CN115120583A - Application of phenylpropanoid derivatives in preparation of drugs for preventing and treating liver failure - Google Patents
Application of phenylpropanoid derivatives in preparation of drugs for preventing and treating liver failure Download PDFInfo
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- CN115120583A CN115120583A CN202210805905.0A CN202210805905A CN115120583A CN 115120583 A CN115120583 A CN 115120583A CN 202210805905 A CN202210805905 A CN 202210805905A CN 115120583 A CN115120583 A CN 115120583A
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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
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses an application of phenylpropanoid derivatives in preparing a medicament for preventing and treating liver failure,
r in the formula (1) 1 And R 2 Each independently is C1-C6 alkyl or C1-C6 alkenyl. The phenylpropanoid derivative disclosed by the invention is applied to prevention and treatment of acute liver failure of mice induced by combination of LPS/D-GlaN. Experimental research shows that 4-methoxy-2- (3-methyl epoxy ethyl) -phenyl isobutyrate can effectively improve liver blood stasis, edema and liver tissue disorder induced by LPS/D-GlaN and effectively reduce serum glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase; simultaneously increasing glutathione, catalase and total superoxide dismutase level of liver tissue, inhibiting hepatocyte apoptosis and reducing malondialdehyde level of lipid peroxidation product, and can be used for treating acute liver failure or chronic acute liver failureThe prevention and treatment of liver failure has important application value and wide application prospect.
Description
(I) the technical field
The invention belongs to the technical field of biological medicines, and relates to an application of phenylpropanoid derivatives in preparation of medicines for preventing and treating acute liver failure or chronic acute liver failure.
(II) background of the invention
Acute Liver Failure (ALF) is a serious disease caused by various factors, and causes massive hepatocyte apoptosis and necrosis in a short time, and causes liver failure, and the death rate is extremely high. Viral infections (such as hepatitis B virus, hepatitis E virus, etc.), Chinese herbal medicines, acetaminophen, etc., and alcoholism are major factors causing ALF, and the incidence rate tends to increase gradually in recent years. However, the clinical application lacks of specific medicines, and the main clinical treatment methods of the traditional Chinese medicine comprise the elimination of causes of diseases, the improvement of liver functions, the prevention of complications, artificial liver treatment, liver transplantation and the like; the latter is the most effective method for treating liver failure, but the liver source is scarce, the cost is high and the clinical requirement is difficult to meet. Therefore, there is still a need to increase the power to find effective therapeutic drugs for preventing or alleviating ALF.
A suitable animal model is a sharp instrument that finds drugs that antagonize liver failure. Lipopolysaccharide (LPS) and D-Galactosamine (D-Galactosamine, D-GlaN) are combined to induce acute liver failure cells, and each index change of an animal model is basically consistent with the acute liver failure induced by factors such as viruses and medicaments in clinic, so that the ALF model is one of the currently accepted ALF models. Therefore, the tracking, guidance, screening and comprehensive evaluation of the medicine for preventing and treating acute liver failure by using the LPS/D-GlaN induced cells and the mouse ALF model have important significance for the discovery of active components for protecting the liver and the development of related medicines.
According to the literature data, no research report on the research on the acute liver failure of the 4-methoxy-2- (3-methyl-ethylene oxide) -phenyl isobutyrate and the 2-methyl, 4-methoxy-2- (3-methyl-2-ethylene oxide) phenyl butyrate phenylpropanoid derivative is found.
Disclosure of the invention
The invention aims to provide an application of phenylpropanoid derivatives in preparation of drugs for preventing and treating acute liver failure or chronic acute liver failure, and particularly provides 4-methoxy-2- (3-methyl oxirane) -phenyl isobutyrate and 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate, which have a good antagonistic effect on acute liver failure induced by LPS/D-GlaN. At present, the clinical treatment of acute liver failure lacks specific drugs, and the phenylpropanoid derivatives such as 4-methoxy-2- (3-methyl oxirane) -phenyl isobutyrate and 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate disclosed by the invention show good development and utilization prospects in the aspect of preparing drugs for preventing and treating acute liver failure.
