CN103356617A - Application of deacetylase inhibitors in preparation of medicaments for promoting insulin secretion - Google Patents
Application of deacetylase inhibitors in preparation of medicaments for promoting insulin secretion Download PDFInfo
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- CN103356617A CN103356617A CN2013103001660A CN201310300166A CN103356617A CN 103356617 A CN103356617 A CN 103356617A CN 2013103001660 A CN2013103001660 A CN 2013103001660A CN 201310300166 A CN201310300166 A CN 201310300166A CN 103356617 A CN103356617 A CN 103356617A
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Abstract
The invention relates to the technical field of medicines, especially relates to an application of deacetylase inhibitors in preparation of medicaments for promoting insulin secretion, and wherein the deacetylase inhibitor is nicotinamide (NAM) or trichostatin A (TSA). The rat islet cells are co-incubated with the deacetylase inhibitor NAM for 1 h, and insulin secretion stimulated by glucose is improved by about 50%; by using the deacetylase inhibitor TSA to treat islet cells for 12 h while the glucose concentration is 3.3 mmol/L, insulin secretion can be improved, and insulin secretion is improved obviously after 16 h; and insulin secretion is mildly up-regulated after islet cells are treated by NAM for 16 h. Therefore, the inhibitors NAM and TSA are applicable to preparation of the medicaments for promoting insulin secretion, and the medicaments will have good treatment effect in diabetes treatment. Also, more scientific bases are provided for more reasonable clinic use of the deacetylase inhibitors NAM and TSA.
Description
Technical field
The present invention relates to medical technical field, the particularly application of deacetylase inhibitor in preparation promotion insulin secretion medicine.
Background technology
The albumen acetylation is important post translational modification means, respectively by combination and the dissociation process of lysine residue in the acetyl group in acetyltransferase (HATs) and deacetylase (HDACs) catalysis S-acetyl-coenzyme-A source and the protein peptide chain.The initial acetylation modification of histone and some nuclear factor of finding participates in the transcriptional expression of controlling gene; appearance along with the proteomics new method; getting more and more exists the protein of acetylation modification to be found, and almost relates to the adjusting that all cells function associated biomolecule is learned process.Research is found except transcribing by histone and transcription factor regulator gene; the albumen acetylation modification can also be realized quick adjustment to many metabolic pathways by extensively affecting the pheron functional status; extensive and deep to cellular metabolism and affects on the growth, open up cellular metabolism and regulated new research mode and the research direction in field.
Diabetes are one of main chronic diseases of serious harm human health, and the quantity of present global diabetics is about 200,000,000 4 thousand ten thousand, and prevalence still increasing, and wherein the type 2 diabetes mellitus patient accounts for 90%-95%.If type 2 diabetes mellitus patient blood glucose situation control is undesirable, than the harassing and wrecking that are easier to be subject to the diabetes multiple complications, losing the sight of both eyes can appear in the patient, uremia, physical disabilities and cardiovascular and cerebrovascular disease.So type 2 diabetes mellitus and complication serious harm human health thereof have been brought huge financial burden to society.Type 2 diabetes mellitus serious harm human health; the islet function disorder is the important step in its generation and the evolution; therefore not only significant to the pathogenic process of understanding type 2 diabetes mellitus in depth to the searching of the research of islet function regulatory mechanism and the protection factor, and also have practical significance for this prevention and treatment of diseases.Delivering of a series of achievements in research such as cellular metabolism and growth regulated in the acetylation wide participation; for the research of islet function provides new scientific research thinking; in the highstrung β cell to metabolic alterations, whether the albumen acetylation participates in regulating insulin secretion is also known little about it.
The Mechanism Study of regulating metabolism along with acetylation receives publicity day by day; multiple deacetylase inhibitor is come out one after another; in albumen acetylation research, be widely used, provide research tool for understanding the albumen acetylation in depth to impact and the regulatory mechanism thereof of cellular metabolism and correlation function.
