CN109010325A - Diphenylethylene compounds from Chinese sesame slices are preparing the application in fat-reducing medicament - Google Patents

Diphenylethylene compounds from Chinese sesame slices are preparing the application in fat-reducing medicament Download PDF

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CN109010325A
CN109010325A CN201810732781.1A CN201810732781A CN109010325A CN 109010325 A CN109010325 A CN 109010325A CN 201810732781 A CN201810732781 A CN 201810732781A CN 109010325 A CN109010325 A CN 109010325A
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protein expression
fat
diphenylethylene compounds
compound
diphenylethylene
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CN109010325B (en
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刘庆超
白乃生
郭甜甜
刘浪浪
李国林
刘甜
韩稳荣
卢英辉
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Northwest University
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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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses the diphenylethylene compounds from Chinese sesame slices to prepare the application in fat-reducing medicament, it is tested by Raw264.7 mouse macrophage and hepatocellular carcinoma H22, the cytotoxicity of 3 kinds of diphenylethylene compounds is above 1mg/L, and by enhancing ABCG1 and SR-B1 protein expression, can make RAW264.7 macrophage [3H]-Cholesterol Efflux improve high density lipoprotein, in 1mg/L with the peculiar significant difference of fenofibrate；The expression of ABCA1, LDLR, SR-B1 and CYP7A1 albumen can be significantly improved, but PCSK9 is not influenced significantly.The above result shows that, 3 kinds of diphenylethylene compounds have lower cytotoxicity and higher activity to RCT correlative protein expression, the protein expression of raising SR-B1 and LDLR can be passed through, and the protein expression by increasing CYP7A1 is come synthetic bile acid, to improve transfer of the cholesterol to liver cell, the new fat-reducing medicament of one kind can be used as to apply.

