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Mian M K Shahzad, Mildred Felder, Kai Ludwig, Hannah R Van Galder, Matthew L Anderson, Jong Kim, Mark E Cook, Arvinder K Kapur, Manish S Patankar
The goal of this study was to investigate the anti-cancer effects of Trans10,cis12 conjugated linoleic acid (t10,c12 CLA). MTT assays and QCM™ chemotaxis 96-wells were used to test the effect of t10,c12 CLA on the proliferation and migration and invasion of cancer cells. qPCR and Western Blotting were used to determine the expression of specific factors. RNA sequencing was conducted using the Illumina platform and apoptosis was measured using a flow cytometry assay. t10,c12 CLA (IC50, 7 μM) inhibited proliferation of ovarian cancer cell lines SKOV-3 and A2780...
2018: PloS One
Paul J Meakin, Susan M Jalicy, Gemma Montagut, David J P Allsop, Daniella L Cavellini, Stuart W Irvine, Christopher McGinley, Mary K Liddell, Alison D McNeilly, Karolina Parmionova, Yu-Ru Liu, Charlotte L S Bailey, J Kim Dale, Lora K Heisler, Rory J McCrimmon, Michael L J Ashford
Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aβ) production with obesity elevating hypothalamic Bace1 activity and Aβ1-42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice...
January 8, 2018: Scientific Reports
Zuo Peng Li, Yeong Hun Song, Zia Uddin, Yan Wang, Ki Hun Park
Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1-12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC50s of (2.4-52.5 µM), and α-glucosidase with IC50 values of (1.7-72.7 µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50 = 2...
December 26, 2017: Bioorganic & Medicinal Chemistry
Varadarajan Sudhahar, Mustafa Nazir Okur, Zsolt Bagi, John P O'Bryan, Nissim Hay, Ayako Makino, Vijay S Patel, Shane A Phillips, David Stepp, Masuko Ushio-Fukai, Tohru Fukai
OBJECTIVE: Copper transporter ATP7A (copper-transporting/exporting ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. We reported that ATP7A protein expression and SOD3 activity are decreased in insulin-deficient type 1 diabetes mellitus vessels, thereby, inducing superoxide-mediated endothelial dysfunction, which are rescued by insulin treatment...
January 4, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Yongli Du, Yanhui Zhang, Hao Ling, Qunyi Li, Jingkang Shen
PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs...
December 20, 2017: European Journal of Medicinal Chemistry
Miryam Pastor, Rosalía Fernández-Calle, Bruno Di Geronimo, Marta Vicente-Rodríguez, José María Zapico, Esther Gramage, Claire Coderch, Carmen Pérez-García, Amy W Lasek, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, Beatriz de Pascual-Teresa, Gonzalo Herradón, Ana Ramos
A new series of blood-brain barrier permeable molecules designed to mimic the activity of Pleiotrophin in the CNS has been designed and synthesized. These compounds exert their action by interacting with the intracellular domain PD1 of the Protein Tyrosine-Phosphatase Receptor Z1 (PTPRZ1), and inhibiting its tyrosine phosphatase activity. The most potent compounds 10a and 12b (IC50 = 0,1 μM) significantly increase the phosphorylation of key tyrosine residues of PTPRZ1 substrates involved in neuronal survival and differentiation, and display protective effects against amphetamine-induced toxicity...
November 28, 2017: European Journal of Medicinal Chemistry
Marie Jazmín Sarabia-Sánchez, Pedro Josué Trejo-Soto, José Miguel Velázquez-López, Carlos Carvente-García, Rafael Castillo, Alicia Hernández-Campos, Claudia Avitia-Domínguez, Daniel Enríquez-Mendiola, Erick Sierra-Campos, Mónica Valdez-Solana, José Manuel Salas-Pacheco, Alfredo Téllez-Valencia
The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance...
