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Cheng-Shi Jiang, Li Zhang, Jing-Xu Gong, Jing-Ya Li, Li-Gong Yao, Jia Li, Yue-Wei Guo
The present study was designed to develop a concise synthetic route for macrolide, with the purpose of confirming the absolute configuration of natural dihydroresorcylide (1) and making it more easily accessible for biological evaluation. The absolute configuration of C-3 in natural 1 was revised to be R by comparison of the rotation sign of synthetic (R)- and (S)-1. The synthetic (R)-1 was found to be a novel highly specific PTP1B inhibitor with an IC50 value of 17.06 μM.
April 24, 2017: Journal of Asian Natural Products Research
Yehua Rui, Jinbo Cheng, Liqiang Qin, Cheng Shan, Jie Chang, Guiping Wang, Zhongxiao Wan
SAMP8 mice exhibit multiple metabolic characteristics associated with age, and it is a suitable candidate for researching aging associated metabolic dysfunction. OBJECTIVES: We aimed to 1) explore how key metabolic markers will be altered in both liver and adipose tissue with aging in SAMP8 mice; and 2) how the combination of vitamin D (VD) with resveratrol (RSV) will affect aging associated metabolic impairment in liver and adipose tissue from SAMP8 mice. METHODS: SAMP8 mice and their control SAMR1 mice were divided into 5 groups, i...
April 11, 2017: Experimental Gerontology
Natalia Ferreira Mendes, Gisele Castro, Dioze Guadagnini, Natalia Tobar, Susana Quiros Cognuck, Lucila Leico Kagohara Elias, Patricia Aline Boer, Patricia Oliveira Prada
OBJECTIVE: Protein tyrosine phosphatase 1B (PTP1B) has been extensively implicated in the regulation of body weight, food intake, and energy expenditure. The role of PTP1B appears to be cell and brain region dependent. RESULTS: Herein, we demonstrated that chronic high-fat feeding enhanced PTP1B expression in the central nucleus of the amygdala (CeA) of rats compared to rats on chow. Knocking down PTP1B with oligonucleotide antisense (ASO) decreased its expression and was sufficient to improve the anorexigenic effect of insulin through IR/Akt signaling in the CeA...
May 2017: Metabolism: Clinical and Experimental
Ning-Bo Qin, Cui-Cui Jia, Jun Xu, Da-Hong Li, Fan-Xing Xu, Jiao Bai, Zhan-Lin Li, Hui-Ming Hua
Two new amide compounds, mariamides A and B (1-2), were obtained together with fourteen known compounds from the seeds of milk thistle (Silybum marianum). Their structures were established on the basis of extensive 1D and 2D NMR analyses, as well as HR-ESI-MS data. Most of the compounds showed significant antioxidant activities than positive control in ABTS and FRAP assays. However, only amide compounds 1-4 showed moderate DPPH radical scavenging activity and compounds 7 and 16 showed the most potent activity against DPPH...
April 8, 2017: Fitoterapia
Renshuai Zhang, Rilei Yu, Qi Xu, Xiangqian Li, Jiao Luo, Bo Jiang, Lijun Wang, Shuju Guo, Ning Wu, Dayong Shi
Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC50 values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP...
April 4, 2017: European Journal of Medicinal Chemistry
Manoj Kumar Mahapatra, Krishnendu Bera, Durg Vijay Singh, Rajnish Kumar, Manoj Kumar
Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signalling pathway, hence it can be considered as a new therapeutic target of intervention for the treatment of type2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e., diabestiy. In order to get more information on identification and optimisation of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold...
April 10, 2017: Journal of Biomolecular Structure & Dynamics
Hiroyuki Yamazaki, Syu-Ichi Kanno, Delfly B Abdjul, Michio Namikoshi
Agelasine G (1), a known bromine-containing diterpene alkaloid, was isolated as a new type of protein tyrosine phosphatase (PTP) 1B inhibitor together with ageline B (2), an inactive debromo-derivative of 1, from the marine sponge Agelas nakamurai collected at Iriomote Island in Okinawa, Japan. Further biological evaluations revealed that compound 1 exhibited selective inhibitory activity against PTP1B over T-cell PTP and CD45 phosphatase. Compound 1 also enhanced the insulin-stimulated phosphorylation levels of Akt in Huh-7 cells more strongly than compound 2...
March 18, 2017: Bioorganic & Medicinal Chemistry Letters
Shi-Chong Liao, Jin-Xin Li, Li Yu, Sheng-Rong Sun
The protein tyrosine phosphatase 1B (PTP1B) is an important regulator of metabolism. The relationship between PTP1B and tumors is quite complex. The purpose of this study is to explore the expression pattern and role of PTP1B in breast cancer. The expression of PTP1B was detected in 67 samples of breast cancer tissue by Western blot. Cell growth assay, Transwell migration assay, and Scratch motility assay were used to examine the proliferation and migration of MCF-7 with and without PTP1B. The total levels and phosphorylated levels of signal transduction and activator of transcription 3 (STAT3) and the expression of C-C motif chemokine ligand 5 (CCL5) were also examined by Western blot...
2017: Journal of Zhejiang University. Science. B
Fengzhi Yang, Fangzhou Xie, Ying Zhang, Yu Xia, Wenlu Liu, Faqin Jiang, Celine Lam, Yixue Qiao, Dongsheng Xie, Jianqi Li, Lei Fu
Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLogP=9...
