CN113694185B - Application of bioactive peptide in preparing medicine for preventing and treating anthracycline cardiotoxicity - Google Patents
Application of bioactive peptide in preparing medicine for preventing and treating anthracycline cardiotoxicity Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
- A61K38/011—Hydrolysed proteins; Derivatives thereof from plants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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Abstract
The invention belongs to the technical field of medicines for preventing and treating cardiotoxicity, and particularly relates to application of bioactive peptide in preparation of medicines for preventing and treating anthracycline cardiotoxicity. Wherein the bioactive peptide is albumin peptide, wheat oligopeptide, soybean peptide or corn oligopeptide, and the anthracycline is doxorubicin or daunorubicin. The invention discovers the biological functions except oxidation resistance and tumor resistance of albumin peptide, wheat oligopeptide, soybean peptide and corn oligopeptide, and expands the application range of bioactive peptide; the bioactive peptide has remarkable effect of preventing and treating anthracycline cardiotoxicity and has no side effect.
Description
Technical Field
The invention relates to the technical field of medicines for preventing and treating cardiotoxicity, in particular to application of bioactive peptide in preparation of medicines for preventing and treating anthracycline cardiotoxicity.
Background
Anthracyclines refer to a class of chemotherapeutic drugs containing an anthracycline, including doxorubicin (doxorubicin), epirubicin (epirubicin), biarubicin, daunorubicin, doxorubicin, idarubicin, and the like. The medicine is clinically used for treating malignant tumors of blood systems and solid tumors, including acute leukemia, lymphoma, breast cancer, ovarian cancer, gastric cancer, soft tissue sarcoma and the like for half a year, is a kind of medicine with milestone significance, and is still a basic medicine for treating many malignant tumors of blood systems and solid tumors even though new therapies such as targeted therapy, immunotherapy and the like are continuously emerging today due to the characteristics of wide antitumor effect, good curative effect and the like. However, adverse reactions such as cardiotoxicity and the like generated by the medicaments seriously affect the clinical application of the medicaments, so the medicaments still have the problem to be solved urgently.
Aiming at the cardiotoxicity of anthracyclines, the currently available cardiotoxicity protective agent dexrazoxane can obtain a certain clinical curative effect in short-term application, but has great uncertainty in the aspects of long-term curative effect and prevention of long-term cardiotoxicity adverse events. And the dexrazoxane can only be injected and administrated, the price is high, and adverse reactions are not ignored. Therefore, the search for safe and effective anthracycline protecting agents has important clinical application value.
The bioactive peptide (Bioactive Pepides) is a peptide substance which is derived from natural products and has a certain bioactivity, and has the bioactivity of resisting oxidation, resisting tumor, improving immunity and the like.
Disclosure of Invention
The existing anthracycline cardiotoxicity protective agent dexrazoxane can only be injected and administrated, has high price and serious adverse reaction, and aims to solve the problem of lack of a safe and effective anthracycline protective agent at present.
The technical scheme of the invention is as follows:
The invention provides application of bioactive peptide in preparing medicines for preventing and treating anthracycline cardiotoxicity.
Further, the bioactive peptide is albumin peptide, wheat oligopeptide, soybean peptide or corn oligopeptide.
Further, the anthracycline is doxorubicin or daunorubicin.
Further, the drug for preventing and treating anthracycline cardiotoxicity is a drug for preventing and treating the reduction of left ventricular ejection fraction and/or left ventricular short axis shortening rate caused by anthracycline.
Further, the drug for preventing and treating anthracycline cardiotoxicity is a drug for preventing and treating the increase of serum lactate dehydrogenase activity and/or the decrease of serum glutathione content caused by anthracycline.
Further, the drug for preventing and treating anthracycline cardiotoxicity is a drug for preventing and treating myocardial superoxide dismutase activity reduction and/or cardiac malondialdehyde content increase caused by anthracycline.
