CN117442603A - Application of schaftoside in preparation of heart failure resistant medicines - Google Patents
Application of schaftoside in preparation of heart failure resistant medicines Download PDFInfo
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- CN117442603A CN117442603A CN202311714066.2A CN202311714066A CN117442603A CN 117442603 A CN117442603 A CN 117442603A CN 202311714066 A CN202311714066 A CN 202311714066A CN 117442603 A CN117442603 A CN 117442603A
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- 206010019280 Heart failures Diseases 0.000 title claims abstract description 46
- MMDUKUSNQNWVET-WMRYYKKOSA-N 5,7-dihydroxy-2-(4-hydroxyphenyl)-6-[(2r,3r,4r,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]-8-[(2s,3r,4s,5s)-3,4,5-trihydroxyoxan-2-yl]chromen-4-one Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1C1=C(O)C([C@H]2[C@@H]([C@@H](O)[C@@H](O)CO2)O)=C(OC(=CC2=O)C=3C=CC(O)=CC=3)C2=C1O MMDUKUSNQNWVET-WMRYYKKOSA-N 0.000 title claims abstract description 39
- NIABBGMPPWXWOJ-UHFFFAOYSA-N schaftoside Natural products OC1C(O)C(O)C(CO)OC1OC1=C(O)C(OC2C(C(O)C(O)CO2)O)=C(OC(=CC2=O)C=3C=CC(O)=CC=3)C2=C1O NIABBGMPPWXWOJ-UHFFFAOYSA-N 0.000 title claims abstract description 39
- MMDUKUSNQNWVET-UHFFFAOYSA-N schaftozide Natural products OC1C(O)C(O)C(CO)OC1C1=C(O)C(C2C(C(O)C(O)CO2)O)=C(OC(=CC2=O)C=3C=CC(O)=CC=3)C2=C1O MMDUKUSNQNWVET-UHFFFAOYSA-N 0.000 title claims abstract description 39
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Classifications
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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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention relates to the field of medicine application, in particular to application of schaftoside in preparing an anti-heart failure medicine. The invention verifies through experiments that the bergamot glycoside can obviously improve the diastolic dysfunction, the cardiac hypertrophy and the myocardial fibrosis for the first time, reduce the oxidative stress level of myocardial cells and activate autophagy. Has protective effect on Ang II induced mouse cardiac hypertrophy and myocardial fibrosis, and can reduce total protein concentration and oxidative stress to inhibit Ang II induced myocardial cell hypertrophy. Schaftoside plays a beneficial role in preventing and treating heart failure by alleviating heart metabolic disorders, thereby preventing and treating cardiac remodeling and dysfunction. The invention takes the schaftoside as the active ingredient and prepares the anti-heart failure medicament with a pharmaceutically acceptable carrier or auxiliary material.
Description
Technical Field
The invention relates to the field of medicine application, in particular to application of schaftoside in preparing an anti-heart failure medicine.
Background
Cardiovascular disease is one of the leading causes of death worldwide. Cardiovascular problems have existed in almost all countries for decades, including high-income countries. Cardiovascular diseases include heart failure, myocardial hypertrophy, arteriosclerosis, and hypertension. Heart failure does not occur alone, but rather results in the final stage from the development of various cardiovascular-related diseases. Therefore, with the increase in incidence of cardiovascular diseases such as hypertension and hyperlipidemia, the occurrence of heart failure has become widespread, and heart failure has become one of the important causes of death. Heart failure is the end-stage manifestation of heart disease and is accompanied by structural and electrical remodeling of the heart, which in turn exacerbates heart failure. Reconstruction of the heart structure refers to structural changes in the heart under the influence of various factors. Cardiac electrical remodeling refers to the occurrence of various forms of adaptive electrical function alterations in the various pathological or physiological factors of heart failure. The structural and electrical remodeling of the heart are interactive, and act to compensate for the initial onset of heart failure, which in turn exacerbates heart failure.
