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Anna King, Anna Brain, Kelsey Hanson, Justin Dittmann, James Vickers, Carmen Fernandez-Martos
Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice...
March 15, 2018: Metabolic Brain Disease
Zia Uddin, Yeong Hun Song, Mahboob Ullah, Zuopeng Li, Jeong Yoon Kim, Ki Hun Park
Diabetes mellitus is one of a major worldwide concerns, regulated by either defects in secretion or action of insulin, or both. Insulin signaling down-regulation has been related with over activity of protein tyrosine phosphatase 1B (PTP1B) enzyme, which has been a promising target for the treatment of diabetes mellitus. Herein, activity guided separation of methanol extract (95%) of Dodonaea viscosa aerial parts afforded nine ( 1 - 9 ) polyphenolic compounds, all of them were identified through spectroscopic data including 2D NMR and HREIMS...
2018: Frontiers in Chemistry
Jing Wu, Wei-Wei Tao, Dan-Yang Chong, Shan-Shan Lai, Chuang Wang, Qi Liu, Tong-Yu Zhang, Bin Xue, Chao-Jun Li
Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity...
March 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Zuo Peng Li, Hyeong-Hwan Lee, Zia Uddin, Yeong Hun Song, Ki Hun Park
Four new caged xanthones (1-4) and two known compounds (5, 6) were isolated from the roots of Cratoxylum cochinchinense, a polyphenol rich plant, collected in China. The structures of the isolated compounds (1-6) were characterized by obtaining their detailed spectroscopic data. In particular, compounds 1 and 6 were fully identified by X-ray crystallographic data. The isolated compounds (1-6) were evaluated against protein tyrosine phosphatase 1B (PTP1B), which plays an important role in diabetes, obesity, and cancer...
March 7, 2018: Bioorganic Chemistry
Junfei Zhou, Junjun Liu, Ting Dang, Haofeng Zhou, Hanqi Zhang, Guangmin Yao
Two highly modified and functionalized diterpenoids, mollebenzylanols A (1) and B (2), and a known grayanane diterpenoid rhodojaponin III (3) were isolated from Rhododendron molle. Their structures were determined by spectroscopic data analysis, an electronic circular dichroism (ECD) exciton chirality method, ECD calculations, and X-ray diffraction analysis of the p-bromobenzoate ester of 1 (1a). Compounds 1 and 2 possess an unprecedented diterpene carbon skeleton featuring a unique 9-benzyl-8,10-dioxatricyclo[5...
March 13, 2018: Organic Letters
Ji-Yuan Zhao, Li Yang, Hu-Hu Bai, Jiang-Ping Liu, Zhan-Wei Suo, Xian Yang, Xiao-Dong Hu
Protein tyrosine phosphatase 1B (PTP1B) has been shown to dephosphorylate and inactivate insulin receptors, which contributes to the pathogenesis of diabetes. Neuropathic pain is one of the severe complications that results from diabetic neuropathy. However, whether PTP1B was involved in the development of diabetic neuropathic pain is largely unknown. The current study illustrated that PTP1B was located in spinal cord dorsal horn neurons of Sprague-Dawley rats. Western blot analysis demonstrated that the diabetic neuropathic pain induced by intraperitoneal injection of streptozotocin was associated with an increased protein expression and a dynamic redistribution of spinal PTP1B into excitatory glutamatergic synapses...
March 8, 2018: European Journal of Pharmacology
Jie Zhang, Tatsunori Sasaki, Wei Li, Kazuya Nagata, Koji Higai, Feng Feng, Jian Wang, Maosheng Cheng, Kazuo Koike
Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes, obesity, and cancer. Ten caffeoylquinic acid derivatives (1-10) from leaves of Artemisia princeps Pamp. (Asteraceae) were identified as natural PTP1B inhibitors. Among them, chlorogenic acid (3) showed the most potent inhibitory activity (IC50 11.1 μM). Compound 3 was demonstrated to be a noncompetitive inhibitor by a kinetic analysis. Molecular docking simulation suggested that compound 3 bound to the allosteric site of PTP1B...
March 6, 2018: Bioorganic & Medicinal Chemistry Letters
Elisa Bellomo, Asma Abro, Christer Hogstrand, Wolfgang Maret, Carmen Domene
Whilst the majority of phosphatases are metalloenzymes, the prevailing model for the reactions catalyzed by protein tyrosine phosphatases does not involve any metal ion. Yet, both metal cations and oxoanions affect their enzymatic activity. Mg2+ and Zn2+ activate and inhibit, respectively, protein tyrosine phosphatase 1B (PTP1B). Molecular dynamics simulations, metadynamics and quantum chemical calculations in combination with experimental investigations demonstrate that Mg2+ and Zn2+ compete for the same binding site in the active site only in the closed conformation of the enzyme in its phosphorylated state...