The beneficial effects of the invention are as follows: the bioactive peptide is derived from natural products, has high safety, easy absorption, wide sources, low price, obvious antioxidant activity, immune function regulation and the like, and becomes a research hotspot. Aiming at toxic and side effects in the treatment process of anthracycline antitumor drugs, no ideal control method exists at present. According to the invention, the first research shows that the bioactive peptide has an obvious inhibition effect on cardiac toxicity caused by anthracyclines, the bioactive peptide can improve the survival rate of mice, and the application range of albumin peptide, wheat oligopeptide, soybean peptide and corn oligopeptide is expanded; the bioactive peptide has remarkable effect of preventing and treating anthracycline cardiotoxicity and has no side effect.
Drawings
FIG. 1 is a graph of the results of the effect of four bioactive peptides of the invention on doxorubicin mouse LVEF;
FIG. 2 is a graph of the results of the effect of four bioactive peptides of the invention on doxorubicin mouse LVFS;
FIG. 3 is a graph of the results of the effect of four bioactive peptides of the invention on doxorubicin mouse LDH;
FIG. 4 is a graph of the results of the effect of four bioactive peptides of the invention on doxorubicin mouse GSH;
FIG. 5 is a graph showing the effect of four bioactive peptides of the present invention on doxorubicin mouse SOD;
FIG. 6 is a graph of the results of the effect of the bioactive peptide of the present invention on doxorubicin mouse MDA;
FIG. 7 is a graph of the results of myocardial histopathology of the present invention (x 200);
FIG. 8 is a graph of the results of the effect of the bioactive peptides of the invention on daunorubicin mouse LVEF;
FIG. 9 is a graph of the results of the effect of the bioactive peptide of the present invention on daunorubicin mouse LVFS;
FIG. 10 is a graph of the results of the effect of the bioactive peptide of the present invention on daunorubicin mouse LDH;
FIG. 11 is a graph of the results of the effect of the bioactive peptides of the invention on daunorubicin mouse GSH;
FIG. 12 is a graph showing the effect of the bioactive peptide of the present invention on daunorubicin mouse SOD;
FIG. 13 is a graph of the results of the effect of the bioactive peptide of the present invention on daunorubicin mouse MDA;
FIG. 14 is a graph of the results of myocardial histopathology of the present invention (x 200);
In all the figures above, P <0.01 compared to the normal control group; compared to the model group, #p <0.05, #p <0.01.
Detailed Description
The following detailed description of the present invention is provided to facilitate understanding of the technical solution of the present invention, but is not intended to limit the scope of the present invention.
The invention provides application of bioactive peptide in medicines for preventing and treating anthracycline cardiotoxicity.
As one embodiment, the bioactive peptide is an albumin peptide, a wheat oligopeptide, a soybean peptide or a corn oligopeptide.
As one embodiment, the anthracycline is doxorubicin or daunorubicin.
As one embodiment, the drug for preventing anthracycline cardiotoxicity is a drug for preventing reduction of left ventricular ejection fraction and/or left ventricular short axis shortening rate caused by anthracycline.
As an embodiment, the drug for preventing and treating anthracycline cardiotoxicity is a drug for preventing and treating an increase in serum lactate dehydrogenase activity and/or a decrease in serum glutathione content caused by anthracycline.
As an embodiment, the drug for preventing and treating anthracycline cardiotoxicity is a drug for preventing and treating reduced serum glutathione content and/or reduced myocardial visceral superoxide dismutase activity and/or increased visceral malondialdehyde content caused by anthracycline.
Albumin peptide (production lot number: 20181072502), wheat oligopeptide (production lot number: 2018081402) and corn oligopeptide (production lot number: 20180801027) used in the present invention were purchased from soyabean peptide, a biotechnology company of Zhongshi Duqing (Shandong): purchased from mountain pine biologicals limited (shandong), production lot number: 20181030.
