CN108704136A - Proteasome inhibitor is preparing the purposes in preventing, treating the drug of angiocardiopathy - Google Patents
Proteasome inhibitor is preparing the purposes in preventing, treating the drug of angiocardiopathy Download PDFInfo
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- CN108704136A CN108704136A CN201810842829.4A CN201810842829A CN108704136A CN 108704136 A CN108704136 A CN 108704136A CN 201810842829 A CN201810842829 A CN 201810842829A CN 108704136 A CN108704136 A CN 108704136A
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- drug
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- proteasome inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The present invention provides proteasome inhibitors to prepare the purposes in preventing, treating the drug of angiocardiopathy, especially application of the cyanidenon as proteasome inhibitor in preventing diabetic cardiomyopathy.Proteasome inhibitor of the present invention, solve the problems, such as traditionally without be effectively prevented and treated for the angiocardiopathies such as diabetic cardiomyopathy and existing clinical drug therapy there are adverse reactions, propose new thinking and concrete application for the prevention angiocardiopathies such as cardiomyopathy and heart failure.
Description
Technical field
The present invention relates to proteasome inhibitors to prepare the purposes in preventing, treating the drug of angiocardiopathy
Background technology
Myocardial hypertrophy is the compensatory response that cardiac muscular tissue generates for adaptation Cardiac haemodynamics excess load.In cellular water
On flat, myocardial hypertrophy is mainly shown as the increase of cell volume and weight；Organ level then show as ventricular weight increase and
Ventricle wall thickening.Pathological cardiac hypertrophy is to lead to a variety of angiocardiopathies (heart failure, atherosclerosis, myocardial infarction
And hypertension etc.) one of incidence and the constantly raised independent hazard factor of case fatality rate.Under the stimulation for the thick factor that causes fat, cardiac muscle
Cell volume increases, and myocardial Mass Measured increases, while with cardiac muscle cell apoptosis and necrosis, Proliferation of Cardiac Fibroblasts and conversion
And the pathological changes such as Myocardial Interstitial Fibrosis.Therefore, various kinds of cell together constitutes the pathology of myocardial hypertrophy complexity in heart
Learn basis.Diabetes (Diabetes Mellitus, DM) are since a variety of internal other factors interact caused insulin not
Lack relatively or absolutely with degree, causes to increase using blood glucose and disorders of lipid metabolism is the chronic disease of main feature.Diabetes
Increase the risk of heart failure close to 2.5 times, independently of coronary artery disease and other cardiovascular complications.Diabetic cardiomyopathy
(diabetic cardiomyopathy, DCM) is the cardiac damage directly resulted in by diabetes, and heart failure is that it faces substantially
Bed feature, myocardial hypertrophy is one of its major pathologic features.The mechanism of diabetic cardiomyopathy includes mainly insulin resistance
Disorder, myocardial hypertrophy, myocardial fibrosis, mitochondrial function exception, oxidative stress, er stress with energetic supersession etc., but
Have no the drug specifically for treatment diabetic cardiomyopathy at present, thus find effective diabetic cardiomyopathy medicine and its
Therapy target is the research emphasis in current angiocardiopathy field.
The essence of myocardial hypertrophy is that breaks down proteins are broken with anabolic dynamic equilibrium, leads to egg in cardiac muscle cell
White matter content increases, and Ubiquitin-proteasome system (ubiquitin-proteasome system, UPS) plays important wherein
Effect.UPS is the important channel of protein degradation in eukaryocyte, includes mainly ubiquitin, ubiquitin kinase E1, ubiquitin binding enzyme
E2, ubiquitin ligase E3, deubiquitinating enzymes DUB and 26S proteasomal system.Ubiquitin is protected by the height that 76 amino acid form
The polypeptide chain kept.Proteasome includes composing type and immunologic pattern, and composing type proteasome is by 20S core granules and 19S adjustings
Grain composition.Four circular layers that 20S core granules are made of α-and β-subunit are folded and are constituted,
Three kinds of catalytic subunit β 1, β 2 and β 5 in β rings are respectively provided with cysteine proteinase (Caspase-like
Activity), trypsase (Trpsin-like activity) and chymotrypsin activity (Chymotripsin-like
activity).β subunits are catalyzed under the action of inflammatory factor, are replaced by the induction type β subunits including β 1i, β 2i and β 5i
And form immunoproteasome.Research confirms that immunoproteasome has very important Pathological Physiology in angiocardiopathy
Meaning, adjustable includes the occurrence and development of the important diseases such as myocardial hypertrophy.
