CN107468683A - The purposes of alantolactone and its derivative in fatty hepatic injury is prevented and treated - Google Patents
The purposes of alantolactone and its derivative in fatty hepatic injury is prevented and treated Download PDFInfo
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Abstract
The invention discloses a kind of new medical application of alantolactone and its derivative, especially preparing the purposes in preventing and treating fatty hepatic injury, the disorders of lipid metabolism situation of liver cell can be alleviated, the horizontal and intracellular fat drips of TG, TC in the liver cell of oxLDL inductions can be suppressed and accumulate situation；The hepatic injury caused by alcoholic fatty liver can be prevented and treated, is effectively improved liver function and dyslipidemia situation；The hepatic injury caused by NASH can be prevented and treated, it is effectively improved liver function and dyslipidemia situation, compared with a variety of fall lipid drugs, have that toxic side effect is small, eutherapeutic feature, there are potentiality of the exploitation into the natural less toxic fat-reducing medicament for having clinical value.
Description
Technical field
The invention discloses a kind of new medical application of alantolactone and its derivative, is especially preparing prevention and is controlling
The purposes in fatty hepatic injury is treated, belongs to biomedicine field.
Background technology
In recent years, because the influence of many factors such as habits and customs, dietary structure, China's pathogenesis of fatty liver rate have gradual increasing
Fatty liver can occur for the crowd of the trend added, all ages and classes and different sexes.Fatty liver turns into common slow of contemporary mankind
One of venereal disease, turn into the second largest hepatopathy for being only second to virus hepatitis.
Fatty liver is that the liver fat venereal disease as caused by many reasons becomes, when liver cell inner lipid is accumulated more than 5%, or group
When knitting upper more than 1/3 liver cell fatty degeneration of per unit area, referred to as fatty liver.Pathogenesis of fatty liver mechanism is not yet clear and definite so far, existing
Thinking for medical science may be relevant with many factors, such as abnormalities of sugar/lipid metabolism, hormonal readiness change, E＆H factor, lipid
Peroxidative damage, immune response, anoxic and hepatic circulatory disturbance etc. play a role in its pathogenic process.Obesity, medicine
And drug poisoning, diabetes, hepatitis viruse or other pathogenic infections etc. can all cause the generation of fatty liver, its clinical manifestation with
Liver fatty infiltration degree is directly proportional, although fatty liver is considered as often benign lesion, great mass of data shows, no matter the origin cause of formation such as
What, has partial fat hepatopath to develop into liver fibrosis, or even hepatic sclerosis, it is believed that fatty liver is liver fibrosis and liver
The cercinoma prophase pathologic change of hardening.
The dysfunction of liver of Patients with Fatty Liver is mainly shown as the rise of transaminase and transpeptidase, wherein glutamic-pyruvic transaminase
（ALT）And glutamic-oxalacetic transaminease（AST）Horizontal rise prompted the presence of fatty liver and metabolic syndrome.There is scholar's research different
The liver enzyme of glycometabolism crowd and the relation of hepatic fat content, as a result find, with the increase of fat content, triglycerides
（TG）, T-CHOL（TC）And fasting blood-glucose presents and substantially increases trend.It is hyperglycaemia to influence another key factor of fatty liver,
It can stimulate insulin secretion increase, make the amount increase of liver synthesis TG and VLDL, cause TG in blood to raise,
Gradually accumulate in liver, form fatty liver.
The main pathogenic of fatty liver is broadly divided into the following aspects：（1）Long-term a large amount of wine-heads are most easily formed
Alcoholic fatty liver；（2）Fat and overweight, internal storage of fat is excessive, can cause fatty liver, and intrahepatic fat is excessive, again
Burden of liver can be aggravated, reduces metabolic rate, the degree of weight fat liver；（3）Hyperglycaemia；（4）Hypertension；（5）High fat of blood；
（6）Other factors.
Fatty liver still aims at prevention at present, in treatment mainly based on fat-reducing liver-protecting, and to have diet and fortune
Dynamic intervention auxiliary treatment.The medicine for the treatment of fatty liver has many kinds, such as lipanthyl, Inositol Hexanicotinate, Lipitor at present.But
That these medicines all reflect different degrees of side effect, thus researcher for many years still constantly look for it is a kind of safely, be directed to
Strong, the eutherapeutic hepatoprotective agent of property.
