CN102462688A - Application of akebiasaponin D in preparing medicines for treating and preventing fatty liver and related diseases - Google Patents
Application of akebiasaponin D in preparing medicines for treating and preventing fatty liver and related diseases Download PDFInfo
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- CN102462688A CN102462688A CN2010105306392A CN201010530639A CN102462688A CN 102462688 A CN102462688 A CN 102462688A CN 2010105306392 A CN2010105306392 A CN 2010105306392A CN 201010530639 A CN201010530639 A CN 201010530639A CN 102462688 A CN102462688 A CN 102462688A
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- fatty liver
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Abstract
The invention aims at providing a new application of akebiasaponin D, particularly an application of akebiasaponin D in preparing medicines and/or health products for treating and preventing fatty liver and related diseases by using akebiasaponin D as an active component, wherein, the fatty liver comprises alcoholic fatty liver and non-alcoholic fatty liver, and fatty liver and hyperlipidemia due to decreased estrogen levels, and the related diseases comprise fatty liver with lipid metabolism abnormality, hormone level disorder, fatty liver with dyslipidemia, steatohepatitis, liver cirrhosis, and the like. Studies of pharmacology, pharmaceutical effect and toxicology prove that the medicines and/or health products prepared by using akebiasaponin D as the active component have remarkable effects on treating and preventing fatty liver and fatty liver with hyperlipidemia, diabete and other related diseases, and have tiny toxicity.
Description
Technical field
The present invention relates to the new application of akebin D, especially preparing treatment and prevention fatty liver and fatty liver and the medicine of relevant diseases such as hyperlipemia and/or the application in the health product are arranged.
Background technology
Fatty liver disease (fatty liver disease; FLD), be called for short fatty liver, be meant the liver fat dysbolismus that multiple factor causes; The dynamic equilibrium imbalance of lipid material; Cause the interior lipopexia of hepatocyte too much, a kind of clinical pathology syndrome of liver generation diffusivity fatty infiltration (steatosis) and a series of pathophysiological change, it comprises alcoholic fatty liver and non-alcoholic fatty liver disease.Fatty liver is the disease of life-style a kind of pilosity, common among the current social crowd; In recent years; The prevalence of fatty liver rises gradually both at home and abroad, and presents the trend of becoming younger, and shows through epidemiology generaI investigation statistics; The prevalence of fatty liver is about 10%, and wherein the merging of obese people more than 50% and diabetics suffers from fatty liver.China hepatopathy researcher points out, Chinese Patients with Fatty Liver is about 1.2 hundred million, surpasses hepatitis B patient 0.93 hundred million; Thereby become Chinese first hepatopathy, wherein urban population about 25% suffers from fatty liver, and the women is higher than male sicken rate; The ratio that the child suffers from fatty liver is also about 10%, all exceeds nearly 1 times of rural area.In addition, fatty liver takes place in chronic alcoholic nearly 60%, and 20%～30% develops into liver cirrhosis the most at last, and the sickness rate of non-alcoholic fatty liver disease generation hepatic fibrosis is 25%.Can predict that following fatty liver will become the main object of domestic and international hepatopathy control, so the lipotropic new drug of research and development is very urgent, necessary.