Animal experiments show that proteasome inhibitor reduces cardiac myocyte hypertrophy signal by protease inhibition body activity
The degradation of access negativity regulatory protein (the anti-myocardial hypertrophy factor), so as to improve myocardial hypertrophy.Facing for proteasome at present
Bed is intervened the initial stage that is still in, and common drug has bortezomib, newborn spore element and epoxy ketone etc..However, being there is no at present for the heart
The proteasome inhibitor of the angiocardiopathies such as myohypertrophia, heart failure and diabetic cardiomyopathy.In addition, existing for said medicine
Adverse reaction (such as decrease of platelet, peripheral nerve disease, neutrophilic granulocytopenia) limits these drugs to a certain extent
Clinical application.
Therefore it needs to identify or develop a kind of proteasome inhibitor that can prevent with prevention and cure of cardiovascular disease.
Cyanidenon (Luteolin) is a kind of flavone compound, is widely present in honeysuckle, chrysanthemum, cabbage, dish
In the vegetables fruit such as flower, beet, cabbage, carrot, celery, capsicum, peanut and the main active of Xinjiang Herba Achilleae.
Studies have shown that cyanidenon can anti-hypertension, anti-inflammatory, anti-oxidation stress etc. there are multiple biological activities, and oxidation is answered
The cardiac muscle cell and blood vessel for swashing damage have significant protective effect.
Invention content
It provides proteasome inhibitor it is an object of the invention to overcome the shortcomings of the prior art place and is making
Purposes in the standby drug for preventing, treating angiocardiopathy.
To achieve the above object, the technical solution taken：Proteasome inhibitor prevents, treats cardiovascular disease in preparation
Purposes in the drug of disease.
The present invention provides proteasome inhibitors to prepare the purposes in preventing, treating the drug of cardiomyopathy.
The present invention provides proteasome inhibitors to prepare the purposes in preventing, treating the drug of myocardial hypertrophy.
The present invention provides proteasome inhibitors to prepare the purposes in preventing, treating the drug of diabetic cardiomyopathy.
The present invention provides proteasome inhibitors to prepare the use in preventing, treating the drug of diabetes myocardial hypertrophy
On the way.
The present invention provides proteasome inhibitors to prepare the purposes in preventing, treating the drug of heart failure.
Preferably, the proteasome inhibitor is cyanidenon.
Present invention discover that cyanidenon is by protease inhibition body, and then activate the work of AMPK and glycogen synthase kinase-3
Property, play its cardiovascular protective effect.
Purposes the present invention provides proteasome as target spot in preparation prevents, treats the drug of angiocardiopathy.
Purposes the present invention provides proteasome as target spot in screening prevents, treats the drug of angiocardiopathy.
Preferably, the angiocardiopathy is diabetic cardiomyopathy.
The beneficial effects of the present invention are：Proteasome inhibitor of the present invention is solved and is not directed to traditionally
The angiocardiopathies such as diabetes myocardial hypertrophy (the shared Physiopathologic proceeding of a variety of angiocardiopathies) are effectively prevented and are controlled
It treats and clinical drug therapy has adverse reaction, proposed for the prevention angiocardiopathies such as cardiomyopathy and heart failure
New thinking and concrete application.The mouse for the 1 patients with type Ⅰ DM myocardial hypertrophy that the present invention is induced using streptozotocin as experiment pair
As horizontal with cardiac proteins enzyme body activity, proteasome subunit protein expression, cardiac ultrasonic, cardiac weight and size, heart
Section Hematoxylin-eosin (hematoxylin-eosin, H&E), Masson Trichrome dyeing is Testing index.As a result it shows
Show, cyanidenon has significant prevention as a kind of natural proteasome inhibitor, to the myocardial hypertrophy of type 1 diabetes mouse
And therapeutic effect, it will play a significant role in the prevention of the angiocardiopathies such as diabetic cardiomyopathy and heart failure.This hair
Bright result inhibits mitigation myocardial hypertrophy to provide new foundation for proteasome, and prevents diabetes and glycosuria for cyanidenon
Sick myocardial hypertrophy provides new mechanism from the angle of protease inhibition body, and then is one, Uygur nationality's authentic medicinal herbs Xinjiang
The utilization of wormwood artemisia bioactivity provide rational basis, this also has great significance to effective and reasonable utilize of people's medicine.And
Target spot exploitation for clinically diabetes myocardial hypertrophy even diabetic cardiomyopathy drug provides new strategy.
