CN101904839A - Application of imperatorin in preparing medicament for preventing and treating hepatitis or liver injury - Google Patents
Application of imperatorin in preparing medicament for preventing and treating hepatitis or liver injury Download PDFInfo
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Abstract
The invention relates to the technical field of medicament, providing a novel application of coumarin compound imperatorin in preparing a medicament for preventing and treating virus hepatitis and resisting immunological liver injury or chemical liver injury. Pharmacological tests prove that the imperatorin has stronger activity of inhibiting hepatitis B surface antigen (HbsAg) and hepatitis B virus e antigen (HbeAg) and resisting the immunological liver injury or the chemical liver injury, so the imperatorin can be used for preparing the medicament for preventing and treating the virus hepatitis and resisting the immunological liver injury or the chemical liver injury. The imperatorin has the advantages of convenient preparation, wide sources, low price and high safety. The invention provides the novel application of the imperatorin, and provides a new medicinal source for preventing and treating the virus hepatitis and resisting the immunological liver injury or the chemical liver injury.
Description
Technical field
The present invention relates to medical technical field, is that the coumarin kind compound imperatorin is used to prepare the new purposes of preventing and treating viral hepatitis and anti-immune or anti-chemical damage medicine.
Background technology
Coumarin kind compound is the lactone compound that the dehydration of cis coumarinic acid forms, this compounds is widely distributed in Umbelliferae, Rutaceae, Compositae, pulse family, plant of Solanaceae, all contain specific examples of such components [Luo Xiongming as Chinese medicines such as Fructus Cnidii, Radix Angelicae Pubescentis, the Radix Angelicae Dahuricae, Radix Peucedani, Cortex Fraxini, Herba Artemisiae Scopariae, Fructus Psoraleae, Euphorbia lathyris, coat with lacquer refined China, Yin Hao, Li Minyi, Yvonne is opened in the elevation sea.The progress of linear type furocoumarin compounds and pharmacologically active thereof.Research and development of natural products.2009;21(B05):230-235]。Imperatorin is a kind of in the coumarin kind compound, has another name called imperatorin, and its chemical structural formula is as follows:
Preparation technology is easy for the coumarin kind compound imperatorin, can extract acquisition from plant, also can adopt the coumarin kind compound precursor to carry out semisynthetic method and obtain.[1. Ministry of Health of the People's Republic of China's committee of pharmacopeia.One one of Pharmacopoeia of People's Republic of China.2010:97-98; 2. " Chinese herbal medicine ", 1986,17 (2): 6].Existing research report, imperatorin has effects such as stronger anticoagulation, calmness, antiinflammatory, antibiotic, antimutagenic, can also suppress to assemble by adenosine diphosphate (ADP) (ADP), arachidonic acid (AA), the inductive rabbit platelet of platelet activating factor (PAF), antagonism tumor necrosis factor (TNF), interleukin 1 (IL-1) are to the short proliferation function of cerebrovascular smooth muscle cell, antagonism TNF promotes Medulla Bovis seu Bubali capillary endothelium and the adherent effect of mononuclear cell, and [1. Liu is thick good, Li Tiejun, Qiu Yan, Rui Yaocheng, Wei Lixin, Wu Mengchao, Zhang Li.Imperatorin is to the protective effect of Human umbilical vein endothelial cells and to the influence of vascular endothelial growth factor expression.The pharmacy practice magazine.2009;27(2):94-98。2. Ji Yang, Ceng Guoqian.Imperatorin and different imperatorin are to the influence of Turnover of Mouse Peritoneal Macrophages release in vitro tumor necrosis factor.The The 2nd Army Medical College journal.1994;15(6):511-513。3. Lee iron army, Xu Tianying, Rui Yaocheng, Qiu Yan, Zhang Li, Yang Pengyuan.Imperatorin is to the protective effect of cerebral ischemia.The The 2nd Army Medical College journal.2004;25(4):431-433。], but do not see as yet that so far relevant imperatorin has the report of viral hepatitis of preventing and treating or hepatic injury effect.
Summary of the invention
The new purposes that the object of the present invention is to provide the coumarin kind compound imperatorin to be used to prepare to prevent and treat viral hepatitis and anti-immune or anti-chemical damage medicine.
