CN109288843A - The effect for reducing blood fat of rutaecarpin - Google Patents
The effect for reducing blood fat of rutaecarpin Download PDFInfo
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- CN109288843A CN109288843A CN201811373273.5A CN201811373273A CN109288843A CN 109288843 A CN109288843 A CN 109288843A CN 201811373273 A CN201811373273 A CN 201811373273A CN 109288843 A CN109288843 A CN 109288843A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61P3/06—Antihyperlipidemics
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Abstract
The invention discloses the effect for reducing blood fat of rutaecarpin, rutaecarpin reaches reducing blood lipid purpose by increasing the outflow of people THP-1 Macrophage cholesterol, and the effect of regulation Cholesterol Efflux is the degradation due to inhibiting ABCA1 albumen and has activated TRPV1 receptor.The beneficial effects of the invention are as follows novel targets are provided for the prevention and treatment of atherosclerosis, the research and development for novel blood lipid-lowering medicine or health care product from now on provide convenient approach.
Description
Technical field
The invention belongs to medicine technology fields, are related to the effect for reducing blood fat of rutaecarpin.
Background technique
Atherosclerosis (atherosclerosis, AS) is that ductus arteriosus wall thickens, is hardened, and is followed the string narrow with lumen
The general name of small degeneration and proliferative lesion.The generation of AS and hyperlipidemia are in close relations, mainly due to gallbladder total in serum
The lipid contents such as sterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) increase extremely, and in intra-arterial
Deposited on film, cause ductus arteriosus wall thicken be hardened, lumen reduce, decline the blood supply level of blood supply organ.Caused by AS
Cardiovascular disease (cardiovascular disease, CVD) be the world today the No.1 lethal cause of disease and China resident
The first cause of the death.Currently, China is calculated, about every 8.5s just has 1 people every year because of CVD death toll about 3,700,000 by the death toll
Die of CVD.China's cardiovascular disease occupies 40% or more of people's disease death composition and still in ascent stage, and urban and rural residents are good for
Health receives serious harm.Along with the height of myocardial infarction and cerebral thrombosis caused by dyslipidemia especially hypercholesterolemia etc.
Hair, the family of such disease and burden on society increasingly aggravate, it has also become great public health problem, it is quick, curative for effect
The clinical demand of blood lipid-lowering medicine is higher and higher, and research and development reducing blood lipid newtype drug is very urgent.
The raising of lipid level is the danger signal that atherosclerosis occurs in blood.Inhibit atherosclerosis
The effective way of development is to reduce lipid level in blood.Traditional hypolipidemic such as Statins, which mainly passes through, inhibits endogenous gallbladder
Effect for reducing blood fat is realized in the synthesis of sterol, or effect helpless to the process for accelerating cholesterol to excrete is smaller, therefore opens
The lipid-lowering medicine for the promotion cholesterol efflux for sending out novel is of great significance.The process that internal cholesterol excretes is called cholesterol
Antiport (reverse cholesterol transport, RCT) refers to that cholesterol is transported to liver from surrounding tissue and carries out
Recycling or the process excreted in the form of cholic acid.The first step of RCT is called Cholesterol Efflux (cholesterol
Efflux, ChE), refer to endocellular liberation cholesterol through cell membrane ATP binding cassette transporters A1 (ATP-binding
Cassette transporter A1, ABCA1), 1 type scavenger receptor (SR-B1) of ABCG1 or B class be transported to extracellularly, with
Apolipoprotein A1 (apolipoproteinA1, apoA1), which combines, generates high-density lipoprotein (high density
Lipoprotein, HDL) process.Wherein, ABCA1 transport protein is to adjust the most important transport protein of Cholesterol Efflux, is born
Load is more than 60% Cholesterol Efflux, is an important target spot for researching and developing reducing blood lipid class drug.The adjusting of ABCA1 protein level is
Important means and the basis of Cholesterol Efflux molecular mechanism are studied, drug enhances by raising the level of ABCA1 transport protein
Cholesterol Efflux achievees the purpose that reducing blood lipid, to inhibit the formation and development of AS.
