CN108653264B - Application of allicin and derivatives thereof in preparation of medicine for preventing and treating kidney injury caused by statin drugs - Google Patents
Application of allicin and derivatives thereof in preparation of medicine for preventing and treating kidney injury caused by statin drugs Download PDFInfo
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Abstract
The invention discloses an application of allicin and a derivative thereof in preparing a medicament for preventing and treating kidney injury caused by statin drugs. The invention proves that the allicin has the effects of inhibiting the toxicity of statin drugs on renal tubular epithelial cells and preventing and treating the renal injury caused by the statin drugs, and has the potential of treating the renal injury caused by the statin drugs. The invention provides a new application of the allicin and the derivative thereof, provides a new selection scheme for preventing and treating the kidney injury caused by statin drugs, provides diallyl sulfide extracted from foods such as natural garlic and the like and the derivative thereof, provides a research basis for the food therapy of the kidney injury caused by the statin drugs based on the garlic, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of biological medicines. More particularly, relates to an application of allicin and derivatives thereof in preparing a medicament for preventing and treating kidney injury caused by statin drugs.
Background
Statins (such as simvastatin), namely 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are the most effective lipid-lowering and lipid-regulating drugs at present. The traditional Chinese medicine composition is mainly used for reducing cholesterol, particularly low-density lipoprotein-cholesterol (LDL-C) in clinic and treating atherosclerosis, and is the most effective medicine for preventing and treating coronary heart disease. In recent years, it has been found that statins have various non-lipid-lowering effects, including inhibiting atherosclerosis and thrombosis, relieving rejection after organ transplantation, treating osteoporosis, resisting tumor, resisting senile dementia, etc., and are suitable for hypercholesterolemia and mixed hyperlipidemia mainly involving cholesterol increase. Preventing and treating coronary heart disease, myocardial infarction and apoplexy, and delaying atherosclerosis.
However, the renal cell injury caused by statins is common in clinic, and improper medication and dosage can cause serious renal injury, renal failure and even death.
Disclosure of Invention
The invention aims to overcome the defects of the existing kidney injury prevention and treatment technology and provides a new drug selection for preventing and treating the kidney injury caused by statins, namely the application of allicin and derivatives thereof in preventing and treating the kidney injury caused by statins.
The invention aims to provide application of allicin and derivatives thereof in preparing a medicament for preventing and treating kidney injury caused by statin drugs.
The above purpose of the invention is realized by the following technical scheme:
the invention takes the renal tubular epithelial cells NRK-52E as a representative object, and researches prove that the allicin can inhibit the toxicity of simvastatin to the renal tubular epithelial cells. Therefore, the following applications should be within the scope of the present invention:
the application of allicin and its derivatives in preparing medicine for preventing and treating kidney injury caused by statin drugs is provided.
The application of the allicin and the derivatives thereof in preparing the medicine for inhibiting the toxicity of simvastatin to renal tubular epithelial cells.
Specifically, the kidney injury refers to renal cell injury.
Preferably, the renal cells are renal tubular epithelial cells.
Preferably, the allicin is allicin, allicin or a metabolite thereof.
Allicin (diallyl trisulfide, DATS); CAS, 2050-87-5, the structural formula is shown below. Allicin (diallyl disulfide, DADS), (CH 2= CH-CH2-S (o) -S-CH2-CH = CH 2); CAS number: 539-86-6, the structural formula is shown below. The structural formulae of Allyl dimethyl sulfone (CAS number 16215-14-8) and Allyl dimethyl sulfoxide (Allyl methyl sulfoxide) are shown below:
allyl dimethyl sulfone allyl dimethyl sulfoxide
Preferably, the derivative of allicin comprises a compound, analog or pharmaceutically acceptable salt thereof having allicin or its metabolites (including diallyl disulfide and diallyl trisulfide, allyl dimethyl sulfone and allyl dimethyl sulfoxide) as a parent nucleus.