March 7, 2018: Journal of the American Chemical Society
Henki Rotinsulu, Hiroyuki Yamazaki, Shino Sugai, Natsuki Iwakura, Defny S Wewengkang, Deiske A Sumilat, Michio Namikoshi
Cladosporamide A (1), a new protein tyrosine phosphatase (PTP) 1B inhibitor, was isolated together with a known prenylated flavanone derivative (2) from the culture broth of an Indonesian marine sponge-derived Cladosporium sp. TPU1507 by solvent extraction, ODS column chromatography, and preparative HPLC (ODS). The structure of 1 was elucidated based on 1D and 2D NMR data. Compound 1 modestly inhibited PTP1B and T-cell PTP (TCPTP) activities with IC50 values of 48 and 54 μM, respectively. The inhibitory activity of 2 against PTP1B (IC50  = 11 μM) was approximately 2-fold stronger than that against TCPTP (IC50  = 27 μM)...
March 5, 2018: Journal of Natural Medicines
Kathryn L Garner, Virginie M S Betin, Vanda Pinto, Mark Graham, Emmanuelle Abgueguen, Matt Barnes, David C Bedford, Craig A McArdle, Richard J M Coward
Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity...
March 2, 2018: Scientific Reports
Małgorzata Zakłos-Szyda, Nina Pawlik
Type 2 diabetes mellitus (T2D) is a chronic diet-related disease which due to many dangerous complications has become a prominent health problem of the world. The aim of the study was to explore the in vitro activity of Japanese quince (Chaenomeles japonica L., family Rosaceae, JQ) fruit polyphenolic extract as modulator of carbohydrates metabolism. The research was designed to investigate the effect of JQ polyphenolic extract on glucose metabolism in human hepatoma HepG2 cell line cultured under normal non-metabolically changed and hyperglycemic conditions...
March 1, 2018: Acta Biochimica Polonica
Shivani Verma, Saurabh Sharma
Protein tyrosine phosphatase (PTP) class of enzymes functions in a unit with protein tyrosine kinases to regulate signaling pathways. Several members of the PTP family link to human disease predisposition such as PTP1B, SH2, DEP1, and inhibition of these enzymes may represent an effective palliative therapy. Protein tyrosine phosphatase inhibition has been intensively investigated as an important therapeutic target against metabolic syndrome and has been documented to improve hepatic insulin sensitivity, reduce liver triglycerides, cholesterol levels, and protects against endoplasmic reticulum (ER) stress...
February 26, 2018: Current Molecular Pharmacology
Seiji Torii, Chisato Kubota, Naoya Saito, Ayumi Kawano, Ni Hou, Masaki Kobayashi, Ryoko Torii, Masahiro Hosaka, Tadahiro Kitamura, Toshiyuki Takeuchi, Hiroshi Gomi
Autocrine insulin signaling is critical for pancreatic β-cell growth and activity and is at least partially controlled by protein-tyrosine phosphatases (PTPs) that act on insulin receptors (IRs). The receptor-type PTP phogrin primarily localizes on insulin secretory granules in pancreatic β cells. We recently reported that phogrin knockdown decreases the protein levels of insulin receptor substrate 2 (IRS2), whereas high glucose stimulation promotes formation of a phogrin-IR complex that stabilizes IRS2. However, the underlying molecular mechanisms by which phogrin affects IRS2 levels are unclear...
February 26, 2018: Journal of Biological Chemistry
M J Nanjan, Manal Mohammed, B R Prashantha Kumar, M J N Chandrasekar
Thiazolidinediones (TZDs) or Glitazones are an important class of insulin sensitizers used in the treatment of Type 2 diabetes mellitus (T2DM). TZDs were reported for their antidiabetic effect through antihyperglycemic, hypoglycemic and hypolipidemic agents. In time, these drugs were known to act by increasing the transactivation activity of Peroxisome Proliferators Activated Receptors (PPARs). The clinically used TZDs that suffered from several serious side effects and hence withdrawn/updated later, were full agonists of PPAR-γ and potent insulin sensitizers...
