CN113577130B - Histidine dipeptide composition for repairing liver injury and application thereof - Google Patents
Histidine dipeptide composition for repairing liver injury and application thereof Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
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- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A61K2236/50—Methods involving additional extraction steps
- A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
Abstract
The invention belongs to the field of biological medicine, and relates to a histidine dipeptide composition for repairing liver injury, which comprises active components of carnosine, anserine, corbicula fluminea extract, a kudzu vine root extract and an astragalus extract, wherein the mass ratio of the carnosine, the anserine, the corbicula fluminea extract, the kudzu vine root extract and the astragalus extract in the composition is 50-60: 20-25: 5-10. The histidine dipeptide composition provided by the invention can effectively prevent and/or treat liver injury within a certain proportion range, particularly has excellent effects on repairing liver cell injury, preventing and/or treating liver injury caused by high uric acid and treating clinical liver cell injury type liver diseases, and has the advantages of cheap raw materials, simple preparation method and no toxic or side effect.
Description
Technical Field
The invention belongs to the field of biomedicine, relates to a histidine dipeptide composition, and particularly relates to a histidine dipeptide composition for repairing liver injury.
Background
Drug-induced Liver damage (Drug-induced Liver Injury DILI) refers to a disease caused by hepatotoxicity damage caused by drugs or their metabolites or allergic reaction of Liver to drugs and their metabolites during the treatment of drugs, and is also called Drug-induced hepatitis. With the increasing of various clinical new drugs, the combined use of various drugs, and the wide application of Chinese herbal medicines and Chinese patent medicine preparations, the incidence of the drug-induced liver damage is increased year by year. Meanwhile, the incidence of liver diseases such as viral hepatitis, liver cirrhosis, liver cancer and the like is high, and the health of people is seriously harmed. Liver damage is a common pathological condition of many liver diseases, and can promote the further deterioration of liver diseases, so the treatment and prevention of liver damage are particularly important.
Histidine-binding dipeptides (HCDPs) are a class of natural water-soluble dipeptides, including Carnosine (β -alkyl-L-Histidine, Car), Anserine (β -alkyl-L-1-methyl Histidine, Ans), whale Carnosine (β -alkyl-L-3-methyl Histidine), N-acetyl-Carnosine, and the like. Histidine dipeptide has the capacity of buffering physiological pH, chelating metal ions, resisting oxidation, resisting aging, regulating nerves and the like. Related researches find that the carnosine and the anserine have obvious effects on treating hyperuricemia, gout and Alzheimer's disease in vitro and in vivo.
Corbicula fluminea (Corbicula fluminea) also known as Corbicula fluminea, Scapharca subcrenata, flat spiral shell and the like is used as a traditional Chinese medicine material and has the effects of removing damp toxin, treating liver diseases and measles, reducing fever, relieving cough and reducing sputum, dispelling the effects of alcohol and the like. The related research shows that the corbicula fluminea extract can obviously inhibit the activity increase of alanine Aminotransferase (ALT), glutamic-oxaloacetic transaminase (AST), glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) of a liver injury mouse, and reduce the increased liver index. Further research shows that the corbicula fluminea extract has a protective effect on alcoholic liver injury by inhibiting lipid peroxidation.
The kudzu root is an effective component extracted from kudzu root which is a plant of leguminosae and contains isoflavone components of Puerarin (Puerarin), Puerarin-xyloside, Daidzein (Daidzein), Daidzin (Daidzin), beta-sitosterol (beta-SitosteIrol), Arachidic acid (Arachidic acid) and a large amount of starch (the content of fresh kudzu root is 19-20%). Radix puerariae is considered as a natural anticancer drug with great potential, and further mechanism research shows that the anti-tumor effect of radix puerariae has a certain relation with the activation of macrophage function and the induction of macrophage to secrete tumor necrosis factor. The kudzu root extract is also found to inhibit the proliferation of 7721 human hepatoma cell line in vitro and to cause significant apoptosis.
Astragalus membranaceus is the dried root of Astragalus membranaceus bge or Astragalus membranaceus bge of leguminous perennial herbaceous plants, and is first reported in the recipe for fifty-two diseases. Referring to the 'Chinese pharmacopoeia' of 2015 edition, astragalus root has sweet taste, warm nature, spleen and lung channels, and has the effects of tonifying qi and invigorating yang, consolidating superficial resistance and arresting sweating, inducing diuresis and reducing edema, promoting the production of body fluid and nourishing blood. Modern medical research shows that astragalus contains saponin, sucrose, polysaccharide, flavone, various amino acids, folic acid, selenium, zinc, copper and other trace elements, and has the functions of enhancing the immunity of the organism, regulating blood pressure and blood sugar in a two-phase mode, protecting heart and kidney, protecting liver, promoting urination, resisting aging, stress, tumors, oxidation and bacteria and the like.
