CN113491702A - Application of crocin-1 and/or crocin-2' in preparation of medicines for reducing blood fat and protecting endothelial cells - Google Patents
Application of crocin-1 and/or crocin-2' in preparation of medicines for reducing blood fat and protecting endothelial cells Download PDFInfo
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- CN113491702A CN113491702A CN202111021836.6A CN202111021836A CN113491702A CN 113491702 A CN113491702 A CN 113491702A CN 202111021836 A CN202111021836 A CN 202111021836A CN 113491702 A CN113491702 A CN 113491702A
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- crocin
- crocetin
- endothelial cells
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Abstract
The invention discloses an application of crocin-1 and/or crocin-2 'in preparing medicaments for reducing blood fat and protecting endothelial cells, wherein crocetin monoglucoside (crocin-1) and crocetin biglucoside (crocin-2') can inhibit the action of MEK/ERK signal channels and reduce the secretion of inflammatory factors TNF-alpha and IL-6, thereby resisting the damage effect of oxidized low-density lipoprotein (ox-LDL) on Human Umbilical Vein Endothelial Cells (HUVECs); in addition, animal experiments show that crocin-1 and crocin-2' can effectively reduce lipid accumulation in the zebra fish juvenile fish, reduce the risk level of an atherosclerosis high-risk zebra fish model, and have potential as a lipid-lowering drug. The invention explores the pharmacological actions of two rare crocetin glycosides crocin-1 and crocin-2' for the first time, and provides a basis for further developing the application of the crocin glycosides crocin reducing blood fat, reducing the risk of atherosclerosis and protecting endothelial cells.
Description
Technical Field
The invention relates to the field of medicines for treating atherosclerosis, and relates to the effects of crocetin monoglucoside (crocin-1) and crocetin biglucoside (crocin-2') in preparing medicines for reducing blood fat and protecting endothelial cells.
Technical Field
In traditional Chinese medicine, saffron has mild nature and sweet taste, can dispel stagnation and resolve stagnation, and can promote blood circulation to remove blood stasis, and is also commonly used for treating gynecological diseases, dysentery, jaundice, hepatosplenomegaly, fever and other diseases (Scientific Reports,2016,6(1): 19809). With the intensive research on saffron crocus, the saffron crocus can prevent and treat atherosclerosis and cardiovascular diseases, can inhibit cancer cell diffusion and resist oxidation, can also treat liver diseases such as cirrhosis and the like, and has the effects of resisting memory loss caused by ethanol, improving the immune function of an organism, preventing retinal degeneration and the like.
The saffron has several active components, mainly concentrated in stigma of saffron, and mainly contains carotenoid and its glucoside, phenolic acid and its glucoside and trace elements. The effective components in crocus sativus stigma which can play pharmacological roles are mainly carotenoids and their glycosides, such as crocetin (crocetin), crocetin glycoside (crocins), dimethyl crocetin (dimetyl-crocetin), picrocin (picrococin) and the like (Phytotherapy Research,2013,27(4): 475-. Wherein, crocetin glycoside is also called as crocin, crocin and the like, is the main effective active ingredient of traditional Chinese medicine saffron, and is a water-soluble carotenoid. The prior studies have confirmed that crocetin glycoside has pharmacological activity for anti-tumor and treatment of cardiovascular and nervous system diseases (Avicenna Journal of phytomedine, 2017,7(4): 345-352). According to the difference of glycosyl type and glycosylation position, crocetin glucoside can be divided into crocetin monoglucoside (crocin-1), crocetin monogentiobioside (crocin-2), crocetin biglucoside (crocin-2'), crocetin glucoside-3 (crocin-3) and crocetin bicholesticoside (crocin-4), and the structural formula is as follows:
in natural plants, crocin-3 and crocin-4 account for more than 94% of total crocetin glucoside in the bodies of the plants, and other rare crocetin glucosides such as crocin-1 and crocin-2' are difficult to separate and obtain, so that the pharmacological activity research on the crocetin glucosides is mainly carried out on the basis of the crocin-4 at present.
He et al (Life Sciences,2005,77(8): 907-. After administration of crocin-4, it is found that crocin-4 not only can reduce EC apoptosis, but also can inhibit smooth muscle cells [ Ca2+]i is increased, thereby regulating gene expression of smooth muscle cells, reducing cholesterol ester in macrophages and inhibiting the formation of foam cells, thereby playing the role of resisting AS. Li et al (International Immunopharmacology,2018,55:120-3(VD3) Induced coronary atherosclerosis model of rat, treatment by administration of crocin-4, results showed that crocin-4 could not only pass throughThe pharmaceutical composition can reduce the blood lipid level by reducing the levels of endothelin, Total Cholesterol (TC), Triglyceride (TG) and low density lipoprotein (LDL-c) and increasing the level of high density lipoprotein (HDL-c), and can effectively relieve inflammatory reaction by inhibiting the expression of proinflammatory cytokines and increasing the level of anti-inflammatory cytokines.