1. Effect of bioactive peptide on Doxorubicin (DOX) mice survival
1. Experimental animal
SPF class C57BL/6 male mice of 6-8 weeks old were purchased from Henan province laboratory animal center (production license: SCXK (Yu) 2017-0001) and fed in Henan province hepatopathy pharmacology important laboratory animal houses. After 5 days of adaptive feeding and observation, healthy and active mice were selected for the experiment.
2. Grouping and administration
60C 57BL/6 mice were randomly divided into 6 groups, A: normal control group was intraperitoneally injected with physiological saline at a dose of 17 mg/kg per day. 30 Distilled water was administered by gavage at a dose of 600 mg/kg after min, 1 time a day. B: DOX group, DOX was intraperitoneally injected daily at a dose of 17 mg/kg. 30 Distilled water was administered by gavage at a dose of 600 mg/kg after min, 1 time a day. C: DOX + albumin peptide group DOX was injected intraperitoneally at a dose of 17 mg/kg per day. 30 Albumin peptide was administered by gavage at a dose of 600 mg/kg 1 day after min. D: DOX + wheat oligopeptide group DOX was intraperitoneally injected daily at a dose of 17 mg/kg. 30 Wheat oligopeptide was given by gavage at a dose of 600 mg/kg after min, 1 time a day. E: DOX + soybean peptide group DOX was injected intraperitoneally at a dose of 17 mg/kg per day. 30 The soybean peptide was administered by gavage at a dose of 600 mg/kg 1 time a day after min. F: DOX + maize oligopeptide group DOX was injected intraperitoneally daily at a dose of 17 mg/kg. 30 After min, the corn oligopeptide was administered by gavage at a dose of 600 mg/kg 1 day. The above treatment lasted 7 days.
3. Survival observations
Mice survival was observed and recorded daily.
4. Results
As shown in table 1, the DOX group mice began to die from day 5. After 7 days, the survival rate of the normal control group mice is 100%, the survival rate of the DOX group mice is only 30%, the survival rate of the DOX+albumin peptide group is 50%, the survival rate of the DOX+wheat oligopeptide group is 40%, the survival rate of the DOX+soybean peptide group is 50%, and the survival rate of the DOX+corn oligopeptide group is 40%, which indicates that the survival rate of the mice can be improved by the bioactive peptide.
Table 1 daily survival (%)
2. Influence of bioactive peptides on toxic side effects of doxorubicin
1. Grouping and administration
The experimental animals and grouping and administration methods described above in "influence of bioactive peptide on Doxorubicin (DOX) mice survival" were used, but the number of units was 6 per group and the observation time was 4 days.
2. Mouse heart function detection
On the 4 th day of the experiment, a proper amount of depilating paste is uniformly smeared on the heart part by using a cotton swab, and the wet towel carefully wipes the depilating paste to completely expose the skin of the heart part. The chloral hydrate is injected into the abdominal cavity at the dosage of 0.04 mL/10 g (or 400 mg/kg), after 5 min, the chest is upwards fixed on an operation board, and a proper amount of special couplant for detection is uniformly smeared on the heart. And then placing the matched probe of the Vevo 2100 high-resolution animal ultrasonic imaging system on the chest of the mouse, observing the image, adjusting the proper position, observing the long-axis section of the sternum through B-type ultrasonic, saving the image, switching to M-type ultrasonic, and saving the image at the position with the largest left ventricle diameter. Processing by the device's own software results in left ventricular ejection fraction (Left Ventricular Ejection Fraction, LVEF) and left ventricular short axis shortening (Left Ventricular Fractional Shortening, LVFS).
Results: as shown in fig. 1 and 2, the DOX mice LVEF and LVFS were both significantly reduced (P values were less than 0.01) compared to the normal control group. The cardiac function of the 4 groups of mice given 4 bioactive peptides was significantly improved compared to the DOX group.
3. Detection of LDH activity and GSH content in mouse serum
On day 4 of the experiment, mice of each group were bled from their eyeballs and serum was centrifuged to detect lactate dehydrogenase (Lactate Dehydrogenase, LDH) and Glutathione (GSH).