In the current research, the combined efficacy of carnosine and anserine mostly focuses on functional researches such as uric acid reduction, antioxidation, inflammatory reaction inhibition, lipid oxidation reduction, telomere shortening inhibition, mitochondrial injury reduction, glycosylation resistance, tumor resistance and the like. There has been no report on the study of the combination of carnosine and anserine on liver function injury repair, particularly hyperuricemia-induced liver function injury repair. The inventor combines and compounds carnosine, anserine, corbicula fluminea extract, radix puerariae extract and radix astragali extract, and the prepared composition can effectively prevent and/or treat liver injury, thereby providing a new idea for preparing medicines for preventing and/or treating liver injury.
Disclosure of Invention
The invention aims to provide a novel application of histidine dipeptide in liver injury treatment and prevention, which aims to more deeply research and develop efficient and low-cost medicine raw materials in the liver injury prevention and treatment.
In view of the above, the present application addresses this need in the art by providing a histidine dipeptide composition for the repair of liver damage.
On one hand, the invention relates to a histidine dipeptide composition, wherein the effective components of the composition comprise carnosine, anserine, corbicula fluminea extract, radix puerariae extract and radix astragali extract, and the mass ratio of the carnosine, the anserine, the corbicula fluminea extract, the radix puerariae extract and the radix astragali extract in the composition is 50-60: 20-25: 5-10.
According to the actual application requirement, the composition can be prepared into tablets, capsules, oral liquid preparations, granules, powder and the like according to the related pharmaceutical requirements and clinical requirements by a method known by a person skilled in the art; preferably, the compositions of the present invention are prepared as a powder.
In another aspect, the present invention provides a use of a histidine dipeptide composition in a medicament for the prevention and/or treatment of liver damage.
Further, the invention provides an application of the histidine dipeptide composition in a medicine for repairing liver cell damage.
Further, the invention provides an application of the histidine dipeptide composition in preparing a medicament for preventing and/or treating liver injury caused by hyperuricemia.
Further, the invention provides an application of the histidine dipeptide composition in a medicine for treating clinical liver cell injury type liver diseases.
On the other hand, the invention provides a method for separating and extracting carnosine and anserine, which specifically comprises the following steps: taking meat of Katsuwonus Pelamis, mincing, homogenizing, and performing enzymolysis for 3h under the enzymolysis conditions of papain addition amount of 500U/g, flavourzyme addition amount of 200U/g, and pH6.5; carrying out water bath enzyme deactivation on the enzymolysis product, centrifuging for 15min (3500 g, 4 ℃), deoiling the obtained supernatant by a tube centrifuge (18000r/m, 20min), and decolorizing the perlite (the addition amount is 3%); performing primary separation and low molecular peptide enrichment by using a ceramic membrane and a multi-stage ultrafiltration membrane, further separating and purifying the low molecular peptide by reverse high performance liquid chromatography (Hydro-RP LC column 150 x 10mm 4 mu m, Fennom) to obtain carnosine and anserine (loading conditions: 50mg/mL, 1mL/min, 0.5% phosphate solution: acetonitrile =98.5: 1.5), collecting a sample, and performing freeze drying (the pre-freezing temperature is-40 ℃, the pressure is 10Pa, and the cold trap temperature is-70 ℃) to obtain dry powder of the carnosine and the anserine.
On the other hand, the invention provides a preparation method of the corbicula fluminea extract, which specifically comprises the following steps: after frozen corbicula fluminea meat is unfrozen, adding water according to the material-water ratio of 1:3 for homogenizing, adjusting the pH =7.5, adding alkaline protease and neutral protease according to 1% -5% of the material mass, carrying out enzymolysis in a constant temperature shaking table at 50-60 ℃, then carrying out enzyme deactivation in a boiling water bath for 10min, cooling in an ice bath, centrifuging at 5000r/min, collecting supernatant, filtering corbicula fluminea enzymatic hydrolysate by adopting an inorganic ceramic membrane with the pore diameter of 200nm, carrying out pre-freezing treatment at-30 ℃ after vacuum concentration, and carrying out freeze drying at constant pressure of 15Pa to constant weight to obtain corbicula fluminea meat extract dry powder.