It was found that crocin-4 is more effective than crocetin by evaluating the in vitro antioxidant and neuroprotective activity of crocin-4 and crocetin (Journal of Agricultural and Food Chemistry,2005,53(18): 7302) 7306). The pharmacokinetic study shows that crocin-4 is finally in the form of crocetin or in the form of derivatives such as monoglucuronide and diglucoside after being hydrolyzed by intestinal flora in vivo (Journal of Chromatography B,2017, 1044: 1045: 1-7).
The invention researches that crocetin glycosyltransferase (Bs-GT) derived from microorganisms with proprietary property rights in a laboratory is adopted, wherein the Bs-GT can transfer glycosyl of uridine diphosphate glucose (UDPG) onto crocetin by taking the crocetin as a substrate, and then dimethyl sulfoxide (DMSO) with different concentrations is added into a system to selectively biosynthesize crocin-1 and crocin-2' (Journal of agricultural and food chemistry,2019,67(45): 12496-.
The invention carries out pharmacological research on crocetin glucoside crocin-1 and crocin-2' obtained by the method. The crocin-1 and crocin-2' can obviously resist the damage effect of oxidized low-density lipoprotein (ox-LDL) on Human Umbilical Vein Endothelial Cells (HUVECs); the crocin-1 and crocin-2' can comprehensively regulate the levels of TG, TC, LDL-c and HDL-c of zebra fish fed by high-cholesterol feed, thereby obviously reducing the atherosclerosis index.
Disclosure of Invention
The invention aims to provide application of crocetin monoglucoside (crocin-1) and/or crocetin biglucoside (crocin-2') in preparation of a medicine for reducing blood fat and protecting vascular endothelial cells.
In order to solve the problems, the invention prepares the rare crocetin glucoside by an enzyme method, separates and purifies the crocetin glucoside, and performs pharmacological research. Crocetin glucoside is an important active ingredient of traditional Chinese medicine saffron, wherein crocetin bischoledocoside (crocin-4) is used as crocetin glucoside with the largest content, and the anti-atherosclerosis effect of the crocetin bischoledocoside is widely researched. The invention firstly researches the pharmacological action of rare crocetin glucoside, i.e. crocetin monoglucoside (crocin-1) or crocetin biglucoside (crocin-2'), and discovers that the crocin diglucoside has obvious effects on reducing blood fat and protecting vascular endothelial cells through cell experiments and animal experiments.
The first purpose of the invention is to provide the application of crocin-1 and/or crocin-2' in preparing vascular endothelial cell protective drugs.
As a preferred embodiment, the concentration of crocetin monoglucoside (crocin-1) is 0.02-6. mu.g/mL, more preferably 2-4. mu.g/mL.
As a preferred embodiment, the concentration of crocetin diglucoside (crocin-2') is 0.02-6 μ g/mL; more preferably 0.1 to 5. mu.g/mL.
As a preferred embodiment, the crocin-1 or crocin-2' inhibits the inflammatory response process of the MEK/ERK signaling pathway.
As a preferred embodiment, the crocin-1 or crocin-2' inhibits the expression levels of proinflammatory cytokines from the MEK/ERK signaling pathway.
As a preferred embodiment, the proinflammatory cytokine comprises TNF- α, IL-6.
The second purpose of the invention is to provide the application of crocin-1 and/or crocin-2' in preparing hypolipidemic drugs.
In a preferred embodiment, the concentration of crocin-1 is 25-100. mu.g/mL; preferably 25-50. mu.g/mL.
In a preferred embodiment, the concentration of crocin-2' is 25-100. mu.g/mL; preferably 50-100. mu.g/mL.
The invention selects HUVECs, pre-protects cells by crocin-4, crocin-1 and crocin-2 ', then treats the cells by ox-LDL, detects the protection effect of crocetin glucoside with different concentrations on the cells by an MTT method, and explores the action mechanisms of the crocin-1 and the crocin-2' by an ELISA method and an RT-PCR method. Cell experiments show that crocin-1 and crocin-2' can effectively protect ox-LDL from cell damage to HUVECs within the concentration range of 0.02-6 mug/mL, and are expected to be used for preparing novel endothelial cell protection medicaments. In addition, one of the discovered pathways of action of crocin-1 and crocin-2' is to reduce the levels of TNF-alpha and IL-6 factors by inhibiting the MRK/ERK pathway to achieve endothelial cell protection.
