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Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima
Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT)...
January 9, 2017: EBioMedicine
Dan Tang, Qi-Bin Chen, Xue-Lei Xin, Haji-Akber Aisa
Diabetes is a metabolic disease with the characteristic of high blood glucose (hyperglycemia). In our previous study, we found that nigelladines A-C (compounds A-C), three norditerpenoid alkaloids from the seeds of Nigella glandulifera Freyn (Ranunculaceae) exhibited protein of tyrosine phosphatase 1B (PTP1B) inhibitory activity in vitro. In the present study, we further investigated their anti-diabetes activities in L6 moytubes and illuminated the mechanisms of action of compounds A-C. Several parameters of glucose metabolism such as glucose consumption, glycogen content and hexokinase activity were increased by compounds A-C...
December 31, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Kyung Oh Jung, Hyewon Youn, Chul-Hee Lee, Keon Wook Kang, June-Key Chung
Cancer cells actively release exosomes carrying specific cellular components, such as proteins, mRNA, and miRNA, to communicate with various cells in the tumor microenvironment. We visualized exosome-mediated transfer of miR-210 from hypoxic breast cancer cells to neighboring cells using a miR-210 specific reporter system. By in vitro and in vivo visualization, we found that exosomes with miR-210 were transferred to cells in the tumor microenvironment and that miR-210 was involved in expression of vascular remodeling related genes, such as Ephrin A3 and PTP1B, to promote angiogenesis...
December 27, 2016: Oncotarget
Hyun Ah Jung, Md Yousof Ali, Jae Sue Choi
The present work aims to evaluate the anti-diabetic potentials of 16 anthraquinones, two naphthopyrone glycosides, and one naphthalene glycoside from Cassia obtusifolia via inhibition against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase. Among them, anthraquinones emodin and alaternin exhibited the highest inhibitory activities on PTP1B and α-glucosidase, respectively. Moreover, we examined the effects of alaternin and emodin on stimulation of glucose uptake by insulin-resistant human HepG2 cells...
December 27, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Cangzhi Jia, Wenying He, Quan Zou
Many oncogenes encode proteins with a tyrosine kinase activity that appears to be directly involved in the process of transformation. Because these kinases are themselves activated for transformation by tyrosine phosphorylation, proteins that remove phosphate from tyrosine residues, protein tyrosine phosphatases (PTPs), are intuitive candidate transformation suppressors. In this study, we developed a novel PTP site prediction model, DephosSitePred, based on bi-profile sequence features. Weight parameters in the support vector machine were applied to improve the low sensitivity due to extremelyimbalanced datasets...
December 28, 2016: Combinatorial Chemistry & High Throughput Screening
Changcheng Jing, Ziyan Li, Kaili Jia, Chen Chen, Xiao Liu, Beibei Wang, Wenhao Hu, Jia Li, Tong Zhu, Suzhen Dong
Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC50 of 2.79 µM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs...
December 28, 2016: Archiv der Pharmazie
Sharat Chandra, Jyotsana Pandey, Akhilesh Kumar Tamrakar, Mohammad Imran Siddiqi
In insulin and leptin signaling pathway, Protein-Tyrosine Phosphatase 1B (PTP1B) plays a crucial controlling role as a negative regulator, which makes it an attractive therapeutic target for both Type-2 Diabetes (T2D) and obesity. In this work, we have generated classification models by using the inhibition data set of known PTP1B inhibitors to identify new inhibitors of PTP1B utilizing multiple machine learning techniques like naïve Bayesian, random forest, support vector machine and k-nearest neighbors, along with structural fingerprints and selected molecular descriptors...
January 2017: Journal of Molecular Graphics & Modelling
Haibing He, Yinghua Ge, Hong Dai, Song Cui, Fei Ye, Jia Jin, Yujun Shi
By imitating the scaffold of lithocholic acid (LCA), a natural steroidal compound displaying Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity, a series of stilbene derivatives containing phenyl-substituted isoxazoles were designed and synthesized. The structures of the title compounds were confirmed by ¹H-NMR, (13)C-NMR and HRMS. Activities of the title compounds were evaluated on PTP1B and the homologous enzyme TCPTP by using a colorimetric assay. Most of the target compounds had good activities against PTP1B...
December 16, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Patrick N Stoney, Diana Rodrigues, Gisela Helfer, Thabat Khatib, Anna Ashton, Elizabeth A Hay, Robert Starr, Dagmara Kociszewska, Peter Morgan, Peter McCaffery
Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod)...
December 18, 2016: Brain, Behavior, and Immunity
Cristina Bertocchi, Yilin Wang, Andrea Ravasio, Yusuke Hara, Yao Wu, Talgat Sailov, Michelle A Baird, Michael W Davidson, Ronen Zaidel-Bar, Yusuke Toyama, Benoit Ladoux, Rene-Marc Mege, Pakorn Kanchanawong
Multicellularity in animals requires dynamic maintenance of cell-cell contacts. Intercellularly ligated cadherins recruit numerous proteins to form supramolecular complexes that connect with the actin cytoskeleton and support force transmission. However, the molecular organization within such structures remains unknown. Here we mapped protein organization in cadherin-based adhesions by super-resolution microscopy, revealing a multi-compartment nanoscale architecture, with the plasma-membrane-proximal cadherin-catenin compartment segregated from the actin cytoskeletal compartment, bridged by an interface zone containing vinculin...