Elecampane (Inula helenium L) it is composite family Inulaplants, it is incorporated in middle traditional Chinese medicines as medicinal plant
In allusion quotation and multi-section European Pharmacopoeia.Sesquiterpene eudesmanolide lactone is rich in radia heleii methanol extraction thing, main component is in elecampane
Ester and isoalantolactone.Alantolactone（Alantolactone）Belong to native compound, molecular formula is C15H20O2, molecule
Amount is 232.32, is soluble in ethanol, chloroform and benzene etc., toxic side effect is smaller.Recognizing for alantolactone pharmacological action in the past
Knowledge be concentrated mainly on antitumor, anti-inflammatory, expelling parasite, antibacterial, it is hypoglycemic and analgesia etc. effect, have no at present report alantolactone or
Effect of its derivative in terms of preventing and treating fatty liver is formed with anti-fatty liver damage.
The content of the invention
The invention discloses a kind of alantolactone and its derivative to prepare the health care of the fatty hepatic injury of prevention and treatment
The purposes of product and medicine.
Alantolactone and its derivative provided by the invention, its general structure are as follows：
Wherein, R1 is methyl, and R2 is methyl, and R3 is hydrogen, and R4 is methylene（Alantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is methylene（Isoalantolactone）；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is benzylamine（13- benzylamines-alantolactone）；’
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is melonia（13- melonias-alantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is melonia（In 13- melonias-different elecampane
Ester）；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is methyl（Dihydroalantolacton）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is methyl（Dihydroisoalantolactone）；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is methyl cyanoacetate（Methyl cyanoacetate alantolactone）；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is dimethyl malenate（Dimethyl malenate alantolactone）；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is diethyl malonate（Diethyl malonate alantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is nitromethane（Nitromethane isoalantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is nitroethane（Nitroethane isoalantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is ethyl acetoacetate（In the different elecampane of ethyl acetoacetate
Ester）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to chlorobenzene（To chlorobenzene isoalantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is benzene（To benzene isoalantolactone）；Or R1 is methyl, R2 is Asia
Methyl, R3 are dihydro, and R4 is to toluene（To toluene isoalantolactone）；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to methoxybenzene（To methoxybenzene isoalantolactone）.
Alantolactone and its derivative of the present invention are preparing the fatty hepatic injury health products of prevention and treatment and medicine
Purposes in thing.
The fatty liver being related in purposes of the present invention refers to Primary Fatty Liver, secondary fatty liver, Drug fat
Fatty liver caused by liver, alcoholic fatty liver, fatty liver caused by hyperlipidemia or glycometabolism syndrome.
The health products and medicine being related in purposes of the present invention can connect by alantolactone or derivatives thereof and pharmaceutically
The carrier composition received.
In health products of the present invention and medicine, alantolactone and its derivative as effective active composition contain
Measure as 1% ~ 99%, the active component of weight between more conventional about 15% to 60%.
Compound alantolactone of the present invention or derivatives thereof can individually or with one or more medicine
Preparation is made for administration in acceptable carrier combinations on.The pharmaceutically acceptable carrier can be obtained in drug field
The common type arrived, including：The adhesive of oral formulations, lubricant, disintegrant, cosolvent, diluent, stabilizer, suspension
Agent, pigment, flavouring etc.；The preservative of injectable formulation, solubilizer, stabilizer etc..Pharmaceutical preparation can by oral administration or stomach
Parenteral mode (such as intravenous, subcutaneous, intraperitoneal) administration, if some drugses are unstable under the conditions of stomach, can be incited somebody to action
It is configured to enteric coated tablets.
Alantolactone and its derivative of the present invention have TG and TC contents in the liver cell for reducing high fat damage,
Alleviate the effect of fat drips levels of accumulation in liver cell.
（1）The effect for reducing fat for the liver cell that alantolactone or derivatives thereof damages to high fat
OxLDL induction L02 cells in employment source prepare the high fat damage model of liver cell, experimental group add simultaneously alantolactone or
Its derivative, model group then add the DMSO of Isodose while oxLDL is added, and blank control group is normally cultivated, and effect is certain
After time, TG and TC contents in cell are detected with TG and TC detection kits, so as to judge alantolactone or derivatives thereof pair
The effect for reducing fat of high fat damaging cells.As a result（Table 1）It was found that alantolactone or derivatives thereof, which has, effectively reduces oxLDL damages
The effect of the TG and TC contents of cell.
（2）Alantolactone or derivatives thereof damages the inhibitory action that the fat drips of liver cell are accumulated to high fat
OxLDL induction L02 cells in employment source prepare the high fat damage model of liver cell, experimental group add simultaneously alantolactone or
Its derivative, model group then add the DMSO of Isodose while oxLDL is added, and blank control group is normally cultivated, and effect is certain
After time, oil red O stain observes intracellular fat drips accumulation situation.As a result（Fig. 1）It was found that alantolactone or derivatives thereof can be with
Reduce the levels of accumulation of intracellular fat drips.
