CN106309457A - Application of ursolic acid-aspirin conjugate in preparing liver-protecting drug - Google Patents
Application of ursolic acid-aspirin conjugate in preparing liver-protecting drug Download PDFInfo
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- CN106309457A CN106309457A CN201610950087.8A CN201610950087A CN106309457A CN 106309457 A CN106309457 A CN 106309457A CN 201610950087 A CN201610950087 A CN 201610950087A CN 106309457 A CN106309457 A CN 106309457A
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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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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Abstract
The invention relates to an application of an ursolic acid-aspirin conjugate as shown in Formula I and specifically relates to the application of the ursolic acid-aspirin conjugate in preparing a liver-protecting drug. The determination for AST, ALT and SOD activity proves that the conjugate has a better liver-protecting effect and has a wide application prospect in preparing the liver-protecting drug.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to the conjugate of a kind of ursolic acid and aspirin, be specifically related to Folium Vaccinii vitis-idaeae
The liver protection function of acid-Aspirin Conjugate and prepare the application of hepatic.
Background technology
The major function of liver, is secretion of bile, storage glycogen, regulates the oldest of protein, fat and carbohydrate
Metabolism, also has removing toxic substances, hemopoietic and Blood clotting.Removing toxic substances organ maximum in liver or human body, the poisonous substance of internal generation, useless
Thing, the poisonous substance eaten into, the medicine damaging liver etc. also must rely on liver detoxification.Liver decomposes by intestinal absorption or health
The noxious substance that other parts manufacture, is then secreted into bile with the form of innocuous substance or blood excretes then, so
Liver is one of most important internal organs of human body.Hepatic disease is the most relatively conventional disease, and hepatic disease is always medical science
One of object of science primary study.Hepatic injury is by operation strike, wound, microorganism infection, hepatic disease, poisonous chemical combination
Hepatocyte that thing, poisonous side effect of medicine, immunologic derangement, hereditary variation, not normal, the physicochemical irritation of metabolism etc. cause, hepatic tissue are even
The pathological change hepatic injury of the form and function of whole liver organ is to endanger one of common clinical disease of human health.Liver damages
The long-term existence of wound frequently can lead to hepatic fibrosis, is and then induction liver cirrhosis, the important initiating of liver failure, even hepatocarcinoma
Factor.Therefore prevent and treat one of the important step that hepatocyte injury is liver disease clinically, being suppression hepatic fibrosis, liver
The basis of the Occurrence and development of diseases such as necrosis, liver cirrhosis and hepatocarcinoma.The most clinical conventional hepatic, or because price is held high
Expensive, or because using inconvenience, or there is bigger side effect, use is restricted.
In research application, classical liver injury model mainly has chemical, immunity, biological, alcoholic hepatic injury model
Deng, the set up the condition of the most biological liver injury model requires height, and pathogen easy infection researcher etc. limits it under study for action
Application, Immune liver injury produces specific antibody by induction immunne response, thus causes hepatocyte injury.At present,
In terms of setting up liver damage animal model, Chinese scholars is most commonly used that chemical induction agent, CCl4, thioacetamide, second
Alcohol is all current modal chemical injury derivant.Showing according to current research, carbon tetrachloride causes the machine of hepatic injury
System includes: (1) causes oxidative stress；(2) internal related enzyme systems is caused to change；(3) cytokine activity is changed；(4) cause carefully
Born of the same parents adjust and die；(5) virulent gene group change.Wherein CCl4CCl3Lipid peroxidation process that free radical causes it is considered to be
Cause the main mechanism of hepatic injury.CCl4After entering body, activate through liver cytochrome P 450, generate CCl3·。CCl3Raw
Cheng Hou, it is possible to generate fatty acid with the unsaturated fatty acids acid reaction on cell membrane, thus cause lipid peroxidation and cause cell
Film, organelle damage.MDA is the stable product during this, and SOD is the main of internal removing ultra-oxygen anion free radical
Enzyme, can suppress body lipid peroxidization.During murder by poisoning, the hurried increase of internal oxygen-derived free radicals to consume substantial amounts of SOD, with
Time produce substantial amounts of MDA.Therefore, Cytochrome P450, SOD, MDA change can antimer inner lipid peroxidization intensity and group
Knit the degree of damage.
Ursolic acid-aspirin (ASP-UA) conjugate that the present invention relates to can suppress tumor cell and extracellular matrix
Adhere to；The motion transfer ability of tumor cell can be suppressed；The invasive ability of tumor cell can be suppressed；Tumor cell surface can be suppressed
The expression of adhesion factor；Can prevent breast carcinoma from pulmonary's transfer (see patent 201510466210.4) occurring.The Bears that the present invention provides
Fruit acid-Aspirin Conjugate (is abbreviated as ASP-UA), the experiment proved that, can significantly reduce carbon tetrachloride cause liver injury model little
Mus Serum ALT, AST activity, strengthens liver SOD activity, has good hepatoprotective effect.
