CN106563038B - Taurine and fat-soluble tea polyphenol compound composition, preparation method and application thereof - Google Patents
Taurine and fat-soluble tea polyphenol compound composition, preparation method and application thereof Download PDFInfo
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- CN106563038B CN106563038B CN201611004969.1A CN201611004969A CN106563038B CN 106563038 B CN106563038 B CN 106563038B CN 201611004969 A CN201611004969 A CN 201611004969A CN 106563038 B CN106563038 B CN 106563038B
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- taurine
- fat
- tea polyphenol
- soluble tea
- compound composition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/82—Theaceae (Tea family), e.g. camellia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Microbiology (AREA)
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- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a taurine-fat-soluble tea polyphenol compound composition, a preparation method and application thereof, wherein the composition comprises 50-75 parts of taurine and 25-50 parts of fat-soluble tea polyphenol according to parts by weight. The compound composition can play roles of reducing blood fat, resisting lipid peroxidation and protecting liver function at the level of animals, and is expected to be developed into a medicament or a health-care product to benefit human beings.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a taurine-fat-soluble tea polyphenol compound composition and a preparation method and application thereof.
Background
Non-alcoholic fatty liver disease (NAFLD) is a clinical pathological syndrome caused by liver lobule, liver cell diffuse steatosis and fat storage without excessive drinking history. Statistically, 42-90% of asymptomatic glutamate pyruvate transaminase (APT) patients are caused by NAFLD after excluding other causes, NAFLD can shorten the life of patients over 50 years by 4 years, and the life of patients under 50 years by 10 years. NAFLD has become a leading cause of liver transplantation in the united states. Epidemiological investigation in developed areas such as Shanghai, Guangzhou and hong Kong in China shows that the prevalence of NAFLD is about 15%. Effective control of NAFLD is expected to prevent further progression of chronic liver disease and improve patient prognosis.
NAFLD mainly includes three types of simple fatty liver (NAFL), steatohepatitis (NASH) and steatohepatitis fibrosis, wherein NASH is a serious type of NAFLD, is a pathological process essential for the development of nonalcoholic simple fatty liver into hepatic fibrosis and cirrhosis, and is a chronic progressive liver disease which can cause adverse clinical consequences. NASH is histopathologically manifested by steatosis with nonspecific inflammation, as well as steatosis with hepatocellular ballooning and mixed inflammatory cell infiltration. The current academia's well-recognized NASH pathogenesis is the "secondary stroke" hypothesis, which considers insulin resistance as the primary stroke, resulting in hepatocellular steatosis (simple fatty liver, NAFL). The viability of the steatosis hepatocytes is insufficient despite their enhanced anti-apoptotic capacity and provides a reaction matrix for further lipid peroxidation; the secondary hit mainly causes oxygen stress/lipid peroxidation damage and related events thereof caused by various reasons, so that the activity of liver cell enzymes and the function of mitochondria are inhibited; hepatic stellate cells activate and proliferate, thereby inducing inflammation and fibrosis.
Imbalance between oxygen stress and body antioxidant capacity may be an important factor affecting the progression of NAFLD. A large number of clinical studies show that the NAFLD is difficult to reverse by means of measures such as controlling blood fat and blood sugar. Thus, for cases of NAFLD (primarily NASH) with liver damage, antioxidant drugs must be added to the combination therapy to prevent progression of chronic liver disease. Although clinical researches on NASH (liver disease and inflammation) treated by antioxidants such as betaine and silybin are carried out, and liver enzyme levels are found to be effectively reduced, B-ultrasonic examination indicates that the degree of fatty liver is reduced to different degrees, but the clinical cases are few, and no pathological evidence supports that inflammation of the liver is really reduced, so that the NASH is not widely applied clinically. Vitamin E is an antioxidant, and students give 11 NASH children oral vitamin E for treatment, and find that liver enzymology indexes are improved after 4-10 months of treatment, but the degree of fatty liver is not reduced in B ultrasonic review, transaminase is restored to the level before treatment after drug withdrawal, and the authors do not find that vitamin E has an intervention effect on a high-fat diet rabbit fatty liver model in animal experiments. All of the above indicate that simple antioxidant therapy has limited effectiveness in treating NASH. At present, no specific effective medicine exists for clinically treating NAFLD, particularly NASH.
