CN111329854A - Application of natural active substance in relieving benzopyrene-induced RAW264.7 cell lipid metabolism disorder - Google Patents
Application of natural active substance in relieving benzopyrene-induced RAW264.7 cell lipid metabolism disorder Download PDFInfo
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- CN111329854A CN111329854A CN202010264423.XA CN202010264423A CN111329854A CN 111329854 A CN111329854 A CN 111329854A CN 202010264423 A CN202010264423 A CN 202010264423A CN 111329854 A CN111329854 A CN 111329854A
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Abstract
The invention belongs to the field of medicines and functional foods, and discloses application of a natural active substance in relieving benzopyrene-induced RAW264.7 cell lipid metabolism disorder. Disturbance of lipid metabolism of macrophages is one of the causes of atherosclerosis. The invention discovers for the first time that the pollutant benzopyrene in the environment or food can cause the lipid accumulation of macrophage RAW264.7, which is shown in the accumulation of intracellular lipid droplets, and the content of total cholesterol and triglyceride is increased. The salidroside, the allicin and the alliin can relieve the influence of benzopyrene on the lipid metabolism of cells to different degrees. Within a safe dose to cells, the three natural actives are able to reduce the accumulation of intracellular lipid droplets; reducing the total cholesterol and triglyceride levels; the protein cAMP playing an important regulation and control role in lipid metabolism is activated to relieve lipid accumulation caused by benzopyrene, and the three natural active substances can relieve cell lipid metabolism disorder induced by benzopyrene to different degrees.
Description
Technical Field
The invention belongs to the field of medicines and functional foods, and particularly relates to a relieving effect of natural active substances on benzopyrene-induced RAW264.7 cell lipid metabolism disorder.
Background
Benzopyrene (a) pyrene, Bap) is a food processing contaminant. The source of the method is that industrial emission influences soil and then indirectly pollutes food; secondly, the food is not properly fried, smoked, cooked, roasted and the like. Benzopyrene is widely contained in smoked foods, has lipotoxicity, teratogenicity, immunity and genetic toxicity, can cause disorder of metabolic function of organisms, and has great harm to human body systems.
Lipids are composed of fats, lipids and their derivatives, and are important constituents of the body. The lipid not only can protect internal organs together with muscles and maintain the normal body temperature of a human body, but also can promote the digestion and absorption of nutrient substances in food; during lipid metabolism, when the body needs energy, fatty acids will break free and act as a back-up energy, and lipid metabolism ensures the functioning of normal physiological functions, which is of great significance for life activities. Disorders of lipid metabolism cause common diseases such as obesity, diabetes, hypertension, cardiovascular diseases, chronic kidney diseases and Alzheimer's disease, and seriously threaten human health. It has been demonstrated that some food additives and food contaminants induce lipid metabolism disorders. Macrophages, which are mature monocytes released from the bone marrow into the blood and migrating to most tissues and organs of the body, play a crucial role in the immune system. Atherosclerosis is a chronic inflammatory cardiovascular disease, lipid accumulation is caused by macrophage internal lipid metabolism disorder in the early stage of atherosclerosis, accumulation is generated in the intima of the damaged arterial wall, adverse immune response is caused, meanwhile, macrophages participate in the formation of atherosclerotic plaques, the plaques are unstable and fall off to form thrombus, various acute cardiovascular and cerebrovascular diseases are finally caused, the death rate is extremely high, the body health is seriously threatened, and therefore, the research value of searching for a protective agent for the macrophage lipid metabolism disorder is very high.
Salidroside is main active ingredient of rhodiola rosea, is a phenolic compound with molecular formula of C14H20O7The molecular weight is 300.30, and the crystal is transparent needle-shaped crystal at normal temperature. Allicin (Allicin) is a trithio allyl ether compound with a molecular formula of C6H10S2O, molecular weight of 162, is a yellowish oily liquid at normal temperature, has a strong garlic flavor, and is mostly present in the bulb of garlic. Alliin (Alliin) is precursor component of garlicin, is a special non-protein sulfur-containing amino acid in garlic, and has a molecular formula of C6H11NO3S, molecular weight of 177.22, yellow powder at normal temperature, and stable property. The three natural active substances are common food-borne plant natural extracts, are economical and are easy to extract. Research shows that the three natural active substances have obvious functions of resisting inflammation, resisting oxidation, resisting bacteria, resisting virus, reducing blood pressure and blood fat, and compared with chemical synthetic components, the natural active substances are safer and have less side effect. At present, the effect of natural active ingredients in lipid metabolism disorder of benzopyrene-induced macrophages is not seen, and the research aims to find the protective effect of the natural active ingredients in the lipid metabolism disorder of benzopyrene-induced macrophages, and simultaneously screen out a natural protective agent with the optimal effect, thereby providing a theoretical basis for the research of lipid-lowering medicines and the development of lipid-lowering functional foods.