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows:
the invention provides application of phenylpropanoid derivatives shown in formula (1) in preparation of a drug for preventing and treating liver failure, wherein the drug is a drug for preventing and treating acute liver failure or chronic acute liver failure;
r in the formula (1) 1 And R 2 Each independently is C1-C6 alkyl or C1-C6 alkenyl, preferably C1-C2 alkyl; wherein R is 1 Preferably methyl, R 2 Preferably methyl or ethyl.
Preferably, the compound of formula (1) is one of the following: 4-methoxy-2- (3-methyloxiranyl) -phenylbutyrate (I) and 2-methyl, 4-methoxy-2- (3-methyl-2-oxiranyl) phenylbutyrate (II) having the following structural formula:
preferably, the medicament is a medicament for reducing serum alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST); the medicine is a medicine for improving the levels of Glutathione (GSH), Catalase (CAT) and total superoxide dismutase (SOD) in liver tissues; the medicine is used for inhibiting hepatocyte apoptosis and reducing lipid peroxidation product Malondialdehyde (MDA).
Preferably, the medicine is a medicine for preventing and treating LPS/D-GlaN-induced acute liver failure or chronic acute liver failure.
The medicine also comprises other medicines for preventing and treating acute liver failure or chronic acute liver failure, namely the medicine takes 4-methoxy-2- (3-methyl oxirane) -phenyl isobutyrate or 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate as a single active ingredient or a mixture of the two or takes other medicines for preventing and treating acute liver failure or chronic acute liver failure as active ingredients together.
The medicine also comprises pharmaceutically acceptable medicine carriers or excipients, and can be prepared into various pharmaceutically acceptable dosage forms, including but not limited to capsules, tablets, injections, granules, emulsions, pastes, patches, pills, syrups and the like.
Compared with the prior art, the invention has the following beneficial effects: the invention provides application of phenylpropanoid derivatives in preparation of drugs for preventing and treating acute liver failure or chronic acute liver failure, in particular application of 4-methoxy-2- (3-methyl oxirane) -phenyl isobutyrate and 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate in prevention and treatment of acute liver failure of mice induced by combination of LPS/D-GlaN. Experimental research shows that 4-methoxy-2- (3-methyl epoxy ethyl) -phenyl isobutyrate can effectively improve liver blood stasis, edema and liver tissue disorder induced by LPS/D-GlaN and effectively reduce serum alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST); simultaneously, the level of Glutathione (GSH), Catalase (CAT) and total superoxide dismutase (SOD) in liver tissues is improved, the apoptosis of liver cells is inhibited, and the level of Malondialdehyde (MDA) which is a lipid peroxidation product is reduced; 4-methoxy-2- (3-methyloxiranyl) -phenyl isobutyrate can also completely protect mice from acute liver failure death induced by LPS/D-GlaN; in addition, the compounds 4-methoxy-2- (3-methyl oxirane) -phenyl isobutyrate and 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate both show significant protective effects on primary hepatocyte injury in mice in vitro.
The 4-methoxy-2- (3-methyl ethylene oxide) -phenyl isobutyrate and the 2-methyl, 4-methoxy-2- (3-methyl-2-ethylene oxide) phenylbutyrate have obvious protective effect on acute liver failure induced by LPS/D-GlaN, have important application value and wide application prospect in preventing and treating the acute liver failure or chronic acute liver failure clinically, and open up new medicinal application of the phenylpropanoid derivatives, namely the 4-methoxy-2- (3-methyl ethylene oxide) -phenyl isobutyrate and the 2-methyl, 4-methoxy-2- (3-methyl-2-ethylene oxide) phenylbutyrate.
Description of the drawings
FIG. 1 is a compound HPLC chromatogram and mass spectrum; a is a semi-preparative liquid chromatogram, B and C are two monomer component analysis type HPLC chromatograms after purification, peaks I and II are respectively a compound 4-methoxy-2- (3-methyl epoxy ethyl) -phenyl isobutyrate and a compound 2-methyl, 4-methoxy-2- (3-methyl-2-epoxy ethyl) phenyl butyrate, and a and B are corresponding peak I and peak II mass spectrograms.