One of the manifestations of heart failure structural remodeling is myocardial hypertrophy, which we can affect heart failure structural remodeling by improving myocardial hypertrophy. Commonly used anti-heart failure drugs are mainly angiotensin converting enzyme inhibitors, angiotensin ii receptor antagonists, calcium antagonists, beta-adrenergic receptor antagonists and the like. Although these drugs have a certain therapeutic effect, they eventually do not completely prevent further deterioration of heart failure.
The schaftoside is a flavonoid component extracted from the desmodium styracifolium at the earliest time, has the functions of promoting bile flow, inhibiting bacteria and resisting inflammation, and is mainly used for treating diseases such as hepatitis, cholecystitis, gall-stone, urinary system infection and the like clinically. Currently, most of the research on the schaftoside is focused on quality research and content measurement, such as the content of schaftoside and isosaftoside in different places of origin of arisaema with the HPLC method (the first stage of volume 11, pages 86-89 of 1 month of 2021 of Chinese medical science). Less research on pharmacological effects is focused on anti-inflammatory and antiviral aspects, for example, chinese patent application publication No. CN115707464A discloses inhibition of novel coronavirus main protease by schaftoside and pharmaceutical application thereof. At present, the effect of the schaftoside on heart vessels is not seen, particularly the report on the aspect of heart failure resistance, and the application of the schaftoside in the aspect of heart failure resistance medicine preparation is not reported.
Disclosure of Invention
According to the invention, experiments prove that the schaftoside can improve diastolic dysfunction, cardiac hypertrophy and myocardial fibrosis for the first time, reduce the oxidative stress level of myocardial cells, activate autophagy, have the effect of remarkably treating heart failure, and have potential value in developing the schaftoside into an anti-heart failure medicament. In view of the above, the invention aims to study the efficacy of the bergamot glycoside in resisting heart failure and provides an application of the bergamot glycoside in preparing an anti-heart failure medicament.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
application of schaftoside in preparing anti-heart failure medicine is provided.
Xiaftoside is a flavonoid compound with a molecular formula of C 26 H 28 O 14 The structural formula is as follows:
preferably, the use of schaftoside in the manufacture of a medicament for treating heart failure with retention of ejection fraction.
Preferably, the use of schaftoside in the preparation of a medicament against cardiac insufficiency caused by heart failure and pathological heart remodeling.
Preferably, the use of schaftoside in the manufacture of a medicament against cardiomyocyte hypertrophy due to heart failure and pathological heart remodeling.
Preferably, the use of schaftoside in the manufacture of a medicament against myocardial interstitial fibrosis caused by heart failure and pathological heart remodeling.
Preferably, the use of schaftoside in the manufacture of a medicament against cardiomyocyte death caused by heart failure and pathological heart remodeling.
Uses the schaftoside as the active ingredient, and adds one or more pharmaceutically acceptable carriers or auxiliary materials to prepare the anti-heart failure medicine. The carrier or auxiliary materials comprise diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.
The medicine is in a clinically acceptable pharmaceutical dosage form, including but not limited to various forms such as tablets, powder, pills, injections, capsules, films, suppositories, pastes, medicinal granules and the like. The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.
Compared with the prior art, the invention has the beneficial effects that:
the invention verifies through experiments that the bergamot glycoside can obviously improve the diastolic dysfunction, the cardiac hypertrophy and the myocardial fibrosis for the first time, reduce the oxidative stress level of myocardial cells and activate autophagy. Has protective effect on Ang II induced mouse cardiac hypertrophy and myocardial fibrosis, and can reduce total protein concentration and oxidative stress to inhibit Ang II induced myocardial cell hypertrophy. The schaftoside plays a beneficial role in preventing and treating heart failure by relieving heart metabolic disorder, thereby preventing and treating heart remodeling and dysfunction, and has potential value for developing an anti-heart failure drug.
Drawings
FIG. 1 is the effect of bergamot glycoside on AngII-induced cardiac function in mice in example 1 of the present invention.