Fatty liver is divided into simple fatty liver, fat hepatitis, fatty liver fibrosis, fatty cirrhosis four-stage by the progress degree of pathological change.Fatty liver is the pathological changes that is caused fatty overheap in the hepatocyte by a variety of causes; Its formation mainly is following several types of reasons: 1) drink for a long time can grievous injury liver because ethanol makes hepatocyte to decomposition of fatty acids and metabolism generation obstacle to hepatocellular toxicity, cause that intrahepatic fat deposits and causes fatty liver; It is many more to drink; Fatty liver is also just serious more, also can bring out hepatic fibrosis, and then cause liver cirrhosis; 2) Animal fat of the long-term Excessive Intake of overnutrition, vegetable oil, protein and carbohydrate, these foods can not be fully utilized in vivo, and superfluous nutrient substance just is converted into fat stores, causes fat, hyperlipidemia and fatty liver; 3) long-term nutrition is bad, lacks protein and vitamin, can cause the deficiency disease fatty liver equally.As because of suffer from chronic intestinal tract disease, long-term anorexia, go on a diet, reasons such as vegetarian diet, malabsorption syndrome and gastrointestinal bypass operation, cause hypoproteinemia, lack choline, aminoacid or drive the fat material, thereby intrahepatic fat is piled up, form fatty liver; 4) chronic disease patients such as diabetes, hepatitis, hyperthyroidism, anemia are owing to the utilization of health to glucose reduces, and body fat acid significantly increases, and makes the lipogenesis of liver hyperfunction, thereby causes fatty liver; 5) medicamentous liver lesion accounts for 1/10th of adult's hepatitis, and fatty liver is a common type; 6) hyperlipemia hypercholesterolemia and fatty liver are in close relations, and be wherein close with the hypertriglyceridemia relation, most with obesity, diabetes and alcoholism.7) it is synthetic and drain that estrogen has also been participated in the liver VLDL, can be with a large amount of synthetic cholesterol transports in the liver in blood and the accumulation of triglyceride reducing in liver.Decrease in estrogen or shortage can cause that liver lipid metabolism is disorderly, and blood fat is raise, and form hyperlipemia, so cause fat, the generation of a series of diseases such as fatty liver, coronary heart disease, hypertension, osteoporosis, have a strong impact on healthy.In addition, some industrial poison, gestation, heredity or spirit, psychology and social factor also have relation with fatty liver.
At present; The treatment of fatty liver has liver cell protective agent, fat-reducing medicament and antioxidant etc.; Like vitamin B, C, E, lecithin, ursodesoxycholic acid, silymarin, inosine, coenzyme A, reduced glutathion, taurine, glucuronolatone, and some fat-reducing medicament or the like.Yet 1. choline is only applicable to the dystrophic fatty liver.2. phospholipid and how unsaturated lecithin such as polyene phosphatidylcholine become though can reduce hepatocellular fat, protect and repair impaired liver plasma membrane and and the inflammation and the fibrosis that have, to can not the careful usefulness of abstainer.3. ursodesoxycholic acid is clinical treatment fatty liver medicine commonly used, once is considered to reduce hepatic fat content, and is effective to fatty liver, but do not confirm its curative effect through 2 years random double blind tests.4. antioxidant such as reduced glutathione, silymarin, vitamin E, taurine etc. have certain alt-reducing and liver-protecting effect; Participate in the intrahepatic fat metabolism; Alleviate the liver inflammatory reaction, promote the hepatocyte rehabilitation of damage, help to treat fatty liver; And can reduce the hepatic fibrosis of bringing out, but its definite curative effect remains to be confirmed.5. research shows; Phytoestrogen can be regulated the lipid metabolism of removal ovary rat effectively; The existing estrogen-like effects of this type medicine does not have estrogenic side effect again; And liver is had protective effect, although for the monomer component and the compound recipe of this type medicine the research report is arranged all, still none phytoestrogen is registered the treatment that is used for the relevant fatty liver of hormonoprivia through medicine at present.In addition, natural drug and Chinese medicine such as DANNING PIAN, Xuezhikang, Herb Gynostemmae Pentaphylli total glycosides, and control fatty liver such as large and small bupleurum root decoction many be main with conditioning, its course of treatment is long, therapeutic effect is very little.
Also there is safety issue in the medicine of treating fatty liver simultaneously, can cause that like the bifendate class glutamic oxaloacetic transaminase, GOT raises and jaundice when reducing glutamate pyruvate transaminase, increases the weight of hepatic injury.In addition, clinical research confirmation, most of blood lipid-lowering medicines all have liver toxicity, can cause intrahepatic cholestasis, cause jaundice or drug induced hepatic injury, even cause liver cirrhosis and liver failure; And blood lipid-lowering medicine has " driving fat " effect, can the lipid in the blood " be driven " liver; And original just existing athero in the liver; So be difficult to handle to gushing the lipid of coming in a large number, fat flushing can be deposited in the liver, makes fatty liver more serious.
Up to the present, still useless in lipotropic active drug, how to prevent the fatty liver severe exacerbation with the treatment of Chinese medicine long-time conditioning.Therefore, research and develop safely and effectively, be used to treat and prevent fatty liver and fatty liver and have the new drug of relevant diseases such as hyperlipemia, diabetes to have important innovative significance and clinical use value.
