CN106389455B - It is a kind of for preventing or treating the polymethoxyflavone, composition and its pharmaceutical preparation of nonalcoholic fatty liver - Google Patents
It is a kind of for preventing or treating the polymethoxyflavone, composition and its pharmaceutical preparation of nonalcoholic fatty liver Download PDFInfo
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- CN106389455B CN106389455B CN201610827919.7A CN201610827919A CN106389455B CN 106389455 B CN106389455 B CN 106389455B CN 201610827919 A CN201610827919 A CN 201610827919A CN 106389455 B CN106389455 B CN 106389455B
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- 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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Abstract
The invention discloses a kind of polymethoxyflavone, composition and its preparations to prevent or treat the application in nonalcoholic fatty liver, this is for preventing or treating the active constituent of the drug of nonalcoholic fatty liver to include polymethoxyflavone, the polymethoxyflavone is 3,5,6,7,8,3', 4'- Heptamethoxyflavone, further include pharmaceutically acceptable carrier or excipient, pharmaceutically acceptable dosage form is made.After giving HMF, liver structure is significantly improved, reduces the accumulation of liver fat caused by high fat diet, and HMF high concentration liver fat drips are close to normal level, the above result shows that 3,5,6,7,8,3', 4'- Heptamethoxyflavone can effectively improve liver lipids accumulation, play the role of prevention or treatment nonalcoholic fatty liver, and there is dose-effect otherness.
Description
Technical field
The invention belongs to field of medicaments, are related to the new application of natural products, and in particular to one kind is for preventing or treating non-
Polymethoxyflavone, composition and its pharmaceutical preparation of alcoholic fatty liver.
Background technique
Non-alcohol fatty liver (Nonalcoholic fatty liver disease, NAFLD) refers to except alcohol
Caused by explicitly being damaged with other outside liver factors, it is comprehensive as the clinical pathology of main feature using over-deposit fatty in liver cell
Sign, with the fashion trend of fat and its associated metabolic syndrome globalization, the disease incidence of NAFLD rises in apparent in recent years
Trend, it has also become the primary cause of disease of the big chronic liver disease of developed country first and dysfunction of liver, normal adult human NAFLD illness rate
It is 17%~33%.Modern medicine there is no the specific medicament for the treatment of NAFLD at present, mainly to dispel the cause of disease and inducement, treatment original
Based on the disease of hair basis, to prevent the development of chronic liver disease, steatohepatitis is prevented and treated, the terminal phase treats then with Liver Transplantation for Treatment
Effect it is unsatisfactory, therefore research and develop effectively treatment NAFLD newtype drug have important clinical meaning.
Polymethoxyflavone (Polymethoxylated Flavones, PMFs) is that one kind contains multiple methoxyl groups, low pole
Property, the flavones ingredient for having strong bioactivity with planar structure, are 3 in phenyl chromone structure, 4,5,6,7,
It is connected with 4 or 4 or more methoxyl groups at the positions such as 8,2', 3', 4', 5', 6', is mainly derived from Rutaceae Citrus, is present in
In the medicinal materials such as dried orange peel, green peel, Exocarpium Citri Rubrum, fingered citron, the dried immature fruit of citron orange.3,5,6,7,8,3', 4'- Heptamethoxyflavone (HMF) are exactly wherein one
Kind, molecular formula C22H24O9, relative molecular mass 432.43, No. CAS is 1178-24-1, and chemical structure is as follows:
Summary of the invention
The polymethoxyflavone that the object of the present invention is to provide a kind of for preventing or treating nonalcoholic fatty liver, combination
Object and its pharmaceutical preparation, the polymethoxyflavone are 3,5,6,7,8,3', 4'- Heptamethoxyflavone (HMF).
Above-mentioned purpose is achieved by the following technical solution:
It is a kind of for preventing or treating the drug of nonalcoholic fatty liver, active constituent includes polymethoxyflavone.
Preferably, the polymethoxyflavone is 3,5,6,7,8,3', 4'- Heptamethoxyflavone.
Preferably, the active constituent further includes paederosidic acid, is the combination of polymethoxyflavone and paederosidic acid
Object.