Taurine is a sulfur-containing beta amino acid converted from cystine, is a conditionally essential amino acid for human body, and is also the most abundant free amino acid in the body. Most of taurine is distributed in cells, and has very wide biological effect, and the liver is an important target organ of taurine. Taurine participates in many important physiological processes of the body, including regulation of osmotic pressure, membrane stabilization, anti-lipid peroxidation, regulation of cellular calcium homeostasis, promotion of glycolysis and glycogen synthesis, etc. Research shows that taurine has the function of reducing blood sugar and can obviously relieve diabetic complications. It also has significant hypolipidemic effect, which is dose-dependent. The application of taurine to the treatment of alcoholic fatty liver in rats has been reported successfully, and the application of taurine to the treatment of 19 patients suffering from NAFLD such as Chenyuexing and the like shows that the taurine can obviously reduce the blood sugar, blood fat and serum transaminase levels of the patients, and B-ultrasonic examination and CT examination show that the degree of fatty liver is obviously improved, but the research for further expanding clinical cases is not seen. The applicant has previously applied taurine to a rat NAFL model induced by feeding high-fat diet for 8 weeks, and the result shows that the taurine can reduce the weight and the liver weight of a rat with simple fatty liver, improve the liver function and the blood fat metabolism of the rat, and reduce the degree of liver steatosis; the taurine is applied to a rat NASH model induced by feeding high-fat diet for 12 weeks, and is found to be capable of improving the liver function of a model rat and reducing the degree of steatosis and inflammation of liver tissues, but the treatment effect of the taurine on NASH is obviously weaker than that on NAFL, and the results of related researches are proved by Gentile CL and the like. Later, the researchers jointly use the taurine and the liver-protecting medicine silibinin to treat the NASH patients, the curative effect is found to be superior to that of the single use of the taurine, the ChenYuexing medicine and the like, the combination of the taurine and the silibinin is also used to treat the NASH patients, and the curative effect is found to be superior to that of the liver-protecting medicine and the silibinin which the liver-protecting medicine is easy to recover in the aspects of improving clinical symptoms and reducing. The clinical research shows that the combined medication is expected to enhance the prevention and treatment effect of the taurine on the NAFLD. However, the above studies have limited clinical observations (up to 50 cases), and most importantly, have not been confirmed by histopathology (gold standard for judging efficacy), and thus have not been widely used.
Disclosure of Invention
At present, no widely accepted effective medicine for treating NASH exists in clinic. The purpose of the invention is:
according to the first aspect, the compound composition of taurine and fat-soluble tea polyphenol capable of preventing and treating non-alcoholic fatty liver disease (particularly NASH) is provided, and comprises the taurine and the fat-soluble tea polyphenol in parts by weight of 50-75 parts and 25-50 parts respectively.
50-70 parts of taurine and 25-40 parts of fat-soluble tea polyphenol.
The weight portion of the taurine is 55-65, and the weight portion of the fat-soluble tea polyphenol is 30-40.
The weight parts of the taurine and the fat-soluble tea polyphenol are respectively 62.5 parts and 37.5 parts.
The feed additive also comprises 0-10 parts by weight of auxiliary materials (preferably 5-8 parts), and the auxiliary materials are preferably sodium stearate.
The taurine-fat-soluble tea polyphenol compound composition solution is prepared by directly and uniformly mixing powdery taurine and powdery fat-soluble tea polyphenol, or by the following steps:
(1) weighing sodium stearate, dissolving the sodium stearate in purified water, and uniformly stirring to obtain a sodium stearate solution;
(2) adding fat-soluble tea polyphenol into the sodium stearate solution obtained in the step (1), and heating and stirring to obtain uniform suspension of the fat-soluble tea polyphenol and the sodium stearate;
(3) and (3) adding taurine into the suspension obtained in the step (2), heating and stirring to obtain a compound composition solution of taurine and fat-soluble tea polyphenol.
In a second aspect, a preparation method of the compound composition of taurine and fat-soluble tea polyphenol is provided, wherein the compound composition of taurine and fat-soluble tea polyphenol is a powdery composition prepared by directly and uniformly mixing powdery taurine and powdery fat-soluble tea polyphenol; or preparing the taurine and fat-soluble tea polyphenol compound composition solution according to the following steps:
(1) weighing sodium stearate, dissolving the sodium stearate in purified water, and uniformly stirring to obtain a sodium stearate solution;
(2) adding fat-soluble tea polyphenol into the sodium stearate solution obtained in the step (1), and heating and stirring to obtain uniform suspension of the fat-soluble tea polyphenol and the sodium stearate;
(3) and (3) adding taurine into the suspension obtained in the step (2), heating and stirring to obtain a compound composition solution of taurine and fat-soluble tea polyphenol.