Akebin D is one of main compound composition of Chinese medicine plant Radix Dipsaci Dispsacus japonicus Miq. or Radix Dipsaci D.asper Wall., is the triterpene saponin constituents.Research for akebin D at present prevents and treats effects such as senile dementia based on its estrogen-like and antioxidation mostly, is used to prevent and treat menopausal syndrome and osteoporosis.
Akebin D
At present, do not see that as yet Radix Dipsaci and akebin D are at preparation treatment and prevention fatty liver and the medicine of relevant disease and/or the report of the application in the health product.
Summary of the invention
The object of the present invention is to provide the new application of akebin D: be active component promptly with akebin D, medicine and/or health product that preparation is used to treat and prevent fatty liver and fatty liver and relevant diseases such as hyperlipemia are arranged.
The invention provides fatty liver and the medicine of hyperlipemia and/or the application in the health product that akebin D causes in preparation treatment and prevention decrease in estrogen.
The invention provides akebin D is preparing treatment and prophylaxis of hyperlipidemia and diabetes and the medicine of fatty liver and/or the application in the health product is being arranged.
The invention provides akebin D in preparation treatment and prevention alcoholic fatty liver and the medicine of non-alcoholic fatty liver disease and/or the application in the health product.
The invention provides akebin D in preparation treatment and the medicine of prevention fatty liver relevant disease and/or the application in the health product; Wherein relevant disease comprises lipid metabolic disorder, the hormonal readiness imbalance that fatty liver causes; Fatty liver also has dyslipidemia, and fat hepatitis, liver cirrhosis etc.
The invention provides the process for extracting, separating and purifying of akebin D.
In the present invention, akebin D can be made into the medicine of multiple dosage forms such as oral formulations, parenteral preparation or external preparation, is preferably injection and tablet.The various dosage forms that the present invention relates to are mixed with by akebin D and pharmacy adjuvant, carrier and form.
The present invention confirms through pharmacology, drug effect and toxicological study thereof; Be the medicine that is prepared from of active component and/or health product to treatment and prevention fatty liver and fatty liver thereof and have relevant disease such as hyperlipemia to have significant action effect with akebin D, and toxicity is minimum.
The specific embodiment
Pharmacology, drug effect and toxicological study thereof to the present invention carried out show; The present invention is to fatty liver and fatty liver and have the treatment of relevant diseases such as hyperlipemia and prevention to obtain beyond thought beneficial effect, and the pharmacology of record, drug effect and toxicological experiment result thereof are following:
The separation and purification of embodiment 1 akebin D
Optimize result of study according to extraction process; Get Radix Dipsaci pharmaceutical decocting piece 5.0kg, add 70% alcohol heating reflux and extract twice, extraction solvent is doubly measured each 10 times (V/W) for raw medicinal herbs; Extraction time is each 2 hours; Merge extracted twice liquid, decompression recycling ethanol, the rate of transform that gets akebin D is 93%.Through the screening experiment result, select for use the AB-8 macroporous adsorbent resin as thick step separation means, the bullion of enrichment akebin D, AB-8 macroporous adsorptive resins are diameter 10cm * length 65cm, the weight ratio of resin demand and medical material is 1: 1.With above-mentioned concentrated medicament thin up to solid content is 8%, and last appearance is used 3 column volume water washings respectively; 3 column volume 70% ethanol elutions are used in 2 column volume 30% ethanol remove impurity at last, collect 70% ethanol elution; Decompression recycling ethanol concentrates evaporate to dryness, gets bullion 450g; The content of this bullion akebin D is 67%, and the rate of transform is 78%.Above-mentioned bullion is separated with normal phase silicagel column, and collecting mobile phase is 7: 3 eluents of chloroform-methanol, and the reclaim under reduced pressure organic solvent concentrates evaporate to dryness; Reuse reverse phase silica gel post carries out purification, and collecting mobile phase is 2: 8 eluents of methanol-water, and methanol is reclaimed in pressurization, and evaporate to dryness gets white powder medicine 200g, i.e. akebin D; Through the normalization method determination and analysis, the content of this white powder medicine akebin D is 98% with HPLC and ELSD.
The formulation preparation of embodiment 2 akebin D
Test the preparation of 1. akebin D injections
Prescription 1: akebin D1000mg, solubilizing agent F68 are 20mg, cosolvent propylene glycol 60mg, antioxidant sodium sulfite 30mg.Anhydrous glucose adjusting etc. is oozed, and buffer salt is regulated pH value to 7, adds redistilled water to 150mL.