It is a kind of for preventing or treating the pharmaceutical preparation of nonalcoholic fatty liver, including above-mentioned active constituent, further include medicine
Acceptable carrier or excipient on, are made pharmaceutically acceptable dosage form.
Preferably, the pharmaceutically acceptable carrier or excipient include one or more solids, semisolid or liquid
Body auxiliary material.
Preferably, the pharmaceutically acceptable dosage form includes tablet, dispersible tablet, capsule, soft capsule, micro-capsule
Agent, granule, injection, powder-injection, freeze drying powder injection, micropill preparation, pill, syrup, powder, extract, soft extract, mouth
Take liquid preparation.
Beneficial effects of the present invention:
After giving HMF, liver structure is significantly improved, reduces the accumulation of liver fat caused by high fat diet, and HMF high
Concentration liver fat drips are close to normal level, the above result shows that 3,5,6,7,8,3', 4'- Heptamethoxyflavone can effectively improve
Liver lipids accumulation plays the role of prevention or treatment nonalcoholic fatty liver, and has dose-effect otherness.
Detailed description of the invention
Fig. 1 is each group liver section result.
Specific embodiment
Technical solution of the present invention is specifically introduced with reference to the accompanying drawings and examples.
Experimental method:
1, the foundation of animal model
C57BL/6 male mice 60, weight 18-20g are taken, 6 week old.Mouse adapts to random grouping after a week are as follows: normal
Feed group (Normal chow diet, NCD), high fat diet group (High fat diet, HFD), Lovastatin group
(Lovastatin, LOV), 3,5,6,7,8,3', 4'- Heptamethoxyflavone low dose group (HMF-L) and 3,5,6,7,8,3',
4'- Heptamethoxyflavone high dose group (HMF-H), other groups are all made of high fat diet in addition to chow diet group.HFD feed formula
Are as follows: 1.25% cholesterol, 20% lard, 5% sucrose, 0.5% cholic acid, vitamin are adjusted to normal level.
2, dosage and administration mode: in HFD Induction experiments, mouse is carried out using the administration mode of stomach-filling.Modeling is opened
Beginning administration, NCD and HFD give the 0.5%CMC-Na solution of same volume, are administered six weeks altogether.LOV group dosage is 30mg/g/
D, HMF-L group dosage are 25mg/g/d, and HMF-L group dosage is 50mg/g/d.LOV and HMF use 0.5CMC-Na respectively
Solution allocation is at suspension.
3, prepared by blood plasma: before experiment terminates, mouse is deprived of food but not water 12h, and eye corner of the eyes venous blood sampling is put into containing heparin sodium
In centrifuge tube, 4000rpm, is centrifuged 10min, -80 DEG C of supernatant preservations by 4 DEG C.
4, blood parameters measure: plasma triglyceride, cholesterol, plasma low density lipoprotein cholesterol, high density
Lipoprotein cholesterol, glutamic-pyruvic transaminase, glutamic-oxalacetic transaminease assay kit build up Bioengineering Research Institute, measurement step purchased from Nanjing
Suddenly it is carried out by corresponding instructions.
5, dissection materials: before experiment terminates, mouse is deprived of food but not water 12h, puts to death mouse, is rapidly separated out liver, takes out
A part, which is fixed in formalin, makes H&E slice.
H&E dyes pathological analysis: 1) fresh liver is placed in formalin, is impregnated for 24 hours；2) it is thick to cut 4 ì m for paraffin embedding
Piece；3) dimethylbenzene dewaxes 2 times, 5-10min/ times；4) 100% ethyl alcohol, 95% ethyl alcohol, 80% ethyl alcohol, 75% ethyl alcohol, distilled water
It embathes respectively 2 times, 1-2min/ times；5) hematoxylin dyes 5min, and distilled water cleans remaining hematoxylin dyeing liquor, and filter paper blots residual
Water；6) 1% acidic alcohol breaks up 1-3s；7) distilled water immersion 15min；8) Yihong liquid dyes 2min；9) with 95% ethyl alcohol,
100% ethyl alcohol impregnate 2 times, 1min/ time, dimethylbenzene carbolic acid solution immersion 1min, xylene soak 2 times, 1min/ times.10) in
Property resin sealing；11) photographic analysis.