Deacetylase can be divided into four large classes: HDAC I, HDAC II, HDAC III and HDAC IV.HDAC I, HDAC II and HDAC IV class deacetylase are with Zn
2+Be prothetic group, the HDAC III claims again sirtuin, with NAD
+Be coenzyme.Niacin amide (Nicotinamide; NAM) be the inhibitor of sirtuin family; Trichostatin A (trichostatin A, TSA) is the inhibitor of HDAC I, II, does not still have at present bibliographical information about the research of deacetylase inhibitor and insulin secretion relation.
Summary of the invention
The purpose of this invention is to provide the application of deacetylase inhibitor in preparation promotion insulin secretion medicine.
Described deacetylase inhibitor is the inhibitor of the deacetylase of inhibition HDAC I, HDAC II or HDAC III class.
Described deacetylase inhibitor is niacin amide.
Described deacetylase inhibitor is Buddhist nun's Trichostatin A.
The albumen acetylation is one of major way of modifying behind the protein translation, and protein function is had important regulating action.Proteomics research in recent years shows; about 2200 protein receptor acetylation modifications are arranged in mammalian cell; these protein that are subjected to the acetylation adjusting are except histone; also comprise transcription factor, kinases, ubiquitin ligase, ribosomal protein, metabolic enzyme etc., the wide participation regulator gene is transcribed, cell cycle; DNA damage is repaired; cytoskeleton is reinvented, and cell autophagy and metabolism etc. it serves to show that acetylation modification is to the importance of cell activities.In the protein that regulated by acetylation; the catalyzing enzyme of metabolic pathway accounts for sizable ratio; at liver; the involved in sugar zymolysis; glyconeogenesis, tricarboxylic acid cycle, fatty acid is synthetic; nearly all enzyme of ornithine cycle and glycogen metabolism is regulated by acetylation all, and many enzymes of oxidative phosphorylation and amino acid metabolism are regulated by acetylation also.The acetylation modification of pheron can change enzymatic activity or stability, and cellular metabolism is regulated in wide participation, and visible acetylation modification has important effect in metabolism is regulated.
Histone is the protein that regulated by acetylation of finding the earliest, and its acetylation modification participates in transcribing of controlling gene, and the acetylation modification of histone carries out under acetyltransferase and deacetylation enzyme catalysis.Mammiferous deacetylase is divided into Four types according to the homology with the yeast deacetylase, i.e. HDAC I, HDAC II, HDAC III and HDAC IV.I, II, IV class HDAC are with Zn
2+Be cofactor, the HDAC III is called again Sirtuins, with NAD
+Be prothetic group.
The present invention processes rat Langerhans islet by deacetylase inhibitor Trichostatin A (trichostatin A, TSA), niacin amide (Nicotinamide, NAM), observes the impact of this insulin secretion.Deacetylase inhibitor NAM and TSA are hatched islets of langerhans 1h; (concentration of glucose is: 3.3mmol/L) under the sugared concentration in basis; on insulin secretion all less than the impact; (concentration of glucose is: insulin secretion (GSIS) rising about 50%, the TSA that 16.7mmol/L) stimulates does not have remarkable effect to GSIS and deacetylase inhibitor NAM can make glucose.Under the sugared concentration in basis (concentration of glucose is: 3.3mmol/L), TSA can promote insulin secretion when processing islets of langerhans 12h, 16, more obvious to the facilitation of insulin secretion during 24h; And NAM can slightly raise insulin secretion more than processing 16h, and the prompting acetylation modification participates in the regulation and control insulin secretion.And NAM is more obvious to the facilitation of acute secretion.TSA is on not impact of acute GSIS, and its long term is more obvious, illustrates that TSA may mainly work by affecting related gene expression.
Beneficial effect of the present invention is:
1, by deacetylase inhibitor NAM, TSA acute test and the chronic test to insulin secretion by rat, illustrate that NAM is obvious to the facilitation of acute insulin secretion, and the TSA long term is more obvious on the insulin secretion impact.So, deacetylase inhibitor NAM and TSA can be applied in the preparation promotion insulin secretion medicine, and this medicine is used for the treatment of diabetes, will play good therapeutic effect.
2, for more rational use deacetylase inhibitor NAM and TSA provide more scientific basis clinically.And provide more medical usage for deacetylase inhibitor NAM and TSA.