Prescription 2: akebin D1000mg, solubilizing agent F68 are 25mg, HP-beta-schardinger dextrin-2000mg, antioxidant sodium sulfite 50mg.Getting recipe quantity HP-beta-schardinger dextrin-is dissolved in the 40mL ethanol, at 600r.min
-1Add people's akebin D powder under stirring, continue to stir 2h, subsequent use; Get the dissolving of sodium sulfite and F68 adding 50mL aqueous solution, stir the HP-beta-schardinger dextrin-alcoholic solution that injects akebin D down, dissolve fully until akebin D, put-60 ℃ of following pre-freezes then, vacuum drying gets the loose freeze-dried powder of off-white color.
Test the preparation of 2. akebin D tablets
The 1. akebin D10g that write out a prescription, hydroxypropyl emthylcellulose 3g, starch 2g, lactose 1g, ethyl cellulose 0.5g, PVP0.5g.Get recipe quantity akebin D, hydroxypropyl emthylcellulose, ethyl cellulose, starch and lactose, cross 80 mesh sieves, mix homogeneously respectively; The PVP aqueous solution system soft material of adding 3% is granulated with 20 eye mesh screens, in 60 ℃ of dry 4h; Behind the 18 eye mesh screen granulate, add an amount of magnesium stearate, fully behind the mixing; With the flat stamping of 6mm, sheet heavily is 0.32g, and every contains akebin D 0.18g.
The 2. akebin D10g that write out a prescription, CMC-Na0.5g, gelling starch 0.5g, microcrystalline Cellulose 2g, 90% alcoholic solution are as adhesive, and an amount of magnesium stearate is made lubricant.Get recipe quantity akebin D, CMC-Na, gelling starch, microcrystalline Cellulose, cross 80 mesh sieves respectively, mix homogeneously is with 90% ethanol system soft material; Granulate with 20 eye mesh screens, in 60 ℃ of dry 4h, behind the 18 eye mesh screen granulate; Add an amount of magnesium stearate, fully behind the mixing, with the flat stamping of 6mm; Sheet heavily is 0.32g, and every contains akebin D 0.25g.
Embodiment 3 akebin D suppress the effect of adipose cell growth, propagation
Material: akebin D content 98% (preparation of hospital general's pharmacy portion of the Second Artillery Force, lot number: 20090926; In the dissolving sterile purified water, 4 ℃ of cold preservation storages are subsequent use, are diluted to desired concn with DMEM/Ham ' the s F12 culture fluid that contains 10% hyclone during dosing).Adipose cell 3T3-L1 (Chinese Academy of Medical Sciences's cell centre) before the mice.DMEM/Ham ' s F12 culture medium (Gibco); Hyclone (FCS, Gibco); NBCS (NCS, Gibco); Dimethyl sulfoxide (DMSO, Sigma); Tetramethyl azo azoles salt (MTT, Sigma); Propidium iodide (PI, Sigma); TritonX-100 (Sigma); Trypsin AMRESCO); 3-isobutyl-1-methylxanthine (IBMX, Sigma); Dexamethasone (Dex, Sigma); Insulin (Insulin, Sigma).LS-1F type superclean bench (Shanghai Suo Pu instrument); 4950E type CO2 cell culture incubator (USA, NUNR); AU640 inverted microscope (Olympus); 550 type ELIASAs (Bio-rad 550); Flow cytometer (EPICS XL, COULTER USA).
Method: 96 well culture plate inoculating cells, be cultured to the 3rd day, change culture fluid, divide into groups and add certain density akebin D, make the final concentration of medicine reach 0,37.5,75,150 respectively, 300,600 μ gmL
-1, 6 repetitions are established in every group of processing, with 0 μ molmL
-1Be contrast, on drug effect 48h time point, carry out MTT and measure.With enzyme join detector at 490nm place mensuration respectively organize absorbance A, and the cell survival rate of experiment with computing group.The result sees table 1.
Table 1 akebin D is to the influence of preceding adipose cell survival rate
Show by table 1 result, little in the survival change of concentration 37.5-300 μ g/mL scope inner cell, and examine under a microscope the in good condition of visible cell.