Experimental result:
Since nonalcoholic fatty liver is using fatty over-deposit as main feature, we have primarily looked at HMF in body
The interior regulating and controlling effect to lipid metaboli, we are using HFD diet induced mouse hyperlipoidemia assessment HMF to internal lipid metaboli
Influence.After HFD is induced 6 weeks, for model group compared with normal group, TG, TC, LDL-c dramatically increase (P < 0.001), illustrate small
Mouse hyperlipemia model modeling success, the content that there is HMF concentration dependent to reduce HFD mice plasma TG, TC, LDL-c, significantly
The content for increasing blood plasma HDL-c has similar trend (table 1-4) with positive drug LOV (Lovastatin).The increase of blood lipid is past
Toward causing lipid to be accumulated in organ, wherein fat and liver are the most significant.Fat liver deposition, and then generate damage make
With as " nonalcoholic fatty liver ", fat is accumulated obviously in liver after H&E coloration result shows HFD modeling, and liver cell becomes
Shape is obvious, illustrates that disorders of lipid metabolism results in hepatic injury, and giving Lovastatin or HMF can significantly reverse liver cell fatty degeneration.For
Influence of the further assessment HMF to fatty liver, we determine the characteristics index ALT and AST of liver function.ALT after modeling,
AST is significantly increased, and illustrates that liver damages, and after giving HMF, ALT, AST are significantly reduced, and HMF high concentration (50mg/kg) is very
ALT and AST content in blood plasma can be extremely set to restore normal (table 5-6).Nonalcoholic fatty liver is the main spy of disorders of lipid metabolism
One of sign shows as fatty excess accumulation in liver cell, and influences liver function.As shown in Figure 1, HFD group is aobvious after HFD modeling
Show the liver cell to swell, irregular liver rope arrangement and a large amount of fat drips.After giving HMF, liver structure is significantly improved, is reduced
Liver fat caused by high fat diet is accumulated, and HMF high concentration liver fat drips are close to normal level, the above result shows that 3,5,
6,7,8,3', 4'- Heptamethoxyflavone can effectively improve liver lipids accumulation, play prevention or treatment nonalcoholic fatty liver
Effect, and have dose-effect otherness.
1 HMF of table to plasma triglyceride (TG) influence (N=12)
| Group | TG(mmol/L) | P value | |
| NCD | 1.46±0.1844 | ||
| HFD | 2.30±0.1794 | 8.68E-7 | ### |
| LOV | 1.73±0.3450 | 9.67E-3 | ** |
| HMF-L | 1.78±0.1644 | 6.62E-4 | * |
| HMF-H | 1.77±0.2899 | 6.13E-3 | * |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD,*P < 0.05,**P <
0.01,***P < 0.001.
2 HMF of table to total plasma cholesterol (TC) influence (N=12)
| Group | TC(mmol/L) | P value | |
| NCD | 2.11±0.1000 | ||
| HFD | 4.80±0.2701 | 9.75E-14 | ### |
| LOV | 3.81±0.2747 | 1.33E-4 | *** |
| HMF-L | 4.37±0.2395 | 3.73E-2 | n.s. |
| HMF-H | 3.90±0.2102 | 1.08E-4 | * |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD, n.s. is poor without conspicuousness
It is different,*P < 0.05,**P < 0.01,***P < 0.001.
3 HMF of table to plasma low density lipoprotein cholesterol (LDL-c) influence (N=12)
| Group | LDL-c(mmol/L) | P value | |
| NCD | 0.21±0.0168 | ||
| HFD | 0.54±0.0416 | 2.06E-11 | ### |
| LOV | 0.38±0.0422 | 1.03E-4 | *** |
| HMF-L | 0.46±0.0504 | 3.75E-2 | * |
| HMF-H | 0.40±0.0387 | 3.12E-4 | *** |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD,*P < 0.05,**P <
0.01,***P < 0.001.