Drugs for dispelling internal cold evodia rutaecarpa is that the drying of rutaceae evodia rutaecarpa (Evodiarutaecarpa (Juss.) Benth.) is close
Ripening fruits is included in the article list that can be used for health food by the Ministry of Public Health of China.Compendium of Material Medica records evodia rutaecarpa and " opens strongly fragrantization
It is stagnant.Acid regurgitation is controlled, negative sputum headache of fainting, insidious abdominal pain, hernia, bloody flux, mouthpiece's aphtha." modern pharmacology research shows evodia rutaecarpa
Have the effects that anti-liver injury, bidirectional modulation blood pressure, inhibit platelet aggregation, antipathogen, lower blood-fat and reduce weight.Evodia rutaecarpa contains more
Kind chemical component, such as alkaloids, terpene, volatile oil, fatty acid.Alkaloid rutaecarpin is mainly having for evodia rutaecarpa
Ingredient is imitated, content is about 5mg/g.The molecular weight of rutaecarpin are as follows: 303, molecular formula are as follows: C19H17N3O.Rutaecarpin reduces small
Mouse serum triglyceride level is it has been reported that rutaecarpin passes through ABCA1 access regulation cholesterol however, there is not been reported
Outflow is to reach reducing blood lipid purpose.The rutaecarpin that the present invention studies can increase Cholesterol Efflux, specific up-regulation ABCA1 albumen
Level has directly effect in the forming process for inhibiting atherosclerotic plaque, is that novel, quick, effective anti-atherogenic is hard
The excavation of chemical drug object provides theoretical and experimental basis.Specific modification of the rutaecarpin to ABCA1 albumen, is conducive to explain
Bright hypolipidemic activity natural materials increase the targeting proteins of Cholesterol Efflux, and drug tar-get and the discovery for disclosing AS prevention and treatment are novel
Hypolipidemic provides convenient approach for medicament research and development from now on.
Summary of the invention
The present invention provides the effect for reducing blood fat of rutaecarpin, i.e. rutaecarpin increases cholesterol stream by ABCA1 access
Out, directly inhibit the formation of atherosclerotic plaque.The beneficial effects of the invention are as follows the prevention and treatments for atherosclerosis to provide new target
Point, the research and development for novel blood lipid-lowering medicine or health care product from now on provide convenient approach.
The present invention is achieved by the following technical solutions:
It is a discovery of the invention that rutaecarpin has effect for reducing blood fat, it can conspicuousness reduction lotus rouge mice serum low-density lipoprotein
White cholesterol (LDL-C), total triglycerides (TG) and total cholesterol (TC) are horizontal, to high-density lipoprotein cholesterol (HDL) water
It is flat also to have certain raising.
The present invention is further discovered that rutaecarpin can increase the Macrophage cholesterol outflow of ABCA1 mediation, is that its is above-mentioned
The mechanism of action of reducing blood lipid.
The macrophage behaviour THP-1 macrophage.Rutaecarpin has no toxicity in cellular level working concentration.
Rutaecarpin of the invention can be made into all pharmaceutically acceptable oral and non-oral formulation forms.
The present invention also provides the mechanisms of action that rutaecarpin increases Cholesterol Efflux, that is, inhibit ABCA1 transport protein
Degradation, on the mRNA level in-site (i.e. genetic transcription approach) of ABCA1 without influence.
Further, the effect for the Cholesterol Efflux that rutaecarpin increase ABCA1 is mediated is related to TRPV1 activation.
The gallbladder that present invention announcement natural active matter rutaecarpin effect for reducing blood fat mechanism is that it increases ABCA1 mediation is solid
Alcohol outflow.
Detailed description of the invention
Fig. 1 is rutaecarpin effect for reducing blood fat schematic diagram；
Fig. 2 is the schematic diagram that rutaecarpin regulates and controls people THP-1 Macrophage cholesterol outflow effect；
Fig. 3 is that rutaecarpin influences people THP-1 macrophage vigor schematic diagram；
Fig. 4 is expression schematic diagram of the transport protein under rutaecarpin effect in THP-1 macrophage；
Fig. 5 is that abca1 gene transcription level and ABCA1 protein degradation rate are made in rutaecarpin in THP-1 macrophage
Schematic diagram under；
Fig. 6 is under the action of TRPV1 receptor antagonist capsicum is flat, and rutaecarpin regulates and controls THP-1 Macrophage cholesterol
The schematic diagram of outflow.