In the present invention alantolactone or derivatives thereof to Primary Fatty Liver, secondary fatty liver, Drug fatty liver,
Fatty liver caused by fatty liver caused by alcoholic fatty liver, hyperlipidemia or glycometabolism syndrome has prevention and treatment to make
With.
（1）Prevention effect of the alantolactone or derivatives thereof to alcoholic liver injury
Male C57BL/6 mouse are randomly divided into control group, model group, alantolactone low dose group（20mg/kg）, high dose
Group（50mg/kg）, isoalantolactone group（20mg/kg）, dihydroalantolacton group（20mg/kg）With MPG group
（150mg/kg）, MPG group is positive control, and model group, compound group and MPG group give the modeling of ethanol gavage daily,
Control group gives distilled water replacement, and compound group and MPG group give respective compound and medicine, control group and mould after 6 hours
Type group is given isometric physiological saline and replaced, and is administered continuously 3 weeks.Experiment detected after terminating ALT, AST in mice serum it is horizontal and
TG, TC content.As a result（Table 2）It was found that alantolactone and its derivative can reduce ALT, AST level and TG, TC content, table
Bright alantolactone and its derivative can prevent mouse liver function indexes and the abnormalities of sugar/lipid metabolism caused by alcohol.
（2）Therapeutic action of the alantolactone or derivatives thereof to alcoholic liver injury
Male C57BL/6 mouse are randomly divided into control group, model group, alantolactone low dose group（20mg/kg）, high dose
Group（50mg/kg）, isoalantolactone group（20mg/kg）, dihydroalantolacton group（20mg/kg）With MPG group
（150mg/kg）, MPG group is positive control, and model group, compound group and MPG group give the modeling of ethanol gavage, control
Group gives distilled water replacement, and after continuing 2 weeks, compound group and MPG group give relative medicine gavage, once a day, control group
Isometric physiological saline is given with model group, continues 1 week.Experiment detects ALT, AST level and TG, TC in mice serum after terminating
Content.As a result（Table 3）It was found that alantolactone and its derivative can reduce ALT, AST level and TG, TC content, show building
Fragrant lactone and its derivative have obvious therapeutic action to the liver function indexes of alcoholic fatty liver mouse with abnormalities of sugar/lipid metabolism.
（3）Prevention effect of the alantolactone or derivatives thereof to non-alcoholic hepatic injury
Male C57BL/6 mouse are randomly divided into control group, model group, alantolactone low dose group（20mg/kg）, high dose
Group（50mg/kg）, isoalantolactone group（20mg/kg）, dihydroalantolacton group（20mg/kg）With Kezhi capsule group
（0.49g/kg）, Kezhi capsule group is positive control, and model group, compound group and Kezhi capsule group use high lipid food（HFD）
Feed, the CCl of volume fraction 5% is subcutaneously injected in limb behind4Edible oil models, and control group gives chow diet and feeds and give
Isometric physiological saline substitutes, and compound group and Kezhi capsule group give relative medicine gavage, control group and model simultaneously for modeling
Group gives isometric physiological saline, continues 4 weeks.Experiment detects ALT, AST level and TG, TC content in mice serum after terminating
Change.As a result（Table 4）Show that alantolactone and its derivative can reduce ALT, AST level and TG, TC content, show elecampane
Lactone and its derivative have prevention effect to non-alcoholic hepatic injury.
（4）Therapeutic action of the alantolactone or derivatives thereof to non-alcoholic hepatic injury
Male C57BL/6 mouse are randomly divided into control group, model group, alantolactone low dose group（20mg/kg）, high dose
Group（50mg/kg）, isoalantolactone group（20mg/kg）, dihydroalantolacton group（20mg/kg）With Kezhi capsule group
（0.49g/kg）, Kezhi capsule group is positive control, and model group, compound group and Kezhi capsule group use high lipid food（HFD）
Feed, 5% CCl is subcutaneously injected in limb behind4Edible oil models, and control group gives chow diet and feeds and give isometric life
Manage salt solution to substitute, after continuing 4 weeks, compound group and Kezhi capsule group give relative medicine gavage, and control group and model group are given
Isometric physiological saline, continue 2 weeks.Experiment detects ALT, AST level and TG, TC changes of contents in mice serum after terminating.
As a result（Table 5）Show that alantolactone and its derivative can reduce ALT, AST level and TG, TC content, show alantolactone
And its derivative has therapeutic action to non-alcoholic hepatic injury.