FIG. 2 is a graph of the effect of MMPI on liver index (A) and serum ALT (B), AST (C); compared with the control group, the compound of the formula, ## P<0.01; in comparison with the set of models, ** P<0.01。
FIG. 3 shows the effect of MMPI on the antioxidant index of the liver; compared with the control group, the compound is added, # P<0.05， ## P<0.01; in comparison with the set of models, * P<0.05， ** P<0.01。
FIG. 4 shows the results of HE staining of liver tissue sections; note: A-E are control group, model group, positive drug group, MMPI low dose and MMPI high dose group, respectively.
FIG. 5 shows Tunel staining results of liver tissue sections.
Figure 6 is the effect of MMPI on mouse survival.
FIG. 7 shows the protective activity of each monomer component against hepatocyte damage.
FIG. 8 is a schematic diagram of MMPI, MMPB, methyl eugenol, and silymarin structures.
(V) detailed description of the preferred embodiments
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The male C57BL/6 mice used in the examples of the present invention, weighing 19-21g, were purchased from the laboratory animals center of the institute of medical sciences, Zhejiang province.
Drugs and reagents: pimpinella diversifolia, collected from Fujianningde, was identified as Pimpinella diversifolia DC of Umbelliferae; silica gel for thin layer chromatography (Qingdao ocean chemical industry, 100-; lipopolysaccharide (LPS, Sigma Aldrich trade company, Inc., Lot: 0000135218), D-galactosamine hydrochloride (D-GlaN, Shanghai Michelin Biotech, Inc., Lot: C13215177); malondialdehyde (MDA), total superoxide dismutase (SOD), Catalase (CAT), glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminase (AST) and Glutathione (GSH) detection kits are purchased from Nanjing to build a bioengineering research institute; PBS Buffer (Morina Biotechnology Ltd., lot number: GP 200809); one-step TUNEL in situ apoptosis assay kit (Elapscience, batch 5HNHLC9S 4P); n-acetylcysteine (Biyuntian, lot: 030619190321); silymarin (Shanghai Xushuo Biotech Co., Ltd., lot number: BT 06); tween-80 (Wuxi, Tantai chemical Co., Ltd., lot No. 2020-01-01); other reagents are analytically pure.
The instrument comprises the following steps: agilent 7250GC-Q/TOF MS chromatography system (Agilent technologies, USA); biological tissue paraffin embedding machine (seimer feishell science); MagNA Lyser full automatic tissue homogenizer (ROCHE, germany); a multi-functional microplate reader (Perkin Elmer Co.); rotary microtomes (Lecia corporation); an upright microscope (Motic Corp.); UltiMate3000 semi-preparative liquid chromatography and analytical liquid chromatography (dean).
Example 1 isolation and characterization of 4-methoxy-2- (3-methyloxirane) -phenylbutyrate and 2-methyl, 4-methoxy-2- (3-methyl-2-oxirane) phenylbutyrate
(1) Extracting volatile oil: cleaning entire plant of pimpinella diversifolia, drying at 60 ℃, pulverizing, and sieving with a 40-mesh sieve; weighing 200g of powder, adding 2L of distilled water, taking 50mL of dichloromethane as an extracting agent, and carrying out reflux extraction for 4 hours by using a simultaneous reflux extraction device; after the extraction, the dichloromethane phase was separated, dried over anhydrous magnesium sulfate overnight, filtered, and the organic solvent was removed from the filtrate under reduced pressure at 35 ℃ to obtain 428.93mg of pale yellow volatile oil.
(2) Separation and purification: 428.93mg of the volatile oil is dissolved in 1mL of petroleum ether, and the solution is loaded onto a silica gel chromatography column (silica gel particle size 100-200 mesh, height 15 cm. times. diameter 2.5cm), and eluted with petroleum ether for 1 column volume, and then eluted with petroleum ether-ethyl acetate (20:1, v/v) for 3 column volumes, and collected in tubes, 2mL of the volatile oil is collected in each tube, and the weight ratio of the petroleum ether: detecting with Thin Layer Chromatography (TLC) using ethyl acetate (18:1, v/v) as developing agent, spraying concentrated sulfuric acid vanillin at 105 deg.C for 5min, and combining with blue target spot tube with Rf value of 0.26; then injecting a semi-preparative liquid chromatograph: a Dian UltiMate3000 semi-preparative liquid chromatograph, a welch UltiMate XB-C18 chromatographic column (250mm × 10mm, 10 μm), a mobile phase A being acetonitrile, and a B being 0.1% formic acid aqueous solution; the elution conditions were: 0-15min, 60% -100% A; 15-20min, 100% A; 20-21min, 100% -60% A; 21-31min, 60% A; the detection wavelength is 265nm, and the column temperature is 30 ℃. Respectively collecting a peak with retention time of 8.5-9.0 min and a peak with retention time of 10.0-10.5 min; evaporating to dryness under reduced pressure to obtain compound I and compound II. Dissolving the two compounds with appropriate amount of chromatographic pure acetonitrile, respectively, filtering with 0.22 μm filter membrane, introducing sample into Ultimate3000 analytical liquid chromatograph,
120C18 chromatographic column (250mm × 4.6mm, 5 μm), and the elution condition, detection condition and column temperature are the same as those of preparative liquid chromatography.