On the other hand, the invention provides a preparation method of the kudzuvine root extract, which specifically comprises the following steps: drying and crushing radix puerariae, sieving the dried powder with a 100-mesh sieve, weighing the dried powder, performing reflux extraction for 3 times by taking 40-70% ethanol as an extraction solvent, performing 1-2 h each time, combining filtrates, performing reduced pressure concentration at 40-50 ℃ to obtain radix puerariae extract, adding equal volume of ethyl acetate, uniformly mixing and extracting, repeating the extraction operation for 3-4 times, combining and collecting ethyl acetate layer extract liquor, performing reduced pressure concentration, and drying to constant weight to obtain the radix puerariae extract.
On the other hand, the invention provides a preparation method of the astragalus extract, which specifically comprises the following steps: selecting radix astragali, cleaning, airing, crushing, sieving with a 100-mesh sieve, adding purified water, performing reflux extraction for 2 times, each time for 2 hours, combining filtrates, performing reduced pressure concentration, adding 60-90% ethanol for extraction, centrifuging, adding chloroform and n-butanol according to the volume ratio of ethanol extract to chloroform to n-butanol of 20-30: 5-8: 1-3 for extraction, centrifuging, taking supernate, repeating the method for 5 times, combining supernate, adding activated carbon, performing ultrasonic treatment, filtering at-30 ℃, performing freeze drying at constant pressure of 15Pa to constant weight, and obtaining the radix astragali extract.
In another aspect, the present invention provides a method for preparing the histidine dipeptide composition, which specifically comprises: the prepared dry powders are uniformly mixed according to the weight ratio of 50-60: 20-25: 5-10 of carnosine, anserine, corbicula fluminea extract, kudzu root extract and astragalus extract to form a composition of histidine dipeptide, corbicula fluminea and traditional Chinese medicine, which is referred to as histidine dipeptide composition for short.
Compared with the prior art, the invention has the following beneficial effects or advantages:
(1) the histidine dipeptide composition provided by the invention shows excellent effect in inhibiting the increase of the enzymatic activities of alkaline phosphatase (ALP) and alanine Aminotransferase (ALT) caused by hyperuricemia;
(2) the histidine dipeptide composition provided by the invention has excellent effect on reducing liver index;
(3) the histidine dipeptide composition provided by the invention has excellent effect on repairing hepatocyte damage;
(4) the histidine dipeptide composition provided by the invention has excellent effects in reducing Malondialdehyde (MDA), improving the activity of superoxide dismutase (SOD) and inhibiting liver lipid peroxidation.
Drawings
FIG. 1 shows alkaline phosphatase (ALP) activity in rat serum;
FIG. 2 shows alanine Aminotransferase (ALT) activity in rat serum;
FIG. 3 is the Malondialdehyde (MDA) content in rat liver;
FIG. 4 shows the activity of superoxide dismutase (SOD) in rat liver;
FIG. 5 shows the results of HE staining of rat liver sections.
In the figure, a, b, c, d, e and f represent significant differences among the groups.
Detailed Description
The following examples are given to illustrate the technical aspects of the present invention, but the present invention is not limited to the following examples.
Example 1
This example provides an animal test of the repair of hepatic function impairment in hyperuricemic rats by a histidine dipeptide composition.
(1) Establishing an experimental model
135 male SD rats (200 + -20 g) were randomly divided into 9 groups (blank group, model group, low dose group of histidine dipeptide composition, medium dose group of histidine dipeptide composition, high dose group of histidine dipeptide composition, anserine group, carnosine + anserine group, corbicula fluminea, Astragalus membranaceus, and Pueraria lobata ternary extract group), and each group had 15 animals. The low-dose group of the composition is divided into 3 groups according to the mass ratio, wherein the mass ratio of the carnosine, the anserine, the corbicula fluminea extract, the kudzuvine root extract and the astragalus extract in the 3 groups is respectively 50:20:5:5:5, 55:22.5:7.5:7.5:7.5, and 60:25:10:10: 10; the middle-dosage group and the high-dosage group of the composition are divided into 3 groups according to the mass ratio. The experimental group (model group, histidine dipeptide composition low dose group, histidine dipeptide composition medium dose group, histidine dipeptide composition high dose group, goose muscle peptide group, histidine dipeptide group, corbicula fluminea, radix astragali and radix puerariae ternary extract group) continuously perfused with stomach and given 750mg/kg of oteracil potassium for 7 days, a rat model with high uric acid was established, and a blank group was perfused with stomach and given 0.5% sodium carboxymethylcellulose in equal amount as a control. After the high uric acid rat model is established, the low, medium and high dose groups are respectively administered with 20mg/kg, 40mg/kg and 80mg/kg histidine dipeptide compositions by intragastric administration, the anserine group is administered with 20mg/kg anserine by intragastric administration, the carnosine group is administered with 40mg/kg carnosine by intragastric administration, the histidine dipeptide group is administered with 60mg/kg carnosine and anserine by intragastric administration, the model group and the blank group are administered with 0.5% sodium carboxymethylcellulose in equal amount by intragastric administration once a day, and after 21 days of continuous administration, CO is administered2The rats were sacrificed and serum and liver were collected. In each index measurement of subsequent experiments, when the mass ratio of carnosine, anserine, corbicula fluminea extract, kudzu root extract and astragalus extract in the composition is 50-60: 20-25: 5-10, no significant difference exists among 3 groups of data of the same dosage group.