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
Delfly B Abdjul, Hiroyuki Yamazaki, Syu-Ichi Kanno, Ayako Tomizawa, Henki Rotinsulu, Defny S Wewengkang, Deiske A Sumilat, Kazuyo Ukai, Magie M Kapojos, Michio Namikoshi
In the course of our studies on anti-mycobacterial substances from marine organisms, the known dimeric sphingolipid, leucettamol A (1), was isolated as an active component, together with the new bromopyrrole alkaloid, 5-bromophakelline (2), and twelve known congeners from the Indonesian marine sponge Agelas sp. The structure of 2 was elucidated based on its spectroscopic data. Compound 1 and its bis TFA salt showed inhibition zones of 12 and 7 mm against Mycobacterium smegmatis at 50 μg/disk, respectively, while the N,N'-diacetyl derivative (1a) was not active at 50 μg/disk...
March 31, 2017: Journal of Natural Medicines
Yu-Mi Jeon, Shinrye Lee, Seyeon Kim, Younghwi Kwon, Kiyoung Kim, Chang Geon Chung, Seongsoo Lee, Sung Bae Lee, Hyung-Jun Kim
Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition...
March 28, 2017: Molecules and Cells
Puminan Punthasee, Adrian R Laciak, Andrea H Cummings, Kasi Viswanatharaju Ruddraraju, Sarah M Lewis, Roman Hillebrand, Harkewal Singh, John J Tanner, Kent S Gates
Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism...
April 3, 2017: Biochemistry
D G Semaan, J O Igoli, L Young, E Marrero, A I Gray, E G Rowan
BACKGROUND: Ethno-botanical information from diabetic patients in Cuba led to the identification of Allophylus cominia as a possible source of new drugs for the treatment of type 2 diabetes mellitus (T2-DM). EXPERIMENTAL: Chemical characterization of the extracts from A. cominia was carried out using chromatographic and spectroscopic methods. The extracts were tested for their activity on PTP1B, DPPIV, α-glucosidase enzymes and α-amylase. RESULTS: The flavonoid rich fractions from A...
May 5, 2017: Journal of Ethnopharmacology
Sujay Basu, Philip Prathipati, Sachin Thorat, Shariq Ansari, Meena Patel, Vaibhav Jain, Ramana R Jinugu, Sanjay Niranjan, Siddhartha De, Satyanarayana Reddy
A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.
January 1, 2017: Bioorganic & Medicinal Chemistry
Lin-Fu Liang, Wen-Ting Chen, Ernesto Mollo, Li-Gong Yao, He-Yao Wang, Wei Xiao, Yue-Wei Guo
Minor metabolic components, six new cembranoids sarcophytrols G - L (1 - 6) along with two known related analogues 7 and 8, were isolated from the South China Sea soft coral Sarcophyton trocheliophorum. Their structures were elucidated by extensive spectroscopic analyses (1D- and 2D-NMR, and ESI-MS.) as well as comparison with literature data. As part of our ongoing research project for discovering bioactive substances from Chinese marine invertebrates, compounds 1 - 8 were tested for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), a key target for the treatment of Type-II diabetes and obesity...
March 21, 2017: Chemistry & Biodiversity
Binh T D Trinh, Tam T T Quach, Dung N Bui, Dan Staerk, Lien-Hoa D Nguyen, Anna K Jäger
Three new xanthones, oblongixanthone F-H (1-3), along with eight known xanthones (4-11), were isolated from an EtOAc extract of the twigs of Garcinia oblongifolia. Their structures were elucidated by spectroscopic analysis including 1D- and 2D-NMR spectroscopy and mass spectrometry. The antidiabetic effects of all isolated compounds were evaluated by in vitro α-glucosidase and PTP1B inhibition assays. Compound 11 was the most active compound, and inhibited α-glucosidase and PTP1B with IC50 values of 1.7±0...
April 2017: Fitoterapia
Xue Fei Tan, Zia Uddin, Chanin Park, Yeong Hun Song, Minky Son, Keun Woo Lee, Ki Hun Park
Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70...
March 6, 2017: Bioorganic & Medicinal Chemistry
James M Lipchock, Patrick S Ginther, Bonnie B Douglas, Kelly E Bird, J Patrick Loria
Here, we present a 10-week project-oriented laboratory module designed to provide a course-based undergraduate research experience in biochemistry that emphasizes the importance of biomolecular structure and dynamics in enzyme function. This module explores the impact of mutagenesis on an important active site loop for a biomedically-relevant human enzyme, protein tyrosine phosphatase 1B (PTP1B). Over the course of the semester students guide their own mutant of PTP1B from conception to characterization in a cost-effective manner and gain exposure to fundamental techniques in biochemistry, including site-directed DNA mutagenesis, bacterial recombinant protein expression, affinity column purification, protein quantitation, SDS-PAGE, and enzyme kinetics...
March 13, 2017: Biochemistry and Molecular Biology Education
Eugénie Delile, Rémi Nevière, Pierre-Alain Thiébaut, Julie Maupoint, Paul Mulder, David Coquerel, Sylvanie Renet, Jennifer Rieusset, Vincent Richard, Fabienne Tamion
Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multi-organ failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. To evaluate the potential therapeutic effect of PTP1B blockade on glucose metabolism and insulin resistance in an experimental model of sepsis, we assessed the effect of PTP1B gene deletion in a cecal ligation and puncture (CLP) model of sepsis...
March 7, 2017: Shock
Yue Zhou, Weirui Zhang, Xiaoyu Liu, Haobing Yu, Xiaoling Lu, Binghua Jiao
The ocean is a huge treasure trove of natural products, from where 11 drugs has been developed for various diseases. (Table 1).Protein tyrosine phosphatase 1B (PTP1B) belongs to the protein tyrosine phosphatase family, which specifically hydrolyses the aromatic phosphate. On one hand, in insulin signaling, it plays a key role as a negative regulator through dephosphorylating activated insulin receptor (IR) and insulin receptor substrate (1IRS-1) This article is protected by copyright. All rights reserved.
March 6, 2017: Chemistry & Biodiversity
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