Results: as shown in fig. 3, the serum LDH activity was significantly increased in the DOX group mice compared to the normal control group (P < 0.01). Whereas in comparison to the DOX group, the LDH activity was significantly reduced in the 4 groups of mice given the bioactive peptide by gavage (P values were less than 0.01).
As shown in fig. 4, the serum GSH content of the mice in the DOX group was significantly reduced (P < 0.01) compared to the normal control group; serum GSH levels were significantly elevated in the 4 groups of mice given 4 bioactive peptides by gavage, compared to the DOX group, with the DOX + albumin peptide group being most significantly elevated.
4. Mouse myocardial SOD activity and heart MDA content detection
The heart of the mice was isolated, 0.07 g heart was weighed and placed in 630 μl of physiological saline, tissue homogenate was prepared with an ULTRA-TURRAX high-speed homogenizer, centrifugation 15 min was performed at 4 ℃, 2000: 2000 rpm, and the supernatant was taken to detect superoxide dismutase (Superoxide Dismutase, SOD) activity and malondialdehyde (Malondialdehyde, MDA) content.
Results: as shown in fig. 5, the DOX group mice showed significantly reduced myocardial SOD activity (P < 0.01) compared to the normal control group; compared with DOX group, the heart SOD activity of 4 groups of mice given 4 bioactive peptides by stomach irrigation is obviously improved.
As shown in fig. 6, the heart MDA content of the mice in the DOX group was significantly increased (P < 0.01) compared to the normal control group; the heart MDA content was significantly reduced in the 4 groups of mice given 4 bioactive peptides by gavage compared to the DOX group, with the DOX + soybean peptide group being most significantly reduced.
5. Myocardial histomorphology observations
On day 4 of the experiment, 1/4 myocardial tissue of the apex of the left ventricle of the mouse heart was fixed with 10% paraformaldehyde solution, dehydrated, tissue-transparent, embedded, sectioned and hematoxylin-eosin (H-E) stained. And observing the myocardial tissue morphology under a light microscope, photographing and comparing for analysis.
Results: FIG. 7 shows the results of HE staining of heart tissue from mice in each group, as can be seen: the normal control group (A) mice have orderly myocardial tissue arrangement and complete structure. DOX group (B) mice had broken myocardial fibers, disordered arrangement, and even disappeared, and had inflammatory reaction in the myocardium stroma. The mouse myocardial tissue of DOX+albumin peptide group (C), DOX+wheat oligopeptide group (D), DOX+soybean peptide group (E) and DOX+corn oligopeptide group (F) is similar to DOX, and myocardial fiber rupture, arrangement disorder, inflammation and the like appear.
Effect of bioactive peptide on Daunorubicin (DNR) mouse survival
1. Experimental animal
SPF class C57BL/6 male mice of 6-8 weeks old were purchased from Henan province laboratory animal center (production license: SCXK (Yu) 2017-0001) and fed in Henan province hepatopathy pharmacology important laboratory animal houses. After 5 days of adaptive feeding and observation, healthy and active mice were selected for the experiment.
2. Grouping and administration
60 SPF-class C57BL/60 mice with the weight of 18-20 g are randomly divided into 6 groups, A: normal control group was intraperitoneally injected with physiological saline at a dose of 11 mg/kg daily. 30 Distilled water was administered by gavage at a dose of 600 mg/kg after min, 1 time a day. B: DNR group DNR was intraperitoneally injected daily at a dose of 11 mg/kg. 30 Distilled water was administered by gavage at a dose of 600 mg/kg after min, 1 time a day. C: DNR+Albumin peptide group DNR was injected intraperitoneally at a dose of 11 mg/kg daily. 30 Albumin peptide was administered by gavage at a dose of 600 mg/kg 1 day after min. D: DNR+wheat oligopeptides DNR was intraperitoneally injected daily at a dose of 11 mg/kg. 30 Wheat oligopeptide was given by gavage at a dose of 600 mg/kg after min, 1 time a day. E: DNR+Soy peptide group DNR was injected intraperitoneally at a dose of 11 mg/kg daily. 30 The soybean peptide was administered by gavage at a dose of 600 mg/kg 1 time a day after min. F: DNR+maize oligopeptide group DNR was injected intraperitoneally daily at a dose of 11 mg/kg. 30 After min, the corn oligopeptide was administered by gavage at a dose of 600 mg/kg 1 day. The above treatment lasted 7 days.