6 porocyte culture plate inoculating cells are divided into the normal cell matched group, induce group, the pharmaceutical intervention group, and normal cell is cultivated with the DMEM/Ham ' s that contains 10%NCS is conventional, induce group and pharmaceutical intervention group cell culture to cell 100% to cover with after; Add induced liquid I (DMEM, 10% hyclone, 0.5mmol/L IBMX; 1 μ mol/L dexamethasone, 1.7 μ mol/L insulins), add variable concentrations medicine (37.5 to be measured among the induced liquid I of pharmaceutical intervention group; 75,150,300 μ gmL
-1), induce group not add medicine and be changed to the PBS that adds equivalent, behind the cultivation 14h, add 0.02% EDTA digestion, the centrifugal 5min of 1000rpm, collecting cell 2 * 10 with 0.25% trypsin
6, PBS washing, the centrifugal 10min of 1000rpm; Repeat 3 times, 75% ethanol of 4 ℃ of pre-coolings in 4 ℃ fixedly behind the 48h with PBS flush away ethanol, 2mL PBS re-suspended cell; After hatching 30min under 37 ℃ of the RNaseA enzyme 50 μ g/mL; Each sample of cooling back adds PI to final concentration 1.5mg/mL, and the ice bath lucifuge is dyed 30min, with detecting cell cycle with flow cytometer behind the 300 order nylon net filters.The result sees table 2.
The effect of lipocyte proliferation before table 2 akebin D suppresses
Show by table 2 result; The propagation of adipose cell before akebin D can effectively suppress; The shared ratio of cell of S phase presents dose-dependence in concentration 37.5-300 μ g/mL scope; And examine under a microscope the in good condition of visible cell, increase the cells ratio that is in division stage with drug level and reduce, think that cell cycle is suppressed.
Embodiment 4 akebin D are to the effect of alcoholic fatty liver
Material: akebin D content 98% (preparation of hospital general's pharmacy portion of the Second Artillery Force, lot number: 20090926).Male Wistar rat, the SPF level, body weight (180 ± 20) g purchases the Experimental Animal Center in the Department Of Medicine, Peking University.Transaminase AST, ALT test kit (all purchasing living biochemical reagents company limited in Beijing), malonaldehyde (MDA) testing cassete (all building up Graduate School of Engineering) available from Nanjing.52 degree Red Star strong, colourless liquor distilled from sorghum, the two Khanh Hoa wine industry in Beijing Co., Ltd produces.Silymarin (Germany, Madaus AG).High lipid food and prescription thereof: 60% normal diet powder, 15% Adeps Sus domestica, 10% yolk powder, 3% sucrose, 2% cholesterol, 10% milk powder, 10/kg of cod-liver oil, five animal center preparations of Military Medical Science Institute.721 type spectrofluorophotometers (Shanghai the 3rd analytical tool factory), High speed refrigerated centrifuge (China, model C T15RT), optical microscope (Japanese OLYMPUS).
Method: 60 rats are divided into two groups at random: normal control group (10), give normal diet, irritate clothes normal saline 15mL/kg; Model group (50), preceding 3 days is that 15% Red Star strong, colourless liquor distilled from sorghum replaces water freely to be drunk with animal with alcohol concentration, it is 52% Red Star Erguotou wine that the 4th day beginning irritated the clothes alcohol concentration by 15mL/kg, 1 time/d, gives high lipid food simultaneously.The model success is one group with 10 animal patterns at random behind the 5wk, irritates clothes normal saline 15mlLkg; Remaining 40 model group rats are divided into 4 groups at random, 10 every group, irritate stomach akebin D (0.35g/kg respectively; 0.70g/kg), (concentration is 5.00mg/mL to silymarin, 15.00mg/d).30d finishes experiment, irritates fasting 12h behind the stomach for 1 time at last, freely drinks water, and puts to death centrifugal (3000rpm, 10min) separated plasma ,-20 ℃ of cryopreservation, AST to be measured and ALT after getting blood; Dissection divides two parts after getting liver, the fixing back section of a part of 10% neutral formalin HE dyeing pathological observation, and a part is preserved for-20 ℃ and is measured MDA.
Adopt SPSS 11.5 softwares to carry out the significance test of statistics and difference.Experimental result representes with mean+SD mean compared between the employing one factor analysis of variance carried out organizing more, checked with t between group and carried out statistical procedures, and P＜0.05 is a significant level.The result sees table 3.