The positive effect of the present invention is：Alantolactone and its a kind of new medical application of derivative, Ke Yihuan are provided
The disorders of lipid metabolism situation of liver cell is solved, can suppress that TG, TC in the liver cell of oxLDL inductions be horizontal and intracellular fat drips
Accumulation situation；The hepatic injury caused by alcoholic fatty liver can be prevented and treated, is effectively improved liver function and dyslipidemia situation；
The hepatic injury caused by NASH can be prevented and treated, is effectively improved liver function and dyslipidemia situation, with having
A variety of fall lipid drugs are compared, and have that toxic side effect is small, eutherapeutic feature, have exploitation into there is the natural of clinical value
The potentiality of the fat-reducing medicament of low toxicity.
Brief description of the drawings
Fig. 1 is the influence for the L02 cells fat drips accumulation that alantolactone of the present invention and its derivative are induced oxLDL.
Embodiment
With reference to example is implemented, the present invention is described further, as described below, is only the preferable reality to the present invention
Example is applied, is not limited the present invention, any person skilled in the art is possibly also with disclosed
Technology contents be changed to the equivalent embodiment changed on an equal basis.It is every without departing from present invention, the skill according to the present invention
Any simple modification or equivalent variations that art is substantially made to following embodiment, all fall within protection scope of the present invention.
The Effect study of the fatty hepatic injury of prevention and treatment of the alantolactone and its derivative of the present invention be by with
What lower method was carried out：
Alantolactone and its derivative can be obtained or are prepared by the following method by commodity purchasing：
The preparation method of alantolactone is shown in Kaur Ramandeep, Chahal, Bhardwai, et al.Asian Journal
of Chemistry,2017,29(3):568-570.；
Isoalantolactone, 13- melonias-alantolactone, 13- melonias-isoalantolactone, dihydro building
The preparation method of fragrant lactone and dihydroisoalantolactone is shown in Marshall, Cphen.Journal of Organic
Chemistry,1964,29:2773.；
The preparation method of 13- benzylamines-alantolactone is shown in patent 201510031441.2（A kind of eucalyptus of the beautiful of Chen Jia, Gao Kun, Yuan Chun
The knowledge production of purposes of leaf alkane type natural products derivative 13- benzylamines-alantolactone and preparation method thereof People's Republic of China (PRC)
Power office）；
Methyl cyanoacetate alantolactone, dimethyl malenate alantolactone, diethyl malonate alantolactone, nitro first
Alkane isoalantolactone, nitroethane isoalantolactone, ethyl acetoacetate isoalantolactone, in the different elecampane of chlorobenzene
Ester, to benzene isoalantolactone, to toluene isoalantolactone, to the preparation method of methoxybenzene isoalantolactone see Guo Rui
The structural modification research Hebei of rosy clouds quercetins, isoalantolactone and alantolactone:Hebei Medical University, 2014..
Test example 1
The improvement result of abnormalities of sugar/lipid metabolism in the L02 cells that alantolactone and its derivative are induced oxLDL
（1）Alantolactone and its derivative reduce the TG contents in the L02 cells of oxLDL processing
Growth period people's normal hepatocytes L02 cells of taking the logarithm, which are inoculated into 6 orifice plates of the DMEM culture mediums containing 10% NBCS, to be trained
Support, cell density is 5 × 105After individual/ml, normal culture 24h, in addition to control group, each group cell adds 80 mg/ml oxLDL
High fat damaging cells model is established in processing, and compound group adds the alantolactone and its derivative of respective concentration, model group simultaneously
Add Isodose DMSO alternatively, administration volume is 2ml/ holes；Cell is containing 5%CO237 DEG C of incubators in continue to cultivate
Each group cell is collected after 24h, is washed 3 times with PBS, according to triglycerides detection kit（Beijing Puli's Lay）Specification operation inspection
Survey TG contents in cell.As a result as shown in table 1, for L02 cells under oxLDL effects, its TG level is significantly raised, and adds
Alantolactone or derivatives thereof rear cell TG levels have a different degrees of reduction, and have statistical significance.
（2）Alantolactone and its derivative reduce the TC contents in the L02 cells of oxLDL processing
Cellular processes are same as above, according to T-CHOL detection kit（Beijing Puli's Lay）TC in specification operation detection cell
Content.As a result as shown in table 1, for L02 cells under oxLDL effects, intracellular TC levels are significantly raised, and add building
The rear cell TC of fragrant lactone or derivatives thereof is horizontal to be reduced in various degree, and has statistical significance.Test above in triplicate
More than, experimental data carries out variance analysis with SPSS statistical softwares, and all data are all represented with mean+SD, t- inspections
Test carry out significance analysis.