More preferably, the structure of the allicin derivative is shown as formula (I), formula (II) or formula (III):
wherein: r isBioisosteres with S; r1 and R2 are the same or different and are each H, substituted or unsubstituted lower alkyl, or other bioisosteres (OH, F, Cl, Br, NH)2Etc.); r3 and R4 are the same or different and are each H, substituted or unsubstituted lower alkyl, double bond O or bioisosteres thereof.
Preferably, the metabolite of allicin is allyl dimethyl sulfone or allyl dimethyl sulfoxide.
Allicin (Allicin) is a sulfoallyl ether compound naturally extracted from bulbs of garlic and garlic of the genus allium of the family alliaceae, onions and other alliaceae, is light yellow powder or light yellow oily liquid, and generally has a strong smell. It is a broad-spectrum antibacterial drug, and has multiple biological functions of diminishing inflammation, reducing blood pressure, reducing blood fat and the like. Before the invention, the allicin has not been reported in the aspect of preventing and treating the kidney injury caused by statins, and the invention firstly researches and discloses the application prospect of the allicin in the aspect of preventing and treating the kidney injury caused by statins.
Allicin is unstable and volatile at normal temperature, and can be further decomposed to generate diallyl disulfide (DADS) with stable properties, which can be further metabolized into allyl dimethyl sulfone and allyl dimethyl sulfoxide in vivo. Thus, in the context of the present invention, allicin and its derivatives may be administered to a patient in the form of a pharmaceutically acceptable salt or pharmaceutical complex. Certain complexes are mixed with appropriate carriers or excipients to form pharmaceutical compositions to ensure effective treatment. The dosage forms include solid dosage forms, semi-solid dosage forms, liquid formulations and aerosol formulations.
The invention has the following beneficial effects:
the invention discovers that the allicin and the derivative thereof have the function of inhibiting the renal cell injury caused by statins through the first research. Provides a new application of the allicin and the derivative thereof, namely the application of the allicin and the derivative thereof in preventing and treating the kidney injury caused by the statins, also provides a new selection scheme for treating the kidney injury caused by the statins, provides diallyl sulfide extracted from foods such as natural garlic and the like and the derivative thereof, provides a research basis for food therapy of the kidney injury caused by the statins based on the garlic, and has good application prospect.
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FIG. 1 is a graph illustrating the effect of simvastatin at various concentrations on the changes in tubular epithelial cell viability and the protective effect of allicin DATS on tubular epithelial cell damage caused by simvastatin. Denotes comparison between groups indicated by bars, P < 0.05.
FIG. 2 is a graph showing the effect of carbenoxolone at different concentrations on the viability of tubular epithelial cells and the protective effect of allicin DATS and DADS on tubular epithelial cell injury caused by carbenoxolone at high concentrations. Denotes comparison between groups indicated by bars, P < 0.05.
FIG. 3 is a graph showing the effect of different concentrations of sodium oxalate (calcium oxalate) on the viability of tubular epithelial cells and the protective effect of DATS on tubular epithelial cell injury caused by sodium oxalate (calcium oxalate) crystals. Denotes comparison between groups indicated by bars, P < 0.05.
Figure 4 illustrates the effect of different concentrations of docetaxel on the changes in renal tubular epithelial cell viability and the non-inhibitory effect of 3, 10, 30 μ M of DATS on docetaxel-induced renal tubular epithelial cell injury in rats.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
Example 1 allicin and its derivatives have a protective effect on simvastatin-induced damage to tubular epithelial cells
Materials and methods
1. Primary reagent
Dulbecco's Modified Eagle's Medium Dry powder (DMEM, Low sugar), Fetal Bovine Serum (FBS), pancreatin (typsin), dimethyl sulfoxide (DMSO), Tris were all purchased from Sigma-Aldrich (St. Louis, MO, USA); simvastatin, Carbenoxolone (CBX), allicin (DADS) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Docetaxel was purchased from selelck. Allicin (DATS) was purchased from the drug institute of Guangdong province. Other commonly used laboratory reagents are all domestic analytical pure grades.
2. Cell culture
At 37 deg.C, 5% CO2And saturation of humidity, we cultured the rat tubular epithelial NRK-52E cells and the human tubular epithelial cells HK-2 in DMEM (low carbohydrate) medium containing 10% fetal bovine serum. The cell culture was performed in a petri dish, and after about 2-3 days, the culture solution was replaced after washing 1-2 times with PBS.