FIG. 2 shows the results of HE staining of AngII-induced myocardial tissue of mice with bergamot glycoside according to example 2 of the present invention.
FIG. 3 shows the results of Masson staining of AngII-induced myocardial tissue of mice with cardiac hypertrophy by bergamot glycoside in example 2 of the present invention.
FIG. 4 shows the WGA staining result of bergamot glycoside on AngII-induced myocardial hypertrophy mice in example 2 of the present invention.
FIG. 5 is the effect of bergamot glycoside on H9C2 cell viability in example 3 of the present invention.
FIG. 6 shows the WGA staining of H9c2 cells treated with Ang II with bergamot in example 3 of the invention.
FIG. 7 is a fluorescent plot of the effect of bergamot glycoside on AngII-induced ROS levels in H9C2 cells in example 4 of the present invention.
Detailed Description
In order to better understand the technical content of the present invention, the following provides specific examples to further illustrate the present invention. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. Modifications and equivalents will occur to those skilled in the art upon understanding the present teachings without departing from the spirit and scope of the present teachings.
Mice are grouped and dosing regimen in examples:
control group: the same volume of physiological saline was infused daily for one month, and after a continuous period, the physiological saline was injected subcutaneously for 3 weeks.
Model group: the same volume of physiological saline was infused daily for one month, and after one month, ang II (0.6mg.kg) -1 ·d -1 ) 3 weeks.
Low dose group of schaftoside: 75 mg/kg of stomach is irrigated every day -1 After one month of the shaftovaoside solution, ang II (0.6mg.kg) -1 ·d -1 ) 3 weeks.
High dose group of schaftoside, 150 mg/kg of stomach is infused every day -1 After one month of the shaftovaoside solution, ang II (0.6mg.kg) -1 ·d -1 ) 3 weeks.
EXAMPLE 1 Charpyoside reduction of cardiac dysfunction in naturally aged mice
Subcutaneous injection of Ang II (0.6mg.kg) -1 ·d -1 ) After 3 weeks, the heart function of the mice was examined using an ultrasound imaging system after anesthesia and M-mode ultrasound images were recorded. The mice were measured for left ventricular end diastole (LVEDD), left Ventricular End Systole (LVESD), and Left Ventricular Ejection Fraction (LVEF) and left ventricular short axis foreshortening rate (LVFS) were calculated.
After the last subcutaneous injection, the diet was fasted for 24 hours. After 3 weeks of subcutaneous injection of Ang II (0.6 mg/kg/d), we assayed the mouse heart function by ultrasound. As shown in fig. 1, we can observe that mice in the model group (Ang II) exhibited significant heart failure characteristics compared to the control group, including impaired diastolic function, increased cardiac load, left ventricular wall thickening, and elevated Left Ventricular Ejection Fraction (LVEF) and left ventricular end diastolic volume (LVSF). However, these adverse effects are alleviated under the treatment of schaftoside, especially the improvement in the schaftoside high dose group is more pronounced.
Example 2 summer bergamot glycoside reduces cardiac hypertrophy and reduces fibrosis
Ang II (0.6mg.kg) -1 ·d -1 ) After 3 weeks, each group of mice was taken, weighed, and then killed by cervical dislocation, quickly fixed on an operating table, and the chest skin was cut off with surgical scissors, the heart and lung were fully exposed, and the heart was removed by cutting off from the aortic root. The heart was rinsed 3 times and weighed after rinsing.
HE staining
(1) Fixing heart with tissue fixing solution, treating with alcohol with different concentration gradients, and embedding the specimen in paraffin.
(2) And (5) freezing and shaping the embedded paraffin blocks at 4 ℃. The paraffin block was cut into 4-5 μm paraffin sections using a blade cutter. (3) placing the slices in hematoxylin aqueous solution for dyeing for 15min; (4) differentiation in ethanol hydrochloride for several seconds; (5) ammonia water is reversed blue for 2min; (6) eosin staining for 5min; (7) 95% ethanol for several seconds; (8) absolute ethanol for 10min; (9) absolute ethanol for 10min; (10) transparent in xylene for 10min; (11) drop neutral gum on the slide, seal the slide.
