CN105168233A - Application of 20(S)-ginsenoside Rg3 as SIRT1 protein agonist - Google Patents
Application of 20(S)-ginsenoside Rg3 as SIRT1 protein agonist Download PDFInfo
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- CN105168233A CN105168233A CN201510612222.3A CN201510612222A CN105168233A CN 105168233 A CN105168233 A CN 105168233A CN 201510612222 A CN201510612222 A CN 201510612222A CN 105168233 A CN105168233 A CN 105168233A
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Abstract
The invention discloses an application of 20(S)-ginsenoside Rg3 as SIRT1 protein agonist and particularly relates to an application of 20(S)-ginsenoside Rg3 in preparing drugs for increasing myocardial energy metabolism, an application of 20(S)-ginsenoside Rg3 in preparing drugs for treating ischemic heart diseases, an application of 20(S)-ginsenoside Rg3 in preparing drugs for adjusting glycometabolism and an application of 20(S)-ginsenoside Rg3 in preparing drugs for treating 2-type diabetes. The invention further provides a drug composition with ginsenoside Rg3 as an effective ingredient. The application of 20(S)-ginsenoside Rg3 as the SIRT1 protein agonist in adjusting myocardial energy metabolism blocks and blood glucose metabolic disorders is disclosed for the first time, and therefore the aim of treating ischemic heart diseases and 2-type diabetes is achieved.
Description
Technical field
The present invention relates to herbal pharmacology field, particularly relate to a kind of 20 (S)-ginsenoside Rgs
3as the purposes of SIRT1 protein agonist.
Background technology
Human body energy metabolism disorder is the Important cause of disease that development occurs various diseases.Mitochondrion is the important organelle of human body energy metabolism.Research shows, body can make the metabolic response of applicable body when environment change, these metabolic adaptabilities are finely tuned the one of mitochondrial function on a cellular level, and this fine setting is generally by the regulable control of PGC-1 α, its meeting boost line plastochondria when body requirement energy is movable, also can reduce mitochondrion quantity when energy requirement is very low simultaneously.PGC-1 α mainly acts on cell, and cell can be made to produce corresponding energy with the change of environment, comprises mitochondrion synthesis enhancing, the raising of Cellular respiration rate, and the utilization etc. of energy substrate.PGC-1 α can promote mitochondrial biosynthesis as cometabolism regulatory factor, is gone the dynamic equilibrium of control line mitochondria function and energy by PGC-1 α action effect device.
Ischemic heart desease and expanding heart failure patient there will be myocardium coronary insufficiency mostly, myocardial contractility weakens, thus result in energy metabolism of myocardial obstacle, and then the development that aggravates one's illness further.Under normal circumstances, the ATP that heart maintenance contractile function and the energy required for basal metabolism are mainly produced by fatty acid and glucose oxidase metabolism provides.Its energy metabolism comprises the utilization to the substrate such as fatty acid, glucose in blood, to the energy-producing oxidation-Phosphorylation events of mitochondrial respiratory chain and to the transfer of ATP and utilization.When myocardial ischemia-anoxemia or myocardial structural change cause myocardial hypertrophy, substrate conversion becomes the ability of ATP to die down by cardiac muscle, and myocardial mitochondrial structure and function also exception can occur, and causes oxidation respiratory function to go down.And ATP transfer and utilize impaired after, average A TP lowering of concentration, creatine kinase can be caused to shift ATP ability and to reduce, finally make cardiac systolic function limited.Therefore, academia proposition in recent years improves the control that energy metabolism can be used for cardiovascular disease.Get involved to improve energy metabolism of myocardial by medicine and can play useful effect in this disease, the cardiac energy regulator of unique list marketing is trimetazidine at present, by blocking 3-KAT enzyme level fatty acid oxidation, and then promotion glucose oxidase, more multi-energy is produced when oxygen-limited condition, maintain the energy metabolism of cell under anoxia or ischemia, improve cardiac function.The exhaustion myocardial metabolism reconstruct concept of VanBilsen also demonstrate that myocardial cell energy metabolism imbalance is one of pathophysiological mechanism of heart failure.
Mitochondrial function damage is one of potential pathogenesis of insulin resistant and type 2 diabetes mellitus, the biosynthesis of PGC-1 α scalable Various Tissues Mitochondria and metabolism.Therefore, raising will become the new method for the treatment of metabolic disease with recovery mitochondrial function and oxidability thereof.