Disclosure of Invention
The invention discovers for the first time that benzopyrene (Bap) can induce RAW264.7 cell lipid metabolism disorder, and particularly shows that RAW264.7 cell lipid drops are increased, the total cholesterol content is increased, and the triglyceride content is increased after the benzopyrene is treated.
The invention aims to solve the problem of finding natural active substances capable of relieving lipid metabolism disorder of macrophages induced by benzopyrene, and lays a foundation for the research of novel lipid-lowering medicines and lipid-lowering functional foods. Based on this, the invention provides the following technical scheme:
the first object of the present invention is to select the treatment concentration of natural active substances having an alleviating effect on the benzopyrene-induced lipid metabolism disorder of RAW264.7 cells.
The natural active substances are salidroside, allicin and alliin.
According to said aim, the changes in cell activity after the administration of different natural active substances are determined by the MTT method, and the natural active substance concentration which has no toxic effect on the RAW264.7 cells is selected for intervention.
Preferably, the concentration of salidroside is 50 μ M to 200 μ M, selected according to the change in cell activity following administration of different concentrations of the natural active substance; the action concentration of the allicin is 25-50 mu M; the action concentration of alliin is 25-1600 μ M.
It is a second object of the present invention to determine the lipid lowering efficacy of natural actives on benzopyrene induced lipid accumulation in RAW264.7 cells.
According to said aim, the following indicators are determined:
1) the accumulation of lipid droplets in the cells after administration of the natural active substance was examined.
2) The total intracellular cholesterol level after administration of the natural active substance is determined.
3) The intracellular triglyceride content is determined after administration of the natural active substance.
4) The expression of cAMP protein is detected after administration of the naturally active substance.
By comparing the lipid-lowering effects of salidroside, allicin and alliin with the same concentration, the three natural active substances can obviously relieve the lipid disorder effect of the benzopyrene-induced RAW264.7 cells.
Drawings
FIG. 1: the MTT method was used to determine the effect of benzopyrene on RAW264.7 cell viability. a: the change of cell activity after the benzopyrene with different concentrations is used for treating the cells for 24 hours; b: change in cell viability after 48h of treatment of cells with different concentrations of benzopyrene. (. p <0.01vs Control)
FIG. 2: changes in intracellular lipid droplet content were measured by oil red O staining for 24h after treatment of RAW264.7 cells with benzopyrene at different concentrations (10. mu.M, 20. mu.M, 40. mu.M). a, shooting the accumulation condition of intracellular lipid droplets after benzopyrene treatment by 400 times under an inverted microscope; and b, quantitatively analyzing the content of the intracellular oil red O after the benzopyrene treatment with different concentrations. (. p <0.05vsControl)
FIG. 3: the change of the total cholesterol and triglyceride content in the cells after the benzopyrene treatment of RAW264.7 cells for 24h at different concentrations (10 muM, 20 muM and 40 muM). a, changing the content of total cholesterol in cells after the benzopyrene treatment with different concentrations; b, changing the content of triglyceride in the cells after the benzopyrene treatment with different concentrations. (p <0.05, p <0.01vs Control)
FIG. 4: the MTT method is used for measuring the influence of salidroside, allicin and alliin on the activity of RAW264.7 cells after 24 hours of treatment. Influence of salidroside on cell activity; the influence of allicin on the activity of cells; c, influence of Alliin on cell Activity. (p <0.05, p <0.01vs Control)
FIG. 5: oil red O measures the improvement in cellular lipid accumulation after 24h administration of different natural actives. a, shooting oil red O staining of intracellular lipid drops after the three natural active substances and benzopyrene are jointly treated by 400 times under an inverted microscope; and b, quantitatively analyzing the content of intracellular oil red O after the three natural active substances and the benzopyrene are jointly treated. (. about. p)<0.01vsControl；#p<0.05,##p<0.01vs Bap)
FIG. 6: after the administration of different natural active substances for 24 hours, the contents of total cholesterol and triglyceride in cells change. a, the change of the total cholesterol content in cells after different natural active substances are treated; b, change of triglyceride content in cells after different natural active substance treatment. (. about. p)<0.01vs Control；#p<0.05,##p<0.01vs Bap)
FIG. 7: measurement of intracellular cAMP protein Activity 24h after administration of different natural active substances. (. about.p)<0.05vsControl；#p<0.05,##p<0.01vs Bap)
Detailed Description
The present invention is further illustrated by the following detailed description in conjunction with the accompanying drawings, which are meant to be exemplary and not limiting. The test methods in the following examples, in which specific conditions are not specified, are generally carried out according to conventional conditions or manufacturer's instructions. Scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 screening of benzopyrene conditions having no effect on RAW264.7 cell activity.