Description of drawings
Fig. 1 is that deacetylase inhibitor NAM and deacetylase inhibitor TSA are to the acute effect comparison diagram of rat Langerhans islet insulin secretion.
Fig. 2 is that deacetylase inhibitor TSA is to the chronic effect comparison diagram of rat Langerhans islet insulin secretion.
Fig. 3 is that deacetylase inhibitor NAM is to the chronic effect comparison diagram of rat Langerhans islet insulin secretion.
The specific embodiment
Below in conjunction with embodiment, the invention will be further described:
Test used rat model and be SPF (Specific pathogen Free) level SD (Sprague-Dawley) rat, male, 8-10 age in week, body weight 200-250g is available from the Si Laike of Shanghai Chinese Academy of Sciences Experimental Animal Center.
Bovine serum albumin (BSA) is available from MP Biomedicals.
Embodiment 1
1, rat Langerhans islet separation and Culture of former generation
1), get the SD rat, 10% chloral hydrate intraperitoneal anesthesia is fixed;
2), open the abdominal cavity, find major duodenal papilla, close major duodenal papilla with curved hemostatic forceps folder;
3), find common bile duct, eye scissors is cut off osculum, and the small hose that is connected with syringe is inserted into common bile duct towards the pancreas direction;
4), be that the XI Collagenase Type (being dissolved in Hank ' the s liquid that contains 1%BSA) of 0.5mg/ml is slowly injected in the pancreas with concentration in the syringe, until whole pancreas is fully full, separates lower pancreas along caecum to duodenal wall and place the 50ml centrifuge tube;
5), after bathing 17min, 37 ℃ of water-bath temperature firmly whole pancreas is thrown away;
6), stop digestion with ice Hank ' the s liquid that contains 0.25%BSA;
7), 1000rpm, 4 ℃ of centrifugal 1min abandon supernatant, add ice Hank ' s liquid block is dispelled rear recentrifuge, repeat above-mentioned steps totally three times;
8), wash finish after, adds about 20ml ice Hank ' s liquid, blow and beat gently, mixing, sieve (diameter 850 μ m) get filter liquor with removal bulk tissue impurity, Hank ' s liquid on the rocks is to 50ml, the centrifugal 3min of 1000rpm removes supernatant again;
9), add 25%BSA300 μ l piping and druming evenly, add successively density and be 1.094,1.061,1.041 histopaque (being dissolved in Hank ' the s liquid) 10ml, 5ml, 5ml, 5ml, 4 ℃, the centrifugal 4min of 400rpm, then 1700rpm is centrifugal 17 minutes;
10), draw the interface cell mass with suction pipe, place the 50ml centrifuge tube of Hank ' s liquid, the centrifugal 3min of 1000rpm;
11), stereomicroscope sets about to pick up islets of langerhans, and is for subsequent use.
2, deacetylase inhibitor NAM, TSA are to the acute test of insulin secretion by rat:
With the rat Langerhans islet that obtains in the step (1), containing 0.25%BSA, 3.3mmol/L after hatching 30min in the KRB buffer of glucose, then change to respectively 3.3mmol/L glucose (CON group), 3.3mmol/L glucose+5mmol/L NAM(NAM group), 3.3mmol/L glucose+200nmol/L TSA(TSA group), 16.7mmol/L glucose (matched group CON), 16.7mmol/L glucose+5mmol/L NAM(NAM group), 16.7mmol/L KRB buffer glucose+200nmol/L TSA(TSA group), cultivate 1h, collect supernatant, measure insulin concentration.Specifically as shown in Figure 1, under basic glucose (3.3mmol/L glucose) concentration, NAM, TSA on insulin secretion all less than the impact, under the 16.7mmol/L glucose stimulates, compare with matched group (CON group), the NAM group makes GSIS raise about 50%, and the TSA group does not have remarkable effect to GSIS.