4 HMF of table to plasma hdl cholesterol (HDL-c) influence (N=12)
| Group | HDL-c(mmol/L) | P value | |
| NCD | 1.40±0.0889 | ||
| HFD | 2.18±0.1512 | 1.10E-7 | ### |
| LOV | 2.68±0.1605 | 7.19E-4 | *** |
| HMF-L | 2.78±0.1940 | 3.80E-4 | *** |
| HMF-H | 2.86±0.1593 | 2.34E-5 | *** |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD,*P < 0.05,**P <
0.01,***P < 0.001.
5 HMF of table to glutamic-pyruvic transaminase (ALT) influence (N=12)
| Group | ALT(IU/L) | P value | |
| NCD | 22.50±2.67 | ||
| HFD | 28.15±2.98 | 3.71E-3 | ### |
| LOV | 23.91±1.40 | 3.30E-2 | n.s. |
| HMF-L | 22.31±2.02 | 7.18E-3 | ** |
| HMF-H | 18.99±1.47 | 4.85E-5 | *** |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD, n.s. is poor without conspicuousness
It is different,*P < 0.05,**P < 0.01,***P < 0.001.
6 HMF of table to glutamic-oxalacetic transaminease (AST) influence (N=12)
| Group | AST(IU/L) | P value | |
| NCD | 104.00±8.87 | ||
| HFD | 114.36±7.36 | 1.03E-2 | # |
| LOV | 101.66±7.81 | 3.61E-2 | n.s. |
| HMF-L | 108.45±7.91 | 3.09E-1 | n.s. |
| HMF-H | 98.95±7.15 | 1.01E-2 | * |
Note: compared with NCD,#P < 0.05,##P < 0.01,###P < 0.001；Compared with HFD, n.s. is poor without conspicuousness
It is different,*P < 0.05,**P < 0.01,***P < 0.001.
It has also been found that, the inhibition nonalcoholic fatty liver effect of HMF can be enhanced in paederosidic acid, according to above-mentioned reality in experiment
Using the HMF and paederosidic acid of a half-value dose in HMF low dose group, (dosage is the 0.1 of HMF dosage to proved recipe method
Times) be applied in combination TG, TC, LDL-c level in mice plasma can be reduced to NCD group level (for 1.46 ± 0.1312,
2.11 ± 0.1231,0.22 ± 0.0144), there was no significant difference (P > 0.05) with NCD group, while can further increase
HDL-c is horizontal, improvement result of the enhancing HMF to liver function (ALT, AST level are better than HMF-H group).But it individually gives above-mentioned
When the paederosidic acid of dosage, to TG, TC, LDL-c level in mice plasma without effect is substantially reduced, with model group without significance difference
Different (respectively 2.31 ± 0.1416,4.81 ± 0.2514,0.53 ± 0.0423) (P > 0.05), ALT, AST level also with HFD
Group is without significant difference (P > 0.05).
The effect of above-described embodiment, which is only that, illustrates essentiality content of the invention, but guarantor of the invention is not limited with this
Protect range.Those skilled in the art should understand that can modify to technical solution of the present invention or equally replace
It changes, without departing from the essence and protection scope of technical solution of the present invention.
Claims (1)
1. the composition of polymethoxyflavone and paederosidic acid is in the drug of preparation prevention or treatment nonalcoholic fatty liver
Application, the polymethoxyflavone is 3,5,6,7,8,3', 4'- Heptamethoxyflavone, and the polymethoxyflavone and chicken droppings
The weight ratio of rattan thuja acid is 10:1.
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| CN104415135A (en) * | 2013-08-29 | 2015-03-18 | 绿茵生技股份有限公司 | Use of hydroxyl polymethoxylated flavonoid compound and/or derivative thereof |
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| CN104415135A (en) * | 2013-08-29 | 2015-03-18 | 绿茵生技股份有限公司 | Use of hydroxyl polymethoxylated flavonoid compound and/or derivative thereof |
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| 广西鸡屎藤的化学成分研究;胡海清 等;《中国中药杂志》;20130831;第38卷(第16期);2657-2660 |
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