1. Experimental methods
1.1 cell culture
RAW264.7 cells were cultured strictly according to the culture instructions provided in the cell bank, the medium used was DMEM high-sugar medium containing L-glutamine and glucose, 10% fetal bovine serum and 1% penicillin streptomycin mixed solution were added to the medium before use, and 5% CO was added at 37 deg.C2The culture was continued under the conditions.
1.2 cell treatment:
benzopyrene was dissolved in 1mL of dimethyl sulfoxide, and the concentration of the mother liquor was 80 mmol/L. Mother solutions with different concentrations are added into the culture solution, and the final concentrations of benzopyrene in experimental groups are set as follows: 0. 2.5, 5, 10, 20, 40, 80. mu.M, and again placed back at 37 ℃ in 5% CO2The culture was continued for 24h under the conditions.
1.3MTT assay of cellular Activity
MTT powder was dissolved in PBS to prepare a 5mg/mL working solution, which was used after filtration. And after the cells are cultured for 20 hours, keeping out of the sun, adding 20 mu L of working solution into each hole, uniformly mixing, placing in a cell culture box for continuous culture for 4 hours, taking out the cells, attaching a sealing plate membrane, placing in a micropore plate centrifuge for centrifugation for 5min, pouring out liquid, sucking residual liquid by using filter paper, adding 150 mu L of dimethyl sulfoxide into each hole, shaking for 5s, and placing in a microplate reader for detecting the absorbance value at 570 nm.
1.4 statistical analysis
All experimental data are expressed as mean ± SEM, and each set of experiments was performed with mean values that were repeated at least 3 times independently. The experimental data were analyzed by SPSS statistics 19.0 software, with p <0.05 considered statistically significant; the histograms were all drawn by origin.9 software.
2. Results of the experiment
The influence of benzopyrene on the viability of RAW264.7 cells was determined by MTT method. As shown in figure 1, after the benzopyrene treatment for 24h and 48h, 0-40 μ M of the benzopyrene has no toxic effect on cells, while the high-dose group 80 μ M of the benzopyrene has toxic effect on cells (p is less than 0.01), and the toxicity is more remarkable in 48h than 24 h. Therefore, it was confirmed that the non-cytotoxic dose of benzopyrene to RAW264.7 was 0-40. mu.M, and the condition having no active effect on RAW264.7 cells was used in the subsequent procedures to induce lipid metabolism disorder.
Example 2 screening of conditions for benzopyrene-induced disorder of lipid metabolism in RAW264.7 cells
1. Test method
1.1 measurement of benzopyrene-induced accumulation of lipid droplets in RAW264.7 cells by oil Red O
Preparing an oil red O stock solution: 0.5g of oil red O dye is weighed by an electronic balance and dissolved in 100mL of isopropanol, the mixture is placed in a water bath kettle at 75 ℃ and kept out of the sun overnight until the dye is completely dissolved, a 0.45 mu m filter membrane is used for filtering, and the mixture is kept out of the sun and stored at 4 ℃ to be prepared for use. Preparing oil red O working solution: the stock solution and distilled water are prepared according to the proportion of 3: 2. After cell culture, washing with PBS for 3 times, adding 4% paraformaldehyde 300 μ L/well, and fixing in 37 deg.C incubator for 45 min; washing with PBS for 3 times, adding oil red O working solution 300 μ L/hole, and reacting in 37 deg.C incubator for 30 min; infiltrating cells with 60% isopropanol for 1-2s, rapidly removing, adding PBS, washing for 3 times, and observing under microscope; and (3) dyeing and quantifying the oil red O, adding 100% isopropanol to dissolve the oil red O, and detecting the absorbance at 570nm by using an enzyme-labeling instrument.
1.2 determination of changes in the Total Cholesterol content in cells
After the cell treatment, the cells were centrifuged at 1000rpm for 5min to remove the residual liquid, and 400. mu.L of total cholesterol cell lysate (5 × 10) was added6cells/100 muL) is cracked at room temperature for 30min, full cracking is guaranteed, centrifugation is carried out for 5min at 2000rpm after cracking is finished, supernate is taken for detection, operation is carried out according to the specification of a total cholesterol determination kit, and an enzyme-linked immunosorbent assay (ELIAS) is used for detecting the absorbance value at the wavelength of 550 nm; intracellular protein concentrations were determined using BCA protein quantification and results were evaluated as total cholesterol content per gram of protein.