December 20, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Ammu Prasanna Kumar, Minh N Nguyen, Chandra Verma, Suryani Lukman
Catalytic proteins such as human protein tyrosine phosphatase 1B (PTP1B), with conserved and highly polar active sites, warrant the discovery of druggable non-active sites, such as allosteric sites, and potentially, therapeutic small molecules that can bind to these sites. Catalyzing the dephosphorylation of numerous substrates, PTP1B is physiologically important in intracellular signal transduction pathways in diverse cell types and tissues. Aberrant PTP1B is associated with obesity, diabetes, cancers, and neurodegenerative disorders...
December 13, 2017: Proteins
Zhou Yang, Congheng Chen, Juan Zhao, Weijie Xu, Yanming He, Hongjie Yang, Ping Zhou
Protein tyrosine phosphatase 1 B (PTP1B) is one of main causes involved in type 2 diabetes, it dephosphorylates insulin receptor substrate (IRS) and dysregulates insulin signaling pathway, thus inducing insulin resistance. Our previous work first reported that FYGL, a neutral hyperbranched proteoglycan ingredient extracted from Ganoderma lucidum, has hypoglycemic activity in vivo and inhibitory potency on PTP1B in vitro, but the underlying mechanism was still unclear. In this study, we sought to investigate effects of FYGL on insulin signaling pathway involved with PTP1B as the targeting point in hepatocytes...
December 9, 2017: European Journal of Pharmacology
Navasona Krishnan, Konstantis F Konidaris, Gilles Gasser, Nicholas K Tonks
The protein tyrosine phosphatase PTP1B is a negative regulator of insulin and leptin signaling, and a highly validated therapeutic target for diabetes and obesity. Conventional approaches to drug development have produced potent and specific PTP1B inhibitors, but these inhibitors lack oral bioavailability, which limits their potential for drug development. Here we report that DPM-1001, an analogue of the specific PTP1B inhibitor trodusquemine (MSI-1436), is a potent, specific and orally bioavailable inhibitor of PTP1B...
December 7, 2017: Journal of Biological Chemistry
Farshid Zargari, Maryam Lotfi, Omolbanin Shahraki, Zahra Nikfarjam, Jafar Shahraki
Protein tyrosine phosphatase 1B (PTP1B) is a member of the PTP superfamily which is considered to be a negative regulator of insulin receptor (IR) signalling pathway. PTP1B is a promising drug target for the treatment of type 2 diabetes, obesity and cancer. The existence of allosteric site in PTP1B has turned the researcher's attention to an alternate strategy for inhibition of this enzyme. Herein, the molecular interactions between the allosteric site of PTP1B with three non-competitive flavonoids, (MOR), (MOK), and (DPO) have been investigated...
December 7, 2017: Journal of Biomolecular Structure & Dynamics
Zhou Yang, Fan Wu, Yanming He, Qiang Zhang, Yuan Zhang, Guangrong Zhou, Hongjie Yang, Ping Zhou
Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels...
December 7, 2017: Food & Function
Bing Tian Zhao, Duc Hung Nguyen, Duc Dat Le, Jae Sue Choi, Byung Sun Min, Mi Hee Woo
Since PTP1B enzyme was discovered in 1988, it has captured the research community's attention. This landmark discovery has stimulated numerous research studies on a variety of human diseases, including cancer, inflammation, and diabetes. Tremendous progress has been made in finding PTP1B inhibitors and exploring PTP1B regulatory mechanisms. This review investigates for the natural PTP1B inhibitors, and focuses on the common characteristics of the discovered structures and structure-activity relationships. To facilitate understanding, all the natural compounds are here divided into five different classes (fatty acids, phenolics, terpenoids, steroids, and alkaloids), according to their skeletons...