Show through experiment in vivo and vitro, imperatorin has the activity of inhibition hepatitis B surface antigen (HbsAg), hepatitis B virus e antigen (HbeAg) and anti-immune or chemical liver injury, therefore can be used for preparing the medicine of preventing and treating viral hepatitis and anti-immune or chemical liver injury.
Easy to prepare, the wide material sources of imperatorin, cheap, safe, have excellent development and utilize prospect.The present invention provides a kind of new purposes for imperatorin, also provides a kind of new medicament sources for preventing and treating viral hepatitis and anti-immune or chemical liver injury.
The specific embodiment
The present invention is further elaborated below in conjunction with embodiment, but embodiment only is used to illustrate the present invention, and protection scope of the present invention is not restricted to this.
Embodiment 1 preparation imperatorin
Radix Angelicae Dahuricae crude drug decoction pieces (Yangpu, Shanghai prepared slices of Chinese crude drugs factory) is pulverized the back and is crossed 120 mesh sieves, gets the 1kg powder, extracts 2 times with 5L 95% alcohol heat reflux, each 2h, and merge extractive liquid,, concentrating under reduced pressure reclaims ethanol, separates water layer while hot.After water layer is placed and solidified,, place crystallize with 40 ℃ of anhydrous alcohol solutions of 100ml.95% ethyl alcohol recrystallization 3 times of 40 ℃ of 10ml is used in the gained crystallization more respectively, uses purification with macroreticular resin, imperatorin 9.6mg.Detect through HPLC, imperatorin purity is 93.2%.
The influence that embodiment 2 imperatorins are expressed hepatitis B virus HBsAg, HBeAg
1. experiment material
DMEM culture medium: U.S. Gibco company product, lot number 13200-035;
Calf serum: U.S. Gibco company product, lot number 16000-036;
HBsAg detection kit: Beijing Ke Wei reagent for clinical diagnosis Bioisystech Co., Ltd product, lot number: 200706003;
HBeAg detection kit: Beijing Ke Wei reagent for clinical diagnosis Bioisystech Co., Ltd product, lot number: 200708008;
HepG 2.2.15 cell, central laboratory provides by Shanghai Changhai Hospital, be that the cotransfection method will be cloned binary HBV DNA and anti-G418 r plasmid cotransfection human hepatoma cell strain HepG2 cell is set up, can transcribe, translate the HBV gene, and can in culture supernatant, secrete HBsAg and HBeAg steadily in the long term, be the cell model of the present anti-HBV medicine of in-vitro evaluation of generally acknowledging both at home and abroad and using always.
Imperatorin, by Shanghai still friendship Chemical Industry Science Co., Ltd purity 98% (down with) is provided.
Acyclovir (Aciclovir, ACV): Hunan Dino Pharmaceutical Co's institute of Pharmaceutical Industry product.
2. cell culture condition
HepG 2.2.15 cell is with the DMEM culture medium that contains 10% hyclone (FBS), at volume fraction 5%CO
2, 37 ℃, cultivate under the saturated humidity.
3. experiment grouping
The blank group does not add cell and medicine, only adds the DMEM culture fluid that equal-volume contains 10%FBS;
Negative control group adds cell and does not add medicine, adds the DMEM culture fluid that equal-volume contains 10%FBS;
Positive controls: cell+acyclovir solution, said acyclovir solution are to be made into the solution that concentration is 0.02 μ mol/mL with the DMEM culture fluid that contains 10%FBS;
Imperatorin variable concentrations group (being called for short the medicine group): the imperatorin solution of cell+variable concentrations, said imperatorin solution are to be made into imperatorin concentration with the DMEM culture fluid that contains 10%FBS to be respectively 0.125,0.25, the solution of 0.5 μ mol/mL.