Description

Diphenylethylene compounds from Chinese sesame slices are preparing the application in fat-reducing medicament
Technical field
The present invention relates to the diphenylethylene compounds from Chinese sesame slices to prepare the application in fat-reducing medicament.
Background technique
Chinese fiber crops are as a kind of natural plant resources, and in China, plantation has had thousands of years of history, are widely used in spinning It knits, the multiple fields such as medicine, food.Up to the present, a monomer chemical combination more than 700 has been isolated to from Chinese hemp plant Object is divided into cannabinol compounds and non-cannabinol compounds, (is divided into 10 kinds of main knots including Cannabinoids compound Structure type and other types, a monomeric compound more than totally 70), flavone compound (a monomeric compound more than 20), stilbene class chemical combination Object, triterpene compound, alkaloid compound and quinones etc..Just because of there is abundantization in Chinese hemp plant It studies point, so that it has many pharmacological activity.The bioactivity research of chemical component in Chinese hemp plant is shown greatly Numb phenolic compound has anticancer, antiemetic, anti-inflammatory, antioedematous and treatment neuropathy, cardiovascular disease, cerebral disorders, green light The effects of eye.
The primary pharmacological activity of diphenylethylene compounds have the induced defence function to plant, plant growth inhibitor and The effect of the suspend mode factor, antibacterial, antiviral, anthelmintic action.According to the literature, diphenylethylene isolated from Chinese hemp plant Compound about 30, bioactivity shows that it, with anti-inflammatory, anticancer, neuroprotection, anti-oxidant and antibacterial action, is also used as Long-lived agent.And the research about the diphenylethylene compounds Lipid-lowering activities in Chinese fiber crops has not been reported.
Summary of the invention
The purpose of the present invention is provide a kind of new application for the diphenylethylene compounds in Chinese fiber crops.
Diphenylethylene compounds in Chinese fiber crops are preparing the application in fat-reducing medicament, the diphenylethylene Closing object is any one in following compounds 1~3:
It is according to the invention of Publication No. CN 104447673A, entitled " Chinese fiber crops compound and its separation method " Method extracting and developing disclosed in patent application obtains.
The present invention is using the diphenylethylene compounds from Chinese sesame slices as effective component, the routinely preparation side of preparation Method, is such as suitable in stomach and the solid or liquid excipient of the organic or inorganic of parenteral administration with pharmaceutically acceptable carrier Agent mixing, is prepared into the drug or health care product with effect for reducing fat for being suitble to oral any dosage form, such as oral solution, tablet, glue Capsule, granule etc.；Or other injection dosage forms, such as injection, emulsion.
Beneficial effects of the present invention are as follows:
The present inventor is tested by Raw264.7 mouse macrophage and hepatocellular carcinoma H22,3 kinds of diphenylethylene chemical combination The cytotoxicity of object is above 1mg/L, especially compound HM3；And ABCG1 and SR-B1 is enhanced by compound HM1~HM3 Protein expression, can make RAW264.7 macrophage [3H]-Cholesterol Efflux raising high density lipoprotein, HM1 and HM2 exist Have significant difference when 1mg/L compared with fenofibrate, 3 kinds of diphenylethylene compounds can also significantly improve ABCA1, LDLR, The expression of SR-B1 and CYP7A1 albumen, but PCSK9 is not influenced significantly.The above result shows that 3 kinds of diphenylethylenes Closing object can be by improving the protein expression of SR-B1 and LDLR, and the protein expression by increasing CYP7A1 is come synthetic bile acid, from And improve transfer of the cholesterol to liver cell, and 3 kinds of diphenylethylene compounds have to RCT correlative protein expression it is lower thin Cellular toxicity and higher activity can be used as the new fat-reducing medicament of one kind to apply.
Detailed description of the invention
Fig. 1 is toxicity test figure of the compound 1 (HM1) to Raw264.7 mouse macrophage and hepatocellular carcinoma H22.
Fig. 2 is toxicity test figure of the compound 2 (HM2) to Raw264.7 mouse macrophage and hepatocellular carcinoma H22.
Fig. 3 is toxicity test figure of the compound 3 (HM3) to Raw264.7 mouse macrophage and hepatocellular carcinoma H22.
Fig. 4 is Cholesterol Efflux lab diagram of the compound 1~3 (HM1~HM3) to Raw264.7 mouse macrophage.
Fig. 5 is compound 1~3 (HM1~HM3) to 4 kinds of protein (ABCG1, ABCA1, SR-B1 and β-actin) electrophoresis Lab diagram.
Fig. 6 is activity experiment figure of the compound 1~3 (HM1~HM3) to ABCG1 albumen.
Fig. 7 is activity experiment figure of the compound 1~3 (HM1~HM3) to ABCA1 albumen.
Fig. 8 is activity experiment figure of the compound 1~3 (HM1~HM3) to SR-B1 albumen.
Fig. 9 is activity experiment figure of the compound 1 (HM1) to LDLR and SR-B1 albumen.
Figure 10 is activity experiment figure of the compound 2 (HM2) to LDLR and SR-B1 albumen.
Figure 11 is activity experiment figure of the compound 3 (HM3) to LDLR and SR-B1 albumen.
Figure 12 is activity experiment figure of the compound 1 (HM1) to PCSK9 and CYP7A1 albumen.
Figure 13 is activity experiment figure of the compound 2 (HM2) to PCSK9 and CYP7A1 albumen.
Figure 14 is activity experiment figure of the compound 3 (HM3) to PCSK9 and CYP7A1 albumen.
Specific embodiment
The present invention is described in more detail with reference to the accompanying drawings and examples, but protection scope of the present invention is not limited only to These embodiments.
ABCG1 represents adenosine triphosphate (ATP) binding cassette transporters G1；ABCA1 represents adenosine triphosphate (ATP) combination Cassette transporters A1；SR-B1 represents I type scavenger receptor protein of B race；LDLR represents low-density lipoprotein；CYP7A1 represents gallbladder 7 α hydroxylase of sterol；PCSK9 represents 9 albumen of proprotein convertase subtilisin inhibitor, and (cholesterol drugs target egg It is white)；RCT GAP-associated protein GAP represents reverse cholesterol GAP-associated protein GAP；FB represents fenofibrate；β-actin represents beta-actin.
Embodiment 1
From the effect for reducing fat of the diphenylethylene compounds 1~3 (HM1~HM3) of Chinese sesame slices
1, Macrophage cholesterol outflow test
Raw264.7 mouse macrophage is placed in 24 orifice plates, and final densities are every hole 5 × 104A cell.After 6 hours, Culture medium is abandoned, phosphate buffer (PBS) gently washs cell 3 times.Contain the Dulbecco of 1% fetal calf serum to 600 μ L Improvement Iger (DMEM) culture medium in be added 1 μ Ci/mL [3H] calculating of-cholesterol [3H]-cholesterol total amount, then be separately added into each Hole is incubated for 24 hours.
PBS is washed 3 times, when existing or lacking 1.0mg/L sample to be tested, then 500 μ L contain 1% fetal calf serum DMEM training It supports and is incubated for 4 hours in base, 100 μ L high-density lipoprotein media are then added, it is small to continue incubation 6 in 20 μ g/mL for ultimate density When.Culture medium is collected in the microfluid pipe of 1.5mL, is centrifuged 10 minutes with 14000 revs/min at room temperature, to remove cell Fragment.Cell handles half an hour with 1mL n-hexane/isopropanol (volume ratio 3:2) mixed solvent room temperature.Extract is transferred to In the microfluid pipe of 1.5mL, continue to be centrifuged 10 minutes with 14000 revs/min at room temperature, to remove cell fragment.After centrifugation, The medium or cell extract of 200 μ L is transferred in 5mL scintillation vial, is uniformly mixed.Control group be [3H]-cholesterol and high density Lipoprotein receptor balance, but there is no drug therapy.Scintillation vial is counted using liquid scintillation counter.Cholesterol Efflux Rate expression [3H] the ratio of-cholesterol from cell to receptor.The calculated result of Cholesterol Efflux rate is as follows: medication therapy groups gallbladder is solid Alcohol discharge rate (%) subtracts control group Cholesterol Efflux rate (%).
In immunoblotting experiment, Raw264.7 mouse macrophage is placed in 6 orifice plates, final densities be every hole 1 × 104A cell.After 6 hours, culture medium is abandoned, PBS is gently washed cell 3 times.In the presence of or missing 1mg/L sample to be tested, cell Continuation is cultivated 4 hours in the DMEM culture medium that 1.0mL contains 1% fetal calf serum.
2, hepatocellular carcinoma H22 test experience
Hepatocellular carcinoma H22 is placed in 6 orifice plates, final densities are every hole 1 × 104A cell.After 6 hours, training is abandoned Base is supported, PBS is gently washed cell 3 times.In the presence of or missing 0.25mg/L (low dosage), 0.5mg/L (middle dosage), 1mg/L (high agent Amount) sample to be tested, cell continuation cultivated 4 hours in the DMEM culture medium that 1.0mL contains 1% fetal calf serum.
3, Separation of Proteins, electrophoresis and Blot experiment
According to the specification of manufacturer, using the RIPA lysis buffer containing complete protease inhibitor from processing and not Total protein is extracted in the cell of processing.The protein of equivalent carries out 12% or 10% polyacrylamide gel electrophoresis, and passes through electricity Trace is transferred on polyvinylidene fluoride film.At room temperature, in the trihydroxy methyl ammonia containing 0.1% Tween-20 and 5% skimmed milk power After blocking 2 hours in methylmethane buffered saline, at 4 DEG C, film and original antibody are incubated with overnight.Contain 0.1% Tween-20 After trimethylolaminomethane buffered saline is washed 3 times, it is small that 2 are incubated for peroxidase-conjugated secondary antibody at room temperature When.Immunoblotting is reacted by electrochemical luminescence to be shown, and is visualized with high performance chemiluminescence film.Using software into Line density measurement analysis, and normalized by internal affairs actin.
From Fig. 1~3 as can be seen that the cytotoxicity of 3 kinds of diphenylethylene compounds is above 1mg/L, especially chemical combination Object HM3.From Fig. 4~8 it is known that passing through the protein expression of enhancing ABCG1 and SR-B1, RAW264.7 macrophage can be made [3H]-Cholesterol Efflux raising high density lipoprotein, HM1 and HM2 have conspicuousness poor in 1mg/L compared with fenofibrate Different, 3 kinds of diphenylethylene compounds can also significantly improve the expression of ABCA1 albumen.Further study HM1~HM3 pairs of compound The influence of LDLR, SR-B1 and CYP7A1 protein expression can be seen that compound HM1 and HM3 performance from the experimental result of Fig. 9~14 Optimal effect out, however they do not influence PCSK9 significantly.The above result shows that 3 kinds of diphenylethylene compounds can By improving the protein expression of SR-B1 and LDLR, and by the protein expression of increase CYP7A1 come synthetic bile acid, to improve Transfer of the cholesterol to liver cell.
In conclusion 3 kinds of diphenylethylene compounds have lower cytotoxicity and higher to RCT correlative protein expression Activity, they can be used as a kind of new fat-reducing medicament to apply.