January 2017: Nature Cell Biology
Hong-Kui Wei, Zhao Deng, Shu-Zhong Jiang, Tong-Xing Song, Yuan-Fei Zhou, Jian Peng, Ya-Xiong Tao
Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) increase insulin signaling in skeletal muscle. In the current study, we investigated the effect of eicosapentaenoic acid (EPA) on insulin-induced mammalian target of rapamycin (mTOR) phosphorylation in myotubes. We showed that EPA did not affect basal and insulin-induced mTOR phosphorylation in myotubes. However, EPA abolished lipopolysaccharide (LPS) -induced deficiency in insulin signaling (P < 0.05). Pre-incubation of nuclear factor κB (NF-κΒ) and c-Jun N-terminal kinases (JNK) inhibitors prevented the decreased insulin-induced mTOR phosphorylation elicited by LPS (P < 0...
October 27, 2016: Molecular and Cellular Endocrinology
Btd Trinh, D Staerk, A K Jäger
No abstract text is available yet for this article.
December 2016: Planta Medica
B Liu, K T Kongstad, A K Jäger, D Staerk
No abstract text is available yet for this article.
December 2016: Planta Medica
James M Lipchock, Heidi P Hendrickson, Bonnie B Douglas, Kelly E Bird, Patrick S Ginther, Ivan Rivalta, Nicholas S Ten, Victor S Batista, J Patrick Loria
Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B...
January 10, 2017: Biochemistry
Chuan Chen, Fan Liang, Bo Chen, Zhongyi Sun, Tongdan Xue, Runlei Yang, Duqiang Luo
Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A3) from Pestalotiopsis sp. HLP46 was reported to have anti-tumor and anti-inflammation activity previously...
December 8, 2016: European Journal of Pharmacology
Junyao Li, Hui Chen, Shengbing Wu, Yuefa Cheng, Qinglin Li, Jing Wang, Guoqi Zhu
Neurotoxins are harmful to nervous system and cause either neuronal cell death or impairment of synaptic activity, which contributes to Parkinson's disease or other neuronal disorders. Hippocampal synaptic plasticity was proposed as a cellular model for memory processing. In this study, we reported a novel effect of neurotoxin, 1-methyl-4-phenylpyridinium (MPP(+)), on metabotropic glutamate receptor 1/5 agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced hippocampal synaptic plasticity, and MPP(+) incubation blocked DHPG-induced hippocampal long-term depression (LTD) in Schaffer collateral-CA1 synapses...
November 29, 2016: European Journal of Pharmacology
Elisa Bellomo, Kshetrimayum Birla Singh, Alberto Massarotti, Christer Hogstrand, Wolfgang Maret
A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn(2+)) inhibit with picomolar to nanomolar affinities...
November 15, 2016: Coordination Chemistry Reviews
Yixuan Zhang, Qiang Li, Ji Youn Youn, Hua Cai
The VEGF/VEGFR2/Akt/eNOS/NO pathway is essential to VEGF-induced angiogenesis. We have previously discovered a novel role of calpain in mediating VEGF-induced PI3K/AMPK/Akt/eNOS activation through Ezrin. Here, we sought to identify possible feedbak regulation of VEGFR2 by calpain via its substrate protein phosphotyrosine phosphatase 1B (PTP1B), and the relevance of this pathway to VEGF-induced angiogenesis, especially in diabetic wound healing. Over-expression of PTP1B inhibited VEGF-induced VEGFR2 and Akt phosphorylation in bovine aortic endothelial cells, while PTP1B siRNA increased both, implicating the negative regulation of VEGFR2 by PTP1B...
November 21, 2016: Journal of Biological Chemistry
Wenlong Sun, Bowei Zhang, Haizhou Zheng, Chunlin Zhuang, Xia Li, Xinhua Lu, Chunshan Quan, Yuesheng Dong, Zhihui Zheng, Zhilong Xiu
AIM: To screen a potential PTP1b inhibitor from the microbial origin-based compound library and to investigate the potential anti-diabetic effects of the inhibitor in vivo and determine its primary anti-diabetic mechanism in vitro and in silico. METHODS: PTP1b inhibitory activity was measured using recombination protein as the enzyme and p-NPP as the substrate. The binding of the inhibitor to PTP1b was analysed by docking in silico and confirmed by ITC experiments...
November 18, 2016: Life Sciences
Wilmar Maarisit, Hiroyuki Yamazaki, Syu-Ichi Kanno, Ayako Tomizawa, Jong-Soo Lee, Michio Namikoshi
The known seco-cucurbitane triterpene, (24E)-3,4-seco-cucurbita-4,24-diene-3,26,29-trioic acid (1), has been isolated as a potent protein tyrosine phosphatase (PTP) 1B inhibitor together with a new analogue, (24E)-3,4-seco-cucurbita-4,24-diene-3-hydroxy-26,29-dioic acid (2), from the fruiting bodies of Russula lepida. Further evaluation of their biological properties against PTPs revealed that compound 1 inhibited T-cell PTP activity similarly to PTP1B and exhibited moderate selectivity against PTP1B over vaccinia H-1-related phosphatase...
November 19, 2016: Journal of Natural Medicines
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