4. experimental technique
Take the logarithm the HepG 2.2.15 cell of trophophase with 1 * 10
5The density in individual/hole is inoculated in 96 orifice plates, and every hole 0.1mL puts 5%CO
2, 37 ℃, to cultivate 24 hours under the saturated humidity, cell attachment and well-grown are absorbed whole culture fluid, by above-mentioned experiment grouping culture fluid or drug solution are added respectively in the respective aperture then, establish 4 multiple holes for every group.At volume fraction 5%CO
2, 37 ℃, cultivate under the saturated humidity.Respectively changed liquid respectively at the 3rd day and the 6th day and once also continue to cultivate, the 9th day collecting cell culture supernatant, centrifugal 5min gets supernatant, and-20 ℃ of stored frozen are standby.With HBsAg and the HBeAg in the ELISA detection kit mensuration supernatant, microplate reader (detecting wavelength 570nm, reference wavelength 630nm) is measured the A value.Suppress percentage rate (%)=[(negative control group A value-medicine group A value)/(negative control group A value-blank group A value)] * 100%.
5. experimental result
Experimental result sees Table 1.
The influence that table 1 imperatorin is expressed HBsAg, HbeAg
By table 1 as seen, imperatorin can suppress HepG 2.2.15 emiocytosis HBsAg, HBeAg, has dose dependent, particularly the imperatorin high dose group, suppression ratio and positive controls are approaching, and the prompting imperatorin has certain preventive and therapeutic effect to Type B viral hepatitis.
Embodiment 3 imperatorins are to the protective effect of immunologic liver injury
1. experiment material
Bacillus calmette-guerin vaccine lyophilized powder (BCG), available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute, being mixed with bacillus calmette-guerin vaccine concentration with normal saline is 25mg/mL solution;
Lipopolysaccharide (LPS), available from SIGMA company, being mixed with lipopolysaccharide concentration with normal saline is 75 μ g/mL solution;
Aspartate transaminase (AST) and alanine aminotransferase (ALT), malonaldehyde (MDA) test kit all build up bio-engineering research institute available from Nanjing;
Imperatorin is mixed with respectively with 0.25%CMC-Na that concentration is 5,10, the suspension of 20mg/mL;
50 of male ICR mouses, body weight 18~25g is provided by the The 2nd Army Medical College Experimental Animal Center, and animal is fed with pellet, freely ingests and drinks water.
2. experimental technique
Mice is equally divided into 5 groups at random, 10 every group, that is:
Negative control group: not modeling of normal mouse gives equal-volume 0.25%CMC-Na solution;
Model group: give equal-volume 0.25%CMC-Na solution after the mice modeling;
The imperatorin low dose group: give imperatorin by body weight after the modeling, every day, dosage was 50mg/kg;
Dosage group in the imperatorin: give imperatorin by body weight after the modeling, every day, dosage was 100mg/kg;
The imperatorin high dose group: give imperatorin by body weight after the modeling, every day, dosage was 200mg/kg;
Each component other places reason is as follows:
Except that negative control group, all the other respectively organize the BCG modeling of mice by body weight tail vein injection 2.5mg/kg.Then, give every group of corresponding solution of mouse stomach respectively by above-mentioned grouping:
Negative control group: irritate stomach 0.25%CMC-Na solution, every day 1 time, continuous 12 days;
Model control group: irritate stomach 0.2mL 0.25%CMC-Na solution after the mice modeling, every day 1 time, continuous 12 days;
The imperatorin low dose group: irritate the imperatorin solution that preparation is stated on the Weishang by body weight after the mice modeling, every day, dosage was 50mg/kg, continuous 12 days;
The imperatorin low dose group: irritate the imperatorin solution that preparation is stated on the Weishang by body weight after the mice modeling, every day, dosage was 100mg/kg, continuous 12 days;
The imperatorin low dose group: irritate the imperatorin solution that preparation is stated on the Weishang by body weight after the mice modeling, every day, dosage was 200mg/kg, continuous 12 days;
Administration was after 2 hours in the 12nd day, the mice of the basic, normal, high dosage group of model control group and imperatorin is by the LPS of body weight through tail vein injection 7.5 μ g/10g, the injection LPS after 6 hours, get eye socket venous plexus blood, 3000rpm/min, centrifugal 10 minutes, separation of serum was pressed test kit description method and is measured aspartate transaminase (AST) and alanine aminotransferase (ALT) level.Other cuts liver specimens, with the liver tissue homogenate of normal saline preparation 10%, gets supernatant routinely, presses malonaldehyde (MDA) content that kit method is measured supernatant.Data result adopts Mean ± SD to represent, carries out variance analysis with SPSS13.0 software.
