1.The Key Laboratory of Plant Resources and Chemistry of Arid Zone,State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization,Xinjiang Technical Institute of Physics and Chemistry,Chinese Academy of Sciences,Urumqi 830011,China
2.Key Laboratory of Molecular Biology,College of Life Science and Technology, Xinjiang University,Xinjiang Key Laboratory of Biological Resources and Genetic Engineering,Urumqi 830046,China
Objective To evaluate hypoglycemic activity of rose extracts in vitro,find insulin-stimulated signaling pathway which rose extracts act on and illuminate its action mechanism. Methods CHO-K1 cell model was transfected to overexpress PTP1B by using liposome-mediated plasmid transfection methods,and the effects of rose extracts on expression of signal regulatory protein molecules were studied in vitro through western blot analysis. Results Rose extracts effectively inhibited PTP1B activity with IC50 value of 62.31 ng·mL-1 and increased glucose consumption, the effects were similar to the positive group; Rose extracts obviously elevated phosphorylated levels of IRS-1、 PDK1、AKT and GSK-3β. Conclusion Rose extracts had good inhibitory activity against PTP1B and promoted glucose consumption in CHO-K1 cell,which suggested it had potential hypoglycemic activity.Furthermore, rose extracts activated PI3K/AKT signaling pathway by increasing phosphorylated levels of IRS-1、PDK1、AKT and GSK-3β,and then promoted insulin signal transduction and glycogen synthesis.By these means, rose extracts ultimately achieved the goal of lowering blood sugar.
Fig.2
Effect of rose extract on the level of phosphorylated-AKT in the CHO-K1 cell line overexpressing PTP1B “+”and“-”:represent “positive”and“negative”,Compared with Di group,t=72.68,46.75,131.50,*1P<0.01;D.blank control group; Di.negative control group; 3 h,6 h and 12 h,represent the incubation time of rose extract
Fig.3
Phosphorylation levels of signaling pathway protein in six groups(x¯±s) “+”and“-”:represent “positive”and“negative”,Compared with Di group,*1P<0.05,*2P<0.01;D.black control group;Di.negative control group;C-2.positive control group
SCHRINER SE,KATOOZI NS,PHAM KQ,et al.Exten-sion of Drosophila lifespan by Rosa damascene associated with an increased sensitivity to heat[J].Biogerontology,2012,13(2):105-117.
Abstract<br/><em class="a-plus-plus">Rosa damascena</em>, or Damask rose, is a rose hybrid commonly harvested for rose oil used in perfumery and for rose water used to flavor food. The petal extract of <em class="a-plus-plus">R. damascena</em> was recently found to decrease <em class="a-plus-plus">Drosophila melanogaster</em> mortality without impairing reproductive fitness or metabolic rate. Here, we report that <em class="a-plus-plus">R. damascena</em> extended both mean and maximum lifespan of the fly. The extract also protected against oxidative stress in flies, predominantly in females. However, it did not alter mitochondrial respiration or content, superoxide production, or the major antioxidant defenses, superoxide dismutase and catalase. The extract increased survival in both sexes when exposed to reduced iron, though surprisingly, it sensitized both sexes to heat stress (survival at 37°C), and appeared to down-regulate the major heat shock protein HSP70 and the small mitochondrial heat shock protein HSP22, at 25°C and after heat shock (4 h at 37°C). We hypothesize that <em class="a-plus-plus">R. damascena</em> extends lifespan by protecting against iron, which concomitantly leads to decreased HSP expression and compromising heat tolerance.<br/>
SUNT,WANGQ,YU ZG,et al.Hyrtiosal,a PTP1B inhibitor from the marine sponge Hyrtios erectus,shows extensive cellular effects on PI3K/AKT activation,glucose transport,and TGFbeta/Smad2 signaling[J].Chem Bio Chem,2007,22(2):187-193.
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Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.
JIANG CS,LIANG LF,GUO YW.Natural products possessing protein tyrosine phosphatase 1B(PTP1B) inhibitory activity found in the last decades[J].Acta Pharmacologica Sinica,2012,33(9):1217-1245.
This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.
BENTO JL,PALMER ND,MYCHALECKYJ JC,et al.Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes[J].Diabetes,2004,53(11):61-63.