Summary of the invention
Ursolic acid-Aspirin Conjugate (being abbreviated as ASP-UA) shown in formula I is in preparing hepatoprotective medicine
Application.
Ursolic acid-Aspirin Conjugate is further studied by the present invention, sets up mouse liver injury models, respectively
Measure the aspirin (80mg/kg, 160mg/kg) of various dose, ursolic acid (80mg/kg, 160mg/kg), ursolic acid-A Si
Woods (20mg/kg, 40mg/kg, 80mg/kg, 160mg/kg), aspirin (80mg/kg) and ursolic acid (80mg/kg) associating
The activity of AST, ALT and SOD in Mice Body after medication group medicine effect, result shows: various dose ASP-UA(20mg/kg
～160mg/Kg) AST activity in liver injury model Mice Body is all significantly inhibited its inhibitory action under effect, and Isodose
It is all higher than aspirin and ursolic acid independent medication group (80mg/kg, 160mg/kg) and aspirin (80mg/kg) and ursolic acid
(80mg/kg) drug combination group, wherein AST activity in liver injury model Mice Body is reduced work by the ASP-UA of 40mg/kg dosage
With the most notable, it reaches 48.37% to AST maximum inhibition；Various dose ASP-UA(20mg/kg～160mg/kg) to liver
In damage model Mice Body, ALT activity all significantly inhibits its inhibitory action under effect, and Isodose and is all higher than aspirin
Medication group (80mg/kg, 160mg/kg) independent with ursolic acid and aspirin (80mg/kg) and ursolic acid (80mg/kg) are combined
Medication group, wherein the ASP-UA of 40mg/kg dosage is the most notable to ALT activity reduction effect in liver injury model Mice Body, and it is right
ALT maximum inhibition reaches 64.48%；Various dose ASP-UA(20mg/kg～160mg/kg) to liver injury model Mice Body
Interior SOD activity all remarkably promotes its facilitation under effect, and Isodose and is more than aspirin and the independent medication of ursolic acid
Group (80mg/kg, 160mg/kg) and aspirin (80mg/kg) and ursolic acid (80mg/kg) drug combination group, wherein 80mg/
The ASP-UA of kg dosage is the most notable to SOD activity promoting in liver injury model Mice Body, and SOD activity promotion rate is reached by it
39.81%.Finding through consulting documents, the dosage that liver protection function is played in independent aspirin medication is that 200mg/kg (accounts for
Moral China. the aspirin protective effect to paraquat poisoning rats'liver renal function. Zhejiang University's Master's thesis, 2012.), individually
It is the gorgeous celery of 100mg/kg(woods that the dosage of liver protection function is played in ursolic acid medication. the Mouse Liver that ursolic acid is induced at CCl4 is damaged
The protective effect research of wound. Medical University Of Fujian, 2015.).Therefore, medication independent with aspirin and ursolic acid and A Si
Woods (80mg/kg) is compared with the liver protection function of ursolic acid (80mg/kg) drug combination, the ASP-UA coupling that the present invention relates to
Thing liver protection function effect is more preferable, and it just can play optimal liver protection function when 40mg/kg dosage, and this effect is better than
Ursolic acid and aspirin itself.
Accompanying drawing explanation
Fig. 1 ASP-UA is to CCCause the impact (n=10) of hepatic injury mice serum AST
Fig. 2 ASP-UA is to CCCause ALT impact (n=10) of hepatic injury mice serum
Fig. 3 ASP-UA is to CCCause mouse liver injury SOD in serum impact (n=10)
Detailed description of the invention
In order to make content of the present invention easily facilitate understanding, below in conjunction with detailed description of the invention to of the present invention
Technical scheme is described further, but the present invention is not limited only to this.
Embodiment 1
ASP-UA conjugate causes the protection of hepatic injury (liver injury model in animal body) to mouse carbon tetrachloride
Medicine and reagent: AST, ALT, SOD test kit is all purchased from Nanjing and builds up Bioengineering Research Institute；Carbon tetrachloride (CCl4, point
Analyse pure), the soybean oil solution of 0.3% it is made into during use with soybean oil；Ursolic acid (UA) standard substance soybean oil before use dissolves and is made into
Solution；Aspirin (ASP) used time first with 7% anhydrous alcohol solution, then add 7% soybean oil dissolve, finally add phosphoric acid buffer
Liquid is configured to solution.
Laboratory animal: male mice in kunming, body weight 18～22g.
110 adaptabilities of male mouse of kunming are fed 3 days after adapting to environment, are divided into blank group, CCl immediately4Model
Group, aspirin group, ursolic acid group, ASP-UA dosage group, aspirin and ursolic acid combination group, often group ten.