3. Main instrument and equipment for experiment
A carbon dioxide incubator (HEPAC CLASS 100, Thermo);
clean bench (Thermo);
a water bath (Shelllab);
an electronic balance (AB 204-S, Mettler Toledo);
a pH meter (InLab 413, Mettler Toledo);
heat source removal type ultra pure water instruments (purelaga classis UF, ELGA);
Nucleic acid and protein analyzer (DU 640，Beckman Coulter)；
Bio Imaging system (Gene Genius)；
inverted microscope (LW 200-27XB, Shanghai photoelectricity);
fluorescence microscopy (IX51, Olympus);
a cryogenic refrigerator (Thermo-fisher);
Bio-Rad protein electrophoresis System;
a 96-well luminescence detector (PROMEGA GloMax ™);
ultracentrifuge (BECKMAN L-100XP)
4. Cell viability by MTT or MTS assay:
cells are firstly inoculated into a 96-well plate according to a certain density (about 3000-. After the medium was aspirated, 15. mu.l of MTT or MTS-containing medium was added to each well, and after 4 hours (MTS time 2-4 hours), absorbance was measured at 490 nm using a microplate reader (Bio-Tek Instruments). Cell viability was expressed as the ratio of absorbance of the control group to absorbance of the blank group after subtraction and conversion to percentage.
5. Statistical method
All experiments were repeated at least three times. Statistical analysis is carried out on experimental data by SPSS16.0 software, Student test comparison is adopted for inter-group comparison of 2 groups, one-factor variance analysis is adopted for inter-group comparison of more than 3 groups, two-two comparison is carried out between groups by an LSD method (when the variances are uniform) or a Dunnett's T3 method (when the variances are not uniform), and the difference P <0.05 is taken as a significance difference; p <0.05 compared to the corresponding group. The results of the histogram in the figure are expressed as mean and standard error.
Second, experimental results
The results show that 1, 3, 10, 30 μ M allicin (DATS) does not cause toxicity in NRK-52E cells; simvastatin 2 μ M and 10 μ M caused toxicity in NRK-52E cells, but allicin (DATS) 10, 30 μ M inhibited the toxicity, as shown in FIG. 1.
Example 2 allicin and its derivatives have inhibitory effect on renal cell injury caused by carbenoxolone
1. Experimental methods
The experimental materials were the same as in example 1. The cell culture, MTT assay and other kit statistical methods were the same as in example 1; after 24 hours of cell seeding into 96-well plates, different drug groups were set and the change was treated for 24 hours with different concentrations of drug to be measured. In the experiment of damage caused by carbenoxolone, allicin (DATS, DADS) and carbenoxolone are added into cells at the same time for 24h, the absorbance of each group is measured after the corresponding MTT is added after 24h, and the survival rate is calculated after the corresponding blank control group is set.
All experiments were repeated at least three times. Statistical analysis is carried out on experimental data by SPSS16.0 software, Student test comparison is adopted for inter-group comparison of 2 groups, one-factor variance analysis is adopted for inter-group comparison of more than 3 groups, two-two comparison is carried out between groups by an LSD method (when the variances are uniform) or a Dunnett's T3 method (when the variances are not uniform), and the difference P <0.05 is taken as a significance difference; p <0.05 compared to the corresponding group. The results of the histogram in the figure are expressed as mean and standard error.
2. Results of the experiment
The results show that 50 μ M Carbenoxolone (CBX) can cause toxicity of NRK-52E cells, while allicin (DATS) can inhibit the toxicity; see fig. 2. 3. 10, 30 μ M allicin (DADS) does not cause toxicity to NRK-52E and HK-2 cells, 30 μ M Carbenoxolone (CBX) causes toxicity to NRK-52E cells, and allicin (DADS) inhibits toxicity to Carbenoxolone (CBX); see fig. 2.