3. Survival observations
Mice were observed daily for survival.
4. Results
As shown in table 2, the survival rate of DNR group mice was 80% from day 5. After 7 days of observation, the survival rate of the normal control mice was 100%, the survival rate of the DNR mice was only 20%, the survival rate of the DNR+albumin peptide mice was 50%, the survival rate of the DNR+wheat oligopeptide mice was 40%, the survival rate of the DNR+soybean peptide mice was 40%, and the survival rate of the DNR+corn oligopeptide mice was 30%, indicating that the survival rate of the mice was improved by the 4 soybean bioactive peptides.
TABLE 2 influence of bioactive peptides on daunorubicin mouse survival (%)
Fourth, research on protection effect of bioactive peptide on toxicity caused by daunorubicin
1. Experimental animal
Healthy C57BL/6 male mice of 6-8 weeks old were purchased from Henan province laboratory animal center (production license: SCXK (Yu) 2017-0001) and fed in Henan province hepatopathy pharmacology important laboratory animal houses. After 5 days of adaptive feeding and observation, healthy mice were selected for the experiment.
2. Grouping and administration
36C 57BL/6 mice weighing 18-22g were randomly divided into 6 groups, A: normal control group, B: DNR group, C is DNR+albumin peptide group, D is DNR+wheat oligopeptide group, E.DNR+soybean oligopeptide group and F.DNR+corn oligopeptide group. B. Group C, D, E, F groups were intraperitoneally injected with DNR at a dose of 1mg/kg, and group A were intraperitoneally injected with an equivalent amount of physiological saline. After 1 hour, four C, D, E, F groups were then each dosed with 600mg/kg (0.2 ml/10 g) of albumin peptide, wheat oligopeptide, soybean oligopeptide, corn oligopeptide, A, B groups were dosed with equal amounts of physiological saline. Once every other day for 4 consecutive days for 2 times. The general status of each group of mice was observed daily.
3. Detection of cardiac function in mice
On the 4 th day of the experiment, a proper amount of depilating paste is uniformly smeared on the heart part by using a cotton swab, and the wet towel carefully wipes the depilating paste to completely expose the skin of the heart part. Injecting chloral hydrate into abdominal cavity with dosage of 0.04 mL/10 g (or 400 mg/kg), opening the main machine of the ultrasonic instrument, taking out the ultrasonic instrument probe (MS-400) of the small animal, anesthetizing the mouse after the installation, placing the mouse on an operation panel with the chest upwards, holding the probe, enabling one face of the incision of the probe to face the head of the animal, finely adjusting the incision to be about 30-45 degrees anticlockwise, searching the parasternal long axis section of the heart through a B-mode picture, and switching to an M-mode interface to record images of the position with the largest left ventricle diameter. The Ejection Fraction (EF), left ventricular short axis shortening rate (FS), left ventricular end systole inner diameter (LVESD) and left ventricular end diastole inner diameter (LVEDD) of the mice were recorded according to the instrument's own data processing software.
Results: as shown in fig. 8 and 9, both the LVEF and LVFS were significantly reduced in the DNR group mice (P values were less than 0.01) compared to the normal control group. Both LVEF and LVFS were significantly increased in the 4 groups of mice given the bioactive peptide compared to the DNR group.
4. Detection of LDH activity and GSH content in mouse serum
On experiment day 4, mice of each group were blood-collected from eyeballs, and serum was collected by centrifugation to detect LDH and GSH.
