CN117298171A - Application of walnut cake extract in preparation of medicine for treating kidney injury - Google Patents
Application of walnut cake extract in preparation of medicine for treating kidney injury Download PDFInfo
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Classifications
-
- 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)
- A61K36/52—Juglandaceae (Walnut family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- Mycology (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of a walnut cake extract in preparation of a medicine for treating kidney injury. Preferably, the kidney injury is an acute kidney injury. The preparation method of the walnut cake extract comprises the following steps: reflux-extracting appropriate amount of semen Juglandis pulp with 10-15 times of 50-80% ethanol solution for 3 times (1-2 hr each time), filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain semen Juglandis pulp extract. The invention effectively expands the development and utilization range of walnut dreg resources, provides reliable data support for developing the walnut dreg resources into functional products with the function of treating kidney injury, and simultaneously provides a new thought and a new method for effectively preventing and treating kidney.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a walnut cake extract in preparation of a medicine for treating kidney injury.
Background
Acute kidney injury (acute kidney injury, AKI) is a clinically common acute critical illness that severely jeopardizes human health and life, with a high incidence of mortality, and approximately 200 million people die of kidney injury annually worldwide. The renal prognosis of AKI surviving patients is also not optimistic, with 30% -70% of AKI surviving patients progressing to chronic kidney disease and about 17% of patients progressing to end-stage renal failure within 1 year, thus AKI has now become a global public health problem.
At present, no effective drug treatment exists for AKI, so that importance on AKI susceptibility is improved, and effective measures are taken, so that the method is a key for preventing and effectively treating AKI. The modern medicine has very limited prevention and treatment methods for the diseases, and often symptomatic treatment such as body fluid management, maintenance of in vivo environment stability, adjustment of metabolic acidosis and the like is not effective for relieving the occurrence and development of the diseases. The traditional Chinese medicine has a profound theoretical basis and practical experience theory for treating kidney diseases, adopts syndrome differentiation and differentiation type in traditional Chinese medicine treatment, is mostly in the form of compound decoction, has the action advantages of multiple ways and multiple targets, and has obvious effect on improving kidney functions. However, the compound decoction of traditional Chinese medicine generally has the problems of undefined drug effect substance basis and action mechanism, long administration period, slow response speed, uneven effect, inconvenient administration and the like.
Semen Juglandis is a dry mature seed of Juglans regia L. Of Juglandaceae, has Wen Weigan, and has effects of invigorating kidney, warming lung, and moisturizing intestine. As a Chinese medicine with homology of medicine and food, the walnut kernels are rich in nutrient substances such as grease, protein, polyphenol, polysaccharide and the like. The walnut cake is the cake part remained after the walnut kernel removes the oil, has strong antioxidant and anti-inflammatory activities, and can regulate the metabolism of glycolipid. The medicinal examination proves that the walnut cake has the effects of tonifying liver and kidney, resolving hard mass and removing blood stasis. Modern pharmacological researches have found that the walnut cake extract has the effects of resisting inflammation, resisting oxidation, reducing blood pressure, reducing blood fat, reducing blood sugar and the like. However, no report on the prevention and treatment effect of walnut cake on kidney diseases is found at present.
The application establishes western medicine and traditional Chinese medicine syndrome models of acute kidney injury, clarifies the improvement effect of the walnut cake extract on kidney diseases from multiple angles, and discovers the effect of the walnut cake extract (DWPE) on treating kidney injury (especially AKI) for the first time.
In view of this, the present invention has been proposed.
Disclosure of Invention
In order to solve the problem of insufficient medicines which are clinically used at present and can effectively treat kidney injury (especially AKI), the invention provides the application of the walnut cake extract in preparing the medicines for treating kidney injury, and provides a new thought and a new method for effectively preventing and treating kidney diseases.
Specifically, the invention is realized through the following technical schemes:
the invention provides application of a walnut cake extract in preparing a medicament for treating kidney injury.
The walnut cake extract can be prepared by any extraction method known in the field of natural pharmaceutical chemistry.
