturation half-time of mNeonGreen is about 3-fold faster than that of monomeric enhanced GFP. However, the cDNA sequence encoding mNeonGreen contains some codons that are rarely used in Homo sapiens. For better expression of mNeonGreen in human cells, we synthesized a human-optimized cDNA encoding mNeonGreen and generated an expression plasmid for humanized mNeonGreen under the control of the cytomegalovirus promoter...
2018: PloS One
https://www.readbyqxmd.com/read/29342166/effects-of-vitamin-d-on-insulin-resistance-and-myosteatosis-in-diet-induced-obese-mice
#4
Elisa Benetti, Raffaella Mastrocola, Fausto Chiazza, Debora Nigro, Giuseppe D'Antona, Valentina Bordano, Roberto Fantozzi, Manuela Aragno, Massimo Collino, Marco Alessandro Minetto
Epidemiological studies pointed out to a strong association between vitamin D deficiency and type 2 diabetes prevalence. However, the role of vitamin D supplementation in the skeletal muscle, a tissue that play a crucial role in the maintenance of glucose homeostasis, has been scarcely investigated so far. On this basis, this study aimed to evaluate the effect of vitamin D supplementation in a murine model of diet-induced insulin resistance with particular attention to the effects evoked on the skeletal muscle...
2018: PloS One
https://www.readbyqxmd.com/read/29342159/prediction-of-novel-target-genes-and-pathways-involved-in-bevacizumab-resistant-colorectal-cancer
#5
Precious Takondwa Makondi, Chia-Hwa Lee, Chien-Yu Huang, Chi-Ming Chu, Yu-Jia Chang, Po-Li Wei
Bevacizumab combined with cytotoxic chemotherapy is the backbone of metastatic colorectal cancer (mCRC) therapy; however, its treatment efficacy is hampered by therapeutic resistance. Therefore, understanding the mechanisms underlying bevacizumab resistance is crucial to increasing the therapeutic efficacy of bevacizumab. The Gene Expression Omnibus (GEO) database (dataset, GSE86525) was used to identify the key genes and pathways involved in bevacizumab-resistant mCRC. The GEO2R web tool was used to identify differentially expressed genes (DEGs)...
2018: PloS One
https://www.readbyqxmd.com/read/29342156/specialized-attachment-structure-of-the-fish-pathogenic-oomycete-saprolegnia-parasitica
#6
Svetlana Rezinciuc, Jose Vladimir Sandoval-Sierra, Yolanda Ruiz-León, Pieter van West, Javier Diéguez-Uribeondo
The secondary cysts of the fish pathogen oomycete Saprolegnia parasitica possess bundles of long hooked hairs that are characteristic to this economically important pathogenic species. Few studies have been carried out on elucidating their specific role in the S. parasitica life cycle and the role they may have in the infection process. We show here their function by employing several strategies that focus on descriptive, developmental and predictive approaches. The strength of attachment of the secondary cysts of this pathogen was compared to other closely related species where bundles of long hooked hairs are absent...
2018: PloS One
https://www.readbyqxmd.com/read/29342138/%C3%AE-klotho-is-a-non-enzymatic-molecular-scaffold-for-fgf23-hormone-signalling
#7
Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman, Ming-Chang Hu, Orson W Moe, Guang Liang, Xiaokun Li, Moosa Mohammadi
The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342135/structures-of-%C3%AE-klotho-reveal-a-zip-code-like-mechanism-for-endocrine-fgf-signalling
#8
Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, Leiliane P Sousa, Francisco Tome, Els Pardon, Jan Steyaert, Mark A Lemmon, Irit Lax, Joseph Schlessinger
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29342117/assessment-of-tspo-in-a-rat-experimental-autoimmune-myocarditis-model-a-comparison-study-between-18f-fluoromethyl-pbr28-and-18f-cb251
#9
Ga Ram Kim, Jin Chul Paeng, Jae Ho Jung, Byung Seok Moon, Antonio Lopalco, Nunzio Denora, Byung Chul Lee, Sang Eun Kim
Overexpression of the 18-kDa translocator protein (TSPO) is closely linked to inflammatory responses in the heart, including myocarditis, which can lead to myocardial necrosis. In vivo assessment of inflammatory responses has enabled the precise diagnosis of myocarditis to improve clinical outcomes. Here, we evaluated TSPO overexpression in a rat model of experimental autoimmune myocarditis (EAM) compared to healthy rats using two TSPO radiotracers, [18F]fluoromethyl-PBR28 ([18F]1) and [18F]CB251 ([18F]2). All radiolabeling methods were successfully applied to an automated module for the reproducible preparation of TSPO radiotracers...