Results: as shown in fig. 10: the DNR group mice had significantly increased serum LDH activity (P < 0.01) compared to the normal control group. Serum LDH activity was significantly reduced in the 4 groups of mice given 4 bioactive peptides compared to the DNR group (P values were less than 0.05).
5. Mouse myocardial SOD activity and myocardial MDA content detection
The heart of the mice was isolated, 0.07 g heart was weighed and placed in 630. Mu.L of physiological saline, and tissue homogenate was prepared by using ULTRA-TURRAX high-speed homogenizer, centrifuged at 2000: 2000 rpm at 4℃for 15: 15 min, and the supernatant was taken to detect SOD and MDA.
Results: as shown in fig. 11, DNR group mice had significantly reduced serum GSH levels (P < 0.01) compared to the normal control group; serum GSH levels were significantly increased in the 4 groups of mice given the bioactive peptide by gavage, compared to the DNR group.
As shown in fig. 12, DNR group mice showed significantly reduced myocardial SOD activity (P < 0.01) compared to the normal control group; compared with DNR group, the myocardial SOD activity of 4 groups of mice given bioactive peptide is obviously improved.
As shown in fig. 13, the DNR group mice had significantly elevated cardiac MDA levels (P < 0.01) compared to the normal control group; compared with DNR group, the heart MDA content of 4 groups of mice subjected to the stomach-infused bioactive peptide is obviously reduced.
6. Myocardial histomorphology observations
On day 4 of the experiment, 1/4 myocardial tissue of the apex of the left ventricle of the mouse heart was fixed with 10% paraformaldehyde solution, dehydrated, tissue-transparent, embedded, sectioned and hematoxylin-eosin (H-E) stained. And observing the myocardial tissue morphology under a light microscope, photographing and comparing for analysis.
Results: FIG. 14 shows the results of HE staining of heart tissue from mice in each group, as can be seen: the normal control group (A) mice have orderly myocardial tissue arrangement and complete structure. DNR group (B) mice had myocardial fiber breaks and arrangement disorders. The mice myocardial fibers of DNR+albumin peptide group (C), DNR+wheat oligopeptide group (D), DNR+soybean peptide group (E) and DNR+corn oligopeptide group (F) are orderly arranged.
The above-described embodiments are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention, so that all equivalent changes or modifications of the structure, characteristics and principles described in the claims should be included in the scope of the present invention.
Claims (5)
1. The application of bioactive peptide in preparing medicine for preventing or treating anthracycline cardiotoxicity is characterized in that the bioactive peptide is wheat oligopeptide or corn oligopeptide.
2. The use of a bioactive peptide according to claim 1 for the preparation of a medicament for the prophylaxis or treatment of cardiotoxicity of anthracyclines, wherein said anthracycline is doxorubicin or daunorubicin.
3. The use of a bioactive peptide according to claim 1 for the preparation of a medicament for preventing or treating anthracycline cardiotoxicity, wherein the medicament for preventing or treating anthracycline cardiotoxicity is a medicament for preventing or treating a decrease in left ventricular ejection fraction and/or left ventricular short axis shortening rate caused by anthracycline.
4. The use of a bioactive peptide according to claim 1 for the preparation of a medicament for preventing or treating anthracycline cardiotoxicity, wherein the medicament for preventing or treating anthracycline cardiotoxicity is a medicament for preventing or treating an increase in serum lactate dehydrogenase activity and/or a decrease in serum glutathione content caused by anthracycline.
5. The use of a bioactive peptide according to claim 1 for the preparation of a medicament for preventing or treating anthracycline cardiotoxicity, wherein the medicament for preventing or treating anthracycline cardiotoxicity is a medicament for preventing or treating a decrease in myocardial superoxide dismutase activity and/or an increase in cardiac malondialdehyde content caused by anthracycline.
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| CN110338326A (en) * | 2019-07-10 | 2019-10-18 | 中慈保健品科技开发有限公司 | Assist in the treatment of the soybean peptide compounding solid beverage and its preparation method and application of cardiovascular and cerebrovascular |
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