The induction of liver damage animal model:
Each group sub-cage rearing, after one week, configures 0.3%CCl4Soybean oil solution, carries out CCl from testing first day4Gavage, every
Mouse stomach amount 0.2mL.In addition to blank group, CCl4Model group, aspirin group, ursolic acid group, ASP-UA conjugate be low, in,
High dose group all fills 0.3%CCl4Soybean oil solution, continuous gavage, after one week, randomly selects a mice from each group and extracts eye
Ball takes blood, measures AST and ALT vigor in serum, and its vigor raises and determines hepatic injury modeling success.
ASP-UA conjugate gavage
After liver injury model is induced successfully, blank group and model group do not process, aspirin (ASP) group gavage solution (80mg/
Kg, 160mg/kg), ursolic acid (UA) group gavage solution (80mg/kg, 160mg/kg), ASP-UA conjugate gavage solution
(20mg/kg, 40mg/kg, 80mg/kg, 160mg/kg) and aspirin (80mg/kg) and ursolic acid (80mg/kg) combine use
Pharmaceutical quantities group, respectively by every mouse stomach 0.2mL of above-mentioned dosage, every 24 h gavages once, the continuous gavage of administration group 20 days
After in 1,4,7 days in addition to blank group other groups add fill 0.3% CCSoybean oil solution, drinking-water of freely ingesting.
Vivisection
Fill CCl for the last time4 After 20h and perfusion 12h, after each group mice fasting 12h, record of weighing.Extract eyeball and take blood, entirely
Blood stands 2h, is centrifuged 10min at 3000r/min, and 4 DEG C save backup；Mice extract eyeball blood sampling after cervical dislocation and dead, quickly
Separate liver, wipe dry with 4 DEG C of normal saline flushings, weigh liver, spleen, thymic weight.
Statistical procedures
All experimental datas all use SPSS16.0 statistical processing software to carry out statistical procedures, and result represents with `x ± s, between group
Relatively use variance analysis.
Experimental result
The impact on Mouse Liver regulating liver-QI weight of the 1.ASP-UA conjugate
CC in experimentLiver injury model group compares with blank group, and liver index is significantly higher than blank group (P < 0.05)；Different agent
The ASP-UA conjugate of the present invention of amount is compared with model group, and liver index is substantially less than model group (P < 0.05), and the present invention is described
ASP-UA conjugate serves certain Conservative restoration effect to liver, reduces the degree of liver damage；Thymus index and spleen
Dirty index reflects the situation of immunologic function from side, the ASP-UA conjugate of the present invention of various dose compared with model group, breast
Gland index and index and spleen index all increase (P < 0.05), and the ASP-UA conjugate of the present invention that various dose is taken in this explanation can promote
Enter the growth promoter of Immune Organs of Body, improve body's immunity；It is proved ASP and UA and there is the effect of hepatoprotective, no
With the ASP-UA conjugate of the present invention of dosage and the thymus index of ASP, UA and spleen index all close to normal group, the present invention is described
ASP-UA conjugate has the effect of hepatoprotective, and specific experiment the results are shown in Table 1.
In table, A is ASP;U is UA;AUA is ASP-UA；Lower same.
2.ASP-UA conjugate is to CCCause the impact of hepatic injury mice serum AST
CC in experimentLiver injury model group AST activity is notable compared with normal group raises (P < 0.01)；Various dose of the present invention
ASP-UA conjugate compared with model group, ground the most in various degree make hepatic injury mice serum AST activity reduce (P < 0.01, P
< 0.05)；The ASP-UA conjugate of the present invention of various dose and the A-in the i.e. Fig. 1 of aspirin (80mg/kg, 160mg/kg) group
80, U-80, the U-160 in A-160 and the i.e. Fig. 1 of ursolic acid (80mg/kg, 160mg/kg) group and aspirin (80mg/kg) and
The AST activity decrease level of the A-80+U-80 group in the i.e. Fig. 1 of ursolic acid (80mg/kg) drug combination group is compared, ASP-of the present invention
The level of UA conjugate AST activity decrease is all higher than ASP group, UA group and A-80+U-80 group；ASP, UA can reduce hepatic injury mice
In serum AST activity, it has therefore proved that ASP, UA have liver protection function, therefore the liver protection function of the present invention be better than ASP,
UA and A-80+U-80, specific experiment result is shown in Fig. 1.