Masson staining
(1) Placing the slices into hematoxylin aqueous solution for dyeing for 15min; (2) differentiation in ethanol hydrochloride for several seconds; (3) ammonia water is reversed blue for 2min; (4) after flushing, dyeing with Masson reddish solution for 10min; (5) immersing and washing with 2% glacial acetic acid aqueous solution; (6) differentiating in 1% phosphomolybdic acid aqueous solution for 5min; (7) aniline blue staining for 5min; (8) 0.2% glacial acetic acid rinse; (9) dehydration of 95% ethanol and absolute ethanol; (10) transparent with xylene; (11) drop neutral gum on the slide, seal the slide.
WGA staining
Cells or myocardial tissue were incubated in 5% bovine serum albumin solution for 30min. Then, incubate overnight at 4 ℃ in WGA dilution. After 4 washes for 5min, myocardial tissue was washed 3 times with PBS and then stained with DAPIDNA stain (cat#d 1306, thermo Scientific) for 15min. WGA staining was analyzed using a laser scanning confocal microscope.
As shown in fig. 2, 3 and 4, mice treated by Ang II in the model group showed significant myocardial hypertrophy, and HE staining showed severe impairment of myocardial tissue structure and cell morphology; masson staining showed significant collagen deposition and fibrosis in myocardial tissue; WGA staining showed a significant increase in myocardial tissue cell surface area. However, these adverse effects were significantly improved after treatment with schaftoside, especially in the schaftoside high dose group improvement details.
When the cardiac muscle is hypertrophic, the collagen of the cardiac muscle tissue is increased. In Masson staining, red represents muscle fibers and blue represents collagen deposition. As shown in fig. 3, the model group had a significantly blue deposition compared to the control group, indicating an increase in collagen in the myocardial tissue of the mice in the model group; compared with the model group, the schaftoside can obviously reduce collagen deposition.
EXAMPLE 3 inhibition of cardiac injury to H9c2 cells by Charpy glycoside effect on cell viability 1 cell culture
The H9c2 cell line was derived from BNCC (beijing, china). The cells were cultured in a medium containing 10% fetal bovine serum (DMEM) and 1% penicillin-streptomycin. Cells at 37℃temperature, 5% CO 2 Growth in a humid environment of +95% air. Heart failure models were established by treating cells with AngII (5 mg/ml) for 24 hours. Schaftoside (80. Mu.g/mL), schaftoside (160. Mu.g/mL) were dissolved in DMSO and added to the medium along with Ang II.
CCK-8 detection of cell viability
When H9C2 cells grew to cover 80% of the area of the flask, the original culture medium was discarded, washed 2 times with 3mLPBS, digested with 0.25% trypsin, centrifuged, the supernatant discarded, and 3mL of complete medium was added for blow mixing and counting under a microscope. Then at 3X 10 5 The cells were seeded into 96-well plates at a concentration of one per mL, 100 μl of cell fluid was added to each well, and 6 multiplex wells were placed in each group. After 24h different concentrations of schaftoside (0, 10, 20, 40, 80, 160, 320 μg/mL) were added. Incubation was continued for 24h. Adding 10 mu LCCK8 solution into each hole of the liquid exchangeAnd (3) incubating for 0-4H by light, and detecting the influence of the schaftoside on the activity of the H9C2 cells by using a 490nm wavelength enzyme-labeled instrument.
The effect of the schaftoside on the activity of the H9C2 cells after 24H intervention is measured by adopting a CCK-8 method, as shown in figure 5, the effect of the schaftoside (0, 10, 20, 40, 80, 160 and 320 mug/mL) with different concentrations on the activity of the H9C2 cells is shown, and the result shows that the survival rate of the H9C2 cells is improved within the range of 0-320 mug/mL.