The invention also selects zebra fish embryos to feed high-cholesterol feed for modeling, and respectively adds crocin-1 and crocin-2' into culture water for administration, and observes the levels of TG, TC, LDL-c and HDL-c in the bodies of the zebra fish embryos so as to indicate the atherosclerosis indexes of the zebra fish embryos. The results show that the crocin-1 and the crocin-2' can effectively reduce the risk level of the zebra fish with high risk of atherosclerosis in the concentration range of 25-100 mu g/mL, have the potential of being used as a blood fat reducing drug and an anti-atherosclerosis drug, and provide a new drug choice for treating blood fat reduction and atherosclerosis.
Drawings
FIG. 1 is a graph of the growth of HUVECs treated with different concentrations of ox-LDL.
FIG. 2 is a comparison of the concentration ranges of lovastatin and crocin-4 administered for vascular endothelial cell protection.
FIG. 3 shows the relative activities of HUVECs after pretreatment with different concentrations of crocin-1, crocin-2', crocin-4 followed by induction of cells with ox-LDL.
FIG. 4 shows the MEK content in cells after ELISA detection of crocin-1 and crocin-2' for pretreatment of HUVECs and induction of cells with ox-LDL.
FIG. 5 shows the content of ERK in cells after ELISA detection of crocin-1 and crocin-2' for pretreatment of HUVECs and induction of cells with ox-LDL.
FIG. 6 shows the mRNA fold difference of TNF-alpha in cells after pretreatment of HUVECs by RT-PCR detection of crocin-1 and crocin-2' and induction of cells with ox-LDL.
FIG. 7 shows the mRNA fold difference of IL-6 in cells after pretreatment of HUVECs by RT-PCR detection of crocin-1 and crocin-2' and induction of cells with ox-LDL.
FIG. 8 shows the TG content in each group of zebrafish.
FIG. 9 shows the LDL-c content in zebrafish per group.
FIG. 10 shows the HDL-c content in each group of zebrafish.
FIG. 11 shows the effect of crocin-1, crocin-2', crocin-4 on the atherosclerotic index of zebrafish.
Detailed Description
Example 1
This example illustrates the selection method of concentration of ox-LDL as an agent for inducing HUVECs in the body and the MTT assay method.
Experiments were divided into blank control and ox-LDL administration groups, HUVECs grown to logarithmic growth phase were inoculated into 96-well plates, 100. mu.L of cell suspension was inoculated per well, and the number of cells per well was 5X 103-104PBS was added to the edge wells. And (5) placing the cells in a cell culture box for culturing for 24 hours until the cells grow completely adherent.
According to the experimental grouping design, 200. mu.L of culture medium containing different concentrations of ox-LDL is added after the original culture medium is aspirated from each well, and 5 multiple wells are arranged in each group. And (3) continuing culturing after adding medicine, and taking out one plate every 24h for MTT detection: adding 20 mu L of MTT solution of 5 mu g/mL into each hole, placing the mixture in a cell culture box for continuous incubation, absorbing the culture solution in each hole after 4h, adding 150 mu L of DMSO, placing the mixture on a horizontal low-speed shaking table, shaking the mixture for 15min to fully dissolve the colored substances in each hole, and measuring A by using a microplate reader570。
As can be seen from FIG. 1, the ox-LDL concentration was 1-10. mu.g/mL, which exhibited a promoting effect on the proliferation of HUVECs and did not exhibit an effect of inhibiting cell growth; in the ox-LDL concentration range of 50-150 mug/mL, the ox-LDL inhibitor has an inhibition effect on the proliferation of HUVECs. After considering the inhibition effect and the cost together, the experiment selects 100 mug/mL of ox-LDL as the cell proliferation inhibitor to carry out the next experiment.
Example 2
This example illustrates the treatment of HUVECs with lovastatin, crocin-4, crocin-1, and crocin-2'.
According to the experimental grouping design, the culture medium of each hole is sucked out and then the culture medium containing drugs with different concentrations is added, 5 multiple holes are arranged in each group, after the drugs are added, the culture is continued for 12 hours, then ox-LDL is added into the holes except for a blank group until the concentration is 100 mug/mL, the same amount of sterile PBS is added into the blank group, the culture is continued for 24 hours, and then the MTT detection is carried out.