For example, the method disclosed in "CN 105012382B walnut cake extract, method of making and use thereof" may be employed.
Alternatively, in the above application, the preparation method of the walnut cake extract includes the following steps: reflux-extracting appropriate amount of semen Juglandis pulp with 10-15 times of 50-80% ethanol solution for 3 times (1-2 hr each time), filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain semen Juglandis pulp extract.
Alternatively, in the above application, the preparation method of the walnut cake extract includes the following steps: reflux-extracting appropriate amount of semen Juglandis cake with 12 times of 60% ethanol solution for 3 times each for 1.5 hr, filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain extract of semen Juglandis cake.
Alternatively, in the above use, the kidney injury is acute kidney injury.
Alternatively, in the above-mentioned use, the acute kidney injury is an acute kidney injury caused by diseases such as chemical-induced acute kidney injury, rhabdomyolysis-induced acute kidney injury, ischemia-reperfusion, and aging.
Alternatively, in the above use, the chemical-induced acute kidney injury is drug-induced acute kidney injury.
For example, the chemical or drug may be cisplatin, hydrocortisone, carbon tetrachloride or a contrast agent, or the like.
Alternatively, the acute kidney injury is an acute kidney injury associated with senile dementia.
Alternatively, in the above use, the medicament reduces tubular necrosis, dilation and glycogen deposition, as well as protects and ameliorates kidney tissue morphology damage.
Alternatively, in the above use, the medicament comprises a therapeutically effective amount of the extract of walnut cake and a pharmaceutically acceptable carrier or excipient.
Alternatively, in the above use, the medicament is an oral preparation.
Alternatively, in the above application, the dosage form of the medicament is a tablet, a capsule, a granule, a pill or an oral liquid.
The medicine of the invention can be prepared by adopting a preparation method conventional in the field, and pharmaceutically acceptable auxiliary materials can be optionally added. Regardless of the various variations in the method of preparation, it is within the scope of the present invention. Pharmaceutical forms thereof include solid forms, semi-solid forms, liquid forms, and the like.
Compared with the prior art, the invention has the following beneficial effects:
the invention combines western medicine and traditional Chinese medicine syndrome models of acute kidney injury to clarify the improvement effect of walnut cake extract on kidney diseases from multiple angles. The walnut cake extract is found to have the effect of treating kidney injury (especially AKI) for the first time. The invention effectively expands the development and utilization range of walnut dreg resources, provides reliable data support for developing the walnut dreg resources into functional products with the function of treating kidney injury, and simultaneously provides a new thought and a new method for effectively preventing and treating kidney.
Drawings
Fig. 1: serum BUN and kidney SOD assay results.
Fig. 2: kidney pathological conditions in rats of each group.
Fig. 3: body weight change in each group of rats.
Fig. 4: serum CRE, BUN, T, CORT assay results. Wherein, compared with the Control group, * P<0.05, ** p is less than 0.01; in comparison with the DYK group, # P<0.05, ## P<0.01, ### P<0.001。
fig. 5: kidney pathological conditions in rats of each group.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1: treatment effect of walnut cake extract (DWPE) on acute kidney injury caused by carbon tetrachloride olive oil solution
Kidneys are the main excretory organ of the body and are the main metabolic sites for the excretion of heterologous substances, and are therefore most susceptible to toxic damage. Chemical and drug-induced nephrotoxicity is a major cause of acute kidney injury, as well as a major cause of morbidity and mortality from kidney injury. CCl (CCl) 4 Is an environmental pollutant which can induce the biochemical and oxidative stress parameters of animal blood to change. There are studies showing that CCl 4 Induces lipid peroxidation, protein oxidation and cell membrane damage in the kidney, and therefore CCl is commonly used 4 As an evaluation of anti-renal injury agentThe drug effect of the drug and the inducer of acute kidney injury for exploring the experimental study of pathogenesis of drug-induced kidney injury and the like.