Being positioned at nucleus and mitochondrial NAD+ dependency deacetylase (SIRT1) is participate in the key protein that cellular energy metabolism regulates.SIRT1 can be deacetylated to multiple lysine sites of PGC-1 α, promotes mitochondrial fatty acid oxidase antagonism low sugar environment.When cellular energy stores minimizing, NAD+ increases, and activates SIRT1, makes the Viability form of PGC-1 α deacetylation subsequently, promotes mitochondrion substrate oxidation ability, produces a large amount of ATP to meet energy requirement.Therefore, Recent study shows, the generation of the chronic disease that SIRT1 protein active is relevant with the age to such as aging, tumor, neurodegenerative diseases etc. develops closely related.SIRT1 protein agonist is considered to play critical function in adjusting energy metabolism etc.
Ginsenoside Rg
3be one of active component extracted in Radix Ginseng, there is the formation effect of the adhesion of inhibition tumor cell, propagation and anti-tumor neovascularization, thus have significant antitumor action.But it is improving energy metabolism thus is also reporting without research in prevention and cure of cardiovascular disease and diabetes.
Summary of the invention
The invention provides a kind of 20 (S)-ginsenoside Rgs
3as the purposes of SIRT1 protein agonist, by activating SIRT1, making the Viability form of PGC-1 α deacetylation, promoting mitochondrion substrate oxidation, producing a large amount of ATP to meet energy requirement, thus reach the object of the disease that treatment causes because of energy metabolism disorder.
Ginsenoside Rg
3molecular formula is C
42h
72o
13, this compound mainly contains 2 kinds of common configuration 20 (S)-ginsenoside Rg
3with 20 (R)-ginsenoside Rgs
3.The present invention relates to 20 (S)-ginsenoside Rgs
3, structural formula is as shown in formula I.
20 (S)-ginsenoside Rgs
3as the purposes of SIRT1 protein agonist.
20 (S)-ginsenoside Rgs
3for colourless powder, applicant finds 20 (S)-ginsenoside Rgs under study for action
3sIRT1 can be activated in concentration dependent ground, now there are some researches show that SIRT1 is the key protein participating in cellular energy metabolism adjustment, therefore 20 (S)-ginsenoside Rgs
3as the agonist of SIRT1, in adjusting energy metabolism, play critical function.
20 (S)-ginsenoside Rgs
3the application in energy metabolism of myocardial medicine is increased in preparation.
Energy metabolism of myocardial obstacle can aggravate the development of the ischemic cardiac functional defect state of an illness, and academia proposes to maintain the energy metabolism of cell under anoxia or ischemia, can improve cardiac function.This research finds, 20 (S)-ginsenoside Rgs
3the biosynthesis of impaired myocardial cell Mitochondria can be promoted, strengthen myocardial cell to the oxidative metabolism of substrate, improve ATP content.
20 (S)-ginsenoside Rgs
3application in preparation treatment ischemic heart medicine.
Research shows, 20 (S)-ginsenoside Rgs
3ejection fraction and the left ventricle Fractional shortening value of ischemic cardiac functional defect model can be significantly improved, improve the symptom of the chronic cardiac insufficiency that ischemia causes, therefore can be applied in the preparation for the treatment of ischemic heart medicine.
20 (S)-ginsenoside Rgs
3the application in carbohydrate metabolism medicine is regulated in preparation.
20 (S)-ginsenoside Rgs
3application in preparation treatment type 2 diabetes mellitus medicine.
Research proves, 20 (S)-ginsenoside Rgs
3can significantly reduce type 2 diabetes mellitus model random blood sugar and fasting blood glucose level, improve metabolism of blood glucose, therefore may be used on treating in the preparation of type 2 diabetes mellitus medicine.
A kind of pharmaceutical composition, comprises 20 (S)-ginsenoside Rgs as effective ingredient
3.
As preferably, comprise drug excipient or the carrier of pharmaceutical preparation permission.This pharmaceutical composition can pass through vein, oral, Sublingual, through muscle or subcutaneous, skin mucosa administration.
As preferably, the dosage form of pharmaceutical composition is liquid preparation or solid preparation.Each dosage form all can be prepared from pharmacy conventional method.
The beneficial effect that the present invention possesses: the present invention makes public for the first time 20 (S)-ginsenoside Rgs
3agonist as SIRT1 is regulating the purposes in energy metabolism of myocardial obstacle and dysglycemia, thus reaches the object for the treatment of ischemic heart desease and type 2 diabetes mellitus.
Accompanying drawing explanation
Fig. 1 is embodiment 1 variable concentrations ginsenoside Rg
3to the graph of a relation of SIRT1 agonism.
Fig. 2 is embodiment 2 ginsenoside Rg
3to the exercising result figure of myocardial cell model of oxidative; Wherein A is ATP content detection results contrast figure, B is mtDNA content detection results contrast figure, and C is reactive oxygen species testing result figure.