3, deacetylase inhibitor NAM, TSA are to the chronic test of insulin secretion by rat:
With the rat Langerhans islet that obtains in the step (1), respectively with containing 0.25%BSA and 3.3mmol/L glucose (matched group CON), 3.3mmol/L glucose+200nmol/L TSA(TSA group) RPMI-1640 hatch islets of langerhans, respectively 1,2,4,8,12,16,24h, collect supernatant, measure insulin concentration.Specifically as shown in Figure 2, the processing time is shorter than 12h, and TSA is on not impact of insulin secretion, and when processing 12h, TSA can promote insulin secretion, and 16, TSA significantly increases the facilitation of insulin secretion during 24h.
With the rat Langerhans islet that obtains in the step (1), respectively with containing 0.25%BSA and 3.3mmol/L glucose (matched group CON), 3.3mmol/L glucose+5mmol/L NAM(NAM group) RPMI-1640 hatch islets of langerhans, respectively 1,2,4,8,12,16,24h, collect supernatant, measure insulin concentration.The result as shown in Figure 3, the processing time is shorter than 16h, NAM processes more than the 16h not impact of Basal insulin secretion, NAM can promote insulin secretion.
In sum, two kinds of different deacetylase inhibitor NAM, TSA can both affect insulin secretion, support the albumen acetylation to participate in regulating islet function; NAM is obvious to the facilitation of acute insulin secretion, and the TSA long term is more obvious on the insulin secretion impact, illustrates that deacetylase inhibitor has regulating action to insulin secretion, can be used as the medicine that preparation promotes insulin secretion.So, if above two kinds of different deacetylase inhibitor NAM, TSA are applied in the medicine of preparation promotion insulin secretion, then this drug regimen is applied in the treatment for the treatment of diabetes, will have good curative effect.
Claims (4)
1. the application of deacetylase inhibitor in preparation promotion insulin secretion medicine.
2. application claimed in claim 1 is characterized in that: described deacetylase inhibitor is for suppressing the inhibitor of HDAC I, HDAC II or HDAC III class deacetylase.
3. claim 1 or 2 described application, it is characterized in that: described deacetylase inhibitor is niacin amide.
4. claim 1 or 2 described application, it is characterized in that: described deacetylase inhibitor is Buddhist nun's Trichostatin A.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108992442A (en) * | 2018-07-12 | 2018-12-14 | 上海交通大学医学院附属瑞金医院 | MS-275 promotes the purposes in insulin secretion drug in preparation |
| CN112156188A (en) * | 2020-11-10 | 2021-01-01 | 上海交通大学医学院附属瑞金医院 | Application of Hsp90 in preparation of drugs for preventing and treating steroid diabetes |
| CN114681446A (en) * | 2020-12-30 | 2022-07-01 | 南京盛德生物科技研究院有限公司 | Application of acetamide compound as glutamate dehydrogenase inhibitor |
-
2013
- 2013-07-17 CN CN2013103001660A patent/CN103356617A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| 张芳婷等: "尼克酰胺、β-细胞调节素、bFGF、HGF联合诱导人脐血CD34~+细胞向胰岛素分泌细胞的分化", 《解剖学报》 * |
| 蔺怡等: "曲古霉素A和5-氮杂胞苷对胰岛β细胞的保护作用", 《中华糖尿病杂志》 * |
| 陈宏等: "尼克酰胺对白介素-1β损伤的离体大鼠胰岛细胞的保护作用", 《中国临床药理学与治疗学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108992442A (en) * | 2018-07-12 | 2018-12-14 | 上海交通大学医学院附属瑞金医院 | MS-275 promotes the purposes in insulin secretion drug in preparation |
| CN112156188A (en) * | 2020-11-10 | 2021-01-01 | 上海交通大学医学院附属瑞金医院 | Application of Hsp90 in preparation of drugs for preventing and treating steroid diabetes |
| CN114681446A (en) * | 2020-12-30 | 2022-07-01 | 南京盛德生物科技研究院有限公司 | Application of acetamide compound as glutamate dehydrogenase inhibitor |
| CN114681446B (en) * | 2020-12-30 | 2024-05-10 | 南京盛德生物科技研究院有限公司 | Application of acetamide compound as glutamate dehydrogenase inhibitor |
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Application publication date: 20131023 |