CN111388490A - Ginsenoside composition with function of preventing and treating alcoholic fatty liver - Google Patents

Ginsenoside composition with function of preventing and treating alcoholic fatty liver Download PDF

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CN111388490A
CN111388490A CN202010305247.XA CN202010305247A CN111388490A CN 111388490 A CN111388490 A CN 111388490A CN 202010305247 A CN202010305247 A CN 202010305247A CN 111388490 A CN111388490 A CN 111388490A
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ginsenoside
pharmaceutical composition
liver
alcoholic fatty
fatty liver
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CN111388490B (en
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范代娣
贺婧
段志广
马晓轩
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Shaanxi Giant Biogene Technology Co ltd
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    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract

The invention discloses a ginsenoside composition with the function of preventing and treating alcoholic fatty liver. The pharmaceutical composition for preventing and/or treating alcoholic fatty liver comprises ginsenoside Rk3 and ginsenoside Rh4 which are used as active ingredients and have effective amounts for preventing and/or treating alcoholic fatty liver, and a pharmaceutically acceptable carrier, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 is 1: 0.5-2, preferably 1: 0.9-1.1. The ginsenoside composition can obviously improve the liver function index abnormality caused by a large amount of drinking; reduce the inflammatory infiltration of liver tissues and the generation of fat vacuoles. The invention provides a synergistic pharmaceutical composition containing ginsenoside Rk3 and Rh4, which has the effect of preventing and/or treating alcoholic fatty liver.

Description

Ginsenoside composition with function of preventing and treating alcoholic fatty liver
Technical Field
The invention relates to the field of biological medicine, in particular to a ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver.
Background
Fatty liver disease is a common disease, and can be classified into alcoholic fatty liver disease (AF L) and non-alcoholic fatty liver disease (NAF L D) according to the existence of a large amount of drinking history, wherein the AF L is alcoholic liver injury caused by long-term drinking of alcohol, and the main reasons are toxic metabolites generated by alcohol metabolism in liver cells, oxidative stress and metabolic disorder caused by the oxidative stress, and the pathogenesis of NAF L D is mainly related to IR, liver fat metabolism abnormity, mitochondrial dysfunction and oxidative stress, genetic variation and metabolic change, susceptibility of cell injury and the like.
Polyene phosphatidyl choline is a common medicine for adjuvant therapy of alcoholic fatty liver, can effectively reduce oxygen free radicals, protect liver cell membranes and delay hepatic fibrosis, thereby promoting recovery of patients, but clinically, single-medicine therapy is considered, patients recover slowly, and intestinal disorders are easily caused, thereby causing diarrhea.
Ginsenoside is an active ingredient in ginseng, is a steroid compound, and can affect multiple metabolic pathways in the body. Research reports that ginsenoside Rk3 and Rh4 have obvious effects of resisting tumor, oxidation and inflammation, inhibiting apoptosis and the like, and literature reports that ginsenoside CK, Rh1 and compositions thereof can be applied to medicines for improving nonalcoholic fatty liver fibrosis and insulin resistance, but the research on the alcoholic fatty liver is not carried out; the ginsenoside Rg1 has certain efficacy in treating metabolic disorder caused by drinking, but whether the liver has a protective effect is not studied, and the combined drug of the ginsenoside Rk3/Rh4 is never applied to improving fatty liver and liver diseases caused by alcohol, reducing liver antioxidant substances and the like.
Disclosure of Invention
The invention aims to provide a ginsenoside Rk3/Rh4 composition with the function of preventing and treating alcoholic fatty liver.
The inventor finds that the ginsenoside Rk3/Rh4 can effectively improve the degree of liver injury and fatty degeneration caused by drinking, and therefore, the ginsenoside Rk3/Rh4 composition is further applied to the treatment and alleviation of alcoholic fatty liver, and the composition is firstly applied to the prevention and treatment of alcoholic fatty liver by taking the ginsenoside Rk3/Rh4 composition as a main component, and has good treatment and improvement effects on the alcoholic fatty liver.