Claims (1)

1. the diphenylethylene compounds from Chinese sesame slices are preparing the application in fat-reducing medicament, the diphenylethylene chemical combination Object is any one in following compounds 1~3:
CN201810732781.1A 2018-07-05 2018-07-05 Application of stilbene compounds derived from hemp leaf in preparing lipid-lowering medicines Expired - Fee Related CN109010325B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824489A (en) * 2019-04-18 2019-05-31 兰州大学 A kind of compound with anti-inflammatory activity extracted from Radix Glycyrrhizae and its application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159688A1 (en) * 2013-03-14 2014-10-02 Sc Laboratories, Inc. Bioactive concentrates and uses thereof
CN104447673A (en) * 2014-12-06 2015-03-25 西北大学 Novel China-hemp compounds and separation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014159688A1 (en) * 2013-03-14 2014-10-02 Sc Laboratories, Inc. Bioactive concentrates and uses thereof
CN104447673A (en) * 2014-12-06 2015-03-25 西北大学 Novel China-hemp compounds and separation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
张黎明 等: "汉麻叶总黄酮和总多酚的同步提取工艺优化及抗氧化活性", 《食品科技》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824489A (en) * 2019-04-18 2019-05-31 兰州大学 A kind of compound with anti-inflammatory activity extracted from Radix Glycyrrhizae and its application

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