Specific implementation mode
To better understand the essence of the present invention, it will be illustrated in pharmaceutical field as experimental subjects with mouse below
New application.
8~10 week old male C57/B6 mouse are selected, type 1 diabetes model is established.Give C57/B6 mouse abdomens within continuous six days
Chamber injects low dose streptozocin STZ (45mg/kg/ days), is protected from light and places on ice lysed STZ, (entire injection operation mistake
Journey should also be protected from light quick progress).Normal group gives the citrate buffer solution of equivalent.Third day after STZ injections terminate, it is empty
Abdomen 6 hours pierces mouse back leg femoral vein blood with three-edged needle, and drop is special in steady bold and unconstrained type blood glucose meter when drop of blood goes out more than 1 μ l
On test paper, blood glucose value is measured.Three days fasting blood-glucoses of tie-in.Blood glucose value is confirmed as type 1 diabetes mouse higher than 16.7mmol/L
It models successfully.Then STZ 45mg/kg/ are injected intraperitoneally according to blood glucose level height is additional respectively in mouse less than 16.7mmol/L
It is 1~3 time.
Experiment packet：The mouse of equivalent citrate buffer solution and fasting blood-glucose higher than 16.7mmol/L will be injected to be randomly divided into
5 groups (every group 8~10)：(1) control group, (2) diabetes group, (3) diabetes+Luteolin low dose group (5mgkg-1·
d-1) group, (4) diabetes+Luteolin middle dose group (10mgkg-1·d-1) group, (5) diabetes+Luteolin high dose
Group (20mgkg-1·d-1) group, Luteolin is dissolved in 0.5% sodium carboxymethylcellulose and 0.5% Tween 80 mixed solution
In, basic, normal, high dosage Luteolin, daily equivalent solvent (0.2% carboxymethyl of control group are then injected intraperitoneally daily by grouping
Sodium cellulosate and 0.1% Tween 80), totally 12 weeks, then using the Vevo2100 high-resolution of Canada Visual Sonics productions
Toy ultrasonic image-forming system, connection 15L8 high frequency probes Siemens Ultrasound Instrument (Contrast Pulse Sequencing TM,
Sequoia 512, Siemens, Germany) mouse heart ultrasound is carried out, detect ventricular wall thickness and heart function.
Ordinary circumstance is observed：Developmental state, action, fur, diet, weight etc..
Mouse core Function detection：After being administered 12 weeks, using toy ultrasonic image system detectio mouse left ventricle antetheca, after
Wall and chamber interval thickness, left ventricular contraction and end-diastolic volume, and calculate left ventricle and shorten score (left ventricular
Fractional shortening, LVFS) and ejection fraction (left ventricular ejection fractions,
) and diastolic function parameter LVEF：The peaks E rate (rate of ventricle phase of rapid filling), the peaks A rate (ventricle reduced filling period
Rate), and calculate EA ratios (E/A).
Mouse heart size and weight measure：After the completion of heart function ultrasound Evaluation, 10% chloraldurate fiber crops are injected intraperitoneally
Liquor-saturated mouse, with 0.9% sodium chloride solution lavation heart of heparin sodium.Heart is won, 0.9% extra sodium chloride solution is removed, by mouse
Heart is put on reproduction plate claps gross cardiac with camera.Then claim quality, calculates cardiac weight and mouse weight ratio
(heart weight/body weight, HW/BW) and cardiac weight and tibial length ratios (heart weight/tibial
length,HW/TL)。
Mouse heart proteasome activity and proteasome subunit protein detection：After being administered 12 weeks, every 6 hearts are weighed
Afterwards, apex of the heart tissue freezing is left and taken.To detect triglycerides and total cholesterol level in mouse blood, fluorescent peptide substrates method detects the heart
Dirty 26S proteasomes chymotrypsinlike activity, Western blot methods detect the protein expression water of immunoproteasome beta 5 subunit
It is flat.