TG the and TC contents for the L02 cells that the alantolactone of table 1. and its derivative are handled oxLDL influence
| Packet | Compound name | TG(mmol/L) | TC(mmol/L) |
| Control group | 198±37 | 220±98 | |
| Model group | 425±24## | 396±44## | |
| ALA | Alantolactone | 237±35** | 279±36** |
| ALA-1 | Isoalantolactone | 280±32** | 303±72* |
| ALA-2 | 13- benzylamines-alantolactone | 364±26* | 334±46* |
| ALA-3 | 13- melonias-alantolactone | 286±47* | 301±75** |
| ALA-4 | 13- melonias-isoalantolactone | 325±35* | 346±38* |
| ALA-5 | Dihydroalantolacton | 288±62** | 306±51** |
| ALA-6 | Dihydroisoalantolactone | 254±26** | 299±30** |
| ALA-7 | Methyl cyanoacetate alantolactone | 307±42* | 307±82* |
| ALA-8 | Dimethyl malenate alantolactone | 371±65* | 374±36 |
| ALA-9 | Diethyl malonate alantolactone | 354±31* | 328±37* |
| ALA-10 | Nitromethane isoalantolactone | 269±18** | 319±58* |
| ALA-11 | Nitroethane isoalantolactone | 287±26* | 305±52** |
| ALA-12 | Ethyl acetoacetate isoalantolactone | 329±62* | 342±31* |
| ALA-13 | To chlorobenzene isoalantolactone | 279±58* | 317±54* |
| ALA-14 | To benzene isoalantolactone | 375±47* | 348±42* |
| ALA-15 | To toluene isoalantolactone | 347±27* | 359±68 |
| ALA-16 | To methoxybenzene isoalantolactone | 326±43* | 356±59* |
Note：## represents p≤0.01 compared with control group；
* represent that p≤0.05 compared with model group, * * represent p≤0.01 compared with model group.
Above result of study shows, alantolactone and its derivative can be obviously improved the disorders of lipid metabolism of liver cell
Situation.
Test example 2
The influence for the L02 cells fat drips accumulation that alantolactone and its derivative are induced oxLDL
In order to further determine that the effect of alantolactone and its derivative to liver cell lipid-metabolism, the present invention is contaminated with oil red O
The method of color has investigated the intracellular fat drips accumulation situations of L02 of oxLDL inductions.Growth period people's normal hepatocytes L02 cells of taking the logarithm connect
Kind is cultivated into 6 orifice plates of the DMEM culture mediums containing 10% NBCS, and cell density is 5 × 105Individual/ml, normal culture
After 24h, it is divided into control group, model group, alantolactone group, isoalantolactone group and dihydroalantolacton group.Except control
Group is outer, and each group cell adds 80 mg/ml oxLDL processing and establishes high fat damaging cells model, and compound group is simultaneously plus corresponding dense
The alantolactone and its derivative of degree, model group add Isodose DMSO simultaneously, and administration volume is 2ml/ holes, and control group is normal
Culture；Cell is containing 5%CO237 DEG C of incubators in continue cultivate 24h after supernatant discarding, washed 3 times with PBS, 4% paraformaldehyde
Fixed 30min, oil red O stain 20min, 60% isopropanol are cleaned 1 time, and intracellular fat drips accumulation situation is observed under simple microscope.
As a result as shown in figure 1, L02 cells to be exposed to intracellular fat drips cumulant during oxLDL significantly raised, and add alantolactone
Or derivatives thereof intracellular fat drips cumulant reduce, the effect of wherein alantolactone is more notable.
Test example 3
The influence of alantolactone and its derivative to alcoholic fatty liver mouse liver injury
（1）The prevention effect of alantolactone and its derivative to alcoholic liver injury
By the male C57BL/6 mouse 70 of health（7 week old, 18-22g,）Adaptability is randomly divided into control group, mould after feeding 7 days
Type group, alantolactone low dose group（20mg/kg）, high dose group（50mg/kg）, isoalantolactone group（20mg/kg）, two
Hydrogen alantolactone group（20mg/kg）With MPG positive controls（150mg/kg）.Each group mouse is given daily during nursing
The basal feed of phase homogenous quantities, normal water, in addition to control group, other each group mouse give 3g/kg ethanol gavages daily, control
Group is given isometric distilled water and replaced, and compound group and MPG group give corresponding dosage after ethanol is given 6 hours respectively
Compound or medicine gavage, control group and model group give isometric physiological saline and replace, and continues 3 weeks.Experiment is prohibited after terminating
12h is eaten, with 4% chloral hydrate anesthesia mouse, heart extracting blood separation serum, detection serum alt, AST levels and TG, TC content
Change.Experimental data carries out variance analysis with SPSS statistical softwares, and t-, which is examined, carries out significance analysis（n=10）.As a result such as table
Shown in 2, alantolactone and its derivative group compare model group, reduce serum alt, AST levels and TG, TC content,
Wherein alantolactone high dose group effect is most notable, illustrates that alantolactone and its derivative pair can prevent alcoholic fatty liver
The liver function indexes and abnormalities of sugar/lipid metabolism of mouse.