Namely, the present invention comprises:
1. a pharmaceutical composition useful for preventing and/or treating alcoholic fatty liver, comprising as active ingredients a prophylactically and/or therapeutically effective amount of ginsenoside Rk3 and ginsenoside Rh4, and a pharmaceutically acceptable carrier,
in the pharmaceutical composition, the weight ratio of the ginsenoside Rk3 to the ginsenoside Rh4 is 1: 0.5-2, preferably 1: 0.9-1.1.
2. The pharmaceutical composition of item 1, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 is 1: 1.
3. the pharmaceutical composition according to item 1, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 contained in the pharmaceutical composition is 10 parts by weight or more based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
4. The pharmaceutical composition according to item 1, comprising ginsenoside Rk3 and ginsenoside Rh4 in a total amount of 100 parts by weight based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
5. The use according to item 1, wherein the pharmaceutical composition does not contain other effective ingredients for preventing and/or treating alcoholic fatty liver than ginsenoside Rk3 and ginsenoside Rh 4.
6. The application of ginsenoside Rk3 and ginsenoside Rh4 in preparing a pharmaceutical composition for preventing and/or treating alcoholic fatty liver, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 in the pharmaceutical composition is 1: 0.5-2, preferably 1: 0.9-1.1.
7. The use of item 6, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 in the pharmaceutical composition is 1: 1.
8. the use according to item 6, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 contained in the pharmaceutical composition is 10 parts by weight or more based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
9. The use according to item 6, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 is 100 parts by weight based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
10. The use according to item 6, wherein the pharmaceutical composition does not contain other effective ingredients for preventing and/or treating alcoholic fatty liver than ginsenoside Rk3 and ginsenoside Rh 4.
The ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver can be a medicament or any other preparation form; can be used for treating related diseases, and can also be used for improving or preventing fatty liver caused by drinking. The preparation can be ginsenoside Rk3/Rh4, or compound preparation comprising ginsenoside Rk3/Rh4 and other components, wherein ginsenoside Rk3/Rh4 are used as main components.
The ginsenoside Rk3/Rh4 can be obtained by extracting, converting and separating ginseng or American ginseng or the like, and can also be obtained by chemical synthesis. Specifically, the ginsenoside Rk3/Rh4 can be obtained by extracting, converting and separating roots, stems and/or leaves of ginseng or American ginseng by using a process method in the prior art.
In addition, the inventor also finds that Rk3 or Rh4 can improve the survival rate of mice drunk, reduce the contents of glutamic-pyruvic transaminase (A L T) and glutamic-oxaloacetic transaminase (AST) in serum, reduce the contents of cholesterol (TC), Triglyceride (TG) and low-density lipoprotein (L D L) in serum and liver, and reduce lipid accumulation (oil drops), inflammatory infiltration of liver tissues and fat vacuole in the liver caused by drinking in a mouse alcoholic fatty liver model.
Therefore, the present invention also includes:
11. the application of the ginsenoside Rk3 in preparing a pharmaceutical composition for preventing and/or treating alcoholic fatty liver.
12. The use according to item 11, wherein ginsenoside Rk3 contained in the pharmaceutical composition is 5 parts by weight or more, preferably 10 parts by weight or more, more preferably 20 parts by weight or more, more preferably 50 parts by weight or more, more preferably 70 parts by weight or more, more preferably 80 parts by weight or more, more preferably 90 parts by weight or more, more preferably 95 parts by weight or more, more preferably 99 parts by weight or more, more preferably 100 parts by weight, based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
13. The use according to item 11, wherein the pharmaceutical composition does not contain an active ingredient other than ginsenoside Rk3 for preventing and/or treating alcoholic fatty liver.
14. Use of ginsenoside Rh4 in the preparation of a pharmaceutical composition for preventing and/or treating alcoholic fatty liver.
15. The use according to item 14, wherein ginsenoside Rh4 contained in the pharmaceutical composition is 5 parts by weight or more, preferably 10 parts by weight or more, more preferably 20 parts by weight or more, more preferably 50 parts by weight or more, more preferably 70 parts by weight or more, more preferably 80 parts by weight or more, more preferably 90 parts by weight or more, more preferably 95 parts by weight or more, more preferably 99 parts by weight or more, more preferably 100 parts by weight, based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
16. The use according to item 14, wherein the pharmaceutical composition does not contain an active ingredient other than ginsenoside Rh4 for preventing and/or treating alcoholic fatty liver.