Murine myocardium Pathomorphology detects：After heart is weighed, part of heart (n=3) is in middle part perpendicular to heart
Long axis is crosscutting, paraffin embedding.It is sliced from heart bottom to the apex of the heart with 5 μ m thicks.Paraffin section de-waxing illustrates to water according to kit,
Carry out H&E and Masson Trichrome dyeing, to detect institutional framework, cardiac muscle cell's profile and the cardiac muscle fibre of heart respectively
Change degree.
As a result
Influence of the cyanidenon intervention to type 1 diabetes mouse cardiac muscle plumpness：
Mouse basic status is observed：Control group mice growth and development is good, fur is smooth, it is movable flexibly, take the photograph water and ingest just
Often.Diabetes group mouse activity reduces, and increase of ingesting, weight is mitigated, but without significant difference.Cyanidenon mouse state
It is improved compared with diabetes group.
Mouse core Function detection：Echocardiogram the results show that compared with the control group, diabetes group mouse LVFS and
LVEF is significantly increased, and compared with diabetes group, diabetes+cyanidenon group mouse LVEF and LVFS is substantially reduced.With compare
Group is compared, diabetes group left ventricular contraction phase front and back walls thickness (LVAW；S, LVPW；S), the forward and backward wall thickness of left ventricular diastolic
Spend (LVAW；D, LVPW；D) obviously increase, and cyanidenon various concentration processing group (5,10,20mgkg-1·d-1), with
Diabetes group is compared, and above-mentioned Testing index significantly reduces, and shows that model group mouse cardiac muscle plumpness obviously increases, but ejection fraction
Also increase with short axle shortening rate and indicate that cardiac systolic function belongs to compensatory enhancing, does not reach heart failure rank in myocardial hypertrophy
Section.Compared with the control group, diabetes group E peak rates and the peaks A rate ratio (E/A ratios) significantly reduce, diabetes group+reseda
Element (5mgkg-1·d-1、10mg·kg-1·d-1、20mg·kg-1·d-1) group and the obvious raising of DM groups, show that ventricle is easypro
Zhang Gongneng is decreased obviously, and giving cyanidenon processing group can obviously reverse.Illustrate that cyanidenon can significantly improve type 1 diabetes
The cardiac diastolic function for the myocardial hypertrophy mouse led.
Mouse heart size and weight measure：Mouse heart is collected in agent after 12 weeks ultrasound detections of administration, and naked eyes are visible
Diabetes group mouse heart volume significantly increases.Compared with the control group, diabetes group mouse HW/BW and HW/TL values significantly increase
Add.Diabetes group+cyanidenon group HW/BW and HW/TL value is substantially reduced compared with diabetes group.Prompt cyanidenon intervention can be significantly
Mouse core increases again caused by mitigating type 1 diabetes evolution.
Lipid of mice level changes：Compared with the control group, diabetes group serum triglyceride (TG), total cholesterol (TC) are bright
It is aobvious to increase, after cyanidenon is administered 12 weeks, three dosage of cyanidenon (5,10,20mgkg-1·d-1) with diabetes group phase
Than triglycerides and total cholesterol are substantially reduced.
Mouse heart proteasome activity and the expression of immunoproteasome protein subunit：It is detected using fluorescent peptide substrates method
It was found that the 26S proteasomes chymotrypsinlike activity of diabetes group mouse heart is significantly raised, cyanidenon intervenes 12 Zhou Houfa
Existing, chymotrypsinlike activity significantly reduces；Western blot, which also show cyanidenon, can obviously lower the diabetic mice heart
Dirty immunoproteasome beta 5 subunit protein expression level.
