CN101669934A - Suppressive activity of mango aglycone on PTP1B and application thereof - Google Patents
Suppressive activity of mango aglycone on PTP1B and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biological pharmacy, and in particular relates to suppressive activity detection of tetrahydroxy norathyriol on protein-tyrosine-phosphatase (PTP) 1B, improvement of resistance function of insulin and accpication in medicament for PTP1B related diseases. Proved by in vitro enzyme suppression experiments, the invention testifies that mango aglycone isthe competitive suppressant of restructuring humanized PTP1B with IC50 value being 9.2 mu m; mango aglycone can ensure the sensitivity of C57BL/6 normal mouse and ob/ob diabetes model mouse on insulin to be obviously improved, and reduce blood sugar of experimental animals, which suggests that mango aglycone is a novel suppressant of PTP1B, and can be taken as potential lead compound to be applied in preparing medicament for curing insulin resistance related diabetes, obesity and other metabolic syndrome, tumor and other PTP1B related diseases.
Description
Technical field
The invention belongs to biological pharmacy technical field, be specifically related to mango aglycone to the inhibition activity of PTP 1B (PTP1B), improve the insulin resistant effect, and the application in the medicine of metabolism syndrome, tumor and other PTP1B relevant diseases such as preparation treatment type ii diabetes, obesity.
Background technology
The phosphorylation level of protein-tyrosine is the important adjusting factor of intracellular signal transduction, it is by protein tyrosine kinase (Proteintyrosine kinase, PTK) and Protein-tyrosine-phosphatase (Protein tyrosine phosphatase, PTP) common regulation and control, PTP1B (Protein tyrosine phosphatase 1B, PTP1B) belong to PTP family, be negative regulatory factor important in the insulin signaling pathway and participate in leptin, multiple somatomedin, prolactin antagonist, integrate plain, the signal transduction process of platelet agglutinin etc., with diabetes, fat insulin resistant and leptin opposing all have substantial connection, with insulin resistant, fat, 4 metabolism syndrome main hazard such as metabolism disorder of blood lipid and hypertension factor significant correlation is in the generation of metabolism syndrome, play an important role in the development.PTP1B knock out mice insulin sensitivity significantly improves, and can keep good sugared stable state.In addition, PTP1B can also suppress the transfer of tumor cell, with apoptosis of tumor cells, associated angiogenesis, plays the negative regulation effect in the signal transduction of prolactin antagonist-prolactin antagonist in mammary gland and epithelial cell.PTP1B has become novel, the important drug targets of multiple disease such as treatment type ii diabetes, obesity, breast carcinoma, plays an important role in diseases such as control metabolism syndrome, tumor, and the research of its inhibitor has also been become present research focus.
Mango aglycone (norathyriol, NL), full name 1,3,6,7-tetrahydroxy
Ketone (1,3,6,7-tetrahydroxyxanthone), its chemical structural formula is as follows:
Modern pharmacological research shows that mango aglycone has multiple physiological action, and as effects such as antidepressant, antiinflammatory, resisting hypertension, antitumor, antioxidation and inhibition growth of bacillus tubercle, wherein the research of antiinflammatory action is comparatively deep.But have not yet to see the research report that it suppresses PTP1B, improves the insulin sensitivity aspect.
Summary of the invention
The objective of the invention is to be devoted to study the inhibition activity of mango aglycone to PTP 1B, for people provide a kind of new protein-tyrosine phosphatase 1B inhibitor, and, further expand the medicinal usage of mango aglycone by the inhibition activity of research mango aglycone to PTP 1B.
For achieving the above object, the applicant studies from the following aspects:
1, sets up Protein-tyrosine-phosphatase and suppress the active reaction system that detects, produce color reaction according to the phosphate group of PTP1B hydrolysis pNPP and detect the inhibition activity of chemical micromolecule, and be used for measuring mango aglycone and suppress activity and comprise IC PTP1B
50Value and inhibitor type.
By above-mentioned in vitro tests, the applicant finds that mango aglycone can significantly suppress the PTP1B activity, is a kind of novel PTP1B inhibitor, and it suppresses type is competitive inhibition;
2, the in vivo test by mice, the applicant finds that mango aglycone can significantly improve the C57BL/6 normal mouse and is the insulin sensitivity of the fat model mice of ob/ob diabetes of feature with the insulin resistant, reduces laboratory animal blood glucose.
Based on above-mentioned research and test, the applicant has confirmed that first mango aglycone is the novel preferably PTP1B competitive inhibitor of activity, can increase insulin sensitivity in vivo, improve the hyperglycemia symptom of laboratory animal, can be used for preparation and improve insulin sensitivity, hypoglycemic medicine, can become potential treatment type ii diabetes, metabolism syndromes such as obesity, the thing of breast carcinoma medicine, and can be used as potential lead compound and carry out anti-diabetic, metabolism syndromes such as obesity, tumor and other are developed with the medicine of PTP1B relevant disease, and can be by the further research metabolism signal path of being correlated with such as chip technology.
