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Su Hui Seong, Anupom Roy, Hyun Ah Jung, Hee Jin Jung, Jae Sue Choi
ETHNOPHARMACOLOGICAL RELEVANCE: Pueraria lobata root was used to treat wasting-thirst regarded as diabetes mellitus and was included in the composition of Okcheonsan, which is prescribed for thirst-waste in traditional Chinese medicine. AIM OF THE STUDY: The objective of this study was to evaluate the anti-diabetic potential of the root of Pueraria lobata and its constituents via protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitory activities. MATERIALS AND METHODS: In this study, anti-diabetic activities of the 70% ethanolic (EtOH) extract from P...
October 18, 2016: Journal of Ethnopharmacology
Mohammad A Ghattas, Noor Raslan, Asil Sadeq, Mohammad Al Sorkhy, Noor Atatreh
Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability...
2016: Drug Design, Development and Therapy
Hao-Wei Teng, Man-Hsin Hung, Li-Ju Chen, Mao-Ju Chang, Feng-Shu Hsieh, Ming-Hsien Tsai, Jui-Wen Huang, Chih-Lung Lin, Hsiang-Wen Tseng, Zong-Keng Kuo, Jeng-Kai Jiang, Shung-Haur Yang, Chung-Wai Shiau, Kuen-Feng Chen
Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y175 and Y179, PTP1B destabilized PITX1, which resulted in downregulation of the PITX1/p120RasGAP axis...
October 18, 2016: Scientific Reports
Tingting Yu, Yong Zuo, Rong Cai, Xian Huang, Shuai Wu, Chenxi Zhang, Y Eugene Chin, Dongdong Li, Zhenning Zhang, Nansong Xia, Qi Wang, Hao Shen, Xuebiao Yao, Zhong-Yin Zhang, Song Xue, Lei Shen, Jinke Cheng
Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK-STAT1 signaling. SOCS1 and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here we identify a novel negative feedback loop mediated by STAT3-SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3...
October 4, 2016: Journal of Molecular Cell Biology
Mengdan Qian, Yaming Shan, Shanshan Guan, Hao Zhang, Song Wang, Weiwei Han
Protein tyrosine phosphatase 1B (PTP1B) has become an outstanding target for the treatment of diabetes and obesity. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of PTP1B, but the specific mechanism remains unclear. Several molecular modeling methods (molecular docking, molecular dynamics simulations, and molecular mechanics/generalized Born surface area calculations) were integrated to provide insight into the binding mode and inhibitory mechanism of the new class of fullerene inhibitors...
October 3, 2016: Journal of Chemical Information and Modeling
Pierre-Alain Thiebaut, Marie Besnier, Elodie Gomez, Vincent Richard
Protein Tyrosine Phosphatase 1B (PTP1B) is mostly involved in negative regulation of signaling mediated by Tyrosine Kinase Receptors, especially the insulin and leptin receptors. This enzyme thus plays a major role in the development of diseases associated with insulin resistance, such as obesity and diabetes. PTP1B inhibition is currently considered as an attractive treatment of insulin resistance and associated metabolic disorders. In parallel, emerging evidence also suggests that PTP1B is widely expressed in cardiovascular tissues, notably in the heart and the endothelium, and that it could also be a potential treatment of several cardiovascular diseases...
September 2, 2016: Journal of Molecular and Cellular Cardiology
Madeleine J Oudin, Miles A Miller, Joelle A Z Klazen, Tatsiana Kosciuk, Alisha Lussiez, Shannon K Hughes, Jenny Tadros, James E Bear, Douglas A Lauffenburger, Frank B Gertler
Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis-the directional movement of cells to soluble cues-and haptotaxis-the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. Mena(INV) has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin α5β1...
October 15, 2016: Molecular Biology of the Cell
Jin-Pyo An, Thi Kim Quy Ha, Jinwoong Kim, Tae Oh Cho, Won Keun Oh
PTP1B deficiency in mouse mammary tumor virus (MMTV)-NeuNT transgenic mice inhibited the onset of MMTV-NeuNT-evoked breast cancer, while its overexpression was observed in breast cancer. Thus, PTP1B inhibitors are considered chemopreventative agents for breast cancer. As part of our program to find PTP1B inhibitors, one new diterpene glycoside (1) and 13 known compounds (2-14) were isolated from the methanol extract of the stems of Akebia quinata. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR and MS...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Hyun Ah Jung, Himanshu Kumar Bhakta, Byung-Sun Min, Jae Sue Choi
Insulin resistance is a characteristic feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. This study investigated the modulatory effects of fucosterol on the insulin signaling pathway in insulin-resistant HepG2 cells by inhibiting protein tyrosine phosphatase 1B (PTP1B). In addition, molecular docking simulation studies were performed to predict binding energies, the specific binding site of fucosterol to PTP1B, and to identify interacting residues using Autodock 4...
October 2016: Archives of Pharmacal Research
Ge Meng, Meilin Zheng, Mei Wang, Jing Tong, Weijuan Ge, Jiehe Zhang, Aqun Zheng, Jingya Li, Lixin Gao, Jia Li
A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group...
October 21, 2016: European Journal of Medicinal Chemistry
Ming-Fo Hsu, Kuan-Ting Pan, Fan-Yu Chang, Kay-Hooi Khoo, Henning Urlaub, Ching-Feng Cheng, Geen-Dong Chang, Fawaz G Haj, Tzu-Ching Meng
Nitric oxide (NO) exerts its biological function through S-nitrosylation of cellular proteins. Due to the labile nature of this modification under physiological condition, identification of S-nitrosylated residue in enzymes involved in signaling regulation remains technically challenging. The present study investigated whether intrinsic NO produced in endothelium-derived MS-1 cells response to insulin stimulation might target endogenous protein tyrosine phosphatases (PTPs). For this, we have developed an approach using a synthetic reagent that introduces a phenylacetamidyl moiety on S-nitrosylated Cys, followed by detection with anti-phenylacetamidyl Cys (PAC) antibody...