Specific embodiment
The present invention is described in detail With reference to embodiment.
1. rutaecarpin is to the effect for reducing blood fat of lotus rouge ICR mouse.
Construct lotus rouge mouse model: mouse feeds high lipid food (lard 10%, cholesterol 3%, Pig cholate 0.5%) 3 weeks,
Establish stable lotus rouge mouse model.ICR mouse used ties up company of tonneau China purchased from Beijing.
Administration and measurement: mouse is randomly divided into 4 groups.It is respectively as follows: normal diet-control group, normal diet-rutaecarpin
Group, high lipid food-control group and high lipid food-rutaecarpin group.Rutaecarpin group gives the rutaecarpin of 10mg/kg, control
Group gives coordinative solvent.After feeding mouse 8 weeks, puts to death and take serum.It is measured respectively using single reagent GPO-PAP method total in serum
TC, total TG, HDL-C and LDL-C are horizontal.
As a result: rutaecarpin can conspicuousness reduce serum LDL-C, the level of TC and TG has the level of HDL-C certain
Raising effect, but no significant difference compared with normal diet-control group, referring to Fig. 1.In Fig. 1, A: serum high-density rouge
Protein cholesterol HDL is horizontal；B: serum LDL cholesterol LDL is horizontal；C: serum total cholesterol TC is horizontal；D: serum
Total triglycerides TG is horizontal.2. rutaecarpin regulates and controls the effect of human macrophage Cholesterol Efflux
Construct THP-1 Macrophage Model: the THP-1 monocyte of logarithmic growth phase, after counting by concentration be 0.2 ×
106For the cell inoculation of a/mL on 24 orifice plates, cell becomes huge with 200nM PMA (being purchased from Sigma company) culture 72h differentiation
Phagocyte.
Administration is measured with Cholesterol Efflux: RPMI-1640 cell culture fluid removed, it is right by control group (solvent), the positive
According to the different experimental group administration such as group (Pioglitazone), administration group (1,3,10,20 μM of rutaecarpin).Meanwhile cell being used
NBD- cholesterol label.After culture for 24 hours, removes culture solution and cell is divided into two groups (blank group and apoA1 groups), continue to cultivate
The fluorescence intensity of intraor extracellular is measured after 6 hours respectively.The calculating of the Cholesterol Efflux of apoA1 mediation is carried out by following formula.
As a result: rutaecarpin can increase to concentration dependent the outflow of THP-1 Macrophage cholesterol, be computed, half
Effective concentration EC50It is 4.15 μM, referring to fig. 2.Wherein, the dose-dependant concentration of 10 μM of positive drug Pioglitazone, rutaecarpin is
1,3,10,20 μM.
3. influence of the rutaecarpin to macrophage vigor
It constructs THP-1 Macrophage Model: being 0.2 × 10 by concentration6The logarithmic growth phase THP-1 monocyte of a/mL
It is inoculated on 96 orifice plates, culture 72h differentiation becomes macrophage under 200nM PMA induction.
Administration is measured with cell viability: RPMI-1640 cell culture fluid being removed, by control group (solvent), positive control
The different experimental group administration such as group (digitonin), administration group (10,20,40 μM of rutaecarpin).After culture for 24 hours, removal
Culture solution simultaneously is continued to measure trap in each hole after cultivating 6h with 0.1% resazurin.
As a result: rutaecarpin does not influence people's THP-1 macrophage in each concentration (10,20,40 μM of rutaecarpin) of test
The vigor of cell does not have toxicity to cell, indicates it for low toxicity, safe and effective reactive compound, referring to Fig. 3.Wherein, positive
Property 50 μ g/mL of medicine digitonin, rutaecarpin concentration is 10,20,40 μM.
4. the influence that rutaecarpin expresses Cholesterol Efflux key protein
Construct THP-1 Macrophage Model: the THP-1 monocyte of logarithmic growth phase, after counting by concentration be 0.2 ×
106For the cell inoculation of a/mL in 6 orifice plates, cell, which cultivates 72h differentiation with 200nM PMA, becomes macrophage.
Administration is measured with protein expression: no by control group (solvent), positive controls (Pioglitazone), rutaecarpin group etc.