1.1 preparation of walnut cake extract:
taking a proper amount of walnut cake sample, adding 12 times of 60% ethanol solution, reflux-extracting for 3 times each for 1.5 hours, filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain the walnut cake extract.
1.2 experimental method:
60 ICR mice were divided into 3 groups, blank (Control) and model (CCl) 4 ) Walnut meal dosing group (DWPE). The walnut cake administration group (15.6 g/kg; according to Chinese resident diet guidelines, the best 30g walnut kernel is taken by adults each day, the experimental dose is 4 times of the clinical dose) is continuously administrated by gastric lavage for two weeks, the blank and model groups are administrated with equal amount of water, the model group and the walnut cake administration group are administrated by gastric lavage on day 14 for 1 hour and then are intraperitoneally injected with 5% carbon tetrachloride olive oil solution, blood is taken after 24 hours, and kidneys are dissected.
1.3, observing items and methods:
serum urea nitrogen (BUN) and SOD levels: after the blood sample was placed at 4℃overnight, it was centrifuged at 4000r/min for 15min, and the supernatant was collected and tested according to the kit instructions. Adding 9 times of physiological saline into kidney tissue, homogenizing, centrifuging at 4000r/min for 15min, collecting supernatant, and detecting according to kit instructions.
Renal pathological changes: kidney tissue was removed, fixed in 4% paraformaldehyde solution, sectioned in conventional paraffin and HE stained.
The statistical analysis method comprises the following steps: experimental data were processed by Graphpad Prism 7.0 statistical software and measured as mean±sd, and single factor analysis of variance (One-Way ANOVA) was used for the data analysis between groups. P < 0.05 is significant in statistical significance.
1.4 experimental results:
as shown in fig. 1, serum urea nitrogen (BUN) and kidney SOD levels: compared with the Control group, the BUN level in the serum of the Model group is obviously increased, and the SOD level of the kidney is obviously reduced, which indicates that the modeling is successful; the walnut cake extract improved serum BUN and kidney SOD levels after administration compared to Model group.
Renal pathological changes: the kidney tissue structure of the Control group mice is normally arranged compactly, the glomerulus structure is clear, the morphology is normal, and abnormal pathological changes are avoided; CCl (CCl) 4 The kidney tissue structure of the mice is loosely arranged, and glomerular epithelial cells are flattened; after DWPE intervention, pathological changes of kidney tissues are reduced, and glomerular epithelial cell flattening is significantly improved (see fig. 2).
Example 2: treatment of acute kidney injury associated with senile dementia by walnut cake extract (DWPE)
The traditional Chinese medicine syndrome animal model is an essential foundation for revealing the theoretical scientific connotation of traditional Chinese medicine, the kidney-yang deficiency syndrome animal model is the earliest established traditional Chinese medicine syndrome animal model, the etiology and the medicine intervention of kidney-yang deficiency are replicated to achieve the same pathological manifestation as the kidney-yang deficiency, the senile dementia type kidney injury composite model is constructed, and the improvement effect of walnut meal on kidney injury accompanied by aging is explored. Hydrocortisone is an exogenous glucocorticoid, and when a large amount of exogenous glucocorticoid is taken in, corticotropin secreted by pituitary gland is inhibited, so that the secretion of adrenocortical hormone is reduced, adrenal atrophy and kidney metabolic disorder are caused, and kidney failure phenomenon occurs in model animals.
1.1 preparation of walnut cake extract:
taking a proper amount of walnut cake sample, adding 12 times of 60% ethanol solution, reflux-extracting for 3 times each for 1.5 hours, filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain the walnut cake extract.