August 10, 2016: Free Radical Biology & Medicine
Xue Liu, Qian Chen, Xu-Gang Hu, Xian-Chao Zhang, Ti-Wei Fu, Qing Liu, Yan Liang, Xi-Long Zhao, Xia Zhang, Yi-Fang Ping, Xiu-Wu Bian
Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues...
July 27, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Ahmed Bettaieb, Shinichiro Koike, Samah Chahed, Santana Bachaalany, Stephen Griffey, Juan Sastre, Fawaz G Haj
Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein- and arginine-induced acute pancreatitis...
August 2016: American Journal of Pathology
Gong-Min Lin, Yu-Han Chen, Pei-Ling Yen, Shang-Tzen Chang
This is the first report concerning the α-glucosidase, α-amylase and protein tyrosine phosphatase 1B (PTP1B) inhibitory activities of cinnamon twig extracts. Comparing the antihyperglycemic activity of renewable plant parts, indigenous cinnamon (Cinnamomum osmophloeum; tǔ ròu guì) twig extracts (CoTE) showed better α-glucosidase and α-amylase activities than leaf, 2-cm branch and 5-cm branch extracts. Chemotype of C. osmophloeum has no influence on the antihyperglycemic activities and proanthocyanidin contents of CoTE...
July 2016: Journal of Traditional and Complementary Medicine
Ammaji Rajala, Yuhong Wang, Raju V S Rajala
In humans, daylight vision is primarily mediated by cone photoreceptors. These cells die in age-related retinal degenerations. Prolonging the life of cones for even one decade would have an enormous beneficial effect on usable vision in an aging population. Photoreceptors are postmitotic, but shed 10% of their outer segments daily, and must synthesize the membrane and protein equivalent of a proliferating cell each day. Although activation of oncogenic tyrosine kinase and inhibition of tyrosine phosphatase signaling is known to be essential for tumor progression, the cellular regulation of this signaling in postmitotic photoreceptor cells has not been studied...
July 6, 2016: Oncotarget
M Zulema Cabail, Emily I Chen, Antonius Koller, W Todd Miller
BACKGROUND: Intermolecular autophosphorylation at Tyr416 is a conserved mechanism of activation among the members of the Src family of nonreceptor tyrosine kinases. Like several other tyrosine kinases, Src can catalyze the thiophosphorylation of peptide and protein substrates using ATPγS as a thiophosphodonor, although the efficiency of the reaction is low. RESULTS: Here, we have characterized the ability of Src to auto-thiophosphorylate. Auto-thiophosphorylation of Src at Tyr416 in the activation loop proceeds efficiently in the presence of Ni(2+), resulting in kinase activation...
2016: BMC Biochemistry
Meiyan Wang, Xiaobo Li, Lei Dong, Xiubo Chen, Weiren Xu, Runling Wang
Megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) is a tyrosine phosphatase expressed in megakaryocytic cells, and causes insulin sensitization when down regulated. Therefore, specific inhibitors of PTP-MEG2 are potential candidates for novel Type 2 Diabetes (T2DM)therapy. In this study, we discovered PTP-MEG2 inhibitors using high throughput and virtual screening (HTS/VS) and structural optimization in silicon.Eight compound-candidates were identified from the interactions with PTP-MEG2, protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP)...
June 30, 2016: Oncotarget
Delfly Booby Abdjul, Hiroyuki Yamazaki, Ohgi Takahashi, Ryota Kirikoshi, Kazuyo Ukai, Michio Namikoshi
A new polyacetylene compound, isopetrosynol (1), was isolated from the Okinawan marine sponge Halichondria cf. panicea together with petrosynol (2), adociacetylene D (3), (5R)-3,15,27-triacontatriene-1,29-diyn-5-ol (4), and petrosterol (5). The structure of 1 was assigned on the basis of spectroscopic data for 1 and 2. Compound 1 inhibited protein tyrosine phosphatase 1B (PTP1B) activity with an IC50 value of 8.2±0.3 µM, while compound 2, a diastereomer of 1, showed only 28.9±4.5% inhibition at 21.6 µM...
2016: Chemical & Pharmaceutical Bulletin
Shan Qian, Man Zhang, Yanying He, Wei Wang, Siyan Liu
Diabetes mellitus is the most serious and prevalent metabolic disorders worldwide, complications of which can decrease significantly the quality of life and contribute to premature death. Resistance to insulin is a predominant pathophysiological factor of Type 2 diabetes (T2D). Protein tyrosine phosphatase 1B (PTP1B) is an important negative factor of insulin signal and a potent therapeutic target in T2D patients. This review highlights recent advances (2012-2015) in research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of T2D, and novel PTP1B inhibitors with an emphasis on their chemical structures and modes of action...
July 2016: Future Medicinal Chemistry
XiangQian Li, LiJun Wang, DaYong Shi
Protein tyrosine phosphatase 1B (PTP1B) has already been well studied as a highly validated therapeutic target for diabetes and obesity. However, the lack of selectivity limited further studies and clinical applications of PTP1B inhibitors, especially over T-cell protein tyrosine phosphatase (TCPTP). In this review, we enumerate the published specific inhibitors of PTP1B, discuss the structure-activity relationships by analysis of their X-ray structures or docking results, and summarize the characteristic of selectivity related residues and groups...
August 15, 2016: Bioorganic & Medicinal Chemistry
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