Table 3 akebin D is to the effect of alcoholic fatty liver
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know that by table 3 result compare with model group, low, the high dose of akebin D have significant reduction effect to transaminase and the malonaldehyde of alcoholic fatty liver rat; And the liver index obviously is reduced to normally.Microscopically is observed the pathological section of liver, compares with model group, and the liver that giving akebin D has the laboratory animal of making returns to normal action effect, does not have tangible pathological phenomenon.
Embodiment 5 akebin D prevention and the effect of treating non-alcoholic fatty liver disease
Material: akebin D content 98% (preparation of hospital general's pharmacy portion of the Second Artillery Force, lot number: 20090926).Kunming mouse, female, body weight 20 ± 2g is provided by the department of the Chinese Academy of Sciences of Department Of Medicine, Peking University's laboratory animal section.Free fatty (NEFA) testing cassete, superoxide dismutase (SOD), malonaldehyde (MDA) test kit, Coomassie brilliant blue testing cassete (all building up Graduate School of Engineering) available from Nanjing; Transaminase AST, ALT test kit (all purchasing living biochemical reagents company limited in Beijing).Oleanolic acid tablet (Beijing WanHui ShuangHe pharmacy Co.,Ltd).High lipid food and prescription thereof: 60% normal diet powder, 15% Adeps Sus domestica, 10% yolk powder, 3% sucrose, 2% cholesterol, 10% milk powder, 10/kg of cod-liver oil, five animal center preparations of Military Medical Science Institute.Electronic analytical balance (Germany, model C P225D); 550 type ELIASAs (Bio-rad 550); High speed refrigerated centrifuge (China, model C T15RT); Ultraviolet spectrophotometer (Chinese Unico, model UV2800A); OLYMPUS inverted microscope (Japan, model AU640); HPLC (day island proper Tianjin, model S1L-20A).
Method: 140 of the female Kunming mouses of healthy adult, body weight is 20 ± 2g, is divided into prevention administration and treatment administration, each 70.Both are divided into two groups at random, and 10 of normal control groups give normal diet, irritate clothes normal saline 10mL/kg; 60 of model group are given and high lipid food, are divided into 6 groups again at random, are respectively model group (normal saline); Akebin D administration group (0.25g/kg, 0.50g/kg, 1.00g/kg), positive controls (oleanolic acid; Concentration is 4.500mg/mL, dosage 0.900mg/d), 10 every group.Prevention administration experimental group is modeling administration simultaneously, and the time is 6wk; The treatment experimental group is first modeling 6wk, administration 4wk again, and administration continues to give high lipid food simultaneously.After finishing experiment, irritate fasting 12h behind the stomach for 1 time at last, freely drink water, eyeball is put to death after getting blood,, separated plasma ,-20 ℃ of cryopreservation, AST to be measured and ALT measure liver MDA, and get the fixing back of the part hepatic tissue 10% neutral formalin HE pathological observation that dyes of cutting into slices.
Adopt SPSS 11.5 softwares to carry out the significance test of statistics and difference.Experimental result representes with mean+SD mean compared between the employing one factor analysis of variance carried out organizing more, checked with t between group and carried out statistical procedures, and P＜0.05 is a significant level.The result sees table 4,5.
Table 4 akebin D is to the preventive effect of non-alcoholic fatty liver disease
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know by table 4 result, with model group relatively, the reduction effect that akebin D has highly significant to transaminase and the malonaldehyde of basic, normal, high dosage non-alcoholic fatty liver disease mice; And the liver index obviously is reduced to normally.Microscopically is observed the pathological section of liver, compares with model group, gives pathological phenomenons such as the fat-free grain of its liver of laboratory animal of akebin D, fatty fibrosis, and the effect of tangible prevention fatty liver is arranged.
Table 5 akebin D is to the therapeutical effect of non-alcoholic fatty liver disease
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know that by table 5 result akebin D has significant reduction effect to transaminase and the malonaldehyde of non-alcoholic fatty liver disease mice; And the middle and high dose groups of akebin D is compared with the fatty liver rat model, and the liver index obviously is reduced to normally.Microscopically is observed the pathological section of liver, compares with model group, gives pathological phenomenons such as the fat-free grain of its liver of laboratory animal of akebin D, fatty fibrosis, returns to normal action effect, has the effect of tangible prevention fatty liver.