(3) Mass spectrum identification: chromatographic conditions are as follows: agilent 7250GC-Q/TOF MS chromatography system, HP-5MS capillary column (30 m. times.0.25 mm. times.0.25 μm, Agilent, USA). Temperature programming process: the initial temperature is 50 deg.C, maintained for 3min, and heated to 280 deg.C at 5 deg.C/min, and maintained for 5 min. Carrier gas: helium, 99.999% purity, 1.0mL/min flow rate. Sample inlet temperature: at 250 ℃ to obtain a mixture. Sample introduction amount: 1 μ L. The split ratio is as follows: 10:1.
Mass spectrum conditions: EI source voltage: 70 eV; ion source temperature: 250 ℃; GC-MS interface temperature: 280 ℃; quadrupole temperature: 150 ℃; data scanning mode: TOF-Scan full Scan, mass scanning range m/z of primary mass spectrum is 40-450, and acquisition rate is 5 spectra/s; solvent retardation: 3.5 min.
(3) Component identification: according to the above chromatographic conditions for C 7 -C 40 The normal alkane mixed reference substance is subjected to GC-MS analysis, and the Retention Index (RI) of the target compound is calculated. And identifying the target compound by comparing RI values, searching a mass spectrum standard library and combining with literature reports.
(4) As a result: separating and enriching by silica gel column chromatography, purifying by semi-preparative liquid phase, and collecting the peak with retention time of 8.5-9.0 min and the peak with retention time of 10.0-10.5 min (see A in figure 1); evaporating to dryness under reduced pressure to obtain compound I68.24 mg and compound II 12.84 mg; from liquid phase analysis, the two components showed essentially a single peak (see B, C in FIG. 1); respectively injecting samples and performing GC-MS analysis to obtain mass spectrograms shown as a and b in the figure 1, wherein the molecular weights of the two compounds are 250.1208Da and 264.1328Da respectively; the compound I is identified as 4-Methoxy-2- (3-methyloxiranyl) -phenyl isobutyrate (4-Methoxy-2- (3-methyloxiranyl) -phenyl isobutryate, MMPI) and the compound II is 2-methyl, 4-Methoxy-2- (3-methyl-2-oxiranyl) phenylbutyrate (Butanoic acid,2-methyl-,4-Methoxy-2- (3-methyloxiranyl) phenyl ester, MMPB) by comparing retention index and mass spectrograms and combining related documents.
Example 2 protection of LPS/D-GlaN induced acute liver failure in C57BL/6 mice by MMPI
(1) Mice were given in groups: c57BL/6 male mice, 48, were randomly divided into 6 groups of 8 mice each. Blank Control (Control) and Model group (Model), were intraperitoneally injected with PBS solution containing tween 80 at a volume concentration of 1%; the positive drug group is injected with 300mg/kg of N-acetylcysteine (NAC) in the abdominal cavity (the solvent is PBS solution containing 1% Tween 80 by volume); the MMPI low-dose group is injected with 20mg/kg of peritoneal cavity (the solvent is PBS solution containing 1 percent of Tween 80 by volume concentration); 30mg/kg of MMPI high-dose group is injected into the abdominal cavity (the solvent is PBS solution containing Tween 80 with the volume concentration of 1%); in addition, a group of Silymarin treatment groups with anti-inflammatory and hepatoprotective drugs, i.e. 50mg/kg of Silymarin (Silymarin) for intraperitoneal injection (solvent is 1% Tween 80PBS solution), is also provided. Continuously administering for 3D 1 time per day, 1h after the last administration, performing intraperitoneal injection of LPS (40 μ g/kg, PBS as solvent) and D-GlaN (500mg/kg, PBS as solvent) on each group except the blank control group, anesthetizing the mice after 6h of molding, taking blood from abdominal aorta, centrifuging at 3500rpm for 10min after coagulation, and taking serum and freezing and storing at-80 deg.C; dissecting and taking liver, weighing, fixing part of tissue with 4% formaldehyde, and quickly freezing the rest tissue with liquid nitrogen, and freezing and storing at-80 deg.C.