1.2 experimental method:
91 ICR mice were divided into 7 groups, which were a blank group (Control), a kidney-yang deficiency type senile dementia complex model group (CM), a single senile dementia model group (D-gal), a single kidney-yang deficiency group (DKY), a Guifu rehmannia pill positive drug Group (GDP), a High-dose administration group (High) and a Low-dose administration group (Low), respectively. Injecting physiological saline subcutaneously in the Control group for 1-6 weeks, and irrigating purified water in the stomach for 7-8 weeks; the CM group was subcutaneously injected with D-gal (250 mg/kg) for 1-6 weeks, and hydrocortisone (20 mg/kg) was administered by intragastric administration for 7 and 8 weeks; d-gal groups were given 1, 2 weeks untreated, 3-8 weeks with subcutaneous injections of D-gal (250 mg/kg); DKY group 1-6 weeks of subcutaneous injection of physiological saline, 7, 8 weeks of intragastric administration of hydrocortisone (20 mg/kg); GDP group 1-6 weeks subcutaneously injecting D-gal (250 mg/kg), 7, 8 weeks intragastrically administering hydrocortisone (20 mg/kg), while continuously intragastrically administering corresponding doses of Guifu Dihuang pills for 8 weeks; the High group and the Low group are subcutaneously injected with D-gal (250 mg/kg) for 1-6 weeks, hydrocortisone (20 mg/kg) is administrated by intragastric administration for 7 and 8 weeks, and meanwhile, corresponding crude drugs (15.6 g/kg and 7.8 g/kg) are administrated by preventive intragastric administration, 30g of walnut kernel is optimal for adults daily according to Chinese resident diet guidelines, and the High and Low doses of the experiment are 4 times and 2 times of clinical doses respectively for 8 weeks.
1.3, observing items and methods:
body weight and general status observations: body weight was measured daily starting on day 1 of dosing, animal status was observed weekly, animal general status was observed daily starting on hydrocortisone dosing and recorded.
Serum Corticosterone (CORT), testosterone (T), creatinine (CRE), urea nitrogen (BUN): after the blood sample was placed at 4℃overnight, it was centrifuged at 4000r/min for 15min, and the supernatant was collected and tested according to the kit instructions.
Renal pathological changes: kidney tissue was removed, fixed in 4% paraformaldehyde solution, sectioned in conventional paraffin and HE stained.
The statistical analysis method comprises the following steps: experimental data were processed by Graphpad Prism 7.0 statistical software and measured as mean±sd, and single factor analysis of variance (One-Way ANOVA) was used for the data analysis between groups. P < 0.05 is significant in statistical significance.
1.4 experimental results:
weight change: as shown in FIG. 3, the weight of the Control group mice in 1-8 weeks was in a steady upward trend; the weight of the CM group mice is wholly in an ascending trend during the period of injecting D-gal 1-6 weeks, but the increasing amplitude is lower than that of the Control group mice, and the weight of the CM group mice is in a descending trend after 7-8 weeks of gastric lavage and hydrocortisone; mice in the D-gal group had a steady rise in body weight during 3-8 weeks of D-gal injection; the body weight of the DKY group mice increased gradually for 1-6 weeks, and the body weight decreased significantly during the 7-8 week injection of hydrocortisone. The overall body weight continues to slowly increase during the 1-6 week injection of D-ga1 in the GDP, DWPE_H, and DWPE_L mice, and the body weight tends to decrease after administration of hydrocortisone at week 7.
General state observation: the Control group mice have good mental state within 8 weeks, are Mao Roushun white and clean in hair color and have larger food intake. After injecting D-gal, the mice in CM group and D-gal have slightly less response than the mice in Control group, and the mice in GDP group, DWPE_H group and DWPE_L group have no obvious change during injecting D-gal; after administration of hydrocortisone, the CM group and DKY group mice showed a state of listlessness, binding, skin relaxation, hair dryness, no luster, ingestion, reduced drinking water, increased urine volume, etc., and the GDP group, dwpe_h group and dwpe_l group showed a state of listlessness, binding, ingestion, reduced drinking water, increased urine volume after administration of hydrocortisone at week 7, but gradually recovered at week 8. The GDP group, DWPE_H group and DWPE_L group mice did not develop a dry and dull coat condition, as compared with the CM group mice, with the DWPE_H group mice being the most preferred condition.