The influence of the alantolactone of table 2. and its derivative to alcohol gavage mice serum biochemical indicator
| Group | TG(mmol/L) | TC(mmol/L) | ALT(IU/L) | AST(IU/L) |
| Control group | 0.98±0.19 | 2.43±0.39 | 29.39±2.57 | 84.25±5.21 |
| Model group | 1.83±0.23## | 4.52±0.93## | 46.31±8.60## | 158.63±13.74## |
| Alantolactone（It is low） | 1.52±0.25** | 3.74±0.29** | 39.20±9.53** | 105.52±14.29** |
| Alantolactone（It is high） | 1.18±0.13** | 3.67±0.23** | 36.65±8.52** | 101.47±9.35** |
| Isoalantolactone | 1.68±0.61* | 3.84±0.57* | 39.82±8.57* | 118.42±32.92* |
| Dihydroalantolacton | 1.57±0.31** | 3.93±0.73* | 38.59±11.49* | 114.58±19.52** |
| MPG | 1.71±0.22* | 3.47±0.33* | 37.69±7.98** | 107.59±15.90* |
Note：## represents p≤0.01 compared with control group；* represent that p≤0.05 compared with model group, * * represent the p compared with model group
≤0.01。
（2）The therapeutic action of alantolactone and its derivative to alcoholic fatty liver mouse
By the male C57BL/6 mouse 70 of health（7 week old, 18-22g,）Adaptability is randomly divided into control group, mould after feeding 7 days
Type group, alantolactone low dose group（20mg/kg）, high dose group（50mg/kg）, isoalantolactone group（20mg/kg）, two
Hydrogen alantolactone group（20mg/kg）With MPG positive controls（150mg/kg）.Each group mouse is given daily during nursing
The basal feed of phase homogenous quantities, normal water, in addition to control group, other each group mouse give 3g/kg ethanol gavages daily, control
Group is given isometric distilled water and replaced, and after continuing 2 weeks, compound group and MPG group give the compound of corresponding dosage respectively
Or medicine, the physiological saline that control group and model group give equal volume replace, and continue 1 week.Experiment terminates rear fasting 12h, uses
4% chloral hydrate anesthesia mouse, heart extracting blood separation serum, detection serum alt, AST levels and TG, TC changes of contents.Experiment
Data carry out variance analysis with SPSS statistical softwares, and t-, which is examined, carries out significance analysis（n=10）.As a result as shown in table 3, soil
Constuslactone and its derivative group compare model group, reduce serum alt, AST levels and TG, TC content, wherein building
Fragrant lactone high dose group effect is most notable, illustrates the liver function indexes of alantolactone and its derivative to alcoholic fatty liver mouse
Improved significantly with abnormalities of sugar/lipid metabolism tool.
The influence of the alantolactone of table 3. and its derivative to alcoholic fatty liver mice serum biochemical indicator
| Group | TG(mmol/L) | TC(mmol/L) | ALT(IU/L) | AST(IU/L) |
| Control group | 0.91±0.24 | 2.13±0.38 | 24.30±2.34 | 80.91±6.48 |
| Model group | 1.45±0.36# | 2.98±0.36## | 35.97±4.07# | 110.85±12.83## |
| Alantolactone（It is low） | 1.11±0.23* | 2.45±0.49* | 29.06±4.16** | 92.37±16.05* |
| Alantolactone（It is high） | 0.96±0.13** | 2.28±0.31** | 27.10±3.21** | 86.44±13.63** |
| Isoalantolactone | 1.27±0.44* | 2.68±0.68* | 30.42±3.79* | 92.53±17.42* |
| Dihydroalantolacton | 1.22±0.38* | 2.53±0.83* | 29.10±4.82** | 90.38±11.52* |
| MPG | 1.07±0.24* | 2.33±0.21* | 28.35±5.01* | 85.69±15.38** |
Note：# represents that p≤0.05 compared with control group, ## represent p≤0.01 compared with control group；* the p compared with model group is represented
≤ 0.05, * * represent p≤0.01 compared with model group.
Above data shows that alantolactone and its derivative have the function that lipid-loweringing, improve lipid-metabolism, and delay
Hepatic injury is solved, there is good prevention and treatment alcoholic fatty liver.