February 12, 2018: Bioorganic Chemistry
Martin Winter, Tom Bretschneider, Carola Kleiner, Robert Ries, Jörg P Hehn, Norbert Redemann, Andreas H Luippold, Daniel Bischoff, Frank H Büttner
Label-free, mass spectrometric (MS) detection is an emerging technology in the field of drug discovery. Unbiased deciphering of enzymatic reactions is a proficient advantage over conventional label-based readouts suffering from compound interference and intricate generation of tailored signal mediators. Significant evolvements of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, as well as associated liquid handling instrumentation, triggered extensive efforts in the drug discovery community to integrate the comprehensive MS readout into the high-throughput screening (HTS) portfolio...
February 1, 2018: SLAS Discovery
Natalie Kofler, Federico Corti, Felix Rivera-Molina, Yong Deng, Derek Toomre, Michael Simons
As a master regulator of endothelial cell function, vascular endothelial growth factor receptor-2 (VEGFR2) activates multiple downstream signaling pathways that are critical for vascular development and normal vessel function. VEGFR2 trafficking through various endosomal compartments modulates its signaling output. Accordingly, proteins that regulate the speed and direction by which VEGFR2 traffics through endosomes have been demonstrated to be particularly important for arteriogenesis. However, little is known about how these proteins control VEGFR2 trafficking and about the implications of this control for endothelial cell function...
February 7, 2018: Journal of Biological Chemistry
Yashi Mi, Wentong Zhang, Haoyu Tian, Runnan Li, Shuxian Huang, Xingyu Li, Guoyuan Qi, Xuebo Liu
As a major nutraceutical component of green tea (-)-epigallocatechin-3-gallate (EGCG) has attracted interest from scientists due to its well-documented antioxidant and antiobesity bioactivities. In the current study, we aimed to investigate the protective effect of EGCG on metabolic misalignment and in balancing the redox status in mice liver and HepG2 cells under insulin resistance condition. Our results indicated that EGCG accelerates the glucose uptake and evokes IRS-1/Akt/GLUT2 signaling pathway via dampening the expression of protein tyrosine phosphatase 1B (PTP1B)...
February 9, 2018: Food & Function
Gabriel Keine Kuga, Vitor Rosetto Muñoz, Rafael Calais Gaspar, Susana Castelo Branco Ramos Nakandakari, Adelino Sanchez Ramos da Silva, José Diego Botezelli, José Alexandre Curiacos de Almeida Leme, Ricardo José Gomes, Leandro Pereira de Moura, Dennys Esper Cintra, Eduardo Rochete Ropelle, José Rodrigo Pauli
The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promotes synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer's Disease (AD). The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies. In this context, our study aims to investigate the age-related changes in PTP1B content, insulin signaling, β-amyloid content, and Tau phosphorylation in the hippocampus of middle-aged rats...
February 5, 2018: Experimental Gerontology
Sandra Álvarez-Carretero, Niki Pavlopoulou, James Adams, Jane Gilsenan, Lydia Tabernero
The use of computational tools for virtual screening provides a cost-efficient approach to select starting points for drug development. We have developed VSpipe, a user-friendly semi-automated pipeline for structure-based virtual screening. VSpipe uses the existing tools AutoDock and OpenBabel together with software developed in-house, to create an end-to-end virtual screening workflow ranging from the preparation of receptor and ligands to the visualisation of results. VSpipe is efficient and flexible, allowing the users to make choices at different steps, and it is amenable to use in both local and cluster mode...
February 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yan Peng, Ri-Ming Huang, Xiu-Ping Lin, Yong-Hong Liu
A new C11-norisoprenoid derivative, sargassumone (1), has been isolated from Sargassum naozhouense together with six known norisoprenoids and a highly oxygenated cyclopentene: (2R,6S,8S,9S)-hexahydro-2,9-dihydroxy-4,4,8-trimethyl-6-acetyloxy-3(2H)-benzofuranone (2), (6S,8S,9R)-hexahydro-6,9-dihydroxy-4,4,8-trimethyl-2(2H)-benzofuranone (3), (6S,8S,9R)-hexahydro-6,9-dihydroxy-4,4,8-trimethyl-2(2H)-benzofuranone (4), loliolide (5), (+)-epiloliolide (6), spheciospongones A (7), and (+)-kjellmanianone (8). Compound 1 was identified on the basis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis, and the absolute stereochemistry was defined by NOESY spectroscopy, minimizing energy calculation, and circular dichroism (CD) spectra...
February 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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