1.3 determination of changes in intracellular triglyceride levels
After the cell treatment, the cells were centrifuged at 1000rpm for 5min to remove the residual liquid, and 400. mu.L of triglyceride cell lysate (5 × 10) was added6cells/100 muL) is cracked at room temperature for 30min, full cracking is guaranteed, centrifugation is carried out for 5min at 2000rpm after cracking is finished, supernate is taken for detection, operation is carried out according to the specification of a total cholesterol determination kit, and an enzyme-linked immunosorbent assay (ELIAS) is used for detecting the absorbance value at the wavelength of 510 nm; intracellular protein concentrations were determined using BCA protein quantification and results were evaluated as total cholesterol content per gram of protein.
1.4 statistical analysis
All experimental data are expressed as mean ± SEM, and each set of experiments was performed with mean values that were repeated at least 3 times independently. The experimental data were analyzed by SPSS statistics 19.0 software, with p <0.05 considered statistically significant; the histograms were all drawn by origin.9 software.
2. Results of the experiment
2.1 benzopyrene causes increased intracellular lipid droplet in RAW264.7 cells
As shown in FIG. 2, after treating RAW264.7 cells with 10. mu.M, 20. mu.M, and 40. mu.M benzopyrene for 24h, there was no significant change in the 10. mu.M, 20. mu.M benzopyrene groups compared to the blank group; when the benzopyrene concentration reached 40. mu.M, a large number of lipid droplets were produced in the cells compared to the blank group, and the accumulation of lipid droplets reached the maximum at 40. mu.M. Quantitative analysis of oil red O staining showed that 40. mu.M benzopyrene caused an increase in intracellular lipid droplets of RAW 264.7.
2.2 benzopyrene causes an increase in the intracellular Total Cholesterol (TC) content of RAW264.7
TC is total cholesterol in cells, and the result is shown in figure 3.a, after the RAW264.7 cells are treated by benzopyrene with different concentrations (10 muM, 20 muM and 40 muM) for 24h, the content of TC increases with the concentration of Bap in a dose-dependent manner compared with a blank group, and when the concentration reaches 40 muM, the content of TC is increased to a significant level (P <0.01) compared with the blank group, so that TC lipid is accumulated.
2.3 benzopyrene causes an increase in the level of RAW264.7 intracellular Triglyceride (TG)
TG is triglyceride in cells, and as shown in figure 3.b, after benzopyrene treatment of RAW264.7 cells for 24h at different concentrations (10. mu.M, 20. mu.M and 40. mu.M), the content of TG increased dose-dependently with the concentration of benzopyrene compared with the blank group, when the concentration reaches 20. mu.M, the content of TG increased significantly (P <0.05) compared with the blank group, and when the concentration of benzopyrene reaches 40. mu.M, the content of TG increased to a very significant level (P <0.01), which results in TG lipid accumulation.
These results indicate that treatment of RAW264.7 cells with 40 μ M benzopyrene for 24h can cause intracellular lipid accumulation, leading to the development of lipid metabolism disorders.
Example 3 selection of intervention concentration of Natural actives
The MTT method is used for measuring the change condition of cell activity after three natural active substances of salidroside, allicin and alliin are given to the cells, and then the safe treatment concentration for the cells is selected.
The results are shown in FIG. 4, and show that 0-100 μ M salidroside has no toxic effect on cells (p >0.05) after salidroside treatment for 24h, while high dose 200-. After the allicin treatment is carried out for 24 hours, 0-50 mu M of allicin has no toxic effect on cells, and more than 50 mu M of allicin has obvious toxic effect on cells (p is less than 0.05). After alliin treatment for 24h, the experimental groups all have no toxic effect on cells. According to experimental data, because the toxic dose of natural active substances has no research significance and provides a basis for subsequent evaluation of the optimal protective agent, the subsequent experiments determine that the experimental concentrations of salidroside, allicin and alliin are all 50 mu M.
Example 4 determination of lipid-lowering efficacy of Natural actives on benzopyrene-induced lipid metabolism disorder of RAW264.7 cells
1. Experimental methods
1.1 determination of the change in intracellular lipid droplet content following the coaction of Natural actives and benzopyrene
The concentrations of three natural active substances of salidroside, allicin and alliin are all 50 mu M, and the three natural active substances and 40 mu M benzopyrene jointly act on RAW264.7 cells for 24h, then oil red O staining is carried out, and the content of intracellular lipid droplets is quantitatively analyzed.