Example 3 allicin and its derivatives have inhibitory effect on renal cell injury caused by sodium oxalate
First, experiment method
The cell culture, MTT or MTS assay and other kit statistical methods were the same as in example 1; after 24 hours of cell seeding into 96-well plates, different drug groups were set and the change was treated for 24 hours with different concentrations of drug to be measured. In the experiment of damage caused by sodium oxalate, allicin (DATS) is added into cells in advance for treatment, and after 3 hours, sodium oxalate with different concentrations is added into the cells (the sodium oxalate is combined with calcium in a culture medium to form calcium oxalate crystals); after 24h, adding corresponding MTS to measure the absorbance of each group, setting corresponding blank control holes (considering that the calcium oxalate crystals and the drugs can influence the absorbance values, the corresponding calcium oxalate crystals and drug blank control holes are also set), and subtracting the corresponding blank absorbance to calculate the survival rate of the NRK-52E cells.
All experiments were repeated at least three times. Statistical analysis is carried out on experimental data by SPSS16.0 software, Student test comparison is adopted for inter-group comparison of 2 groups, one-factor variance analysis is adopted for inter-group comparison of more than 3 groups, two-two comparison is carried out between groups by an LSD method (when the variances are uniform) or a Dunnett's T3 method (when the variances are not uniform), and the difference P <0.05 is taken as a significance difference; p <0.05 compared to the corresponding group. The results of the histogram in the figure are expressed as mean and standard error.
Second, experimental results
The results show that after sodium oxalate is added into cells, crystals are formed and precipitated on the cell surface; sodium oxalate at 0.5, 1, 2mM can cause toxicity in NRK-52E cells; DATS can inhibit cytotoxicity caused by sodium oxalate, and DATS of 3, 10 and 30 mu M has protective effect on injury caused by 2mM sodium oxalate; see fig. 3.
Example 4 allicin and its derivatives have no inhibitory effect on renal cell injury caused by docetaxel
First, experiment method
The cell culture, MTT or MTS assay and other kit statistical methods were the same as in example 1; after 24 hours of cell seeding into 96-well plates, different drug groups were set and the change was treated for 24 hours with different concentrations of drug to be measured. In the injury experiment caused by docetaxel (docetaxel), allicin (DATS) is added into cells in advance for treatment, and after 3 hours, docetaxel (0.3 mu M, 1 mu M and 3 mu M) with certain concentration is added into the cells; after 24h, adding corresponding MTT to measure the absorbance of each group, and calculating the survival rate of the NRK-52E cells by setting corresponding blank control holes and subtracting the absorbance of the corresponding control holes.
All experiments were repeated at least three times. Statistical analysis is carried out on experimental data by SPSS16.0 software, Student test comparison is adopted for inter-group comparison of 2 groups, one-factor variance analysis is adopted for inter-group comparison of more than 3 groups, two-two comparison is carried out between groups by an LSD method (when the variances are uniform) or a Dunnett's T3 method (when the variances are not uniform), and the difference P <0.05 is taken as a significance difference; p <0.05 compared to control. The results of the histogram in the figure are expressed as mean and standard error.
Second, experimental results
The results show that the survival rate of the cells is obviously reduced after docetaxel (0.3 mu M, 1 mu M and 3 mu M) is added into the cells for 24 hours; while 3, 10 and 30 mu M of DATS has no protective effect on the injury of rat renal tubular epithelial cells NRK-52E caused by docetaxel; see fig. 4.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (1)
1. The allicin is applied to the preparation of the medicine for preventing and treating the damage of the renal tubular epithelial cells caused by simvastatin.
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Non-Patent Citations (2)
| Title |
|---|
| Diallyl trisulfide, a garlic polysulfide protects against As-induced renal oxidative nephrotoxicity, apoptosis and inflammation in rats by activating the Nrf2/ARE signaling pathway;S. Miltonprabu等;《International Immunopharmacology》;20171231;第50卷;第107-120页 * |
| Protective effects of diallyl disulfide against acetaminophen-induced nephrotoxicity: a possible role of CYP2E1 and NF-κB;Je-Won Ko等;《Food and Chemical Toxicology》;20170217;第102卷;第156-165页 * |
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