(2) ALT and AST content determination in serum: serum levels of ALT and AST were determined for each group of mice according to the procedures of ALT and AST kits.
(3) Biochemical index determination of liver tissue: weighing each group of liver tissue samples, adding precooled PBS solution according to the volume ratio of 1:9, homogenizing in a full-automatic tissue homogenizer at 6000rpm for 30s, centrifuging the homogenate at 2500rpm for 10min, and taking the supernatant; and measuring various biochemical indexes in the liver tissue according to the operation of MDA, CAT, GSH and total SOD kit instructions.
(4) And (3) liver tissue HE staining: and (5) slicing the normal paraffin, and performing HE staining to compare and analyze the damage condition of the liver.
(5) Liver tissue apoptosis Tunel staining: according to the operation of the kit specification, the method adopts a one-step TUNEL in-situ apoptosis detection kit of Elapscience corporation to perform apoptosis staining on each liver tissue section, finally, a mounting agent mounting containing DAPI nuclear dye is dripped, and the fluorescent microscope is used for photographing, recording and analyzing.
(6) As a result: LPS combined with D-GlaN treatment can cause severe inflammatory reaction in a short time, and a large amount of liver cells are subjected to apoptosis and necrosis, which are shown as liver tissue edema and liver weight increase. From the results in FIG. 2, the liver index of the model group reaches (53.713 + -3.642) mg/g body weight, which is significantly higher than that of the blank control group (36.251 + -1.286); the positive drugs NAC and MMPI low and high dose groups can both significantly reduce the liver index (see A in figure 2), and show better improvement effect on liver tissue enlargement. The serum ALT and AST of the model group are obviously increased, further the liver tissue damage after model building is serious, and the ALT and AST levels of each administration group can be effectively reduced, particularly the ALT and AST levels of the MMPI high-dose group are obviously lower than those of the NAC group serving as a positive medicament, and the high-dose group has no obvious difference with a blank control group (see B, C in figure 2); generally, from the perspective of liver index, ALT and AST levels, the MMPI low and high dose group shows better protection effect on LPS/D-GlaN induced acute liver failure. In addition, the silymarin (phenylpropanoid derivative) which is a common anti-inflammatory and liver-protecting drug has no protective effect on liver failure induced by LPS/D-GlaN under the condition of 50mg/kg dose, and on the contrary, all mice die after about 4 hours of model building; the drug is administrated by gastric lavage according to the literature, and the drug also fails to play a good protection role; it can be seen that the MMPI compound has other special protection mechanisms besides anti-inflammation.
Researches show that LPS/D-GlaN can cause the unbalance of a liver antioxidant system, and excessive oxidative stress of liver tissues causes the apoptosis and necrosis of liver cells, so that the antioxidant enzyme system and MDA level of the liver tissues are measured. From the results in fig. 3, it can be seen that the level of lipid peroxidation product MDA in the liver of the model group is significantly increased, and the levels of GSH and SOD in the antioxidant system are significantly decreased, indicating that the liver tissue is in oxidative stress damage state. Compared with the model group, the positive drug NAC and the monomer compound MMPI low and high dose groups can better maintain the GSH and SOD levels, thereby obviously reducing the MDA content of the liver tissues; particularly, the MDA level in the high-dose group is obviously lower than that in the normal group, and the result shows that the compound MMPI can play a liver protection role by regulating the oxidative stress system of the liver.