WGA staining was performed on Ang II-treated H9c2 cells to assess the effect of schaftoside on Ang II-induced myocardial hypertrophy of H9c2 cells. The results show that schaftoside significantly improved Ang II-induced myocardial hypertrophy in H9c2 cells, with more pronounced effects observed in the high dose group as shown in figure 6.
EXAMPLE 4 Charpyoside reduces cellular ROS levels in cardiac hypertrophy
Detection of cellular ROS levels
Rat cardiomyocytes H9C2 were counted, inoculated in 6-well plates, grouped as above, 3 multiplex wells were set, cultured for 24 hours, and DCFH-DA diluted 1000-fold. The culture medium was discarded, and 1mL of DCFH-DA was added. The tinfoil paper is wrapped in a dark place and placed in an incubator at 37 ℃ for 15min. The serum-free culture medium was washed to clean the cells, and the cells were photographed in a dark place using a fluorescence microscope.
Ang ii can induce oxidase activation and produce excess reactive oxygen species, and excessive ROS production can trigger cellular dysfunction, lipid peroxidation and DNA mutation, and can lead to cell injury or death, inducing myocardial hypertrophy. ROS have been considered as one of the key factors in the development of myocardial hypertrophy. The effect of the bergamot glycoside extract on the ROS levels of Ang ii-induced H9C2 cells was tested using the ROS kit. As shown in figure 7, the level of the ROS in the Ang II group is obviously increased, the increase of the level of the ROS induced by the Ang II can be inhibited by the schaftoside, the oxidative stress induced by myocardial injury is improved, and the effect of the high-dose group is more obvious.
Claims (8)
1. Application of schaftoside in preparing anti-heart failure medicine is provided.
2. Use according to claim 1, in the preparation of a medicament for heart failure with anti-ejection fraction retention.
3. Use according to claim 1, in the preparation of a medicament for combating cardiac insufficiency caused by heart failure or by pathological heart remodeling.
4. Use according to claim 1, in the preparation of a medicament against cardiomyocyte hypertrophy due to heart failure or pathological heart remodeling.
5. Use according to claim 1, in the preparation of a medicament for the treatment of myocardial interstitial fibrosis caused by heart failure or pathological heart remodeling.
6. Use according to claim 1, in the preparation of a medicament for combating cardiomyocyte death caused by heart failure or pathological heart remodeling.
7. An anti-heart failure medicine is characterized by comprising Charpy as an active ingredient.
8. The anti-heart failure medicament according to claim 7, wherein the medicament further comprises one or more pharmaceutically acceptable carriers or excipients and is prepared into clinically acceptable pharmaceutical dosage forms.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241709A (en) * | 2011-05-06 | 2011-11-16 | 南京泽朗医药科技有限公司 | High efficiency separation method for shcaftoside |
| CN115707464A (en) * | 2021-08-19 | 2023-02-21 | 北京大学 | Inhibition of schaftoside on novel coronavirus main protease and medicinal application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241709A (en) * | 2011-05-06 | 2011-11-16 | 南京泽朗医药科技有限公司 | High efficiency separation method for shcaftoside |
| CN115707464A (en) * | 2021-08-19 | 2023-02-21 | 北京大学 | Inhibition of schaftoside on novel coronavirus main protease and medicinal application thereof |
Non-Patent Citations (2)
| Title |
|---|
| PENG ZHOU等: "Prediction of material foundation of Ling-Gui-Zhu-Gan decoction for chronic heart failure based on molecular docking", 《PAKISTAN JOURNAL OF PHARMACEUTICAL SCIENCES》, vol. 33, no. 4, 31 July 2020 (2020-07-31), pages 1459 * |
| XU WANG等: "Revealment study on the regulation of lipid metabolism by Lingguizhugan Decoction in heart failure treatment based on integrated lipidomics and proteomics", 《BIOMEDICINE & PHARMACOTHERAPY》, vol. 158, 16 December 2022 (2022-12-16), pages 6 * |
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