The above pharmaceutical composition may be, for example, an oral preparation or an injection preparation. The oral preparation can be, for example, hard capsules, soft capsules, sustained-release capsules, sugar-coated tablets, powders, granules, tablets, granules, dripping pills, water-honeyed pills, syrup or oral liquid; the injection is in a solution type, a suspension type, an emulsion type or a freeze-dried powder type. The pharmaceutical composition may also be in the form of a topical formulation, such as a paste, gel, spray or patch. The pharmaceutical composition may comprise adjuvants or other pharmaceutically acceptable carriers. The ratio of the auxiliary material to the pharmaceutically active ingredient may be, for example, 30 to 50% by weight of the active ingredient and 70 to 50% by weight of the auxiliary material. The auxiliary material can be one or more of sodium hyaluronate, magnesium stearate, sodium alginate, starch, microcrystalline cellulose, chitosan, stachyose, adhesive or collagen.
Drawings
FIG. 1 shows the chemical structural formula of ginsenoside Rk3
FIG. 2 shows the chemical structural formula of ginsenoside Rh4
FIG. 3 is a graph showing the results of HE staining of mouse liver tissues in example 4. Wherein,
1: HE staining pattern of liver tissue of control mice;
2: a liver tissue HE staining pattern of model group mice;
3: HE staining pattern of liver tissue of mice in the positive drug control group;
4: HE staining pattern of liver tissue of mice in ginsenoside Rk3 group;
5: the HE staining pattern of liver tissue of mice in the ginsenoside Rh4 group;
6: the HE staining pattern of liver tissue of 1 group of mice of the ginsenoside Rk3/Rh4 composition;
7: the HE staining pattern of liver tissue of 2 groups of mice of the ginsenoside Rk3/Rh4 composition;
8: the HE staining pattern of liver tissue of 3 groups of mice of the ginsenoside Rk3/Rh4 composition;
9: HE staining pattern of liver tissue of mice in ginsenoside Rg1 group;
10: HE staining pattern of liver tissue of CK/Rh1 group mouse;
detailed description of the invention
First, in one aspect, the present invention provides a pharmaceutical composition useful for preventing and/or treating alcoholic fatty liver, comprising ginsenoside Rk3 and ginsenoside Rh4 in an amount effective for preventing and/or treating alcoholic fatty liver as an active ingredient, and a pharmaceutically acceptable carrier,
in the pharmaceutical composition, the weight ratio of the ginsenoside Rk3 to the ginsenoside Rh4 is 1: 0.5-2.
In the present specification, ginsenoside Rk3 refers to a compound represented by formula C shown in FIG. 136H60O8。
The ginsenoside Rk3 is a known compound, and can be prepared by methods known in the technical field, for example, a crude product of ginsenoside Rk3 with high purity is obtained by adding an organic acid solution into panaxatriol ginsenoside and performing directional conversion reaction under the conditions of high temperature and high pressure, and the purified product of ginsenoside Rk3 with purity of more than or equal to 98% is obtained by purification through methods such as high performance liquid separation and the like.
In the present specification, ginsenoside Rh4 refers to a compound represented by the formula C shown in FIG. 236H60O8。
The ginsenoside Rh4 is a known compound, and can be prepared by the method known in the technical field, for example, the ginsenoside Rh4 with purity more than or equal to 98% is obtained by adding organic acid solution into triol ginsenoside, performing directional conversion reaction under the condition of high temperature and high pressure, and then separating and purifying.
The inventors have found that the combination of ginsenoside Rk3 and ginsenoside Rh4 in the ratio range defined in the present invention shows synergistic effect (CI value less than 1, preferably CI value less than 0.8, more preferably less than 0.7) in preventing and/or treating alcoholic fatty liver. The inventors have also found that, within the above ratio range, ginsenoside Rk3 and ginsenoside Rh4 are also of low toxicity. Furthermore, the inventors found that if the contents of ginsenoside Rk3 and ginsenoside Rh4 in the pharmaceutical composition are not within the ratio range defined in the present invention, there is no synergistic effect. In view of remarkable synergistic effect, the weight ratio of the ginsenoside Rk3 to the ginsenoside Rh4 in the composition is preferably 1: 0.9-1.1, and more preferably 1: 1.