3. experimental result sees Table 2.
Table 2 imperatorin to the influence of immunologic liver injury mice ALT, AST and MDA level (Mean ± SD, n=10)
Annotate: * and model control group compare, P<0.05
By table 2 as seen, compare with model control group, the basic, normal, high dosage group of imperatorin all can significantly be improved AST, ALT and the MDA index of immunologic liver injury mice, shows that imperatorin has the effect of treatment immunologic liver injury.
Embodiment 4 imperatorins are to the protective effect of chemical liver injury
1. experiment material
Carbon tetrachloride (CCl
4), analytical pure, traditional Chinese medicines group Shanghai chemical reagent company limited product;
Edible soybean oil, golden imperial fish edible oil company product;
Aspartate transaminase (AST) and alanine aminotransferase (ALT), malonaldehyde (MDA) test kit all build up bio-engineering research institute available from Nanjing;
Imperatorin is mixed with respectively with 0.25%CMC-Na that concentration is 5,10, the suspension of 20mg/mL;
50 of ICR mices, male and female half and half, body weight 18~25g is provided by the The 2nd Army Medical College Experimental Animal Center.
2. experimental technique
Mice is equally divided into 5 groups at random, 10 every group, male and female half and half, that is:
Negative control group: normal mouse, not administration, not modeling;
Model control group: not administration, use CCl
4Cause liver injury model;
The imperatorin low dose group: irritate the stomach imperatorin by body weight, every day, dosage was 50mg/kg;
Dosage group in the imperatorin: give imperatorin by body weight, every day, dosage was 100mg/kg;
The imperatorin high dose group: give imperatorin by body weight, every day, dosage was 200mg/kg;
Negative control group, model control group are irritated stomach equal-volume 0.25%CMC-Na, and gastric infusion is 7 days continuously; After the last administration 1 hour, negative control group mouse peritoneal injection soybean oil (by body weight 20ml/kg).The high, medium and low dosage group of imperatorin was by the imperatorin medicine of above-mentioned grouping filling stomach various dose, continuous 7 days.After the last administration 1 hour, with model control group and imperatorin medicine group mice together, all contain 0.1%CCl by the body weight lumbar injection
4Soybean oil solution 20ml/kg.All animals after 16 hours, is got eye socket venous plexus blood in last 1 administration, 3000rpm/min, and centrifugal 10 minutes, separation of serum was pressed the test kit description and is measured aspartate transaminase (AST) and alanine aminotransferase (ALT) level.Other cuts liver specimens, with the liver tissue homogenate of normal saline preparation 10%, gets supernatant and measures malonaldehyde (MDA) content by the test kit description.Data result adopts Mean ± SD to represent, carries out variance analysis with SPSS13.0 software.
3. experimental result: the results are shown in Table 3.
Table 3 imperatorin to the influence of chemical liver injury mice ALT, AST and MDA level (Mean ± SD, n=10)
Annotate: * and model group compare, P<0.05
By table 3 as seen, compare with model control group, the high, medium and low dosage group of imperatorin all can significantly reduce the level of AST, ALT and MDA, and has dose dependent.The prompting imperatorin has the effect that improves liver function, can prevent the mice chemical liver injury.
The acute toxicity testing of embodiment 5 imperatorins
1. experiment material:
50 of ICR mices are provided by the The 2nd Army Medical College animal center, male and female half and half, and body weight 18~25g, animal is fed with pellet, freely ingests and drinks water.
Imperatorin is mixed with the suspension that concentration is 450mg/mL and 270mg/mL by embodiment 1 preparation respectively with 0.25%CMC-Na.