January 17, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29342083/regulation-of-mitochondrial-dynamics-by-proteolytic-processing-and-protein-turnover
#10
REVIEW
Sumaira Ali, Gavin P McStay
The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as adenosine triphosphate (ATP) synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside in or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space...
January 17, 2018: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/29341885/deletion-of-the-duffy-antigen-receptor-for-chemokines-darc-promotes-insulin-resistance-and-adipose-tissue-inflammation-during-high-fat-feeding
#11
Tyler W Benson, Daniel S Weintraub, Matthew Crowe, Nicole K H Yiew, Orishebawo Popoola, Ajay Pillai, Joel Joseph, Krystal Archer, Charlotte Greenway, Tapan K Chatterjee, James Mintz, David W Stepp, Brian K Stansfield, Weiqin Chen, Julia Brittain, Vladimir Y Bogdanov, Yan Gao, James G Wilson, Yaoliang Tang, Ha Won Kim, Neal L Weintraub
OBJECTIVE: Inflammation in adipose tissues in obesity promotes insulin resistance and metabolic disease. The Duffy antigen receptor for chemokines (DARC) is a promiscuous non-signaling receptor expressed on erythrocytes and other cell types that modulates tissue inflammation by binding chemokines such as monocyte chemoattractant protein-1 (MCP-1) and by acting as a chemokine reservoir. DARC allelic variants are common in humans, but the role of DARC in modulating obesity-related metabolic disease is unknown...
January 13, 2018: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29341830/pregnancy-related-hormones-progesterone-and-human-chorionic-gonadotrophin-upregulate-expression-of-maternal-plasma-gelsolin
#12
Renu Garg, Nagesh Peddada, Kunzes Dolma, Neeraj Khatri, Ashish Ashish
Plasma gelsolin (pGSN), a protein primarily involved in clearance of circulating actin filaments, is an upcoming novel biomarker. Its level changes in multiple disease and injury conditions, attributable mainly to its consumption during actin clearance, the endogenous regulation of its expression, however, remains elusive as well as unexplored. Here, we are reporting first isolation of the promoter region of pGSN gene and investigation of its transcriptional regulation during pregnancy (a natural process associated with a well programmed injury course of parturition)...
January 17, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29341828/biosensors-for-spatiotemporal-detection-of-reactive-oxygen-species-in-cells-and-tissues
#13
Marie Erard, Sophie Dupre-Crochet, Oliver Nusse
Redox biology has become a major issue in numerous areas of physiology. Reactive oxygen species (ROS) have a broad range of roles from signal transduction to growth control and cell death. To understand the nature of these roles, accurate measurement of the reactive compounds is required. An increasing number of tools for ROS detection is available; however, specificity and sensitivity of these tools are often insufficient. Furthermore, their specificity has been rarely evaluated in complex physiological conditions...
January 17, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29341802/portulaca-oleracea-l-extract-enhances-glucose-uptake-by-stimulating-glut4-translocation-to-the-plasma-membrane-in-3t3-l1-adipocytes
#14
Jae Eun Park, Ji Soo Lee, Hyun Ah Lee, Ji Sook Han
This study investigated the effects of Portulaca oleracea L. extract on glucose uptake in 3T3-L1 adipocytes. P. oleracea extract (POE) markedly enhanced glucose uptake, which was caused by increased GLUT4 expression at the plasma membrane (PM) in 3T3-L1 adipocytes. This increase in PM-GLUT4 expression was associated with insulin receptor substrate-1 (IRS-1) phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation, and Akt phosphorylation, and finally, enhanced intracellular glucose uptake. POE was not associated with protein kinase C (PKC)λ/ζ phosphorylation in the insulin signaling pathway, but did promote 5'-AMP-activated kinase (AMPK) phosphorylation...
January 17, 2018: Journal of Medicinal Food
https://www.readbyqxmd.com/read/29341593/analysis-of-cellular-tyrosine-phosphorylation-via-chemical-rescue-of-conditionally-active-abl-kinase
#15
Zhihong Wang, Min-Sik Kim, Isabel Martinez Ferrando, Anthony John Koleske, Akhilesh Pandey, Philip Arthur Cole
Identifying direct substrates targeted by protein kinases is important in understanding cellular physiology and intracellular signal transduction. Mass-spectrometry based quantitative proteomics provides a powerful tool for comprehensively characterizing the downstream substrates of protein kinases. This approach is efficiently applied to receptor kinases which can be precisely, directly, and rapidly activated by some agent, such as a growth factor. However, non-receptor tyrosine kinase Abl lacks the experimental advantage of extracellular growth factors as immediate and direct stimuli...
