CN103223161A - Application of manganese superoxide dismutase stimulant in preparing liver-protecting drug - Google Patents
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Abstract
The invention provides novel medical application of a manganese superoxide dismutase stimulant MnSODm in preparing a liver-protecting drug. By investigating the protective effect of a manganese superoxide dismutase stimulant compound to mice acute liver injury induced by carbon tetrachloride, the MnSODm has an obvious protective effect to the mice acute liver injury induced by CCI4, and therefore, the manganese superoxide dismutase stimulant can be used for preparing the liver-protecting drug, i.e., pharmaceutically acceptable preparation can be prepared by using the manganese superoxide dismutase stimulant as an active ingredient according to a conventional process and auxiliary materials.
Description
Technical field
The invention belongs to medical technical field, relate to the new medical use of a kind of manganese superoxide dismutase analogies MnSODm---the application in the preparation hepatic.
Background technology
Liver is an extremely important organ in the animal body, participates in multiple functions such as digestion, metabolism, drainage, detoxifcation and immunity.Liver is the important target spot that all kinds of materials are attacked.The hepatic insufficiency that hepatic injury causes is the common pathological manifestations of various hepatic disease, and injurious factor is attacked target cell and caused cell injury, produces and discharges a series of inflammatory mediator, causes apoptosis or necrosis, finally causes the generation of various hepatic disease.The mechanism of hepatic injury is very complicated, is the result of multiple factor in a plurality of aspects, many target spots, multipath comprehensive function.The hepatic injury that various harmful factors cause has hepatocellular degeneration necrosis, fatty liver, hepatic fibrosis, liver cirrhosis even hepatocarcinoma.At present, the treatment to hepatic injury is still a global severe problem.Set up the experiment liver damage animal model, some general character mechanism that the research hepatic injury takes place to screening liver-protecting activity composition, are explored the hepatic mechanism of action, are of great practical significance.
Organism is accompanied by oxygen metabolism in the normal activities process can produce active oxygen.Organism has very perfect oxygen scavenging activity system, comprises various antioxidant reductases and polyphenoils, so the active oxygen of normal physiological conditions lower body is in dynamic balance state.But under pathological state or under the adverse environmental factor, the interior active oxygen metabolism of body might be unbalance, causes active oxygen to accumulate and the initiated oxidation damage, quickens aging or cause disease.Superoxide dismutase (SOD) is the important member of biological antioxidant enzyme, is one of organism important enzyme of effectively removing active oxygen.People are by to the research extensively and profoundly of SOD, and are greatly abundant and promoted the biological develop rapidly of free radical.At present, the research of SOD has been extended to the applied research of aspects such as cosmetics, food and medicine from antioxidation and defying age mechanism.Press bind metal ion kind difference, SOD is divided into three kinds: the superoxide dismutase of cupric and zinc (CuZnSOD), manganiferous superoxide dismutase (MnSOD) and ferruginous superoxide dismutase (FeSOD), three kinds of SOD have catalysis superoxide anion free radical (O
2 -) effect of dismutation reaction takes place.MnSOD mainly is present in eukaryotic cell, prokaryotic cell and the mitochondrial substrate, and it plays an important role in the process of body defence disease as a kind of important antioxidants.Natural MnSOD have molecular mass greatly, in vivo half-life weak point, poor stability, easily by protease hydrolysis, and long term injections uses deficiencies such as can bringing out immunity and anaphylaxis, limited its clinical practice.In order to address this problem, Chinese scholars is mainly used the molecular engineering method SOD is carried out molecular modification or makes liposome.Chemical simulation to MnSOD has become the favourable instrument of being familiar with native enzyme, substitutes natural SOD with synthetic manganese superoxide dismutase analogies and is applied to the clinical new research focus that become.
Manganese superoxide dismutase analogies (MnSODm) are with flexible preferably fatty amine of water solublity and the synthetic MnSOD simulated compound that contains dual-core architecture of o-vanillin with good biological intermiscibility, its synthetic method is referring to Dou Wei. and " flexible open chain schiff base ligand metal supermolecular Study on Complexes ", Lanzhou University, thesis for the doctorate, 2007.Its molecular formula is (C
40H
57Mn
2N
9O
21), structural formula is as follows.