The liver tissue section can visually reflect the pathological condition of the liver, and as can be seen from the staining result of the HE in FIG. 4, the structure of the liver cells of the blank control group is clear, and no obvious red blood cell distribution is seen among the cells (see A in FIG. 4); the model group had shriveled liver cells, enlarged gaps, a large amount of red blood cells exuded, and serious liver tissue lesions (see B in figure 4); compared with the model group, the positive medicine NAC treatment group has reduced clearance, the erythrocyte distribution in the clearance of the liver cells is obviously reduced, and the damage of the liver tissue is improved (see C in figure 4); the MMPI is low (shown as D in figure 4) and the cell morphology of the high-dose group (shown as E in figure 4) is greatly improved compared with that of the model group, although the hepatocyte clearance of the low-dose group is enlarged compared with that of the normal group, a large amount of erythrocyte exudation and aggregation are not seen, and only the individual erythrocyte distribution is occasionally seen locally (shown as D in figure 4); the morphological characteristics of the MMPI high-dose group liver cells are basically consistent with the cell structure of normal liver tissues, and the MMPI high-dose group liver cells show obvious liver protection activity. The compound MMPI has extremely remarkable protective effect on LPS/D-GlaN induced liver injury by combining the biochemical indexes of the serum and the liver tissue and further proved by an HE dyeing result.
Massive apoptosis and necrosis of hepatocytes in a short time are important causes and important pathological features of acute liver failure, and therefore, the apoptosis of hepatocytes induced by LPS/D-GlaN is analyzed. Tunel staining results indicated that the proportion of model group cyan fluorescent cells (double staining with green and blue fluorescence) accounted for approximately (39.062 + -5.085)% of the total number of hepatocytes (see FIG. 5), indicating that the model group hepatocytes were severely injured. The positive medicine NAC has stronger antioxidant and anti-inflammatory activity, the apoptosis (3.822 +/-1.092)% is obviously reduced, but the distribution of red blood cells among hepatic cells can be seen (green fluorescence single staining). The compound MMPI low and high dose treatment groups can effectively reduce the apoptosis rate of liver cells, particularly the apoptosis rate (0.026 +/-0.036)% of the MMPI high dose group is lower than that (0.104 +/-0.097)% of a blank control group, and the compound has extremely strong liver protection activity.
Example 3 effects of MMPI and MMPB on LPS/D-GlaN induced survival Rate in C57BL/6 mice over 48h
(1) Mice were given in groups: 56C 57BL/6 male mice were randomly divided into 7 groups of 8 mice each. A blank Control group (Control) and a Model group (Model) were injected intraperitoneally with 1% tween 80PBS solution; the positive drug group is injected with 300mg/kg of N-acetylcysteine (NAC) in the abdominal cavity; the MMPI low-dose group is injected into the abdominal cavity with 20 mg/kg; 30mg/kg of MMPI high-dose group is injected in the abdominal cavity; the MMPB low-dose group is injected into the abdominal cavity with 20 mg/kg; the MMPB high dose group is injected into the abdominal cavity with 30 mg/kg. The administration is carried out for 3 days continuously, 1 time per day, and after 1 hour of the last administration, LPS (40 mu g/kg) and D-GlaN (500mg/kg) are respectively injected into the abdominal cavity of each group except a blank control group, all the medicaments are prepared by 1 percent Tween 80PBS solution, and the survival rate of the mice within 48 hours is observed and counted after the model is built.
(2) As a result: the mice begin to die after 8 hours after the model is built, and all mice die after 10 hours; the mortality rate of the positive drug group reaches 20% after about 12h, but no mice die later; the mice in the low and high dose groups of the MMPI and the MMPB have no mice death; the result proves that the MMPI and the MMPB have obvious antagonistic effect on the hepatic failure of mice induced by LPS/D-GlaN, and have great development and application potential.