Embodiment 6 akebin D are to the influence of simple fatty liver mice blood fat
According to the method for embodiment 5, the laboratory animal serum that collects is carried out blood biochemistry index T-CHOL (TC) simultaneously, triglyceride (TG), high density lipoprotein (HDL), the detection of low density lipoprotein, LDL (LDL).The result sees table 6,7.
Table 6 akebin D is to the influence of prevention administration simple fatty liver mice blood fat
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Table 7 akebin D is to the influence of treatment administration simple fatty liver mice blood fat
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know by table 6,7 results; Compare with model group; The level of the T-CHOL (TC) of the middle and high dose groups of akebin D, triglyceride (TG) and low density lipoprotein, LDL (LDL) significantly reduces; And the level of high density lipoprotein (HDL) significantly raises, and visible akebin D has the blood fat balance action effect of regulating the simple fatty liver mice.
Embodiment 7 akebin D are to the influence of simple fatty liver mouse liver oxidative damage
According to the method for embodiment 5, biochemical indicator total protein (TP) is carried out in treatment group liver of laboratory animal homogenate that collects and serum simultaneously, free fatty (FFA), the detection of superoxide dismutase (SOD).The result sees table 8.
Table 8 akebin D is to the influence of serum albumin and the free fatty of simple fatty liver mice
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Show by table 8 result; Compare with model group; The middle and high dosage of akebin D can obviously improve total protein and the superoxide dismutase of simple fatty liver mice, reduces the free fatty in the serum, the effect that the hepar damnification that fatty liver is caused has protection and repairs.
Embodiment 8 akebin D are to the influence of simple fatty liver blood glucose
According to the method for embodiment 5, the laboratory animal serum that collects is also carried out simultaneously the detection of blood glucose.The result sees table 9.
Table 9 akebin D is to the influence of simple fatty liver mouse blood sugar
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Show that by table 9 result compare with model group, akebin D can obviously reduce the blood glucose in the simple fatty liver mice serum.
Embodiment 8 akebin D are to the therapeutical effect of removal ovary serum lipids in rats and fatty liver
Material: akebin D content 98% (preparation of hospital general's pharmacy portion of the Second Artillery Force, lot number: 20090926).Estradiol valerate (German Schering Corp produces, the accurate word J2009008 of traditional Chinese medicines).Health not the female 3 monthly age S rat body weights of copulation (205 ± 18g), provide by Beijing dimension tonneau China laboratory animal Science and Technology Ltd., the animal rank is a secondary.Free fatty (NEFA) testing cassete, SOD detection kit, malonaldehyde (MDA) testing cassete, Coomassie brilliant blue testing cassete (all building up Graduate School of Engineering) available from Nanjing; Cholesterol (TC), triglyceride (TG), high low-density lipoprotein (HDL-C), the white cholesterol of low-density (LDL-C) (all available from living biochemical reagents company limited in Beijing).Electronic analytical balance (Germany, model C P225D); High speed refrigerated centrifuge centrifuge (China, model C T15RT); Ultraviolet spectrophotometer (China, model UV2800A); OLYMPUS microscope (Japan, model AU640); HPLC (day island proper Tianjin, model S1L-20A).
Method: the female sd inbred rats at 70 3 monthly ages of health; Be divided into 7 groups every group each 10 at random, be respectively normal group, sham operated rats, model group, estradiol valerate group, high dose akebin D group (700mg/kg), middle dosage akebin D group (350mg/kg), low dosage akebin D organizes (175mg/kg).After rats by intraperitoneal injection pentobarbital sodium (40mg/kg) anesthesia, extract operation on ovary.The same method of sham operated rats is opened the abdominal cavity, exposes ovary, only cuts the part fat lump but does not extract ovary.The rat of normal group does not award any processing.Postoperative is respectively organized 1 week of rat normal diet and is recovered wound, and observes the no oestrous cycle variation of vaginal smear 5d confirmation continuously.Respectively according to dosage gastric infusion every day of each group once, normal group, sham operated rats and model group give normal saline 10mL/kg subsequently.In 7 weeks of successive administration, water 12h is can't help in fasting after the last administration, with pentobarbital sodium anesthesia, and the ventral aorta blood sampling, institute's blood of getting is got serum and is used for each item blood biochemistry index mensuration in the centrifugal 5min of 3000r/min; Get liver, cut the neat lobules of liver of a die edge after weighing and be put in 4% formalin fixingly, the remainder back of weighing is frozen in-20 ℃ refrigerator.