Same experimental group administration.After cell culture for 24 hours, is washed twice with 4 DEG C of PBS, 180 hole μ L/ of NP40 cell pyrolysis liquid is added.
Lysate is collected after 30min, centrifuging and taking supernatant measures protein concentration.It takes 20 μ g samples for polyacrylamide gel electrophoresis, turns
For film to cellulose nitrate film, 5% skim milk closes 1h, and primary antibody (ABCA1 antibody, ABCG1 antibody and SR- is added in 1:1000
B1 antibody is purchased from Novus company) 4 DEG C be incubated overnight, wash 3 times, each 15min, add secondary antibody 1:1000 to be incubated at room temperature 1h, wash 3
It is secondary, each 15min, chemiluminescence detection protein band.
As a result: rutaecarpin can conspicuousness increase transport protein ABCA1 to flat, to the level of ABCG1 and SR-B1 without shadow
It rings, referring to fig. 4.Wherein, A:ABCA1 protein expression level；B:ABCG1 protein expression level；C:SR-B1 protein expression level.
5. influence of the rutaecarpin to abca1 gene transcription level
Construct THP-1 Macrophage Model: the THP-1 monocyte of logarithmic growth phase, after counting by concentration be 0.2 ×
106For the cell inoculation of a/mL in 6 orifice plates, cell, which cultivates 72h differentiation with 200nM PMA, becomes macrophage.
Administration is measured with mRNA level in-site: no by control group (solvent), positive controls (Pioglitazone), rutaecarpin group etc.
Same experimental group administration.After culture for 24 hours, after cell is washed twice with 4 DEG C of PBS, tried using peqGOLD Total RNAKit
Agent box (being purchased from PeqLab company) extracts total serum IgE.RNA is quantified using Nano drop.Take 1 μ g RNA according to high capacity
CDNA reverse transcription reagent box (being purchased from Thermo fisher company) step illustrates to carry out cDNA reverse transcription synthesis, after synthesis
CDNA and real-time polymerase chain reaction measurement is carried out using ABCA1 primer (be purchased from Qiagen company).
As a result: rutaecarpin on the transcriptional level of abca1 gene without influence, referring to Fig. 5, in Fig. 5, A:ABCA1 mRNA water
It is flat.
6. influence of the rutaecarpin to ABCA1 protein degradation rate
Construct THP-1 Macrophage Model: the THP-1 monocyte of logarithmic growth phase, after counting by concentration be 0.2 ×
106The cell inoculation of a/mL is in 6 orifice plates, and differentiation becomes macrophage after cell cultivates 72h with 200nM PMA.
Administration and ABCA1 protein degradation rate determination: control group (solvent), positive controls (Pioglitazone), Wu Zhu are pressed
The different experimental group administration such as cornel alkali group.After cell culture for 24 hours, is washed twice with 37 DEG C of PBS, Protein synthesis is added
Inhibitor cycloheximide (being purchased from Sigma company) continues to cultivate.Respectively after time point 0,10,20,40min, with 4 DEG C
PBS wash cell twice and be added 180 holes μ L/ NP40 cell pyrolysis liquid make cell cracking.Lysate is collected after 30min, from
The heart takes supernatant, measures protein concentration.Take 20 μ g samples for polyacrylamide gel electrophoresis, transferring film to cellulose nitrate film,
5% skim milk closes 1h, and 1:1000 is added 4 DEG C of primary antibody (ABCA1 antibody be purchased from Novus company) and is incubated overnight, and washes 3 times, often
Secondary 15min adds secondary antibody 1:1000 to be incubated at room temperature 1h, washes 3 times, each 15min, chemiluminescence detection protein band.
As a result: it is to increase the stability of albumen that rutaecarpin conspicuousness, which inhibits the degradation of ABCA1 albumen, referring in Fig. 5
B: under eukaryocyte protein synthesis inhibitor cycloheximide effect, ABCA1 is at time point 0,10,20,40min
Protein level.
7. rutaecarpin regulates and controls the effect of Cholesterol Efflux by the flat antagonism of capsicum
Construct THP-1 Macrophage Model: the THP-1 monocyte of logarithmic growth phase, after counting by concentration be 0.2 ×
106For the cell inoculation of a/mL in 6 orifice plates, cell, which cultivates 72h differentiation with 200nM PMA, becomes macrophage.