In a third aspect, the application of the taurine-fat soluble tea polyphenol compound composition or the taurine-fat soluble tea polyphenol compound composition obtained by the preparation method in preparing a product for preventing and treating non-alcoholic fatty liver disease, in particular in preparing a product for preventing and treating steatohepatitis (NASH) is provided.
The product is a health-care product or a medicine containing the taurine and fat-soluble tea polyphenol compound composition, and the taurine and fat-soluble tea polyphenol compound composition is a health-care active ingredient or a medicine active ingredient; the health product or medicine is tablet, capsule, powder, granule or oral liquid.
The product can also be a functional food containing the taurine and fat-soluble tea polyphenol compound composition; the functional food is buccal tablet, solid beverage or liquid beverage.
The invention firstly prepares the compound composition of taurine and fat-soluble tea polyphenol and discovers the prevention and treatment effect of the compound composition of taurine and fat-soluble tea polyphenol on rat non-alcoholic steatohepatitis. The compound composition has the functions of reducing lipid and reducing transaminase of taurine or fat-soluble tea polyphenol, and also has obvious antioxidation, the prevention and treatment effect of the compound composition on rat non-alcoholic steatohepatitis is obviously stronger than that of the taurine or the fat-soluble tea polyphenol, and the prevention and treatment effect of the taurine and fat-soluble tea polyphenol compound composition on NASH (NASH) can be enhanced, so that the compound composition has good clinical application prospect.
Drawings
FIG. 1 shows the results of pathological examination of liver of each group of rats in the first experimental example;
FIG. 2 shows the results of pathological examination of liver of each group of rats in Experimental example II.
Detailed Description
Taurine of molecular formula C2H5NO3S, relative molecular mass of 125, melting point of 305-310 ℃, and pure product is colorless or white inclined crystal, odorless, stable in chemical property, soluble in water, alcohol and polar solvent, and insoluble in organic solvent such as ethanol. The taurine is rich in marine shellfish and fish, natural taurine can be extracted from meat of fish and shellfish mollusks, and scallop edges are good materials for extracting taurine. China has a long coastline and abundant marine resources, extracts taurine, applies the taurine to the pharmaceutical industry, and has unique advantages.
The tea polyphenol is a water-soluble compound complex separated and extracted from fresh tea leaves, is a general name of polyphenol substances in the tea leaves, consists of more than 30 polyphenol substances, is a well-known natural antioxidant, and has research reports that the antioxidant effect of the tea polyphenol is 18 times higher than that of vitamin E, and the average life of animals taking the tea polyphenol can be prolonged by 36.1-49.9%. In recent years, a plurality of researches show that the tea polyphenol has good therapeutic effect on the fatty liver disease. While Wistar rats fed with high-cholesterol feed are fed with tea polyphenols by Raederstoff and the like, the serum total cholesterol and low-density lipoprotein cholesterol levels of the Wistar rats are found to be obviously lower than those of a control group, and the tea polyphenols are observed to obviously reduce the absorption of cholesterol by intestinal tracts. Random, double blind, control studies by Maron et al on 240 patients with mild to moderate hypercholesterolemia revealed that capsules made of theaflavin-rich green tea extract taken orally daily significantly reduced serum total cholesterol and low density lipoprotein cholesterol concentrations. By feeding high-fat feed to New Zealand rabbits by Zhang Xiaogang, etc. to prepare fatty liver models, the tea polyphenol can reduce blood fat, increase the activity of liver lipase in liver tissues, reduce the content of lipid peroxide in liver tissues, reduce the degree of fatty degeneration of liver cells, and has certain effect of preventing and treating non-alcoholic fatty liver of rabbits. The study of Liu Shaofeng et al and Xiao J et al also confirmed the prevention and cure effect of tea polyphenol on rat NAFL.
However, in the previous experiments, the NASH model was prepared by feeding rats with high-fat feed for 12 weeks, and the model rats were fed with tea polyphenol solution in the molding process, wherein the feeding dose is 600mg/kg, and the body weight of the model rats is also observed to be obviously reduced, and the levels of serum low-density lipoprotein cholesterol and total cholesterol are also obviously reduced, but the activity of the rats is also observed to be obviously deteriorated, the hair is dark and lusterless, and the body weight is even obviously lower than that of the rats in a normal control group. After the modeling is finished, the liver tissues of rats in each group are taken for pathological examination, and the results show that the liver steatosis degree of the rats in the tea polyphenol treatment group is not obvious, and even the liver inflammation is aggravated compared with that of a model group.