Example 4 protective Effect of MMPI and MMPB on Primary hepatocyte injury in vitro
(1) C57BL/6 mouse primary hepatocytes and RAW264.7 mouse macrophages are respectively diluted by DMEM (DMEM medium) (Gibco, containing 10% fetal bovine serum, penicillin 100U/mL and streptomycin 100 mu g/mL), 2 ten thousand hepatocytes and 8 thousand macrophages are mixed and inoculated into a 96-well plate, after adherent co-culture is carried out overnight, a culture solution is discarded, and culture wells are divided into a blank control group, a model group, an MMPI group, an MMPB group and an ME group. 150 mu L of DMEM medium is respectively added into a blank control group and a model group, 150 mu L of DMEM medium containing MMPI with different concentrations (2, 4 and 6 mu g/mL) is respectively added into an MMPI group, 150 mu L of DMEM medium containing MMPB with different concentrations (2, 4 and 6 mu g/mL) is respectively added into an MMPB group, 150 mu L of DMEM medium containing Methyl Eugenol (ME) with different concentrations (10, 20 and 30 mu g/mL) is respectively added into an ME group, each group is pre-treated for 1h at 37 ℃, and then 50 mu L of DMEM medium is added into the blank control group, the other components were added with 50. mu.L of DMEM medium containing LPS and D-GlaN, making the final concentration of LPS and D-GlaN respectively 1 μ g/mL and 5mg/mL, stimulating and culturing for 24h, centrifuging at 3000rpm for 5min, collecting supernatant, determining ALT level by using kit, and analyzing the liver protection activity of the drug.
(2) As a result: the results are shown in FIG. 7, and in the co-culture case, ALT level in the culture supernatant is obviously increased after stimulation of LPS and D-GlaN, and reaches (182.806 +/-21.020) U/L, which indicates that the liver cells are seriously damaged, and the phenomenon is consistent with the results of an in-vivo animal model. Both MMPI and MMPB pretreatment dose-dependently reduced ALT levels, half inhibitory concentration I of ALT releaseC 50 The values are (3.272 +/-0.181) mu g/mL and (2.924 +/-0.213) mu g/mL respectively, and the activity is stronger. From examples 1-3, it can be seen that MMPI has significant hepatoprotective activity at the animal level, and MMPB is substantially identical to MMPI mother nucleus in structure (see fig. 8), and it can be seen that both MMPB and MMPI have very strong hepatoprotective activity. Methyl eugenol also belongs to phenylpropanoid derivatives (see figure 8), however, the hepatoprotective activity of the methyl eugenol is very limited, and the ALT level is still as high as (153.334 +/-11.426) U/L at the treatment concentration of 30 mu g/mL; it is not seen that general phenylpropanoid compounds have hepatoprotective activity. From the MMPB and MMPI structures, a special structure formed by 2-position (3-methyl-2-ethylene oxide group), 4-position methoxyl and 1-position short-chain fatty acid ester on a benzene ring probably plays an important role in playing the liver protection activity.
In addition, compared with silymarin (structural formula shown in figure 8) and N-acetylcysteine which are clinical liver-protecting drugs in example 2 and example 3, the phenylpropanoid derivatives MMPI and MMPB disclosed by the invention have significant advantages in the protection effect of LPS combined with D-GlaN induced acute liver failure. Therefore, the compounds MMPI and MMPB disclosed by the invention have wide development and application prospects in the aspects of preparing liver-protecting medicines and preventing and treating acute liver failure.
Claims (8)
1. An application of phenylpropanoid derivatives shown in formula (1) in preparing medicine for preventing and treating hepatic failure,
r in the formula (1) 1 And R 2 Each independently is C1-C6 alkyl or C1-C6 alkenyl.
2. The use of claim 1, wherein R is 1 Is methyl, R 2 Is methyl or ethyl.
3. The use of claim 1, wherein the medicament is a medicament for lowering serum glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, or for increasing levels of glutathione, catalase, or total superoxide dismutase in liver tissue.
4. The use of claim 1, wherein the medicament is a medicament for inhibiting apoptosis in hepatocytes, reducing the lipid peroxidation product malondialdehyde.
5. The use of claim 1, wherein the medicament is a medicament for the prevention and treatment of LPS/D-GlaN-induced acute liver failure or chronic plus acute liver failure.
6. The use of claim 1, wherein the medicament comprises other medicaments for preventing and treating acute liver failure or chronic plus acute liver failure.
7. The use of claim 1, wherein the medicament comprises a pharmaceutically acceptable pharmaceutical carrier.
8. The use of claim 1, wherein the pharmaceutical dosage form includes, but is not limited to, capsules, tablets, injections, granules, emulsions, pastes, patches, pills, syrups.
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| CN115120583B (en) | 2023-06-27 |
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