Administration is measured with Cholesterol Efflux: RPMI-1640 cell culture fluid being removed, by control group (solvent), evodia rutaecarpa
The different realities such as alkali group (10 μM), flat group of capsicum (10 μM) and co-administered group (10 μM of rutaecarpin and 10 μM of capsicum are flat)
Test grouping administration.Meanwhile cell NBD- cholesterol being marked.After culture for 24 hours, removes culture solution and cell is divided into two groups
(blank group and apoA1 group) measures the fluorescence intensity of intraor extracellular after continuing culture 6 hours respectively and carries out apoA1 mediation
The calculating of Cholesterol Efflux.
As a result: under the action of TRPV1 antagonist capsicum is flat, rutaecarpin increases the outflow of THP-1 Macrophage cholesterol
Event resolves, prompt rutaecarpin increase Cholesterol Efflux effect it is related as TRPV1 agonist to it.This is the discovery that
It is disclosed for the first time in people's THP-1 macrophage.Referring to Fig. 6.
Present invention firstly discovers that rutaecarpin effect for reducing blood fat increases the Cholesterol Efflux activity phase of ABCA1 mediation with it
Close, and disclose for the first time rutaecarpin increase Cholesterol Efflux be degradation due to inhibiting ABCA1 albumen and have activated TRPV1 by
Body.The activation of ABCA1 protein stability and TRPV1, related signal path is that rutaecarpin increases cholesterol between the two
The mechanism of action of hypolipidemic activity is flowed out and had, and inhibits a new mechanism of atherosclerosis occurrence and development.This hair
It is bright that the molecular mechanism that AS occurs is illustrated from new visual angle, and novel targets are provided for the prevention and treatment of AS.
The above is only not to make limit in any form to the present invention to better embodiment of the invention
System, any simple modification that embodiment of above is made according to the technical essence of the invention, equivalent variations and modification,
Belong in the range of technical solution of the present invention.
Claims (2)
1. the effect for reducing blood fat of rutaecarpin.
2. according to the effect for reducing blood fat of rutaecarpin described in claim 1, it is characterised in that: the rutaecarpin can reduce serum
LDL-C, total TG and total TC are horizontal, and the mechanism of action is to increase Macrophage cholesterol outflow；Rutaecarpin increases cholesterol
Outflow be due to inhibit ABCA1 albumen degradation and it is related to the activation of TRPV1 receptor.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1312075A (en) * | 1996-06-12 | 2001-09-12 | 协和发酵工业株式会社 | Lipid-matabolizing improvement agent |
| CN102014944A (en) * | 2008-04-29 | 2011-04-13 | (株)柳柳制药 | Pharmaceutical composition using herbal extract for prevention and treatment of obesity and metabolic disorders |
| CN103301134A (en) * | 2013-06-29 | 2013-09-18 | 成都中医药大学 | Pharmaceutical composition for treating hyperlipidemia as well as preparation method and applications |
| KR20140086213A (en) * | 2012-12-28 | 2014-07-08 | 한국식품연구원 | COMPOSITION COMPRISING Evodiamine FOR TREATING OBESITY-INDUCED INFLAMMATION |
-
2018
- 2018-11-19 CN CN201811373273.5A patent/CN109288843A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1312075A (en) * | 1996-06-12 | 2001-09-12 | 协和发酵工业株式会社 | Lipid-matabolizing improvement agent |
| CN102014944A (en) * | 2008-04-29 | 2011-04-13 | (株)柳柳制药 | Pharmaceutical composition using herbal extract for prevention and treatment of obesity and metabolic disorders |
| KR20140086213A (en) * | 2012-12-28 | 2014-07-08 | 한국식품연구원 | COMPOSITION COMPRISING Evodiamine FOR TREATING OBESITY-INDUCED INFLAMMATION |
| CN103301134A (en) * | 2013-06-29 | 2013-09-18 | 成都中医药大学 | Pharmaceutical composition for treating hyperlipidemia as well as preparation method and applications |
Non-Patent Citations (1)
| Title |
|---|
| 张秋方: "吴茱萸碱对高脂血症小鼠血脂水平及血液黏稠度的影响", 《河南中医》 * |
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