Description of drawings
Fig. 1: sodium vanadate is to PTP1B suppression ratio curve chart partially.
Measure the inclined to one side sodium vanadate (NaVO of positive control of variable concentrations
3) to recombined human source protein tyrosine phosphatase 1B suppression ratio, the relative concentration mapping obtains NaVO
3IC
50Be 0.32 μ M.
Fig. 2: mango aglycone is to PTP1B suppression ratio curve chart.
Measure the variable concentrations mango aglycone to recombined human source protein tyrosine phosphatase 1B suppression ratio curve, relative concentration mapping, its IC
50Be 9.2 μ M.
Fig. 3: the double reciprocal plot that mango aglycone suppresses PTP1B.
Under the condition that enzyme exists, the fixing concentration of inhibitor, change the concentration of substrate, use the Lineweaver-Burk method, with 1/s is that abscissa, 1/V are that the vertical coordinate mapping obtains five regression straight lines, these five straight lines meet at Y-axis, thereby judge that mango aglycone is a competitive inhibition to the inhibition type of PTP1B.
Fig. 4: mango aglycone is to normal ip in mice. the change of blood sugar figure of insulin.
Data are carried out statistical procedures (n=11) with the ANOVA method, wherein respectively organize blood sugar level and compare with matched group, NL (5,40mg/kg) 30,60,90, four time points of 120min have significant difference * p＜0.05.
Fig. 5: mango aglycone is to the ob/ob ip in mice. the change of blood sugar figure of insulin.
Data are carried out statistical procedures (n=5) with the ANOVA method, wherein respectively organize blood sugar level and compare with matched group, NL (40mg/kg) 60,90, three time points of 120min have significant difference * p＜0.05.
The specific embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not subjected to any restriction of these embodiment.
Material and source:
Reagent: mango aglycone; Recombination human source PTP1B (Merck); P-nitrophenyl disodium hydrogen phosphate pNPP (Sigma); Inclined to one side sodium vanadate (Sigma); MOPS (Sigma); DTT (Sigma); Insulin (Jiangsu Wanbang Biological Pharmaceutical Co., Ltd.); C57BL/6 mice (Military Medical Science Institute's Experimental Animal Center), ob/ob mice (Jackson Lab).
Equipment: XFLOUR4 microplate reader; Constant incubator; The steady bold and unconstrained blood glucose meter of Johnson ﹠ Johnson
Mango aglycone dilutes with the MOPS buffer with a small amount of DMSO dissolving back, get 10 μ l and be added to that (pH 7.0 in the 100 μ l reaction systems, 25mM mops, 1mM EDTA, 2mM DTT, 0.1M NaCl), make its final concentration be respectively 1500,150,15,1.5,0.15 μ M, add substrate pNPP to 16mM, add recombined human PTP1B 5ng and be placed on 37 ℃ of reaction 30min.Add 10 μ l1M NaOH cessation reactions, put the absorption value A that measures on the microplate reader under the 405nm wavelength condition, with inclined to one side sodium vanadate (NaVO
3) as positive control, be blank not add PTP1B, calculate suppression ratio.With suppression ratio concentration is figure, obtains mango aglycone IC
50Be 9.2 μ M, inclined to one side sodium vanadate IC
50Be 0.32 μ M.
Prepare the pNPP (32,16,8,4,2mM) of variable concentrations and the NL solution (1.25,2.5,5,10,20 μ M) of variable concentrations respectively.The corresponding 5 groups of pNPP concentration of each NL concentration are done the inhibition determination of activity, obtain V according to the variation of OD405, and corresponding concentration of substrate is S, maps respectively according to the L-B equation.The result shows that each bar straight line meets at Y-axis, is the state of conflict inhibitor of PTP1B so can judge NL.
The C57BL/6 mice is divided into 5 groups at random, 11 every group, is respectively matched group, NL various dose administration group (100,60,40,15mg/kg).The administration group is irritated the NL (with 0.5%CMC-Na aqueous solution suspendible) that stomach gives variable concentrations respectively, and matched group is irritated stomach and given 0.5%CMC-Na aqueous solution.Successive administration 7 days, fasting 12h after the last administration presses 1U/kg lumbar injection insulin, respectively at 0,15,30,60,90,120min gets blood measuring blood value.
Insulin tolerance experiment (Insulin Tolerance Test, ITT) experiment shows, NL (5,40mg/kg) can significantly improve the plain sensitivity of C57BL/6 mouse islets, reduces its blood glucose, at back four time points significant difference (p＜0.05) is arranged.
The ob/ob mice is divided into 2 groups at random, and 5 every group, be respectively matched group and administration group, the administration group is irritated stomach and is given 40mg/kg NL solution (with 0.5%CMC-Na aqueous solution suspendible), and matched group is irritated stomach and is given 0.5%CMC-Na aqueous solution.Continuous irrigation stomach 7 days, fasting 12h after the last administration presses 1U/kg lumbar injection insulin, respectively 0,15,30,60,90,120min gets blood measuring blood value.