The pharmaceutical composition of the present invention may or may not contain other ginsenosides. In the case where another ginsenoside is contained in the pharmaceutical composition of the present invention, the contents of the ginsenoside Rk3 and the ginsenoside Rh4 are preferably 50 parts by weight or more, more preferably 60 parts by weight or more, more preferably 70 parts by weight or more, more preferably 80 parts by weight or more, more preferably 90 parts by weight or more, more preferably 95 parts by weight or more, more preferably 99 parts by weight or more, and more preferably 100 parts by weight (i.e., the pharmaceutical composition contains only the two ginsenosides) from the viewpoint of better exerting a synergistic effect, based on 100 parts by weight of the total ginsenosides contained in the pharmaceutical composition. The ginsenoside Rk3 used in the pharmaceutical composition has a purity of more than 98%, and the ginsenoside Rh4 has a purity of more than 98%.
The content of the total ginsenoside can be determined by vanillin method, and the contents of ginsenoside Rk3 and Rh4 can be determined by HP L C method.
The pharmaceutical composition of the present invention may or may not contain other active ingredients for preventing and/or treating alcoholic fatty liver disease (i.e., ginsenoside Rk3 and ginsenoside Rh4 as the only active ingredients for preventing and/or treating alcoholic fatty liver disease).
On the other hand, the inventors found that the pharmaceutical composition of the present invention has a significant effect of preventing and/or treating alcoholic fatty liver. Therefore, the invention also provides the application of the pharmaceutical composition in preparing a medicament for preventing and/or treating alcoholic fatty liver.
Pharmaceutically acceptable carriers, such as adjuvants, may be included in the pharmaceutical compositions of the invention. The excipients in the pharmaceutical composition of the present invention are not particularly limited, and for example, excipients generally used in pharmaceutical products or health products in the art may be used. Specifically, the auxiliary materials are starch, dextrin, lactose, mannitol, hydroxypropyl sodium methylcellulose, xanthan gum, aspartame and the like.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and may be, for example, an oral dosage form or an injectable dosage form. The oral dosage form may be a liquid dosage form or a solid dosage form. The oral dosage form can be, for example, hard capsules, soft capsules, sustained-release capsules, tablets, sugar-coated tablets, powders, granules, pills, water-honeyed pills, syrups or oral liquids; the injection formulation may be, for example, a solution type, a suspension type, an emulsion type or a lyophilized powder. The administration mode of the pharmaceutical composition for preventing and/or treating alcoholic fatty liver may be, for example, oral, instillation or injection.
When preparing a solid preparation for oral administration, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, etc. are added to the main drug, and then the mixture is prepared into tablets, coated tablets, granules, fine granules, powders, capsules, etc. according to a conventional method.
As the excipient, for example, lactose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose, silicon dioxide, or the like; as the binder, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and the like; as the lubricant, for example, magnesium stearate, talc, silica, etc.; as the colorant, a colorant that allows addition in a pharmaceutical product; as correctant, cocoa powder, Mentholum, aromatic acid, oleum Menthae Dementholatum, Borneolum Syntheticum, and cortex Cinnamomi Japonici powder can be used. Of course, sugar coating, gelatin coating, and other necessary coatings may be applied to the tablets and granules.
When preparing the injection, pH regulator, buffer, suspending agent, solubilizer, stabilizer, isotonic agent, preservative and the like can be added into the main drug according to the needs, and then the injection for intravenous injection, subcutaneous injection and intramuscular injection can be prepared according to the conventional method. In this case, a freeze-dried product may be prepared by a conventional method as needed.
Examples of the suspending aid include methyl cellulose, tween 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, and polyoxyethylene sorbitol monolaurate.
Examples of the solubilizer include polyoxyethylene hydrogenated castor oil, tween 80, niacinamide, polyoxyethylene sorbitol monolaurate, polyethylene glycol, and castor oil fatty acid ethyl ester.