The inventor research analysis considers that the reason for the failure of tea polyphenol to treat NASH at the animal level is as follows: 1. tea polyphenols act to lower serum cholesterol levels mainly by reducing the intestinal absorption of cholesterol, one of the major components of cell membranes and involved in many important physiological processes in the body, a precursor substance in the synthesis of steroid hormones. Steroid hormones are chemical messengers that coordinate the metabolism of different cells in a multicellular organism, participate in the metabolism of various substances in the organism, and are very important for maintaining the normal physiological functions of the human body. Too high a dose of tea polyphenols will result in too low serum cholesterol levels, resulting in reduced levels of body steroid hormones, resulting in significantly poor rat vitality, dull and dull hair, and reduced body weight. The inventors therefore tried various doses of tea polyphenols and found that the appropriate tea polyphenol dose to be administered was chosen to maintain the serum cholesterol level within the normal range in order to be effective in the treatment of NASH. 2. The lipid peroxidation of tea polyphenol has been accepted by academia, and it exerts the lipid peroxidation resistance mainly by reducing Reactive Oxygen Species (ROS). Lipid peroxidation is a process of oxidizing a biological membrane by Reactive Oxygen Species (ROS), namely, the ROS performs lipid peroxidation reaction with macromolecular substances such as phospholipid, enzyme and membrane receptor related polyunsaturated fatty acid side chains and nucleic acid of the biological membrane, so that the fluidity and permeability of a cell membrane are changed, and finally, the structure and function of a cell are changed. The commonly used tea polyphenol is water-soluble tea polyphenol, cannot permeate cell membranes and cannot directly interfere the lipid peroxidation process of the cell membranes. Therefore, if the chemical structure of tea polyphenol is modified to be fat-soluble, the tea polyphenol can pass through cell membranes and directly inhibit ROS from being combined with the cell membranes, and the anti-lipid peroxidation is expected to be better exerted.
Therefore, the invention not only can play roles of reducing fat and protecting liver, but also can not influence the normal physiological function of cholesterol in vivo by exploring the respective contents of the fat-soluble tea polyphenol and the taurine when being matched. The compound composition prepared by combining the fat-soluble tea polyphenol with the taurine is further explored, and the compound composition has a prevention and treatment effect on animal experimental non-alcoholic fatty liver, particularly has an obvious treatment effect on NASH (chronic obstructive pulmonary disease), and simultaneously reduces the influence of the tea polyphenol on cholesterol, so that the side effect of the compound composition is eliminated, and a new direction is provided for developing and developing a medicament for clinically treating the non-alcoholic fatty liver.
The compound composition of taurine and fat-soluble tea polyphenol provided by the invention comprises taurine, fat-soluble tea polyphenol and auxiliary materials, and the compound composition contains 50-75 parts of taurine, 25-50 parts of fat-soluble tea polyphenol and 0-10 parts of auxiliary materials (preferably 5-8 parts) according to parts by weight; if the compound composition is a solution, auxiliary materials are required to be added, the auxiliary materials can be sodium stearate, and if the compound composition is a powder compound composition, the auxiliary materials are not required. Wherein, the taurine and the fat-soluble tea polyphenol are purchased from Wuhan, a pioneer science and technology company, and the sodium stearate is purchased from a chemical reagent company, Inc. of the national drug group.
The invention also provides a method for preparing the compound composition of taurine and fat-soluble tea polyphenol, which comprises the following steps: weighing taurine and fat-soluble tea polyphenol, and mixing uniformly to obtain a compound composition; or preparing the taurine and fat-soluble tea polyphenol compound composition solution according to the following steps:
(1) weighing sodium stearate, dissolving the sodium stearate in purified water, and uniformly stirring the sodium stearate by using a magnetic stirrer to obtain a sodium stearate solution;
(2) adding fat-soluble tea polyphenol into the sodium stearate solution obtained in the step (1), and heating and stirring to obtain uniform suspension of the fat-soluble tea polyphenol and the sodium stearate;
(3) and (3) adding taurine into the suspension obtained in the step (2), heating and stirring to obtain a compound composition solution of taurine and fat-soluble tea polyphenol.
Further, the powder compound composition or liquid compound composition can be prepared into health products or medicines such as tablets, powder, granules, capsules and oral liquid according to a conventional method, and can also be prepared into functional foods such as buccal tablets, solid beverages and liquid beverages.
The present invention will be described more specifically and further illustrated with reference to specific examples, which are by no means intended to limit the scope of the present invention.