Fig. 3 is embodiment 3 ginsenoside Rg
3to the exercising result figure of ischemic cardiac functional defect model.
Detailed description of the invention
Further illustrate flesh and blood of the present invention and beneficial effect below in conjunction with drawings and Examples, this embodiment is only for illustration of the present invention but not limitation of the present invention.
Embodiment 1 ginsenoside Rg
3to SIRT1 albumen agonism
At SIRT1, lysyl endopeptidase, NAD
+and variable concentrations ginsenoside Rg
3in sample mixture, add fluorescent probe TPE-GK (Ac) YDD, with reaction buffer polishing to equal volume.Hatch 2 hours, after reaction terminates, adopt TECAN microplate reader to measure each hole fluorescence intensity, fluorescence exciting wavelength is 320nm, and emission wavelength is 465nm.Ginsenoside Rg is calculated according to fluorescence intensity
3to the regulating action of SIRT1.
Result as shown in Figure 1, ginsenoside Rg
3sIRT1 can be activated in concentration dependent ground, thus play adjusting energy metabolism.
Embodiment 2 myocardial cell model of oxidative
According to literature method (KimDH, ParkCH, ParkD, etal.GinsenosideRcmodulatesAkt/FoxO1pathwaysandsuppresse soxidativestress [J] .Archivesofpharmacalresearch, 2014,37 (6): 813-820.) tert-butyl group hydrogen peroxide damaged cardiomyocytes, is utilized.H9c2 cell kind, in 96 orifice plates, adds ginsenoside Rg after 24 hours
3(20mM), pre-protection, after 24 hours, adds the damage of tert-butyl group hydrogen peroxide.
Experimental result as shown in Figure 2, ginsenoside Rg
3improve the ATP content of the myocardial cell of oxidative damage, mtDNA content, improves myocardial cell base respiration, reduces intracellular active oxygen, has protective effect to Myocytes Anoxia damage.
Embodiment 3 ischemic cardiac functional defect model
Coronary ligation method induction SD rat is adopted to produce chronic cardiac insufficiency model.First, Banded Rats ramus descendens anterior arteriae coronariae sinistrae (LAD) sets up acute myocardial infarction (AMI) model: SD rat, with after the anesthesia of 5% chloral hydrate (by 0.6ml/100g dosage) solution, is fixed on Mus plate.Operative site loses hair or feathers, iodine tincture, alcohol disinfecting, circulation of qi promoting cannula, along left side parasternal diagonal otch, the upper bound is two forelimb trailing edge lines, lower bound is the 5th intercostal, successively the shallow fascia of percutaneous incision and deep fascia, and with mosquito forceps blunt separation pectoralis major and serratus anterior intersection, breast is being entered by sternal border place mosquito forceps blunt separation the 3rd, 4 intercostals, open thoracic cavity, cut off pericardium, expose heart.Under stereomicroscope, between left auricle and pulmonary conus, find coronary artery, 2-3mm place below coronary artery starting point, with 6 ~ No. 0 silk thread ligation.Rapid closedown thoracic cavity, layer-by-layer suture muscle and skin, partly sterilised is antibacterial.Postoperatively give penicillin 400,000 U/ only.Postoperative 28 days, according to ultrasonic experiments (ejection fraction value is less than 35%) and serum BNP (BNP) horizontal Confirming model, grouping.If 1, model group (Model), 5; 2, ginsenoside Rg
3group, 5; With sham operated rats (a threading not ligation) as a control group, 5.
Rg
3standard substance are purchased from upper Hiroad standing grain, and be dissolved in the injection of normal saline pneumoretroperitoneum, dosage is 5mg/kg/ days, administration 28 days.Detect ejection fraction value and the left ventricle Fractional shortening value of each experimental group rat.Rats in sham-operated group ejection fraction value is about about 80%.
Experimental result as shown in Figure 3 shows, ginsenoside Rg
3ejection fraction value and the left ventricle Fractional shortening value of rat model can be improved, the symptom of the chronic cardiac insufficiency that ischemia causes can be improved.Therefore, may be used for treating ischemic heart desease.