(2) Liver injury repair index determination
The liver weight was weighed, and the liver index was calculated according to the formula liver index = (liver weight/body weight) × 100%. The activity of alkaline phosphatase (ALP) and alanine Aminotransferase (ALT) in the serum of the rat, the activity of superoxide dismutase (SOD) and the content of Malondialdehyde (MDA) in the liver are measured, and the measuring method is operated according to the instruction of a detection kit. Wherein, the alkaline phosphatase (ALP) activity in rat serum is shown in FIG. 1; alanine Aminotransferase (ALT) activity in rat serum is shown in FIG. 2; the Malondialdehyde (MDA) content in rat liver is shown in figure 3; superoxide dismutase (SOD) activity in rat liver is shown in FIG. 4.
(3) Pathological observation of rat liver
The same part of the largest leaf of rat liver was taken, fixed with 4% paraformaldehyde, embedded in paraffin, sectioned with the largest face, HE stained, and observed for tissue morphology under an optical microscope (x 400). The results of HE staining of rat liver sections are shown in fig. 5.
(4) Conclusion of the experiment
The experimental results show that the histidine dipeptide composition can effectively reduce the liver index of the rat with high uric acid, obviously inhibit the increase of the activities of alkaline phosphatase (ALP) and alanine Aminotransferase (ALT) of the rat with high uric acid (figure 1 and figure 2), effectively repair the damage of liver cells, simultaneously reduce the content of Malondialdehyde (MDA) and improve the activity of superoxide dismutase (SOD) (figure 3 and figure 4), and effectively inhibit the peroxidation of liver lipid.
Compared with ternary extract, the composition of carnosine, anserine, carnosine + anserine and histidine dipeptide has stronger capability of repairing liver cell damage. Wherein, the histidine dipeptide composition with high dose shows the highest repair capability, and the ALP enzyme activity and ALT enzyme activity of the rats after treatment are respectively reduced by 40.2 percent and 41.5 percent; the carnosine and anserine also show better liver cell injury repair capacity, and the ALP enzyme activity and ALT enzyme activity of the treated rat are respectively reduced by 28.1 percent and 33.4 percent. The results show that the combination of histidine dipeptide and ternary extract has a synergistic effect on hepatocyte injury repair.
Compared with the model group, the Malondialdehyde (MDA) content and the superoxide dismutase (SOD) activity of rats in the ternary extract group, the carnosine group, the anserine group, the carnosine + anserine and histidine dipeptide composition group are reduced and improved, but the difference of the ternary extract group is not obvious. Compared with the model group, the content of MDA and the activity of SOD of the rat with the histidine dipeptide composition in the high dose group are respectively reduced by 47.6 percent and improved by 52.8 percent, the content of MDA and the activity of SOD of the rat with the histidine dipeptide composition in the high dose group are respectively reduced by 36.2 percent and improved by 43.3 percent, and the content of MDA and the activity of SOD of the control group with the ternary extract in the high dose group are respectively reduced by 9.9 percent and improved by 11.3 percent. From this result, it can be seen that the combination of histidine dipeptide and ternary extract significantly improves the anti-lipid oxidation effect and shows a better gain effect, compared to histidine dipeptide or ternary extract.
Pathological observation shows that the liver cells of the rats in the blank group are compact in arrangement and complete in structure (figure 5); the hepatocytes of the model group mice were loosely arranged, swollen, and balloon-like degenerated. The composition resulted in different degrees of recovery of rat liver after drying.
Example 2
This example provides a clinical trial of the liver repair effect of a histidine dipeptide composition on hepatitis patients.
(1) Study subjects and methods of treatment
According to the classification standard established by the International medical organization and society for medical science and hepatopathy, which is revised by the Chinese medical society for medical science and hepatology, alanine Aminotransferase (ALT) is not less than 3 reference value Upper Limit (ULN), and R [ R = (ALT measured value/ALT ULN)/(ALP measured value/ALP ULN) ], 138 clinical hepatocyte injury patients who receive treatment in Guangdong medical subsidiary hospitals from 3 months to 2021 months in 2020 were selected and randomly divided into a histidine dipeptide composition treatment group and a placebo group, and each group of 69 patients has no statistical difference in the demographic and baseline data comparison, such as sex ratio, average age, average course of disease and the like. Both groups of patients were treated conventionally with histidine dipeptide composition and placebo (main ingredients: alanine, histidine, glucose) for 2 weeks, 3 g/time, 2 times/d, and taken with warm water after breakfast and supper.