Examples
Corresponding raw materials are weighed according to the weight ratio of the taurine to the fat-soluble tea polyphenol in the table 1 respectively to prepare the compound composition.
TABLE 1 combination of the Compound compositions of the present invention
The solid compound composition or the liquid compound composition can be further prepared into a preparation by using a conventional method, not only to mention.
The first experimental example: prevention and treatment effect of taurine or fat-soluble tea polyphenol on rat NASH
1. Animal grouping and treatment: 48 male SD rats (body weight 205 ± 14.3g) were purchased from the center of medical laboratory animals of Guangdong province, and randomly divided into 4 groups, each:
feeding 12 normal groups with common feed for 12 weeks;
② 12 models of the group, feeding high fat feed (common feed + 10% lard + 2% cholesterol), starting from 29 days, simultaneously feeding 0.5 wt% sodium stearate solution (0.4 ml/one) per day for intragastric administration until 12 weeks end;
feeding 12 taurine groups with high-fat feed (same model group), and feeding 120mg/ml taurine aqueous solution for intragastric administration from 29 days until 12 weeks finish;
fourthly, 12 fat-soluble tea groups are fed with high-fat feed, 72mg/ml fat-soluble tea polyphenol sodium stearate solution (the concentration of sodium stearate is 0.5 wt%) is fed into the stomach every day from 29 days, and the stomach filling dosage is 75mg/Kg until 12 weeks end.
2. Detection indexes are as follows: after 12 weeks (i.e., day 85), the rats were sacrificed by intraperitoneal injection of excess chloral hydrate. Cutting open the chest and the abdomen, taking blood from the heart, naturally solidifying at room temperature for 10-20min, centrifuging at 3000 rpm at 2000 and 20min, collecting supernatant, detecting serum glutamic acid Aminotransferase (ALT), aspartate Aminotransferase (AST), triglyceride, cholesterol and low-density lipoprotein cholesterol levels by liver function detection kit and blood fat detection kit of Nanjing institute of bioengineering, and observing the influence of taurine and fat-soluble tea polyphenol on blood fat and liver function of NASH rat. Fixing part of liver tissues by using 10% formaldehyde solution, then carrying out HE dyeing, oil red dyeing and Masson dyeing, and grading the liver fat infiltration, inflammation infiltration and fibrosis degree according to the currently accepted pharmacological evaluation method of non-alcoholic fatty liver diseases. From the perspective of pathological gold standard, the prevention and treatment effects of taurine and fat-soluble tea polyphenol on NASH in rats were observed, and the results are shown in table 2-table 4 and fig. 1. In FIG. 1, "HE X400" refers to HE staining, 400-fold magnified, showing the infiltration of steatosis hepatocytes (indicated by black arrows) and inflammatory cells (indicated by white arrows); "Masson × 200" refers to Masson staining, magnified 200 times, used to observe the degree of liver fibrosis; "oil Red X100" refers to oil red staining, magnified 100 times, from the range of hepatocytes which are generally reflective of steatosis, the gray portion being the range of steatosis hepatocytes.
3. Statistical analysis: all data were analyzed using SPSS10.0 statistical software, with P values less than 0.05 indicating significant statistical significance and P values less than 0.01 indicating very significant statistical significance.
TABLE 2 Effect of taurine and fat-soluble tea polyphenols on weight and liver index of NASH rats
TABLE 3 Effect of taurine and fat-soluble tea polyphenols on liver function in NASH rats
TABLE 4 influence of taurine and fat-soluble tea polyphenols on the lipid metabolism in NASH rats
4. And (4) conclusion:
from the test indexes of the model group and the normal group, the cholesterol of the model group is obviously higher than that of the normal group (see table 4), which shows that the blood fat of the model group is increased, the liver function is damaged (see ALT and AST levels of the model group in table 3 are obviously higher than those of the normal group), inflammation appears pathologically (figure 1 and figure 2), and the high-fat feed successfully constructs a rat non-alcoholic steatohepatitis (NASH) model; and the data in tables 2-4 show that the body weight, liver index (liver weight/body weight), cholesterol, ALT and AST levels of the rat are obviously increased after the rat is fed with the high fat feed and the sodium stearate (P is less than 0.01), and the body weight, liver index (liver weight/body weight), cholesterol, ALT and AST levels of the rat are obviously lower than the levels of the model rat which is fed with the high fat feed and the sodium stearate only (P is less than 0.01) after the rat is treated with the taurine or the fat-soluble tea polyphenol. Even, low density lipoprotein cholesterol levels were significantly lower than those of model rats (P < 0.01). Pathological examination revealed that in the model rats fed with high fat diet plus sodium stearate alone, significant liver fat infiltration and inflammatory cell infiltration were observed, but fibrous deposition was not significant (see Masson x 200 line in fig. 1), i.e., typical NASH expression, while the degree of liver tissue fat infiltration was significantly reduced (see black arrow on HE x 400 line and "oil red x 100" line in fig. 1) and inflammatory cell infiltration was also reduced to different degrees (see white arrow on HE x 400 line in fig. 1) after treatment with taurine or fat-soluble tea polyphenols.