December 6, 2017: Archives of Pharmacal Research
Mei-Tang Feng, Ting Wang, Ai-Hong Liu, Jia Li, Li-Gong Yao, Bin Wang, Yue-Wei Guo, Shui-Chun Mao
Ten stigmastane-type steroids bearing unusual Δ28-24-hydroxy side chains, dictyopterisins A-J, including three pairs of C-24 epimers, dictyopterisins B/C, F/G, and I/J, were isolated from the brown alga Dictyopteris undulata Holmes, together with two previously reported analogues, (24S)- and (24R)-saringosterol. Their structures were elucidated on the basis of extensive spectroscopic analysis, with their absolute configurations at the stereogenic center C-24 of the side chain being assigned by a direct comparison of 1H NMR data with those of related known compounds...
December 2, 2017: Phytochemistry
Juliana Mikaelly Dias Soares, Ana Ediléia Barbosa Pereira Leal, Juliane Cabral Silva, Jackson R G S Almeida, Helinando Pequeno de Oliveira
Background: The development of alternatives for insulin secretion control in vivo or in vitro represents an important aspect to be investigated. In this direction, natural products have been progressively explored with this aim. In particular, flavonoids are potential candidates to act as insulin secretagogue. Objective: To study the influence of flavonoid on overall modulation mechanisms of insulin secretion. Methods: The research was conducted in the following databases and platforms: PubMed, Scopus, ISI Web of Knowledge, SciELO, LILACS, and ScienceDirect, and the MeSH terms used for the search were flavonoids, flavones, islets of Langerhans, and insulin-secreting cells...
October 2017: Pharmacognosy Magazine
Ko Morishita, Yoshimichi Shoji, Shunkichi Tanaka, Masaki Fukui, Yuma Ito, Tatsuya Kitao, Shin-Ichiro Ozawa, Shuichi Hirono, Hiroaki Shirahase
A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzamide (compound 18K) was identified as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with potent and selective inhibitory activity against PTP1B (IC50=0.25 µM). Compound 18K functioned as a non-competitive inhibitor and bound to the allosteric site of PTP1B. It also showed high oral absorption in mice (the maximum drug concentration (Cmax)=45...
2017: Chemical & Pharmaceutical Bulletin
Md Yousof Ali, Da Hye Kim, Su Hui Seong, Hyeung-Rak Kim, Hyun Ah Jung, Jae Sue Choi
Sargassum serratifolium C. Agardh (Phaeophyceae, Fucales) is a marine brown alga that belongs to the family Sargassaceae. It is widely distributed throughout coastal areas of Korea and Japan. S. serratifolium has been found to contain high concentrations of plastoquinones, which have strong anti-cancer, anti-inflammatory, antioxidant, and neuroprotective activity. This study aims to investigate the anti-diabetic activity of S. serratifolium and its major constituents through inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO--mediated albumin nitration...
December 1, 2017: Marine Drugs
(no author information available yet)
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2-6 were isolated from the entomogenous fungus Isaria fumosorosea...
November 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
S S Anusree, G Sindhu, M R Preetha Rani, K G Raghu
Insulin resistance (IR) has become a major threat to public health due to its role in metabolic syndrome. Inflammation associated with IR is an interesting area of biomedical researchers in recent years and is expected to affect insulin signalling pathway via downregulating glucose transporters. In the present study, we evaluate the potential of punicic acid (PA), a nutraceutical found in pomegranate seed oil, against TNF-α induced alteration in 3T3-L1 adipocytes on glucose metabolism, endocrine function and inflammation...
November 24, 2017: Biochimie
Hee Jin Jung, Su Hui Seong, Md Yousof Ali, Byung-Sun Min, Hyun Ah Jung, Jae Sue Choi
Diabetes mellitus is one of the greatest global health issues and much research effort continues to be directed toward identifying novel therapeutic agents. Insulin resistance is a challenging integrally related topic and molecules capable of overcoming it are of considerable therapeutic interest in the context of type 2 diabetes mellitus (T2DM). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling transduction and is regarded a novel therapeutic target in T2DM. Here, we investigated the inhibitory effect of α-methyl artoflavanocoumarin (MAFC), a natural flavanocoumarin isolated from Juniperus chinensis, on PTP1B in insulin-resistant HepG2 cells...
November 24, 2017: Archives of Pharmacal Research
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