(2) Serum index detection
5mL of fasting venous blood in the early morning before and after treatment of two groups of patients are extracted, centrifuged at 4000r/min for 10min, and the upper layer serum is taken and stored in an environment with the temperature of minus 80 ℃ for detection.
The levels of alanine Aminotransferase (ALT) and alkaline phosphatase (ALP) which are liver function indexes of two groups of patients are detected by a full-automatic biochemical analyzer.
(3) The result of the detection
The 2 groups of patients are subjected to 2-week follow-up treatment, and the ALP and ALT levels of the patients taking the carnosine, the radix puerariae extract and the radix astragali extract after 1-week treatment are obviously lower than those of the patients taking the placebo, the ALP level of the patients taking the medicine is reduced by 23 percent compared with that before taking, and the ALT level is reduced by 18 percent; after two weeks of treatment, ALP and ALT levels in the patients in the drug group were substantially normal, while ALT and ALP levels in the patients in the placebo group remained above normal.
(4) Conclusion of the experiment
The results show that the histidine dipeptide composition can effectively recover the hepatic cell damage of patients, and compared with other pure traditional Chinese medicine treatment, the medicament has more excellent treatment effect.
As described above, the present invention can be preferably implemented, and the above-mentioned embodiments only describe the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various changes and modifications of the technical solution of the present invention made by those skilled in the art without departing from the design spirit of the present invention shall fall within the protection scope defined by the present invention.
Claims (6)
1. The histidine dipeptide composition for repairing liver injury is characterized in that effective components of the composition comprise carnosine, anserine, corbicula fluminea extract, kudzu vine root extract and astragalus extract, and the mass ratio of the carnosine, the anserine, the corbicula fluminea extract, the kudzu vine root extract and the astragalus extract in the composition is 50-60: 20-25: 5-10.
2. Use of the composition of claim 1 for the preparation of a medicament for the prevention and/or treatment of liver damage caused by hyperuricemia.
3. The use of claim 2, wherein the composition is used in the preparation of a medicament for repairing liver cell damage.
4. The use of claim 2, wherein the composition is used for the preparation of a medicament for the treatment of clinical liver cell injury type liver disease.
5. A pharmaceutical comprising the histidine dipeptide composition of claim 1 as an active ingredient.
6. A drug for repairing liver damage, which comprises the histidine dipeptide composition of claim 1 as an active ingredient.
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| CN202111168989.3A CN113577130B (en) | 2021-10-08 | 2021-10-08 | Histidine dipeptide composition for repairing liver injury and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199668A (en) * | 2006-12-11 | 2008-06-18 | 孙蓉 | Chinese medicine agent for treating alcohol fatty liver and preparing method thereof |
| CN105533708A (en) * | 2015-12-29 | 2016-05-04 | 淮阴工学院 | Sobering-up and liver-protecting functional product made of Corbicula fluminea extract compound and preparation method thereof |
| CN106474454A (en) * | 2016-12-07 | 2017-03-08 | 谢灵均 | A kind of compositionss and its purposes reducing uric acid, treatment or prevention gout |
| CN109045273A (en) * | 2018-11-09 | 2018-12-21 | 何蓉蓉 | A kind of Chinese medicinal alcoholism-relieving composition and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101199668A (en) * | 2006-12-11 | 2008-06-18 | 孙蓉 | Chinese medicine agent for treating alcohol fatty liver and preparing method thereof |
| CN105533708A (en) * | 2015-12-29 | 2016-05-04 | 淮阴工学院 | Sobering-up and liver-protecting functional product made of Corbicula fluminea extract compound and preparation method thereof |
| CN106474454A (en) * | 2016-12-07 | 2017-03-08 | 谢灵均 | A kind of compositionss and its purposes reducing uric acid, treatment or prevention gout |
| CN109045273A (en) * | 2018-11-09 | 2018-12-21 | 何蓉蓉 | A kind of Chinese medicinal alcoholism-relieving composition and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 肌肽对小鼠化学性肝损伤氧化应激和炎症因子的影响;聂星等;《免疫学杂志》;20181231;第1063页右栏第1-3段 * |
| 鹅肌肽降低高尿酸小鼠尿酸;张雅琳等;《解剖科学进展》;20190731;全文 * |
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