2. experimental technique:
The ICR mice is irritated stomach imperatorin 4.5g/kg by the body weight single, or the ICR mice is by body weight single intraperitoneal injection imperatorin 2.7g/kg, observes toxic reaction and death condition in the animal after the administration 14 days.Found that behind the mice single gastric infusion, the mice activity is slow, it is moving to repose less, promptly recovers normal after 30-50 minute.In 14 days, death does not appear in mice after the administration, and the 15th day, all mice was put to death, and dissected, and each internal organs of macroscopy there is no obvious pathological changes.Behind the mouse peritoneal drug administration by injection 20 minutes, 3 mices lethargy occurred, roll up, and movable the minimizing is after the administration behind the 1h, all mice recovers normal, and in 14 days, death does not appear in mice after the administration, the 15th day, all mice is put to death, and dissects, and each internal organs of macroscopy there is no obvious pathological changes.
3. experimental result:
Above-mentioned acute toxicity testing result shows that gastric infusion maximum tolerated dose MTD is not less than 4.5g/Kg, and intraperitoneal injection maximum tolerated dose MTD is not less than 2.7g/Kg, illustrates that the toxicity of imperatorin is lower.
Claims (2)
1. the coumarin kind compound imperatorin is prevented and treated application in the viral hepatitis medicine in preparation.
2. the coumarin kind compound imperatorin is prevented and treated application in immunity or the chemical liver injury medicine in preparation.
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Cited By (6)
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CN102028701A (en) * | 2010-12-29 | 2011-04-27 | 王喜军 | Active ingredient composition for treating alcoholic liver injury |
CN107753480A (en) * | 2017-12-05 | 2018-03-06 | 云南中医学院 | Application of the Praeruptorin D in drug induced hepatic injury protection medicine is prepared |
CN107875147A (en) * | 2017-12-05 | 2018-04-06 | 云南中医学院 | Purposes of the RADIX PEUCEDANI E elements in drug induced hepatic injury protection medicine is prepared |
CN108030781A (en) * | 2017-12-05 | 2018-05-15 | 云南中医学院 | Purposes of the Isomperatorin in drug induced hepatic injury protection medicine is prepared |
CN108042527A (en) * | 2017-12-05 | 2018-05-18 | 云南中医学院 | Purposes of the Praeruptorin B in drug induced hepatic injury protection drug is prepared |
WO2022237007A1 (en) * | 2021-05-11 | 2022-11-17 | 重庆医科大学 | Use of cow parsnip as active ingredient in preparing drug for treating hepatitis b |
Citations (1)
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JPH1129471A (en) * | 1997-07-04 | 1999-02-02 | Nippon Chemiphar Co Ltd | Medicine containing cumarin-derivative as active ingredient for liver disease |
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JPH1129471A (en) * | 1997-07-04 | 1999-02-02 | Nippon Chemiphar Co Ltd | Medicine containing cumarin-derivative as active ingredient for liver disease |
Cited By (9)
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CN102028701A (en) * | 2010-12-29 | 2011-04-27 | 王喜军 | Active ingredient composition for treating alcoholic liver injury |
CN102028701B (en) * | 2010-12-29 | 2012-09-19 | 王喜军 | Active ingredient composition for treating alcoholic liver injury |
CN107753480A (en) * | 2017-12-05 | 2018-03-06 | 云南中医学院 | Application of the Praeruptorin D in drug induced hepatic injury protection medicine is prepared |
CN107875147A (en) * | 2017-12-05 | 2018-04-06 | 云南中医学院 | Purposes of the RADIX PEUCEDANI E elements in drug induced hepatic injury protection medicine is prepared |
CN108030781A (en) * | 2017-12-05 | 2018-05-15 | 云南中医学院 | Purposes of the Isomperatorin in drug induced hepatic injury protection medicine is prepared |
CN108042527A (en) * | 2017-12-05 | 2018-05-18 | 云南中医学院 | Purposes of the Praeruptorin B in drug induced hepatic injury protection drug is prepared |
CN108042527B (en) * | 2017-12-05 | 2020-02-07 | 云南中医学院 | Application of peucedanum praeruptorum dunn in preparing medicine for protecting liver injury |
CN107875147B (en) * | 2017-12-05 | 2020-02-07 | 云南中医学院 | Application of peucedanum praeruptorum dunn E in preparing drug for protecting liver injury |
WO2022237007A1 (en) * | 2021-05-11 | 2022-11-17 | 重庆医科大学 | Use of cow parsnip as active ingredient in preparing drug for treating hepatitis b |
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