Firstly, lovastatin is used as a positive control, and compared with the administration concentration of crocetin glycoside-4, appropriate administration concentration is preliminarily screened, and as can be seen from figure 2, lovastatin presents a protective effect on vascular endothelial cells at the administration concentration of 50-150 μ g/mL, and crocetin glycoside-4 presents a stronger protective effect on endothelial cells at the administration concentration of 1-5 μ g/mL respectively, which indicates that the protective effect of crocetin glycoside-4 on vascular endothelial cells at low concentration is more significant. The structure of crocetin glucoside-4 is similar to that of two rare crocetin glucosides to be researched in the experiment, and the significant human umbilical vein endothelial cell protection effect can be displayed under low concentration, so that the effect of the rare crocetin glucoside on cells is further researched, and the concentration range is preliminarily set between 0.02 and 6 mu g/mL.
Next, by exploring the effect of crocetin glycoside-4, crocetin glycoside-1 (crocin-1) and crocetin glycoside-2 '(crocin-2') at different concentrations on the protective effect of HUVECs, it can be seen from FIG. 3 that the dose-dependent effect of crocin-1 and crocin-2 'on the cytoprotective effect is observed in the concentration ranges of 0.02-4 μ g/mL and 0.02-5 μ g/mL, respectively, and the cytoprotective effect of crocin-2' is more significant in the concentration range of 0.02-6 μ g/mL than that of crocin-1 and crocin-4 at the same concentration.
Example 3
This example illustrates an ELISA method for measuring MEK and ERK levels in HUVECs.
Designing an experimental group: control group, model group, administration group. HUVECs grown to logarithmic growth phase were seeded in 6-well plates, 2mL of cell suspension per well, approximately 1 x 10 cells per well5And culturing for 24h until the cells grow completely adherent. Adding culture solution containing different concentrations of drugs according to experimental groups, culturing for 12 hr, adding ox-LDL toThe concentration was 100. mu.g/mL, and the cell culture broth was collected after further culturing for 24 hours. After centrifugation at 2500rpm/min for 15min, the centrifugation supernatant was collected.
The expression level of MEK and ERK in each group of cells was determined according to the kit instructions. As can be seen from fig. 4 and 5, the ox-LDL induced MEK and ERK levels significantly increased, whereas the cells were treated with different concentrations of rare crocetin glycoside and then induced with ox-LDL, the ERK and MEK expression levels of the cells were decreased compared to the model group, and gradually tended to the blank control group as the administration concentration of crocetin glycoside increased. Previous studies have shown that ox-LDL causes reduced proliferation of HUVECs, while MEK and ERK levels tend to increase, indicating that the proliferation inhibition effect of ox-LDL on HUVECs and the protective effect of crocin-1 and crocin-2' on HUVECs may not be related to the proliferation promoting effect of MEK/ERK signaling pathway, and may be related to the inflammation promoting effect of ERK pathway.
Example 4
This example illustrates a method for RT-PCR detection of TNF- α and IL-6 levels in HUVECs.
Designing an experimental group: control group, model group, administration group. Extracting total RNA of cells according to the instruction of the kit, then carrying out reverse transcription to synthesize cDNA, then carrying out RT-PCR of target genes, and selecting beta-actin as an internal reference gene. Through 2-ΔΔCtMethod for analyzing the expression level of a gene. As can be seen from FIGS. 6 and 7, the expression levels of TNF- α and IL-6 in the cells treated with ox-LDL increased significantly, while those in the cells pretreated with crocin-1 and crocin-2' decreased, and gradually increased toward the control level with the increase in the administration concentration of the rare crocetin glycoside. Therefore, crocin-1 and crocin-2' play a role in protecting HUVECs by reducing inflammatory response of cells in a certain concentration range.
Example 5
This example illustrates a method for breeding adult wild zebrafish and zebrafish embryos.
The method comprises the following steps of (1) feeding conditions of adult zebra fish: feeding in a zebra fish culture system, wherein the circulating water temperature is 28 +/-0.5 ℃, and the illumination period is 14h (Ming): the feed is fed to tropical fish for 10h (dark) in the morning and at night.
The zebra fish juvenile fish breeding conditions are as follows: in 90mm plastic culture dishes, 50 juvenile fishes per culture dish are cultured in 60mL of culture water, the water temperature is 28 +/-0.5 ℃, and the illumination period is 14h (Ming): the special feed for the zebra fish juvenile fish is fed for one time in the morning and at night for 10h (dark). The culture water is directly taken from a pH and conductivity regulator connected with the zebra fish culture system, the pH value range is 7.2-7.6, and the conductivity range is 500-550.