Examples of the stabilizer include sodium sulfite, sodium metabisulfite, and the like; examples of the preservative include methyl paraben, ethyl paraben, sorbic acid, phenol, cresol, chlorocresol, and the like.
The pharmaceutical composition of the present invention is administered to a subject, and tumors can be treated. The subject may be a mammal, for example, a human, rat, rabbit, sheep, pig, cow, cat, dog, monkey, etc., preferably a human.
The pharmaceutical composition of the present invention may be administered orally or non-orally. The amount to be administered varies depending on the degree of symptoms, age, sex, body weight, sensitivity of patients, administration method, administration period, administration interval, properties of pharmaceutical preparations, kinds of active ingredients, and the like, but is not particularly limited, but is usually 1 to 30000mg, preferably 10 to 3000mg, more preferably 100 to 2000mg, more preferably 1 to 1000mg, more preferably 5 to 900mg, more preferably 10 to 500mg, more preferably 100 to 300mg (based on the total amount of ginsenoside Rk3 and ginsenoside Rh 4) per day for an adult (body weight 60Kg), and the amount to be administered may be usually administered in 1 to 3 times per day.
Examples
The invention is further illustrated by the following specific examples, which are given by way of illustration only, without limiting the scope of the invention.
EXAMPLE 1 preparation of tablets with ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver
Taking ginsenoside Rk 3100 g with the purity of more than or equal to 98 percent, ginsenoside Rh 4200 g with the purity of more than or equal to 98 percent and 500g of common pharmaceutic adjuvants for preparing tablets, uniformly mixing, tabletting, drying and packaging to obtain 2000 tablets of the invention, wherein each tablet contains 150mg of active ingredients.
Example 2 preparation of a Capsule with ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver
Uniformly mixing ginsenoside Rk 3100 g with the purity of more than or equal to 98%, ginsenoside Rh 4100 g with the purity of more than or equal to 98% and 600g of common pharmaceutical excipients, and filling the mixture into capsules sold on the market at present to obtain 2000 capsules, wherein the content of active ingredients in each capsule is 100 mg.
EXAMPLE 3 preparation of ginsenoside Rk3/Rh4 composition oral liquid having effect of preventing and treating alcoholic fatty liver
Taking ginsenoside Rk 340 g with the purity of more than or equal to 98 percent and ginsenoside Rh 480 g with the purity of more than or equal to 98 percent, uniformly mixing, adding a proper amount of flavoring agent crystalline fructose, stachyose, citric acid, pectin and diluent water by adopting a conventional method, heating for dissolving, homogenizing, filling and sterilizing to prepare 1000 bottles of oral liquid, wherein each bottle of oral liquid contains 120mg of effective components.
Example 4 efficacy test of ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver
100 adult male mice (18-22 g) are randomly divided into a normal control group, a model group, an administration dose group, a composition 1 group (Rk 315 mg/kg, Rh 415 mg) in example 2, a composition 2 group (Rk 37.5 mg/kg, Rh422.5mg), a composition 3 group (Rk322.5mg/kg, Rh47.5 mg), ginsenoside Rk3(30mg/kg), ginsenoside Rh4(30mg/kg), a polyene phosphatidyl choline (30mg/kg) positive drug control group, ginsenoside Rg1(30mg/kg), ginsenoside CK/Rh1(CK 15mg/kg, Rh 115 mg/kg) group, 10 groups, except the normal control group, the mice in each group are administrated with 50% ethanol for 1 time every day, the ethanol dose is 12m 6/kg, the normal control group is continuously filled with 4 weeks, the stomach of the normal control group is adjusted by adding equal amount of gastric lavage fluid, the normal control group is prepared by adding equal amount of the normal control solution, the normal control group with the normal control group, the normal control group is filled with the normal control solution for 24 kg, the stomach tissue is filled with equal amount of the normal control solution, the normal control group is filled with the normal control solution after the normal control group is filled with the normal control group filled with the normal control solution for twice, the stomach test sample is filled with the normal test sample, the normal test sample is filled with the normal test sample for 24 kg, the test sample, the normal test sample is filled with the test sample, the test sample is filled with equal amount of the normal control group filled with the normal test sample for once every day, the test sample is filled with the normal test sample, the normal test sample is filled with the normal test sample for once, the normal test sample for once every day, the test sample is filled with the test sample, the test sample filled with the test sample for once, the test sample is filled with the test sample for once, the test sample for the test
Figure BDA0002455544680000071
Representation, statisticsThe chemical treatment method adopts single-factor variance analysis to calculate the interaction index CI of two medicines, namely AB/(A × B), wherein T is the index value determined by a dosing group, C is the index value determined by a model group, AB is the T/C value of a combination group of the two medicines, A, B is the T/C value of a single medicine action group, when CI is less than 1, the two medicines have synergistic action, and when CI is less than or equal to 0.7, the synergistic action is very obvious (refer to David H.Kern, Carol R.Morgan, and Susanne U.Hildebrand-Zanki.In vitamin and in v interaction between peptide and topotecan in aromatic hydrocarbon systems [ J.J]Cancer Research,1988,48, and Li Xing Lidamycin Research on glioma inhibition and synergy with temozolomide [ D]China university of cooperative medical science, 2009).