ITT tests demonstration, and 40mg/kg dosage NL can significantly improve the plain sensitivity of ob/ob mouse islets, reduces its hyperglycemia symptom, at back three time points significant difference (p＜0.05) is arranged.
Claims (4)
1, mango aglycone is as the application of the inhibitor of PTP 1B.
2, the described mango aglycone of claim 1 is as the application of the state of conflict inhibitor of PTP 1B.
3, the application of mango aglycone in preparation raising insulin sensitivity, hypoglycemic medicine.
4, mango aglycone comprises application in the medicine of the metabolism syndrome, tumor of diabetes, obesity and other and PTP 1B relevant disease in preparation treatment.
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| CN200910184185.5A CN101669934B (en) | 2009-08-21 | 2009-08-21 | application of mango aglycone in preparing medicine for obesity |
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| CN200910184185.5A CN101669934B (en) | 2009-08-21 | 2009-08-21 | application of mango aglycone in preparing medicine for obesity |
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| CN2012101019063A Division CN102670582A (en) | 2009-08-21 | 2009-08-21 | Inhibitory activity of norathyriol to protein tyrosine phosphatase 1B (PTP1B) and application thereof |
| CN2012101040859A Division CN102657640A (en) | 2009-08-21 | 2009-08-21 | PTP1B (protein tyrosine phosphatase 1B) inhibition activity of norathyriol, and application of norathyriol |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102590367A (en) * | 2011-01-07 | 2012-07-18 | 昆明制药集团股份有限公司 | Method for detecting mangiferin aglycon |
| CN102807548A (en) * | 2011-05-30 | 2012-12-05 | 昆明制药集团股份有限公司 | Norathyriol crystal I and preparation method thereof |
| CN102920696A (en) * | 2012-09-27 | 2013-02-13 | 戴好富 | Application of mangiferin compound or mango extraction as pancreatic lipase inhibitor and to preparation of medicament or food for preventing and treating obesity |
| CN104288139A (en) * | 2014-09-17 | 2015-01-21 | 昆明制药集团股份有限公司 | Application of mangiferin aglycon derivatives in preparation of medicines for preventing and treating diabetes and complications thereof |
| CN107362159A (en) * | 2016-05-13 | 2017-11-21 | 上海交通大学医学院 | The application of Xanthones ketone compounds and its derivative in blood lipid-lowering medicine is prepared |
| CN112479849A (en) * | 2020-12-15 | 2021-03-12 | 北京工商大学 | Compound and application thereof |
| CN114288296A (en) * | 2022-01-27 | 2022-04-08 | 浙江省中医药研究院 | Pharmaceutical composition and application thereof in preparing anti-osteoporosis medicine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101284001B (en) * | 2008-01-23 | 2010-07-21 | 南京大学 | Application of mangiferin in treating type II diabetes and vitro trial model thereof |
| CN101367787A (en) * | 2008-10-13 | 2009-02-18 | 南京大学 | Mango aglycone, preparation purification process and uses thereof |
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| CN102590367A (en) * | 2011-01-07 | 2012-07-18 | 昆明制药集团股份有限公司 | Method for detecting mangiferin aglycon |
| CN102807548A (en) * | 2011-05-30 | 2012-12-05 | 昆明制药集团股份有限公司 | Norathyriol crystal I and preparation method thereof |
| WO2012162945A1 (en) * | 2011-05-30 | 2012-12-06 | 昆明制药集团股份有限公司 | Mangiferin aglycone crystal form i and preparation method thereof |
| CN102807548B (en) * | 2011-05-30 | 2014-10-22 | 昆明制药集团股份有限公司 | Norathyriol crystal I and preparation method thereof |
| CN102920696A (en) * | 2012-09-27 | 2013-02-13 | 戴好富 | Application of mangiferin compound or mango extraction as pancreatic lipase inhibitor and to preparation of medicament or food for preventing and treating obesity |
| CN102920696B (en) * | 2012-09-27 | 2015-03-18 | 戴好富 | Application of mangiferin compound or mango extraction as pancreatic lipase inhibitor and in preparation of medicament or food for preventing and treating obesity |
| CN104288139A (en) * | 2014-09-17 | 2015-01-21 | 昆明制药集团股份有限公司 | Application of mangiferin aglycon derivatives in preparation of medicines for preventing and treating diabetes and complications thereof |
| CN107362159A (en) * | 2016-05-13 | 2017-11-21 | 上海交通大学医学院 | The application of Xanthones ketone compounds and its derivative in blood lipid-lowering medicine is prepared |
| CN112479849A (en) * | 2020-12-15 | 2021-03-12 | 北京工商大学 | Compound and application thereof |
| CN114288296A (en) * | 2022-01-27 | 2022-04-08 | 浙江省中医药研究院 | Pharmaceutical composition and application thereof in preparing anti-osteoporosis medicine |
| CN114288296B (en) * | 2022-01-27 | 2022-11-29 | 浙江省中医药研究院 | Pharmaceutical composition and application thereof in preparing anti-osteoporosis medicine |
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