Test example 4
The influence of alantolactone and its derivative to NASH mouse
（1）The prevention effect of alantolactone and its derivative to NASH mouse liver injury
By the male C57BL/6 mouse 70 of health（7 week old, 18-22g,）Adaptability is randomly divided into control group, mould after feeding 7 days
Type group, alantolactone low dose group（20mg/kg）, high dose group（50mg/kg）, isoalantolactone group（20mg/kg）, two
Hydrogen alantolactone group（20mg/kg）With Kezhi capsule positive controls（0.49g/kg）.In addition to control group, other groups are given
High lipid food is fed, and the CCl of volume fraction 5% is subcutaneously injected in mouse hind leg4Edible oil solution（Prepared with corn oil）Build
Mould, dosage 0.1ml/10g, 2 times/week, control group gives normal diet nursing, and injecting normal saline replaces.Model simultaneously,
Compound group and Kezhi capsule group give the compound or medicine gavage of corresponding dosage, and 1 time a day, control group and model group are given
Isometric physiological saline is given to replace.After testing 4 weeks, fasting 12h after last dose, with 4% chloral hydrate anesthesia mouse, heart takes
Blood system is from serum, detection serum alt, AST levels and TG, TC changes of contents.Experimental data is carried out with SPSS statistical softwares
Variance analysis, t-, which is examined, carries out significance analysis（n=10）.As a result as shown in table 4, alantolactone and its derivative group are compared
Model group, serum alt, AST levels and TG, TC content being reduced, wherein alantolactone high dose group effect is most notable,
Illustrate that alantolactone and its derivative can prevent the liver function indexes and abnormalities of sugar/lipid metabolism of NASH mouse.
The influence of the alantolactone of table 4 and its derivative to NASH mice serum biochemical indicator
| Group | TG(mmol/L) | TC(mmol/L) | ALT(IU/L) | AST(IU/L) |
| Control group | 2.08±0.15 | 2.71±0.57 | 28.08±6.52 | 108.31±14.45 |
| Model group | 2.87±0.71# | 4.64±0.83## | 163.31±42.64## | 257.88±34.23## |
| Alantolactone（It is low） | 2.34±0.27* | 2.98±0.81** | 57.52±2.63** | 183.57±37.26** |
| Alantolactone（It is high） | 2.18±0.48* | 2.74±0.78** | 52.31±6.47** | 154.10±38.76** |
| Isoalantolactone | 2.57±0.32* | 3.45±0.67* | 137.42±26.93** | 205.16±44.76** |
| Dihydroalantolacton | 2.63±0.52* | 3.01±0.38* | 125.85±35.37** | 214.76±36.75* |
| Kezhi capsule | 2.07±0.61** | 2.86±0.60** | 36.15±5.01** | 137.25±26.63** |
Note：## represents p≤0.01 compared with control group；* p≤0.05 compared with model group is represented,
* represents p≤0.01 compared with model group.
（2）The therapeutic action of alantolactone and its derivative to NASH mouse
By the male C57BL/6 mouse 70 of health（7 week old, 18-22g,）Adaptability is randomly divided into control group, mould after feeding 7 days
Type group, alantolactone low dose group（20mg/kg）, high dose group（50mg/kg）, isoalantolactone group（20mg/kg）, two
Hydrogen alantolactone group（20mg/kg）With Kezhi capsule positive controls（0.49g/kg）.In addition to control group, other groups are given
High lipid food is fed, and the CCl of volume fraction 5% is subcutaneously injected in mouse hind leg4Edible oil solution（Prepared with corn oil）Build
Mould, dosage 0.1ml/10g, 2 times/week, control group gives normal diet nursing, and injecting normal saline replaces, and continues 4 weeks
Afterwards, compound group and Kezhi capsule group give the compound or medicine gavage of corresponding dosage, 1 time a day, control group and model group
Isometric physiological saline is given to replace.After testing 2 weeks, fasting 12h after last dose, with 4% chloral hydrate anesthesia mouse, the heart
It is dirty to take blood system from serum, detection serum alt, AST levels and TG, TC changes of contents.Experimental data uses SPSS statistical softwares
Variance analysis is carried out, t-, which is examined, carries out significance analysis（n=10）.As a result as shown in table 5, alantolactone and its derivative group
Compared to model group, serum alt, AST levels and TG, TC content, the wherein effect of alantolactone high dose group are reduced most
Significantly, illustrate that alantolactone and its derivative have to the liver function indexes of NASH mouse with abnormalities of sugar/lipid metabolism
Significant improvement result.