3.ASP-UA conjugate is to CCl4Cause the impact of hepatic injury mice serum ALT
CC in experimentLiver injury model group ALT activity is notable compared with normal group raises (P < 0.01), difference agent of the present invention
Amount ASP-UA conjugate compared with model group, the most in various degree make hepatic injury mice serum ALT activity decrease (P < 0.01, P
< 0.05)；The ASP-UA conjugate of various dose of the present invention and the A-in the i.e. Fig. 2 of aspirin (80mg/kg, 160mg/kg) group
80, A-160 compares, and the level of ASP-UA conjugate group ALT activity decrease of the present invention is all higher than ASP group；Various dose of the present invention
ASP-UA conjugate compared with U-80, the U-160 in the i.e. Fig. 2 of ursolic acid (80mg/kg, 160mg/kg) group and aspirin
(80mg/kg) the ALT activity decrease level phase of the A-80+U-80 group and in the i.e. Fig. 2 of ursolic acid (80mg/kg) drug combination group
Ratio, ASP-UA conjugate group ALT activity decrease level of the present invention is all higher than UA and A-80+U-80 group；ASP, UA can reduce liver damage
Hinder the ALT of mice serum, it has therefore proved that ASP, UA have the effect of hepatoprotective, and therefore the liver protection function of the present invention is better than
ASP, UA and A-80+U-80, specific experiment result is shown in Fig. 2.
4.ASP-UA conjugate is to CCCause the impact of hepatic injury mice serum SOD
CC in experimentLiver injury model group compares with normal group, and mice serum SOD activity substantially reduces (P < 0.01)；This
The ASP-UA conjugate of bright various dose is compared with model group, and ground the most in various degree makes hepatic injury mice serum SOD activity liter
High (P < 0.01, P < 0.05)；The ASP-UA conjugate of various dose of the present invention and aspirin (80mg/kg, 160mg/kg) group
A-80, A-160 in i.e. Fig. 3 and U-80, the U-160 in the i.e. Fig. 3 of ursolic acid (80mg/kg, 160mg/kg) group and aspirin
(80mg/kg) compare with the A-80+U-80 group SOD activity decrease level in the i.e. Fig. 3 of ursolic acid (80mg/kg) drug combination group,
ASP-UA conjugate SOD elevated levels of the present invention is all higher than ASP group, UA group and A-80+U-80 group SOD activity decrease level；UA
Hepatic injury mice serum SOD activity can be made to raise, it has therefore proved that ASP, UA have liver protection function, and therefore protecting the liver of the present invention is protected
Liver effect is better than ASP, UA and A-80+U-80, and specific experiment result is shown in Fig. 3.
Experiment conclusion: ASP-UA conjugate is to CCCause mouse liver injury and there is protection activity, prove that ASP-UA is even with this
Connection thing has the effect of preferable hepatoprotective, can play optimal liver protection function, and this effect when 40mg/kg dosage
It is better than ursolic acid and aspirin itself.
Claims (1)
- The application in preparing hepatoprotective medicine of the ursolic acid-Aspirin Conjugate the most shown in formula I.
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| CN201610950087.8A CN106309457B (en) | 2016-11-03 | 2016-11-03 | A kind of ursolic acid-Aspirin Conjugate is preparing the application in liver protecting drug |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2786695B1 (en) * | 1998-12-07 | 2001-02-02 | Clarins | COSMETIC COMPOSITION BASED ON ACETYLSALICYLIC ACID AND Rosemary Extract |
| CN102066397A (en) * | 2008-04-18 | 2011-05-18 | 里亚塔医药公司 | Compounds including an anti-inflammatory pharmacore and methods of use |
| CN102976962A (en) * | 2012-11-20 | 2013-03-20 | 万红贵 | L-ornithine-aspirin double salt and its preparation method and use |
| CN103933048A (en) * | 2014-05-07 | 2014-07-23 | 福州大学 | Applications of ursolic acid derivatives in preparation of drug for preventing and treating tumor metastasis |
| CN105111271A (en) * | 2015-08-03 | 2015-12-02 | 福州大学 | Ursolic acid-aspirin conjugate and application thereof in preparing drugs for preventing tumor metastasis |
-
2016
- 2016-11-03 CN CN201610950087.8A patent/CN106309457B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2786695B1 (en) * | 1998-12-07 | 2001-02-02 | Clarins | COSMETIC COMPOSITION BASED ON ACETYLSALICYLIC ACID AND Rosemary Extract |
| CN102066397A (en) * | 2008-04-18 | 2011-05-18 | 里亚塔医药公司 | Compounds including an anti-inflammatory pharmacore and methods of use |
| CN102976962A (en) * | 2012-11-20 | 2013-03-20 | 万红贵 | L-ornithine-aspirin double salt and its preparation method and use |
| CN103933048A (en) * | 2014-05-07 | 2014-07-23 | 福州大学 | Applications of ursolic acid derivatives in preparation of drug for preventing and treating tumor metastasis |
| CN105111271A (en) * | 2015-08-03 | 2015-12-02 | 福州大学 | Ursolic acid-aspirin conjugate and application thereof in preparing drugs for preventing tumor metastasis |
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