The experimental results are as follows:
TABLE 1 Effect of the compositions of the present invention on body weight, liver factor in mice
Figure BDA0002455544680000081
Figure BDA0002455544680000082
Note: p is less than or equal to 0.01, P is less than or equal to 0.05vs blank control;ΔΔP≤0.01，Δp is less than or equal to 0.05vs model group
The weight difference of each group has no statistical significance (P is more than or equal to 0.05); compared with a blank group, the liver quality and the liver coefficient of the model group are obviously increased (P is less than or equal to 0.01), compared with the model group, the liver coefficient of each administration group is obviously reduced (P is less than or equal to 0.05), wherein the liver coefficient of the Rk3/Rh4 group is extremely obviously reduced (P is less than or equal to 0.01), the test result shows that each administration group has an obvious inhibiting effect on mouse liver swelling caused by alcohol, and the composition 1 has a better effect than each single component under the same dosage, has a synergistic effect (the CI value is less than 1), and has a more obvious effect of reducing the liver coefficient compared with a polyene phosphatidyl choline group, ginsenoside Rg1 and ginsenoside CK/Rh 1.
TABLE 2 Effect of the composition of the present invention on the Activity of serum A L T, AST in alcoholic fatty liver mice
Figure BDA0002455544680000091
Figure BDA0002455544680000092
Note: p is less than or equal to 0.01, P is less than or equal to 0.05vs blank control;ΔΔP≤0.01，Δp is less than or equal to 0.05vs model group
A L T, AST is a marker index of liver injury, the content of A L T, AST in normal serum is very low, only after liver injury, A L T, AST in liver cells is released into blood due to cell rupture, and active oxygen generated by ethanol in a liver metabolism process directly causes oxidative damage to liver cells, Table 2 shows that the activity of A L T and AST of animals in each administration group is remarkably different from that of a model group (P is less than or equal to 0.05), wherein the activity of A L T and AST of animals in Rk3/Rh4 groups is remarkably different from that of the model group (P is less than or equal to 0.01) and is remarkably lower than that of the model group, and the activity of A L T, AST which is abnormally increased in the serum of alcoholic fatty liver mice is not remarkably different from that of a blank control group (P is more than 0.86505), the test result shows that the composition 1 of the invention can remarkably reduce the activity of A L T, AST which is abnormally increased in the serum of alcoholic fatty liver mice, and the composition 1 of the invention has a synergistic effect on the combination of a polyene phosphatidylcholine group, ginsenoside 1, ginsenoside CK/Rh1, ginsenoside A364 and CI 3, and CI 1 and CI 3.