The architectural feature of MnSODm is: contain two manganese active center in a complex molecule, increased the active concentration in same site, have higher activity.To compare with natural MnSOD that stable in properties, molecular weight are little, water fat is held concurrently molten, easily stride film and active high characteristics, and simple synthetic method, with low cost, the purity height, and the productive rate height has overcome the limitation of natural MnSOD preferably.At present, the research of MnSODm is mainly concentrated on the inhibitory action to tumor.Yet we find that MnSODm has extremely strong antioxidation, removes oxygen-derived free radicals effect and anti-inflammatory activity.Free radical plays an important role in the process of hepatic injury, and MnSODm has not yet to see report to the research of hepatic injury.
Summary of the invention
The new medical use that the purpose of this invention is to provide a kind of manganese superoxide dismutase analogies MnSODm---the application in the preparation hepatic.
Intend adopting carbon tetrachloride (CCI below
4) cause the chmice acute liver injury model, observe the protective effect of MnSODm to acute liver damage.
Experiment material and method
1.
1 animal
Kunming mouse, body weight 18～22 g, ♂ is provided by Lanzhou University's Experimental Animal Center.
Medicine and reagent
Manganese superoxide dismutase simulated compound (MnSODm, C
40H
63Cl
3Mn
2N
6O
16), provide by professor Liu Weisheng of chemical engineering institute of Lanzhou University; Bifendate drop pill (Zhejiang medicine limited company, lot number: 111013).CCI
4(analytical pure); Oleum Arachidis hypogaeae semen (Shandong, Shandong flower); Glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), superoxide dismutase (SOD), malonaldehyde (MDA), glutathion peroxidase (GSH-Px) and Coomassie brilliant blue test kit all build up bio-engineering research institute, lot number: 20121120 available from Nanjing.
Key instrument
Desk centrifuge (KA-1000, Anting Scientific Instrument Factory, Shanghai makes); Electric driven glass refiner (DY-2, NingBo XinZhi Biology Science Co., Ltd makes); Visible spectrophotometer (722S, Shanghai Precision Scientific Apparatus Co., Ltd makes), SPX-250B-D type shaken cultivation case, Medical Equipment Plant of Shanghai Boxun Industrial Co., Ltd.; EL
X800 type microplate reader are purchased the INSTRUMENTS in BIO-TEK, Inc. US Α.
The foundation of model and Drug therapy
Male mice in kunming is divided into 6 groups at random by body weight, is respectively: normal control group, model control group, bifendate group and MnSODm(10 mg ﹒ kg
-1), in (20 mg ﹒ kg
-1), high (40 mg ﹒ kg
-1) the dosage group.Each is organized the mice adaptability and feeds behind 2 d gastric infusion every day, normal control group and model control group are irritated stomach with normal saline, the bifendate group gives bifendate solution and irritates stomach, and the basic, normal, high dosage group of MnSODm is irritated stomach, equal 0.1 mL ﹒ 10g with the basic, normal, high solution of MnSODm respectively
-1, administration every day 1 time, successive administration 7 d.Except that the normal control group, all the other are respectively organized mice and irritate behind last administration 24 h that stomach is given and 5% CCI
4Peanut oil solution 10 mL ﹒ kg
-1
The collection of sample and processing
All mices are won eyeball and get blood behind modeling 24 h, behind 4 ℃ of placement 2 h, with 1000
gCentrifugal 10 min, separation of serum is used for serum biochemistry and measures.Take out liver, with cold normal saline remaining serum on the liver, after rinsing well, wipe away driedly with filter paper, the whole liver of weighing is used to calculate the mouse liver coefficient.The most obvious place of clip pathological changes organizes sub-fraction, fixes paraffin embedding, HE dyeing, the degree of injury of observation liver with 4% formalin.Clip part pathological tissues piece is accurately weighed again, shreds with eye scissors, adds cold saline low temperature and makes 10 % tissue homogenates, 1000
gCentrifugal 10 min, separation of supernatant ,-20 ℃ of refrigerators are preserved and are used to organize biochemical measurement.
Tissue is measured with serum middle finger target
1.6.1 tissue and serum alt vitality test
ALT acts on the substrate of alanine and a-ketoglutaric acid composition under suitable temperature and pH condition, give birth to keto acid and glutamic acid, react to defined and add 2 after the time, molten ending reacts sumptuous (the DNPH)-hydrochloric acid of 4 one dinitro benzenes, while 2, group basic addition of 4-dinitro benzene umbilicus and acetone acid generates acetone acid benzene track.Be rufous under the benzene track condition, determine the enzyme activity power according to shade.Concrete operations are carried out according to the test kit explanation.