January 17, 2018: Biochemistry
https://www.readbyqxmd.com/read/29341478/translational-systems-pharmacology-based-predictive-assessment-of-drug-induced-cardiomyopathy
#16
Dimitris E Messinis, Ioannis N Melas, Junguk Hur, Navya Varshney, Leonidas G Alexopoulos, Jane P F Bai
Drug-induced cardiomyopathy contributes to drug attrition. We compared two pipelines of predictive modeling: (1) applying elastic net (EN) to differentially expressed genes (DEGs) of drugs; (2) applying integer linear programming (ILP) to construct each drug's signaling pathway starting from its targets to downstream proteins, to transcription factors, and to its DEGs in human cardiomyocytes, and then subjecting the genes/proteins in the drugs' signaling networks to EN regression. We classified 31 drugs with availability of DEGs into 13 toxic and 18 nontoxic drugs based on a clinical cardiomyopathy incidence cutoff of 0...
January 17, 2018: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29341469/downregulation-of-csn6-attenuates-papillary-thyroid-carcinoma-progression-by-reducing-wnt-%C3%AE-catenin-signaling-and-sensitizes-cancer-cells-to-fh535-therapy
#17
Duo Wen, Tian Liao, Ben Ma, Ning Qu, Rong-Liang Shi, Zhong-Wu Lu, Yu-Long Wang, Wen-Jun Wei, Qing-Hai Ji
The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short-hairpin RNA-mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability...
January 17, 2018: Cancer Medicine
https://www.readbyqxmd.com/read/29341468/downregulation-of-barh-like-homeobox-2-promotes-cell-proliferation-migration-and-aerobic-glycolysis-through-wnt-%C3%AE-catenin-signaling-and-predicts-a-poor-prognosis-in-non-small-cell-lung-carcinoma
#18
Hao Chen, Maowei Zhang, Wenhui Zhang, Yuanqin Li, Jiechen Zhu, Xiaojiao Zhang, Li Zhao, Shuyang Zhu, Bi Chen
BACKGROUND: Human BarH-like homeobox 2 (Barx2), a homeodomain factor of the Bar family, plays a critical role in cell adhesion and cytoskeleton remodeling, and has been reported in an increasing array of tumor types except non-small cell lung carcinoma (NSCLC). The purpose of the current study was to characterize the expression of Barx2 and assess the clinical significance of Barx2 in NSCLC. METHODS: Quantitative real-time polymerase chain reaction, immunohistochemistry and western blot analysis were used to examine mRNA and protein expression, respectively...
January 17, 2018: Thoracic Cancer
https://www.readbyqxmd.com/read/29341465/p2y12-deficiency-in-mouse-impairs-noradrenergic-system-in-brain-and-alters-anxiety-like-neurobehavior-and-memory
#19
Fang Zheng, Qiang Zhou, Yin Cao, Hailian Shi, Hui Wu, Beibei Zhang, Fei Huang, Xiaojun Wu
Purinergic receptor P2Y12 (P2Y12 ), a G protein-coupled (GPCR) purinergic receptor, is widely distributed in nervous system and involved in the progression of neurological diseases such as multiple sclerosis and neuropathic pain. The central noradrenergic system actively participates in a number of neurophysiological processes. Nevertheless, whether there is any direct relevance between P2Y12 and noradrenergic signal transduction remains unknown. In the present study, we tested the hypothesis that lack of P2Y12 impaired noradrenergic signal transduction in mouse brain...
January 17, 2018: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29341462/dna-origami-scaffolds-as-templates-for-functional-tetrameric-kir3-k-channels
#20
Tatsuki Kurokawa, Shigeki Kiyonaka, Eiji Nakata, Masayuki Endo, Shohei Koyama, Emiko Mori, Nam Ha Tran, Huyen Dinh, Yuki Suzuki, Kumi Hidaka, Masaaki Kawata, Chikara Sato, Hiroshi Sugiyama, Takashi Morii, Yasuo Mori
In native systems, scaffolding proteins play important roles in assembling proteins into complexes to transduce signals. This concept is yet to be incorporated in assembling functional transmembrane protein complexes in artificial systems. To address this issue, DNA origami has potentiality to serve as scaffolds that arrange proteins at specific positions in complexes. Here, we report that Kir3 K+ channel proteins are assembled through zinc-finger protein (ZFP)-adaptors at specific locations on DNA origami scaffolds...
January 16, 2018: Angewandte Chemie
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