As for the low-density lipoprotein cholesterol of the model group in Table 4, which is not different from that of the normal group, it was suggested that the hyperlipidemia of the NASH model may be merely manifested as hypercholesterolemia, excluding the hyper-low-density lipoprotein cholesterolemia. The low-density lipoprotein cholesterol of the taurine group and the lipid tea group has obvious difference with the model group, which shows that the low-density lipoprotein cholesterol of the model group is not increased compared with the low-density lipoprotein cholesterol of the normal group, and the low-density lipoprotein cholesterol of the model group and the lipid tea group can be reduced by the taurine or the tea polyphenol.
The results show that 125mg/Kg of taurine and 75mg/Kg of fat-soluble tea polyphenol have ideal effects of preventing and treating non-alcoholic steatohepatitis.
Experiment example two: prevention and treatment effect of taurine-fat-soluble tea polyphenol combined compound composition on rat NASH
1. Preparing a taurine and fat-soluble tea polyphenol compound composition: the compound composition of taurine and fat-soluble tea polyphenol of the embodiment 4 is prepared into a liquid compound composition of taurine and fat-soluble tea polyphenol.
2. Animal grouping and handling: 90 male SD rats (body weight 215 + -20.1 g) were purchased from the center of Guangdong provincial medical laboratory animals and randomly divided into 9 groups, which were:
feeding 10 normal groups with common feed for 12 weeks;
② 10 model groups are fed with high-fat feed (common feed + 10% lard + 2% cholesterol), and from 29 days, sodium stearate solution (5mg/ml) (0.4 ml/mouse) is added into the stomach every day until 12 weeks are over;
feeding 10 taurine groups with high-fat feed (same model group), and performing intragastric administration with 120mg/ml taurine aqueous solution every day from 29 days until 12 weeks are finished;
feeding 10 fat-soluble tea polyphenols (same model group) with high-fat feed, and performing intragastric gavage with fat-soluble tea polyphenols + sodium stearate solution (wherein the concentration of sodium stearate is 5mg/ml) every day from 29 days until 12 weeks are over;
compound composition A group (hereinafter referred to as beef tallow tea group A) of taurine and fat-soluble tea polyphenol 10: high-fat feed (same model group) is fed, and the liquid compound composition of the example 3 is simultaneously gavaged from the 29 th day, wherein the gavage dosage is 55mg taurine/Kg and 45mg fat-soluble tea polyphenol/Kg until the end of 12 weeks.
Sixthly, 10 compound compositions B (hereinafter referred to as beef tallow tea B) of taurine and fat-soluble tea polyphenol: high-fat feed (same model group) is fed, and the liquid compound composition of the example 4 is simultaneously gavaged from the 29 th day, wherein the gavage dosage is 62.5mg taurine/Kg and 37.5mg fat-soluble tea polyphenol/Kg until the end of 12 weeks.
Seventhly, 10 compound compositions C (hereinafter referred to as beef fat tea C) of taurine and fat-soluble tea polyphenol: high-fat feed (same model group) is fed, and the liquid compound composition of the example 5 is simultaneously gavaged from the 29 th day, wherein the gavage dosage is 70mg taurine/Kg and 30mg fat-soluble tea polyphenol/Kg until the end of 12 weeks.
Compound composition D group (hereinafter abbreviated as beef tallow tea D group) of 10 taurine and fat-soluble tea polyphenol: high-fat feed (same model group) is fed, and the liquid compound composition of the example 6 is simultaneously gavaged from the 29 th day, wherein the gavage dosage is 75mg taurine/Kg and 25mg fat-soluble tea polyphenol/Kg until the end of 12 weeks.
Ninthly, 10 compound compositions of taurine and fat-soluble tea polyphenol in a group E (hereinafter referred to as a beef fat tea group E for short): high-fat feed (same model group) is fed, and the liquid compound composition of the comparative example 1 is simultaneously gavaged from the 29 th day, wherein the gavage dosage is 40mg taurine/Kg and 60mg fat-soluble tea polyphenol/Kg until the end of 12 weeks.