TABLE 3 Effect of the compositions of the present invention on the serum TC, TG, L D L and TG levels in liver tissue of alcoholic fatty liver mice
Figure BDA0002455544680000101
Figure BDA0002455544680000102
Note: p is less than or equal to 0.01, P is less than or equal to 0.05vs blank control；ΔΔP≤0.01，ΔP is less than or equal to 0.05vs model group
The long-term alcohol intake can cause the abnormal increase of the content of TC and TG in the serum of mice, and the accumulation of cholesterol and triglyceride in the liver, as shown in Table 3, the content of TC, TG and L D L in the serum of animals of each administration group and the content of TG in liver tissue are all significantly different from those of a model group (P is less than or equal to 0.05), wherein the content of TC, TG and L D L in the serum of animals of the composition group and the content of TG in liver tissue are significantly different from those of the model group (P is less than or equal to 0.01), the combination index CI of the composition 1 is less than 1 through calculation, and the combination index of the composition 2 and the combination index of the composition 3 is more than 1, so that the composition 1 has good synergistic effect, and the composition Rk3 and the ginsenoside Rh4 do not have synergistic effect outside the proportion range of the composition, the damage of alcohol to liver cells is realized through lipid peroxidation mediated by free radicals, and the composition 1 can effectively reduce the content of TC and TG in the serum of mice, improve the L D L level, inhibit the synthesis of endogenous TC and the lipid in vivo, and improve.
The pathological section of the mouse liver can be obviously seen, and the control group mouse liver is normal in size, red, soft and sharp in edge; the liver of the model group mouse is obviously enlarged, and is gray, granular and greasy in section; liver morphology was improved in each treatment group compared to the model group, but the Rk3/Rh4 composition was closer to the control group than in the other treatment groups. The results of liver HE staining (FIGS. 3, 1-10) show that the control group of hepatocytes were normal in size and morphology, aligned, large and round nuclei were visible in the center, and the cytoplasm was uniformly stained. No fat drop deposition in liver cells, normal morphological structure, no steatosis and no inflammation change; the liver cells of the model group were swollen and poorly defined. Large vacuole-like lipid drops can be seen in cells, the size of the lipid drops is different, cells with steatosis are distributed in a focus shape, liver tissues are almost replaced by fat vacuoles, the liver cells are in balloon-like degeneration, and inflammatory cells infiltrate in a sink region; the liver tissues of the individual action groups of the human saponins Rk3 and Rh4, the group of the composition 2, the group of the composition 3, the positive drug control group, the group of the ginsenoside Rg1 and the group of the ginsenoside CK/Rh1 have loose and dispersed fat vacuoles, the accumulation of lipid (oil drops) is reduced, and no obvious inflammatory cells are seen. The mice fed with the Rk3/Rh4 composition 1 have almost no fat drop deposition in liver cells in liver tissues, nearly normal morphological structure and no steatosis, and the effect is better than the medium dosage effect, so that the Rk3/Rh4 composition disclosed by the invention can better improve the degree of steatosis degree of the liver of the mice caused by alcohol.
Example 5 mechanism of ginsenoside Rk3/Rh4 composition for preventing and treating alcoholic fatty liver
The normal control group in example 4 was assayed; a model group; liver superoxide dismutase (SOD), liver reductive Glutathione (GSH), and Malondialdehyde (MDA) levels in liver in Rk3, Rh4, Rk3/Rh 4; and screening and determining the expression level of related genes in the liver cells by a molecular chip, and adding or subtracting standard deviation from the mean of the test results
Figure BDA0002455544680000111
Representing that a statistical processing method adopts single-factor analysis of variance;
the experimental results are as follows:
TABLE 4 Effect of the inventive compositions on liver SOD, GSH and MDA in alcoholic fatty liver mice
Figure BDA0002455544680000121
Figure BDA0002455544680000122
Note: p is less than or equal to 0.01, P is less than or equal to 0.05vs blank control;ΔΔP≤0.01，Δp is less than or equal to 0.05vs model group
Liver cells of alcoholic fatty liver are easily subjected to oxidative stress, the oxidation resistance of a model group mouse body is weakened, the levels of alcohol metabolism harmful products MDA are increased, the SOD activity of liver tissues is reduced, the content of reduced glutathione GSH is reduced, compared with the model group, the liver tissue SOD activity and the GSH content of Rk3, Rh4, Rk3/Rh4 groups are obviously increased (P is less than or equal to 0.01) and the MDA content is obviously reduced (P is less than or equal to 0.01), and Rk3 and Rh4 have oxidation resistance activity and can effectively improve the liver oxidative damage caused by drinking.