The PTPN1 gene codes for protein tyrosine phosphatase 1B (PTP1B) (EC 3.1.3.48), which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. PTPN1 is located in 20q13, a genomic region linked to type 2 diabetes in multiple genetic studies. Surveys of the gene have previously identified only a few uncommon coding single nucleotide polymorphisms (SNPs). We have carried out a detailed association analysis of 23 noncoding SNPs spanning the 161-kb genomic region, which includes the PTPN1 gene. These SNPs have been assessed for association with type 2 diabetes in two independently ascertained collections of Caucasian subjects with type 2 diabetes and two control groups. Association is observed between multiple SNPs and type 2 diabetes. The most consistent evidence for association occurred with SNPs spanning the 3' end of intron 1 of PTPN1 through intron 8 (P values ranging from 0.043 to 0.004 in one case-control set and 0.038-0.002 in a second case-control set). Analysis of the combined case-control data increased the evidence of SNP association with type 2 diabetes (P = 0.005-0.0016). All of the associated SNPs lie in a single 100-kb haplotype block that encompasses the PTPN1 gene. Analysis of haplotypes indicates a significant difference between haplotype frequencies in type 2 diabetes case and control subjects (P = 0.0035-0.0056), with one common haplotype (36%) contributing strongly to the evidence for association with type 2 diabetes. Odds ratios calculated from single SNP or haplotype data are in the proximity of 1.3. Haplotype-based calculation of population-attributable risk (PAR) results in an estimated PAR of 17-20% based on different models and assumptions. These results suggest that PTPN1 is a significant contributor to type 2 diabetes susceptibility in the Caucasian population. This risk is likely due to noncoding polymorphisms.
CHEN CH,ZHANG YB,HUANGC,et al.Berberine inhibits PTP1B activity and mimics insulin action[J].Biochem Biophy Res Commun,2010,397(14):543-547.
Type 2 diabetes patients show defects in insulin signal transduction that include lack of insulin receptor, decrease in insulin stimulated receptor tyrosine kinase activity and receptor-mediated phosphorylation of insulin receptor substrates (IRSs). A small molecule that could target insulin signaling would be of significant advantage in the treatment of diabetes. Berberine (BBR) has recently been shown to lower blood glucose levels and to improve insulin resistance in db/db mice partly through the activation of AMP-activated protein kinase (AMPK) signaling and induction of phosphorylation of insulin receptor (IR). However, the underlying mechanism remains largely unknown. Here we report that BBR mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes and L6 myocytes in an insulin-independent manner, inhibiting phosphatase activity of protein tyrosine phosphatase 1B (PTP1B), and increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. In diabetic mice, BBR lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis. The results suggest that BBR represents a different class of anti-hyperglycemic agents.
LIH,DUSSEAULTJ,LAROSEL.Nck1 depletion induces activation of the PI3K/Akt pathway by attenuating PTP1B protein expression[J].Cell Commun Signa,2014,12(11):71.
BACKGROUND: Activation of the PI3K/Akt pathway mediates crucial cellular functions regulated by receptor tyrosine kinases, such as cell growth, proliferation, survival and metabolism. Previously, we reported that the whole-body knockout of the Src homology domain-containing adaptor protein Nck1 improves overall glucose homeostasis and insulin-induced activation of the PI3K/Akt pathway in liver of obese mice. The aim of the current study is to elucidate the mechanism by which Nck1 depletion regulates hepatic insulin signaling. RESULTS: Here, we demonstrate that Nck1 regulates the activation of the PI3K/Akt pathway in a protein tyrosine phosphatase 1B (PTP1B)-dependent mechanism. Indeed, depletion of Nck1 by siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation. In accordance, primary hepatocytes isolated from Nck1 (-/-) mice also display enhanced Akt activation in response to insulin. Activation of the PI3K/Akt pathway in Nck1-depleted HepG2 cells relies on higher levels of tyrosine-phosphorylated proteins and correlates with decreased PTP1B levels. Interestingly, Nck1 and PTP1B in cells are found in a common molecular complex and their interaction is dependent on the SH3 domains of Nck1. Finally, Nck1 depletion in HepG2 cells neither affects PTP1B gene transcription nor PTP1B protein stability, suggesting that Nck1 modulates PTP1B expression at the translational level. CONCLUSION: Our study provides strong evidence supporting that the adaptor protein Nck1 interacts with PTP1B and also regulates PTP1B expression. In this manner, Nck1 plays a role in regulating the PI3K/Akt pathway.
COHENP.The twentieth century struggle to decipher insulin signaling[J].Nat Rev Mol Cell Biol,2006,34(7):867-873.
Following the discovery of insulin, it took the rest of the twentieth century to understand how this hormone regulates intracellular metabolism. What are the main discoveries that led to our current understanding of this process? And how is this new knowledge being exploited in an attempt to develop improved drugs to treat the epidemic of type-2 diabetes?
, 汤丹