3. Detection indexes and statistical analysis: in the same experimental example one, in addition, a part of liver tissues are collected and pre-frozen in a storage tube, after being homogenized by a tissue homogenizer, MDA and SOD levels of the liver tissue homogenate are respectively detected by a Malondialdehyde (MDA) and superoxide dismutase (SOD) detection kit of Nanjing institute of bioengineering, and the influence of taurine, fat-soluble tea polyphenol and compound composition thereof on the liver lipid peroxidation level of the rat with NASH is obtained. The results are shown in tables 5-12 and FIG. 2.
TABLE 5 influence of taurine, tea polyphenols and their compound composition on liver function of NASH rats
As can be seen from Table 5, the averages of ALT and AST values were decreased to different degrees in example 6 (tallow tea D group) and comparative example 1 (tallow tea E group) than in the model group. Accordingly, we conclude that the amounts of the components of the combination composition of the present invention should be between those of example 6 and comparative example 1, and the ALT value and AST value of example 2 were found to be close to those of example 6 by experiment (not shown in Table 5), thus determining the amounts of the components.
Further, three value points were selected in the range of the values of example 2 and example 6 to verify the difference in the effects. As seen from table 5, ALT and AST were significantly reduced compared to the model group for example 3 (tallow tea group a), example 4 (tallow tea group B) and example 5 (tallow tea group C), with statistically significant differences (P <0.05 or P < 0.01). In the case of the 3 groups mentioned above, the mean of ALT and AST in example 4 (beef tallow tea group B) was the lowest and its protective effect on liver function should be the highest in the 3 groups. It can also be seen from table 5 that the ALT and AST levels of example 3 (tallow tea group a) and example 5 (tallow tea group C) were significantly different (P <0.05) compared to example 4 (tallow tea group B). As can be seen, example 4 is the optimal formulation of the taurine and fat-soluble tea polyphenol compound composition, and therefore, subsequent studies are conducted by adopting example 4 (beef tallow tea group B).
TABLE 6 Effect of the combination of example 4 on weight and liver index in NASH rats
TABLE 7 Effect of the combination of example 4 on NASH rat blood lipid metabolism
TABLE 8 Effect of the combination of example 4 on lipid peroxidation in NASH rats
TABLE 9 comparison of the combination of example 4 with the single agent (P value)
| Body weight | Liver index | ALT | AST | Cholesterol | LDL-C | MDA | SOD | |
| Compared with taurine alone | 0.6168 | 0.0936 | 0.0000 | 0.0000 | 0.0902 | 0.5642 | 0.0000 | 0.8420 |
| Fat-soluble tea used singlyComparison of polyphenols | 0.9410 | 0.1265 | 0.0004 | 0.0005 | 0.6809 | 0.6263 | 0.0012 | 0.0019 |
4. The research conclusion is that:
from the data in tables 5 to 9, it is known that the body weight, liver index, serum cholesterol, ldl cholesterol, ALT, AST levels of rats treated with three drugs, taurine, fat-soluble tea polyphenol, and the combination composition of example 4, are significantly lower than the levels of the corresponding model control rats (P < 0.01). The body weight, liver index, serum cholesterol, low density lipoprotein cholesterol, ALT and AST levels of the rat treated by the combination of the taurine and the fat-soluble tea polyphenol are also obviously lower than the levels of the corresponding model control rat (P is less than 0.01). Compared with rats treated by taurine and fat-soluble tea polyphenol, the effect of reducing transaminase is obviously enhanced (P <0.01), but the effect of reducing blood fat is not obviously enhanced (P > 0.01).
In addition, the influence of taurine, fat-soluble tea polyphenol and compound composition thereof on the levels of Malondialdehyde (MDA) and superoxide dismutase (SOD) of liver tissue homogenate of rats is observed, wherein the MDA is a toxic product generated in the lipid peroxidation process, and the SOD is an endogenous enzyme with antioxidation. The results show that the liver tissue homogenate MDA level of the model group rat is obviously higher than that of the normal group, and the SOD level is obviously lower than that of the normal group, so that the 'secondary theory of attack' of the pathogenesis of NASH is verified, and the lipid peroxidation injury plays an important role in the formation process of NASH. The liver tissue homogenate MDA level of the rats in the taurine processing group, the fat-soluble tea polyphenol processing group and the taurine and fat-soluble tea polyphenol combined processing group is obviously reduced compared with that of the model rats, wherein the MDA level of the rats in the taurine and fat-soluble tea polyphenol combined processing group is obviously reduced. The liver tissue homogenate SOD level of the rats in the taurine processing group, the fat-soluble tea polyphenol processing group and the taurine and fat-soluble tea polyphenol combined processing group is obviously increased compared with that of the rats in the model group, wherein the SOD level of the rats in the taurine and fat-soluble tea polyphenol combined processing group is obviously increased. The results show that the combined use of taurine and fat-soluble tea polyphenol can effectively reduce the lipid peroxidation damage of liver tissues of rats with NASH, and the effect of the combined use of taurine and fat-soluble tea polyphenol is obviously better than that of the combined use of taurine or tea polyphenol.