AST vitality test in tissue and the serum
AST can make a-ketoglutaric acid and aspartic acid move and change amino and ketone group, generate glutamic acid and careless phthalein acetic acid.Grass phthalein acetic acid can take off shuttle voluntarily and become acetone acid in reaction.Acetone acid and 2, the reaction of 4-dinitro benzene umbilicus generates 2, and 4-dinitro benzene track shows rufous in alkaline solution.In 505 nm colorimetrics, measure absorbance, look into standard curve, can try to achieve enzyme activity unit.Concrete operations are carried out according to the test kit explanation.
SOD vitality test in tissue and the serum
Adopt xanthine-xanthine oxidase to detect.Produce ultra-oxygen anion free radical by xanthine-xanthine oxidase response system, latter's oxidation azanol forms nitrite, is aubergine under the effect of developer, measures its absorbance at 550 nm places with visible spectrophotometer.When containing SOD in the sample, then superoxide anion there is the specificity inhibitory action, the nitrite of formation is reduced, the absorbance of measuring pipe during colorimetric is lower than the absorbance of control tube, calculates the SOD vigor that can obtain in the sample by formula.The tissue homogenate supernatant 50 μ L that get serum 20 μ L and 1% respectively operate by the test kit description, extrapolate SOD in SOD vigor (U/mL) in the serum and the tissue live (U/mg prot).To reach 50% o'clock pairing SOD amount be a SOD unit of activity (U) to SOD suppression ratio in 1 mL reactant liquor with every milligram of histone or every milliliter of serum.
GSH-Px vitality test in tissue and the serum
Glutathione peroxidase (GSH-Px) is the enzyme that the extensive a kind of important catalyzing hydrogen peroxide that exists decomposes in the body.GSH-Px can promote H
2O
2Generate H with reduced form glutathione (GSH) reaction
2O and oxidized form glutathione (GSSG), the vigor of GSH-Px can be represented with the speed of its enzymatic, measure the consumption of GSH in this enzymatic reaction, can obtain the vigor of enzyme.Get 5% colon homogenate supernatant, 200 μ L by test kit description step measurements, survey its absorbance at 412 nm places and extrapolate the GSH-Px vigor.GSH-Px vitality test principle is the same in the serum, getting 100 μ L after undiluted serum dilutes by 1:4 with normal saline measures by the test kit description, GSH-Px enzyme activity regulation in the serum: per 0.1 mL serum or every milligram of histone, deduct non-enzymatic reaction effect, making in the reaction system GSH concentration reduce by 1 mol/L is an enzyme activity unit.
MDA assay in tissue and the serum
MDA is a lipid peroxide.Adopt thiobarbituricacid (TBA) colorimetry, promptly lipid peroxide catabolite malonaldehyde can with the thiobarbituricacid condensation, form red product, at 532 nm places maximum absorption band is arranged.Get 10% colon homogenate supernatant, 100 μ L and serum 50 μ L respectively, operate by the test kit description, extrapolate MDA content in tissue and the serum thereby decide absorbance, with every milligram of histone nanomole number (nmol/mg prot) or every milliliter (nmol/mL) expression at 532 nm places.
Statistical procedures
Experimental data is carried out statistical analysis with expression with SPSS 15 softwares.Group difference adopts one factor analysis of variance (ANVOA), relatively adopts the LSD-t check between group in twos,
P＜0.05 has statistical significance for difference.
Experimental result
2.1 the manganese superoxide dismutase simulated compound is to CCI
4
The influence of inductive hepatic injury murine liver tissue function and hepatic tissue form
With the normal control group relatively, in model control group mice serum and the tissue ALT, AST vigor and liver index obviously increase (
P＜0.01), proves that liver injury model duplicates successfully.With model control group relatively, basic, normal, high group of mouse tissue of bifendate and MnSODm and serum alt, AST vigor and liver index obviously reduce (
P＜0.05 or
P＜0.01) (sees Table 1).
Table 1. manganese superoxide dismutase simulated compound is to CCI 4 Due to hepatic injury mouse liver and serum alt, AST vigor and liver coefficient influence (,
N=8-10)
Compare with the normal control group: * *
P＜0.01; compare with model control group:
# P＜0.05 or
# # P＜0.01.
Mouse liver anatomy finds that the shape and the color and luster of normal group mouse liver are normal, and color and luster is vivid, and the profile slyness is full; More serious damage phenomenon appears in the liver of model group mice, the color and luster dimness, and the profile atrophy, the surface is thicker, and the hepatocyte edema is obvious.Compare with model control group, basic, normal, high group of murine liver tissue damage of bifendate group and MnSODm is all than light (see figure 1).