Measurement of serum Corticosterone (CORT), testosterone (T), creatinine (CRE), urea nitrogen (BUN): as shown in fig. 4, the CM group and DKY group showed an increase in CRE level (CM group P <0.001, dky group P < 0.01) compared to the Control group, the D-gal group showed an increase trend, and the GDP group, dwpe_h group, and dwpe_l group showed no significant difference, and the CRE level was lower (P < 0.001) than the CM group; the BUN levels of the CM group and the DKY group are obviously increased compared with that of the Control group (the CM group P is less than 0.01, the DKY group P is less than 0.05), the D-gal group is increased, but no obvious difference exists, and the BUN levels of the GDP group, the DWPE_H group and the DWPE_L group are obviously reduced compared with that of the CM group (the GDP group P is less than 0.05, the DWPE_H group P is less than 0.001 and the DWPE_L group P is less than 0.01); the T levels of the CM group and the DKY group are remarkably reduced compared with the Control group (the CM group P is less than 0.01, the DKY group P is less than 0.05), the D-gal has a descending trend, and the T levels of the GDP group, the DWPE_H group and the DWPE_L group are remarkably increased compared with the CM group (the DWPE_H group P is less than 0.001, the GDP group and the DWPE_L group P is less than 0.01); the CORT levels of the CM group and the DKY group are obviously reduced (P is smaller than 0.05) compared with the Control group, the D-gal has a downward trend, the CORT levels of the GDP group, the DWPE_H group and the DWPE_L group are obviously increased compared with the CM group, and the DWPE_H group and the DWPE_L group have obvious differences (P is smaller than 0.05). The walnut cake extract can obviously improve the kidney injury degree, and the improvement effect of the DWPE_H group is better than that of the GDP group and the DWPE L group.
Renal pathological changes: as shown in fig. 5, the Control group has complete kidney tissue, the glomerulus structure is clear, and the tubular ducts are orderly arranged; obvious pathological changes occur in CM group and DKY group, glomerular atrophy, tubular dilation or atrophy, vacuolation of tubular epithelial cells, and inflammatory cell increases; the glomerular tubule of the D-gal group has no obvious lesion, but the inflammatory cells are obviously increased compared with the Control group; while some lesions still exist in the glomeruli and tubules in the GDP, DWPE_H and DWPE_L groups, the morphology of the tubules tends to be normal, the vacuolation is obviously reduced, and inflammatory cells are reduced compared with the CM group.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. Use of semen Juglandis extract in preparing medicine for treating kidney injury is provided.
2. Use according to claim 1, characterized in that: the preparation method of the walnut cake extract comprises the following steps: reflux-extracting appropriate amount of semen Juglandis pulp with 10-15 times of 50-80% ethanol solution for 3 times (1-2 hr each time), filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain semen Juglandis pulp extract.
3. Use according to claim 2, characterized in that: the preparation method of the walnut cake extract comprises the following steps: reflux-extracting appropriate amount of semen Juglandis cake with 12 times of 60% ethanol solution for 3 times each for 1.5 hr, filtering, concentrating the filtrate, drying under reduced pressure, and pulverizing to obtain extract of semen Juglandis cake.
4. Use according to claim 1, characterized in that: the kidney injury is an acute kidney injury.
5. Use according to claim 4, characterized in that: the acute kidney injury is acute kidney injury caused by chemical substance induced acute kidney injury, acute kidney injury induced by rhabdomyolysis or acute kidney injury caused by ischemia-reperfusion, aging and other diseases.
6. Use according to claim 5, characterized in that: the chemical induced acute kidney injury is drug induced acute kidney injury.
7. Use according to claim 4, characterized in that: the medicament reduces tubular necrosis, dilation and glycogen deposition, and protects and ameliorates morphological damage to kidney tissue.
8. Use according to claim 1, characterized in that: the medicament comprises a therapeutically effective amount of walnut cake extract and a pharmaceutically acceptable carrier or excipient.
9. Use according to claim 1, characterized in that: the medicine is an oral preparation.
10. Use according to claim 9, characterized in that: the dosage form of the medicine is tablets, capsules, granules, pills or oral liquid.
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