Further pathological examination shows that the combined application of taurine and fat-soluble tea polyphenol can also obviously reduce fat infiltration (black arrow) and inflammatory cell infiltration (white arrow) of liver tissues of rats with NASH, and the improvement degree of pathological damage is obviously better than that of the single application of taurine or the single application of fat-soluble tea polyphenol, as shown in figure 2.
The results are integrated, and the combined application of 62.5mg/Kg of taurine and 37.5mg/Kg of fat-soluble tea polyphenol can further enhance the prevention and treatment effect of the taurine or the fat-soluble tea polyphenol on rat NASH, so that the composition has good clinical application prospect, the effective doses of human are 10 mg/Kg/day and 6 mg/Kg/day respectively according to the calculation of the conversion coefficient of the drug dose of human and rat being 0.16, and the effective dose of adult is 600 mg/day and 360 mg/day according to the calculation of 60Kg of body weight.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. The compound composition comprises 55-65 parts by weight of taurine, 30-40 parts by weight of fat-soluble tea polyphenol and 5-8 parts by weight of sodium stearate.
2. The taurine-fat soluble tea polyphenol compound composition according to claim 1, wherein the weight parts of the taurine and the fat soluble tea polyphenol are respectively 62.5 parts and 37.5 parts.
3. The taurine-fat soluble tea polyphenol compound composition according to claim 1 or 2, wherein the composition is a powdery composition prepared by directly and uniformly mixing powdery taurine and powdery fat soluble tea polyphenol when the composition is composed of taurine and fat soluble tea polyphenol, and when the composition is composed of taurine, fat soluble tea polyphenol and sodium stearate, a taurine-fat soluble tea polyphenol compound composition solution is prepared by the following steps:
(1) weighing sodium stearate, dissolving the sodium stearate in purified water, and uniformly stirring to obtain a sodium stearate solution;
(2) adding fat-soluble tea polyphenol into the sodium stearate solution obtained in the step (1), and heating and stirring to obtain uniform suspension of the fat-soluble tea polyphenol and the sodium stearate;
(3) and (3) adding taurine into the suspension obtained in the step (2), heating and stirring to obtain a compound composition solution of taurine and fat-soluble tea polyphenol.
4. The method for preparing the taurine-fat soluble tea polyphenol compound composition as claimed in any one of claims 1 to 3, wherein when the composition consists of taurine and fat soluble tea polyphenol, the taurine-fat soluble tea polyphenol compound composition is a powdery composition prepared by directly and uniformly mixing powdery taurine and powdery fat soluble tea polyphenol; when the composition consists of taurine, fat-soluble tea polyphenol and sodium stearate, a taurine and fat-soluble tea polyphenol compound composition solution is prepared according to the following steps:
(1) weighing sodium stearate, dissolving the sodium stearate in purified water, and uniformly stirring to obtain a sodium stearate solution;
(2) adding fat-soluble tea polyphenol into the sodium stearate solution obtained in the step (1), and heating and stirring to obtain uniform suspension of the fat-soluble tea polyphenol and the sodium stearate;
(3) and (3) adding taurine into the suspension obtained in the step (2), heating and stirring to obtain a compound composition solution of taurine and fat-soluble tea polyphenol.
5. The application of the taurine-fat soluble tea polyphenol compound composition as defined in any one of claims 1 to 3 or the taurine-fat soluble tea polyphenol compound composition obtained by the preparation method as defined in claim 4 in preparing medicaments for preventing and treating steatohepatitis.
6. The use of claim 5, wherein the medicament is a tablet, capsule, powder, granule or oral liquid.
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| 牛磺酸对实验性非酒精性脂肪性肝炎的防治作用;陈思文等;《第五届全国肝脏疾病临床暨中华肝脏病杂志成立十周年学术会议论文集》;20060531;第364页，尤其是第1段 * |
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