The manganese superoxide dismutase simulated compound is to the influence of acute liver damage murine liver tissue pathological change
Find that by sections observation any pathological changes and unusual does not appear in the intravital hepatocyte of normal mouse, the hepatocyte regular shape, cell boundary is obvious, arranges fine and close, homogeneous, and nucleus is high-visible, shown in Fig. 2 A.And the model group mice, hepatocyte obscure boundary Chu, the cell arrangement disorder, hypochromatosis or pyknosis, the obvious swelling of hepatocyte, it is big that intercellular substance becomes, tangible downright bad phenomenon has appearred near the hepatocyte the mice central vein, the visible serious inflammatory cell infiltration of hepatocyte, steatosis, symptoms such as edema are as Fig. 2 B.Compare with the degree of injury of model control group, MnSODm administration group hepatic lesions obviously alleviates (Fig. 2 D-F), further specifies MnSODm to CCI
4The induced mice hepatocyte injury has significant protective effect.
The manganese superoxide dismutase simulated compound is to the influence of SOD, GSH-Px vigor in the hepatic injury mice serum of tetrachloro-methane induction and the hepatic tissue
SOD, GSH-Px vigor in model control group rat blood serum and the hepatic tissue, obviously reduce with normal control group ratio (
P＜0.05 or
P＜0.01); After treating with medicine bifendate and MnSODm, all obviously risings of SOD, GSH-Px vigor in mice serum and the liver organization (
P＜0.05 or
P＜0.01, see Table 2).
Table 2. manganese superoxide dismutase simulated compound (MnSODm) is to CCI 4 Due to SOD and the active influence of GSH-Px in hepatic injury mouse liver and the serum (,
N=8-10)
Compare with the normal control group: *
P＜0.05 or * *
P＜0.01; compare with model control group:
# P＜0.05 or
# # P＜0.01.
To CCI
4
The influence of MDA content in inductive hepatic injury mice serum and the hepatic tissue
With the normal control group relatively, in model control group mice serum and the hepatic tissue MDA content significantly raise (
P＜0.01); compare with model control group, all significantly reductions of MDA content in each administration group mice serum and the hepatic tissue (
P＜0.01, table 3), wherein, along with the increase of MnSODm dosage, in mice serum and the hepatic tissue MDA content be dose dependent reduce gradually (
P＜0.01).
Table 3. manganese superoxide dismutase simulated compound is to CCI
4
Due to MDA in hepatic injury mouse liver and the serum
The influence of content (,
N=8-10)
Compare with the normal control group: * *
P＜0.01; Administration group and model control group compare:
# P＜0.05 or
# # P＜0.01.
Discuss
Carbon tetrachloride (CCl
4) be a kind of chemicals that brings out the acute liver damage animal model that is often used as, it is similar in variation and the viral hepatitis aspect a lot of such as pathological anatomy, Pathophysiology.Simultaneously, in view of CCl
4Bring out advantages such as liver damage animal model condition easy operating, good reliability, good reproducibility, CCl is adopted in this experiment
4Bring out the acute liver damage animal model.
Aspartate transaminase (AST) and alanine aminotransferase (ALT) are two kinds of serum transaminases of normal check clinically, and these enzymes extensively are present in the animal tissue.ALT mainly is distributed in liver, secondly is in the tissues such as skeletal muscle, cardiac muscle.AST mainly is distributed in cardiac muscle, secondly in tissues such as liver, kidney.Therefore, ALT and AST are functional enzyme in the non-specific cell, and just often, content is very low in tissue and the serum, but when above histiocyte was impaired, intracytoplasmic ALT and AST will be discharged in the blood, cause the activity of enzyme in the serum to raise.This experimental result shows that model group mouse tissue and serum alt, the active rising of AST obviously reduce and ALT, AST are active in each dosage group mice serum of Aesculus hippocastanum extract, illustrate that MnSODm is to CCl
4Inductive acute liver damage has significant protective effect.