The influence of the alantolactone of table 5 and its derivative to NASH mice serum biochemical indicator
| Group | TG(mmol/L) | TC(mmol/L) | ALT(U/L) | AST(U/L) |
| Control group | 1.88±0.84 | 2.67±0.28 | 35.08±5.37 | 107.72±9.23 |
| Model group | 3.05±0.37## | 5.04±0.68## | 227.52±6.49## | 306.57±25.47## |
| Alantolactone（It is low） | 2.64±0.29** | 3.11±0.41* | 147.85±12.52** | 208.57±42.84** |
| Alantolactone（It is high） | 2.38±0.73** | 2.93±0.35** | 124.50±36.97** | 169.10±39.26** |
| Isoalantolactone | 2.89±0.53** | 4.53±0.75* | 185.52±47.85** | 248.57±61.75* |
| Dihydroalantolacton | 2.75±0.68** | 3.85±0.85* | 193.78±49.42* | 221.32±52.67** |
| Kezhi capsule | 2.07±0.30** | 3.04±0.17** | 128.74±8.43** | 154.25±28.30** |
Note：## represents p≤0.01 compared with control group；* p≤0.05 compared with model group is represented,
* represents p≤0.01 compared with model group.
Above experimental study as shown by data, alantolactone and its derivative have the function that lipid-loweringing, improve lipid-metabolism,
And alleviate hepatic injury, there is good prevention and treatment NASH.
Claims (4)
1. alantolactone and its derivative are preparing the purposes in preventing and treating fatty hepatic injury health products and medicine, described
Alantolactone and its derivative, molecular formula C15H20O2, molecular weight 232.32, general structure is as follows：
Wherein, R1 is methyl, and R2 is methyl, and R3 is hydrogen, and R4 is methylene, then is alantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is methylene, then is isoalantolactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is benzylamine, then is 13- benzylamines-alantolactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is melonia, then is 13- melonias-alantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is melonia, then is 13- melonias-different elecampane
Lactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is methyl, then is dihydroalantolacton；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is methyl, then is dihydroisoalantolactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is methyl cyanoacetate, then is methyl cyanoacetate alantolactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is dimethyl malenate, then is dimethyl malenate alantolactone；
Or R1 is methyl, R2 is methyl, and R3 is hydrogen, and R4 is diethyl malonate, then is diethyl malonate alantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is nitromethane, then is nitromethane isoalantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is nitroethane, then is nitroethane isoalantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is ethyl acetoacetate, then is the different elecampane of ethyl acetoacetate
Lactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to chlorobenzene, then for chlorobenzene isoalantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to benzene, then for benzene isoalantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to toluene, then for toluene isoalantolactone；
Or R1 is methyl, R2 is methylene, and R3 is dihydro, and R4 is to methoxybenzene, then for methoxybenzene isoalantolactone.
2. the fatty liver being related in purposes as claimed in claim 1 refers to Primary Fatty Liver, secondary fatty liver, Drug fat
Fatty liver caused by fat liver, alcoholic fatty liver, fatty liver caused by hyperlipidemia or glycometabolism syndrome.
3. the health products and medicine that are related in purposes as claimed in claim 1 are by alantolactone or derivatives thereof and pharmaceutically may be used
The carrier composition of receiving.
4. the health products and medicine that are related in purposes as claimed in claim 1, it is characterised in that：Soil as effective active composition
Constuslactone and its derivative content are 1% ~ 99%.
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Cited By (3)
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| CN113262218A (en) * | 2020-02-14 | 2021-08-17 | 无锡杰西医药股份有限公司 | Application of isothiocyanate compounds |
| CN114886889A (en) * | 2022-04-27 | 2022-08-12 | 清华大学 | Application of alantolactone or derivatives thereof in preparation of medicines, health products or foods for preventing or treating obesity |
| CN115414352A (en) * | 2022-10-09 | 2022-12-02 | 吉林大学 | Application of isoalantolactone in preparation of medicine for treating acute liver injury |
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|---|---|---|---|---|
| CN107157983A (en) * | 2017-05-19 | 2017-09-15 | 苏州大学附属第医院 | Application of the alantolactone in preventing and treating hepar damnification medicine is prepared |
-
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|---|---|---|---|---|
| CN107157983A (en) * | 2017-05-19 | 2017-09-15 | 苏州大学附属第医院 | Application of the alantolactone in preventing and treating hepar damnification medicine is prepared |
Non-Patent Citations (1)
| Title |
|---|
| 郑文奎等主编: "《临床常见疾病及基本药物应用指南》", 31 July 2014, 第四军医大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113262218A (en) * | 2020-02-14 | 2021-08-17 | 无锡杰西医药股份有限公司 | Application of isothiocyanate compounds |
| CN114886889A (en) * | 2022-04-27 | 2022-08-12 | 清华大学 | Application of alantolactone or derivatives thereof in preparation of medicines, health products or foods for preventing or treating obesity |
| CN115414352A (en) * | 2022-10-09 | 2022-12-02 | 吉林大学 | Application of isoalantolactone in preparation of medicine for treating acute liver injury |
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