1.2 determination of the changes in the intracellular Total Cholesterol and triglyceride levels after the Co-action of Natural actives and benzopyrene
The concentrations of three intervention agents of salidroside, allicin and alliin are all 50 mu M, and the three intervention agents and 40 mu M benzopyrene jointly act on RAW264.7 cells for 24h, and then the contents of total cholesterol and triglyceride in the cells are measured.
1.3 determination of the expression of intracellular cAMP protein after the interaction of Natural active substances with benzopyrene
After the cells are treated, the original culture solution is discarded, PBS is added for washing twice, the cells are collected by scraping with the cells, the cells are centrifuged for 5min at 1000rpm, the supernatant is removed, 20-30 mul of cell lysate (RIPA cell lysate: PMSF ═ 100:1) is added, the cells are lysed for 30min at 4 ℃ to ensure full lysis, the cells are centrifuged for 20min at 4 ℃ and 3000rpm after lysis is finished, the supernatant is collected, and the cAMP protein expression condition is detected by using a cAMP ELISA detection kit.
2. Results of the experiment
2.1 Natural active substance can alleviate benzopyrene-induced increase of lipid droplets in RAW264.7 cells
The experimental results are shown in figure 5, and after the combined action of the active substances and salidroside, allicin and alliin for 24 hours, 50 mu M of each natural active substance respectively discovers that after oil red O staining, 40 mu M benzopyrene treatment on cells causes lipid accumulation, and has statistical significance (P is less than 0.01), and the natural active substances with different concentrations are added to improve the phenomenon to different degrees. Compared with benzopyrene group, 50 μ M salidroside can significantly reduce lipid accumulation (P <0.05), and both 50 μ M allicin and 50 μ M alliin can significantly reduce lipid accumulation (P < 0.01).
2.2 Natural active substance can relieve benzopyrene induced increase of Total Cholesterol (TC) and Triglyceride (TG) in RAW264.7 cell
The experimental result is shown in figure 6, compared with the blank group, the TC and TG contents in the cells are obviously increased (P is less than 0.01) after the benzopyrene treatment at 40 mu M, and after different natural active substances are added, compared with the benzopyrene group, the TC content can be reduced (P is less than 0.05) by 50 mu M of salidroside, but the TG content in the cells can not be obviously reduced; 50 mu M allicin and 50 mu M alliin can obviously reduce TC and TG contents (P is less than 0.01).
2.3 Natural active substances improve the Activity of cAMP proteins
cAMP is also an important signaling protein in lipid metabolism, and plays an important regulatory role in lipid metabolism. Results as shown in fig. 7, benzopyrene-treated cells significantly reduced cAMP activity compared to the blank group (P < 0.01); compared with benzopyrene group, different natural active substances are added, salidroside, allicin and alliin respectively improve the activity of cAMP to different degrees, and salidroside has obvious effect (P <0.05), and allicin and alliin have very obvious effect (P < 0.01).
In conclusion, the selected three natural active substances, namely salidroside, allicin and alliin, can play a role in reducing lipid levels to different degrees by reducing the accumulation of intracellular lipid drops, reducing the content of total cholesterol and triglyceride in cells and improving the activity of cAMP protein, and can relieve the lipid metabolism disorder of RAW264.7 cells induced by benzopyrene.
Claims (8)
1. Application of natural active substance in relieving lipid metabolism disorder of RAW264.7 cells induced by benzopyrene (Bap).
2. Use according to claim 1, characterized in that the natural active substance is used for benzopyrene-induced disorders of lipid metabolism.
3. The use according to claim 1, wherein the natural active substances are salidroside, allicin and alliin.
4. Use according to any one of claims 1 to 3, wherein the concentration of salidroside is from 50 μ M to 200 μ M.
5. Use according to any one of claims 1 to 3, wherein the allicin is used in a concentration of 25 μ M to 50 μ M.
6. The use according to any one of claims 1-3, wherein the concentration of alliin is 25 μ M to 1600 μ M.
7. The use according to any one of claims 1 to 6, wherein the natural active substance protects against lipid metabolism disorders induced by benzopyrene via at least one of the following pathways 1), 2), 3) and 4);
1) reducing the amount of lipid droplets in the cell;
2) reducing the total cholesterol level in the cells;
3) reducing intracellular triglyceride levels;
4) increasing the expression of cAMP protein.
8. The use according to claim 1 for screening natural active substances having a protective effect on lipid metabolism disorders induced by benzopyrene for use in the fields of medicine and functional foods.
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