Murine myocardium Pathomorphology detects：Compared with the control group, diabetes group mouse ventricle wall obviously thickens, the heart
Chamber significantly increases, and cardiac muscle cell significantly increases；Cardiac interstitium and circumvascular fibrosis area dramatically increase.And it is above-mentioned
Index is significantly improved after cyanidenon intervention.
In conclusion cyanidenon has prevention as a kind of natural proteasome inhibitor, to diabetes myocardial hypertrophy
And therapeutic effect.Proteasome inhibitor cyanidenon can be used as the prevention angiocardiopathies such as diabetic cardiomyopathy and heart failure
A kind of new method.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than is protected to the present invention
The limitation of range is protected, although being explained in detail to the present invention with reference to preferred embodiment, those skilled in the art should
Understand, technical scheme of the present invention can be modified or replaced equivalently, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
1. proteasome inhibitor is preparing the purposes in preventing, treating the drug of angiocardiopathy.
2. proteasome inhibitor is preparing the purposes in preventing, treating the drug of cardiomyopathy.
3. proteasome inhibitor is preparing the purposes in preventing, treating the drug of myocardial hypertrophy.
4. proteasome inhibitor is preparing the purposes in preventing, treating the drug of diabetic cardiomyopathy.
5. proteasome inhibitor is preparing the purposes in preventing, treating the drug of diabetes myocardial hypertrophy.
6. proteasome inhibitor is preparing the purposes in preventing, treating the drug of heart failure.
7. according to any purposes of claim 1-6, which is characterized in that the proteasome inhibitor is cyanidenon.
8. proteasome is preparing the purposes in preventing, treating the drug of angiocardiopathy as target spot.
9. purposes of the proteasome as target spot in screening prevents, treats the drug of angiocardiopathy.
10. purposes according to claim 8 or claim 9, which is characterized in that the angiocardiopathy is diabetic cardiomyopathy.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810842829.4A CN108704136A (en) | 2018-07-27 | 2018-07-27 | Proteasome inhibitor is preparing the purposes in preventing, treating the drug of angiocardiopathy |
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| CN201810842829.4A CN108704136A (en) | 2018-07-27 | 2018-07-27 | Proteasome inhibitor is preparing the purposes in preventing, treating the drug of angiocardiopathy |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112156091A (en) * | 2020-09-30 | 2021-01-01 | 中山大学附属第一医院 | Application of hispidulin in preparation of medicine for treating and/or preventing cardiovascular diseases |
| CN113304149A (en) * | 2021-06-23 | 2021-08-27 | 广州医科大学 | Application of compound in preparation of medicine for treating type 2 diabetic cardiomyopathy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811997A (en) * | 2017-11-10 | 2018-03-20 | 大连医科大学附属第医院 | Application of the proteasome inhibitor resveratrol in angiocardiopathy is prevented and treated |
-
2018
- 2018-07-27 CN CN201810842829.4A patent/CN108704136A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811997A (en) * | 2017-11-10 | 2018-03-20 | 大连医科大学附属第医院 | Application of the proteasome inhibitor resveratrol in angiocardiopathy is prevented and treated |
Non-Patent Citations (4)
| Title |
|---|
| ATSUKO NAKAYAMA等: "A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling", 《PLOS ONE》 * |
| KUIXIANG CHEN等: "Quercetin Prevents In Vivo and In Vitro Myocardial Hypertrophy Through the Proteasome-GSK-3 Pathway", 《CARDIOVASCULAR DRUGS AND THERAPY》 * |
| MIN SHEN等: "Targeting Tumor Ubiquitin-Proteasome Pathway with Polyphenols for Chemosensitization", 《ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY》 * |
| 杜小燕等: "木犀草素抑制AngiotensinⅡ诱导的心肌细胞肥大", 《科学技术与工程》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112156091A (en) * | 2020-09-30 | 2021-01-01 | 中山大学附属第一医院 | Application of hispidulin in preparation of medicine for treating and/or preventing cardiovascular diseases |
| CN113304149A (en) * | 2021-06-23 | 2021-08-27 | 广州医科大学 | Application of compound in preparation of medicine for treating type 2 diabetic cardiomyopathy |
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