TABLE 5 statistical table of relative expression levels of genes related to important metabolic pathways of alcoholic fatty liver mice by using the composition of the present invention
Figure BDA0002455544680000123
Note: in the table, ↓ corresponding gene was down-regulated in the liver cell mRNA expression, and ↓ indicates the corresponding gene was up-regulated in the liver cell mRNA expression.
Fatty acid synthetase (Fasn), which plays a crucial role in fatty acid synthesis, is responsible for all catalytic steps of the de novo synthesis of a long-chain palmitic acid (palmitate) from acetyl-CoA and malonyl-CoA, and the expression of this gene directly affects the amount of fatty acid synthetase, playing an important role in controlling the deposition of animal fat.Lipoprotein lipase (L P L), which is one of the key enzymes of fat metabolism, acts on lipoproteins, mainly breaks down triacylglycerol in lipoproteins, is the rate-limiting enzyme for triacylglycerol elimination in plasma, and promotes the transfer of cholesterol, phospholipids and apolipoprotein to lipoproteins; L P L also has the ability to increase chylomicron binding to the L P receptor, and promotes chylomicron uptake.sterol-CoA desaturase 1(Scd1), which is the rate-limiting enzyme of monounsaturated fatty acid biosynthesis, plays a central regulatory role in fatty acid metabolism, and is one of the target genes of leptin (L eptin) action, and leptin has a close relationship with diabetes, obesity, and fatty liver disease in recent years.
The model group can increase Fasn synthesis, reduce L p L synthesis and is the chief factor of excessive deposition of liver cell fat, and cause fatty liver, and administration groups can reduce Fasn synthesis, administration group Rh4 and the composition Rk3/Rh4 can significantly increase L p L synthesis, reduce fatty acid synthesis of liver tissues and enhance lipolysis, and has positive significance for relieving liver fatty degeneration.
From the above pharmacodynamic experiments, it is clear that the composition of the present invention has an effect of preventing and treating alcoholic fatty liver and has no side effects after long-term administration.
Finally, it should be noted that the above-mentioned description is only a preferred embodiment of the present invention, and those skilled in the art can make various similar expressions without departing from the spirit and scope of the present invention.
Industrial applicability
The invention provides a synergistic pharmaceutical composition containing ginsenoside Rk3 and Rh4, which has the effect of preventing and/or treating alcoholic fatty liver.

Claims (10)

1. A pharmaceutical composition useful for preventing and/or treating alcoholic fatty liver, comprising as active ingredients a prophylactically and/or therapeutically effective amount of ginsenoside Rk3 and ginsenoside Rh4, and a pharmaceutically acceptable carrier,
in the pharmaceutical composition, the weight ratio of the ginsenoside Rk3 to the ginsenoside Rh4 is 1: 0.5-2, preferably 1: 0.9-1.1.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 is 1: 1.
3. the pharmaceutical composition according to claim 1, wherein the total amount of ginsenoside Rk3 and ginsenoside Rh4 contained in the pharmaceutical composition is 10 parts by weight or more based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
4. The pharmaceutical composition according to claim 1, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 is 100 parts by weight based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
5. The use according to claim 1, wherein the pharmaceutical composition does not contain other effective ingredients for preventing and/or treating alcoholic fatty liver than ginsenoside Rk3 and ginsenoside Rh 4.
6. The application of ginsenoside Rk3 and ginsenoside Rh4 in preparing a pharmaceutical composition for preventing and/or treating alcoholic fatty liver, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 in the pharmaceutical composition is 1: 0.5-2, preferably 1: 0.9-1.1.
7. The use according to claim 6, wherein the weight ratio of ginsenoside Rk3 to ginsenoside Rh4 in the pharmaceutical composition is 1: 1.
8. the use according to claim 6, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 in the pharmaceutical composition is 10 parts by weight or more based on 100 parts by weight of total ginsenoside contained in the pharmaceutical composition.
9. The use according to claim 6, wherein the total of ginsenoside Rk3 and ginsenoside Rh4 in the pharmaceutical composition is 100 parts by weight based on 100 parts by weight of the total ginsenoside in the pharmaceutical composition.
10. The use according to claim 6, wherein the pharmaceutical composition does not contain other effective ingredients for preventing and/or treating alcoholic fatty liver than ginsenoside Rk3 and ginsenoside Rh 4.
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