Embodiment 4 diabetes model
Adopt spontaneous type 2 diabetes mellitus mice KKAy and control group mice C57BL/6J to carry out ginsenoside Rg3 and regulate metabolism of blood glucose Effect study.Wherein, KKAy mice (SPF level, male, 6-8 week), C57BL/6J mice (SPF level, male, 18-20g), purchased from Beijing HFK Bio-Technology Co., Ltd., the equal adaptability of all laboratory animals is fed after 10 days for experiment.C57BL/6J mice mice in contrast; Hyperglycemia KKAy mice is divided into 3 groups at random, is respectively model group, ginsenoside Rg
3group (50mg/kg), positive drug metformin group (300mg/kg).Medicine is dissolved in 0.5% carboxymethylcellulose sodium solution, and once, matched group and model group mice give equal volume solvent 0.5% carboxymethylcellulose sodium solution to the medicine of all mice gavage every day corresponding dosage.
Blood sugar detection: the random blood sugar and the fasting glucose that measure weekly a mice before administration and after administration, concrete operations are as follows: after administration, tail vein blood test glucose level is random blood sugar, and water 6h is can't help in animal fasting subsequently, and tail vein blood test glucose level is fasting glucose.
After successive administration the 1st, 2,3 week mice random blood sugar and fasting glucose numerical value as shown in table 1, ginsenoside Rg as can be seen from the table
3can significantly reduce diabetic mice random blood sugar and fasting blood glucose level, improve metabolism of blood glucose.Compared with existing antidiabetic drug metformin, it improves glucose metabolism ability and is not weaker than metformin.
Table 1
Claims (8)
1.20 (S)-ginsenoside Rgs
3as the purposes of SIRT1 protein agonist.
2.20 (S)-ginsenoside Rgs
3the application in energy metabolism of myocardial medicine is increased in preparation.
3.20 (S)-ginsenoside Rgs
3application in preparation treatment ischemic heart medicine.
4.20 (S)-ginsenoside Rgs
3the application in carbohydrate metabolism medicine is regulated in preparation.
5.20 (S)-ginsenoside Rgs
3application in preparation treatment type 2 diabetes mellitus medicine.
6. a pharmaceutical composition, is characterized in that, comprises 20 (S)-ginsenoside Rgs as effective ingredient
3.
7. pharmaceutical composition as claimed in claim 6, is characterized in that, comprises drug excipient or the carrier of pharmaceutical preparation permission.
8. pharmaceutical composition as claimed in claim 6, it is characterized in that, the dosage form of pharmaceutical composition is liquid preparation or solid preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108295249A (en) * | 2018-03-09 | 2018-07-20 | 南方医科大学南方医院 | Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage |
| CN113712987A (en) * | 2021-07-28 | 2021-11-30 | 澳门科技大学 | For increasing NAD+Horizontal composition and use thereof |
| CN113768833A (en) * | 2021-08-16 | 2021-12-10 | 楚香(上海)生物科技有限公司 | Pure natural deacetylase activator and application thereof |
| CN115337317A (en) * | 2021-05-14 | 2022-11-15 | 中国科学院大连化学物理研究所 | 20 Application of (S) -ginsenoside Rg3 and medicine or GPR35 receptor antagonist |
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| CN1593442A (en) * | 2003-07-23 | 2005-03-16 | 山东绿叶天然药物研究开发有限公司 | Application of 20(S)-ginsenoside-Rg#[3] in the preparing process of medicine for treating or preventing cardiovascular and cerebrovascular disease |
| CN1879640A (en) * | 2005-06-19 | 2006-12-20 | 彭康康 | Use of ginsenosides Rh2, Ck and Rg3 in increasing myocardial contractility |
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2015
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Patent Citations (3)
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| CN1879640A (en) * | 2005-06-19 | 2006-12-20 | 彭康康 | Use of ginsenosides Rh2, Ck and Rg3 in increasing myocardial contractility |
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|---|
| 谷金宁: "20(S)-人参皂苷Rg3对糖尿病大鼠心脏的保护作用研究", 《中国博士学位论文全文数据库医药卫生科技辑》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108295249A (en) * | 2018-03-09 | 2018-07-20 | 南方医科大学南方医院 | Applications of the Sirt1 in the drug for preparing treatment treating myocardial ischemia damage |
| CN115337317A (en) * | 2021-05-14 | 2022-11-15 | 中国科学院大连化学物理研究所 | 20 Application of (S) -ginsenoside Rg3 and medicine or GPR35 receptor antagonist |
| CN113712987A (en) * | 2021-07-28 | 2021-11-30 | 澳门科技大学 | For increasing NAD+Horizontal composition and use thereof |
| CN113712987B (en) * | 2021-07-28 | 2023-10-31 | 澳门科技大学 | For improving NAD + Horizontal composition and use thereof |
| CN113768833A (en) * | 2021-08-16 | 2021-12-10 | 楚香(上海)生物科技有限公司 | Pure natural deacetylase activator and application thereof |
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