Adopt SPSS 11.5 softwares to carry out the significance test of statistics and difference.Experimental result representes with mean+SD mean compared between the employing one factor analysis of variance carried out organizing then, checked with t between group and carried out statistical procedures, and P＜0.05 is a significant level.The result sees table 10-12.
Table 10 akebin D is to the influence of liver function
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know that by table 10 result compare with model group, akebin D has significant reduction effect to transaminase and the malonaldehyde of removal ovary rat, and the middle and high dosage of wooden barrel saponin D has tangible rising effect to superoxide dismutase.
Table 11 akebin is to liver tissues of rats triglyceride and the pure influence of gallbladder week
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know that by table 11 result compare with model group, akebin D high dose has significant reduction effect to the T-CHOL and the triglyceride of removal ovary rat liver.
Table 12 akebin D is to the influence of rat blood serum blood fat
# and normal control group be p＜0.05 relatively, and ## and model be p＜0.01 relatively; * compare p＜0.05 with model, * * and model be p＜0.01 relatively.
Can know by table 12 result; Compare with model group; The high dose of wooden barrel saponin D can significantly reduce the level of T-CHOL (TC), triglyceride (TG) and low density lipoprotein, LDL (LDL); And the level of high density lipoprotein (HDL) can significantly raise, so akebin D can regulate removal ovary rat fat balance.
The toxicological study of embodiment 9 akebin D
Material: akebin D content 98% (preparation of hospital general's pharmacy portion of the Second Artillery Force, lot number: 20090926).Kunming mouse, male and female half and half, body weight 20 ± 2g is provided by the department of the Chinese Academy of Sciences of Department Of Medicine, Peking University's laboratory animal section.
Method: use distilled water that akebin D concentration of ordinary dissolution is 0.5g/mL, get 20 Kunming mouses, male and female half and half, body weight 20 ± 2g according to 0.8ml/20g, in disposable gastric infusion at 10 o'clock in the morning, observed 7 days then continuously.
The result: under this dosage, poisoning and the phenomena of mortality does not appear in mice.Dosage is equivalent to 40 times of Coming-of-Age Day usual amounts.The safety of proof akebin D is good.
Claims (6)
1. akebin D is in preparation treatment and the medicine of prevention alcoholic fatty liver, simple fatty liver and relevant disease thereof and/or the application in the health product.
2. akebin D is in preparation treatment and the fatty liver and the medicine of hyperlipemia and/or the application in the health product that prevent decrease in estrogen to cause.
3. application as claimed in claim 1 is characterized in that: said relevant disease comprises fatty liver and the imbalance of lipid metabolic disorder, hormonal readiness arranged, and fatty liver also has dyslipidemia, and fat hepatitis, liver cirrhosis etc.
4. like claim 1,2,3 described application, it is characterized in that: said medicine contains at pharmaceutically acceptable component and/or carrier.
5. like claim 1,2,3 described application, it is characterized in that: said medicine is oral formulations, parenteral preparation or external preparation.
6. like claim 1,2,3 described application, it is characterized in that: the active component of said medicine and/or health product is akebin D.
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| CN103622972A (en) * | 2013-12-04 | 2014-03-12 | 中国科学院华南植物园 | Preparation method for compound 3 alpha-Akebonolic acid and application of compound to preparation of glycosidase inhibitor drug |
| WO2015188428A1 (en) * | 2014-06-10 | 2015-12-17 | 刘丽宏 | 一种应用于治疗代谢综合征的药物 drug for treating metabolic syndrome |
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| CN115645422A (en) * | 2022-11-07 | 2023-01-31 | 中日友好医院(中日友好临床医学研究所) | Compositions for preventing and treating metabolic syndrome and uses thereof |
| CN116425821A (en) * | 2022-09-21 | 2023-07-14 | 刘丽宏 | Dipsacus asperoides saponin compound, preparation method thereof and application thereof in preparing medicine for preventing and treating fatty liver |
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| CN111217885A (en) * | 2020-02-27 | 2020-06-02 | 首都医科大学附属北京朝阳医院 | Medicinal cocrystal of akebia saponin D-organic acid and use thereof |
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Application publication date: 20120523 |