Example 6
This example illustrates the formulation of a 5% (w/w) cholesterol zebrafish feed.
Weighing cholesterol according to the proportion of 5% (w/w) and zebra fish feed, dissolving with a small amount of diethyl ether in a fume hood, stirring until the cholesterol is completely dissolved, adding the feed, continuously stirring until the diethyl ether is volatilized to uniformly attach the cholesterol to the feed, and airing for 4h in the fume hood.
Example 7
This example illustrates the method of obtaining zebrafish embryos.
Putting adult zebra fish in a mating box at 9:00 night, wherein the number ratio of female fish to male fish is 2:1, separating male fish from female fish by using a partition plate, taking out the partition plate at 8:00 morning after keeping out of the sun overnight, mating for 0.5-1h, fishing out the adult fish, collecting fertilized eggs settled at the bottom of the box, observing the fertilized eggs by using a magnifying lens, selecting healthy and plump semitransparent eggs, putting the eggs in a 90mm plastic culture dish filled with culture water, and changing the water once a day.
Example 8
This example illustrates the feeding pattern of zebrafish embryos in experimental groups.
Healthy 5dpf zebra fish larvae were selected for the grouping experiment. Drug-containing solutions of different concentrations were prepared from the culture solutions, and used as water for culture in the drug administration groups. Groups were designed according to the experiment as follows: blank group, high-cholesterol feed group and administration group, wherein each group contains 50 juvenile fishes. Feeding the zebra fish in groups according to experiments, and detecting each group of zebra fish at 15 dpf.
Example 9
This example illustrates the detection of TG, LDL-c and HDL-c in zebrafish larvae.
And (3) adding 500 mu L of double distilled water into 30 young fishes per group, carrying out ultrasonic disruption for 5min by using an ultrasonic disruptor, centrifuging at 2000rpm/min for 10min, collecting supernatant, and respectively detecting the lipid level of each group of zebra fishes according to the specification of TG, LDL-c and HDL-c detection kits.
From fig. 8 to fig. 10, it can be seen that the TG, TC, and LDL-c levels of zebra fish in the administration group decreased with the increase of the administration concentration and the HDL-c level increased with the increase of the administration concentration, compared to the model group, indicating that both of the rare crocetin glycosides were effective in reducing the increase of lipid levels due to the high cholesterol feed.
According to the relevant research standard of the atherosclerosis index, AIP less than 0.11 is low risk, AIP more than or equal to 0.11 and less than or equal to 0.21 is medium risk, and AIP more than 0.21 is high risk. As can be seen from fig. 11, the AIP of zebrafish was elevated to a high risk level by feeding high cholesterol feed, while the AIP of zebrafish gradually decreased to a low risk level after administration by feeding water. Therefore, it can be found that in a certain concentration range, the crocin-1 and the crocin-2' have better potential as lipid-lowering drugs and anti-atherosclerosis drugs by taking the crocin-4 as a contrast; under the test conditions, the control crocin-4 can reduce the atherosclerosis index of the high-fat zebra fish to low risk under the condition of 100 mu g/mL of administration concentration, and the administration concentrations of the two crocetin glycosides crocin-1 and crocin-2' for reducing the atherosclerosis index of the high-fat zebra fish to low risk are respectively 25 mu g/mL and 50 mu g/mL.
Claims (9)
1. Application of crocin-1 and/or crocin-2' in preparation of vascular endothelial cell protective drugs.
2. The use according to claim 1, wherein the concentration of crocin-1 is 0.02-6 μ g/mL; preferably 2-4 mug/mL.
3. The use according to claim 1, wherein the concentration of crocin-2' is 0.02-6 μ g/mL; preferably 0.1-5 mug/mL.
4. The use according to any one of claims 1 to 3, wherein crocin-1 or crocin-2' inhibits the inflammatory response process of the MEK/ERK signalling pathway.
5. The use according to any one of claims 1 to 3, wherein crocin-1 or crocin-2' inhibits the expression level of pro-inflammatory cytokines in the MEK/ERK signalling pathway.
6. The use according to claim 5, wherein the proinflammatory cytokines comprise TNF- α, IL-6.
7. Application of crocin-1 and/or crocin-2' in preparing medicines for reducing blood lipid and atherosclerosis risk.
8. The use according to claim 7, wherein the concentration of crocin-1 is 25-100 μ g/mL; preferably 25-50 mug/mL.
9. The use according to claim 7, wherein the concentration of crocin-2' is 25-100 μ g/mL; preferably 50-100 mug/mL.
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