Lipid peroxidation is considered to playing important effect aspect animal physiological and the pathology.It has been generally acknowledged that lipid peroxidation is started by free radical.In vivo, most of lipids contain unsaturated fatty acid, particularly biomembranous phospholipid, and unsaturated fatty acid content is the highest.The maximum characteristics of unsaturated fatty acid are that two bonding electron cloud density are big, and chemical property is extremely unstable, is easy to be subjected to the attack of free radical, produce to have Cytotoxic lipid peroxide, cause membrane structure destroyed, mobile reduction, afunction.Lipid peroxidation cascade reaction that oxidative damage causes and tissue injury, cell death and some acute and close peroxidizations of chronic disease are the end products of lipid peroxidation.Malonaldehyde (MDA) also is a very important index weighing the free radical basal metabolic state, is that oxygen-derived free radicals is attacked the polyunsaturated fatty acids in the biofilm structure, and the generation lipid peroxidation generates, and is the end product of lipid peroxidation.Can react the lipid peroxidation injury degree by the content of measuring MDA in blood plasma or the tissue, indirect reaction goes out the situation of cell injury.Therefore, the content of MDA when the hepatic injury of determination experiment chmice acute is passed through in this experiment is investigated the possibility mechanism of MnSODm to the acute liver damage protective effect.MDA content obviously raise during we observed the model group mice serum and organize in this experiment, and CCI is described
4The free radical that produces in the inductive acute liver damage process increases the liver plasma membrane lipid peroxidation, and hepatocyte is badly damaged.Simultaneously, each dosage group of MnSODm can stop lipid peroxidation in the hepatic tissue, and the growing amount of MDA is significantly reduced.These presentation of results MnSODm protects hepatocyte by suppressing lipid peroxidation, and also further specifying MnSODm may be relevant with its free radical resisting damage to the protective effect of acute liver damage, and this may be the main mechanism that protects the liver.
SOD and GSH-Px play crucial effects to the oxidation and the antioxidation balance of body, can remove superoxide anion (O), and the protection cell is avoided damage.This experimental result shows that the normal matched group of SOD and GSH-Px vigor obviously reduces in model group murine liver tissue and the serum, illustrates that the liver of mice is being subjected to CCl
4Damage after, organize oxidation resistance to descend, thereby cause oxygen-derived free radicals to be piled up, the oxygen free radical injury biomembrane makes MDA content raise.SOD and GSH-Px vigor are higher than model control group in each dosage group murine liver tissue of MnSODm and the serum, show, MnSODm is by removing free radical, make endogenous SOD, the loss of antioxidases such as GSH-Px reduces, SOD and GSH-Px activity in the body that raises indirectly, the oxidation resistance of raising body, prevent the peroxide injury of body, thereby alleviate hepar damnification and inflammation.That is to say that MnSODm may be relevant with its antioxidation to the protective effect of the hepatic injury of mice.From cardinal principle and pathological study, MnSODm also has improvement preferably to the hepatocyte injury necrosis.
In sum, manganese superoxide dismutase simulated compound MnSODm is to CCI
4The induced mice hepatocyte injury has significant protective effect; therefore can be used for the preparation of hepatic; be active component with the manganese superoxide dismutase analogies promptly, technology and adjuvant are prepared into the acceptable preparation of pharmaceutics routinely, as granule, capsule, drop pill, injection etc.
Description of drawings
Fig. 1 is that the manganese superoxide dismutase simulated compound is to CCI
4The influence of inductive hepatic tissue form: (A) normal control group; (B) model control group; (C) bifendate group; (D) MnSODm low dose group; (E) dosage group among the MnSODm; (F) MnSODm high dose group;
Fig. 2 is the influence of manganese superoxide dismutase simulated compound to acute liver damage murine liver tissue pathological change (section form): (A) normal control group; (B) model control group; (C) bifendate group; (D) MnSODm low dose group; (E) dosage group among the MnSODm; (F) MnSODm high dose group.
The specific embodiment
Below by specific embodiment MnSODm of the present invention is used in the hepatic in preparation and to be described further.
Embodiment 1, protect the liver particulate preparation
Proportioning raw materials: MnSODm 200 mg, starch 500 g, Icing Sugar 500 g;
Preparation technology: after MnSODm sieves, in MnSODm, add starch, Icing Sugar and suitable quantity of water, mix homogeneously, the system soft material is crossed 14 order nylon mesh and is granulated, wet granular is in 60 ℃ of dryings, dried granule is crossed 14 mesh sieve granulate, goes fine powder, packing then after No. 4 sieves (65 order) sieve, sealing, packing promptly.Specification: 2mg:10g
Dose: 2 times on the one, one time 1 bag.
The preparation of embodiment 2, liver protecting capsule
Proportioning raw materials: MnSODm 200 mg, 10% starch slurry is an amount of, and food coloring is an amount of, makes 100 of hard capsules altogether.
After preparation technology: MnSODm crosses 80 mesh sieves, add 10% starch, food coloring and suitable quantity of water, mix homogeneously, the system soft material is crossed 14 order nylon mesh and is granulated, and is dried to moisture below 3% in 70 ℃, inserts in the capsulae vacuus, promptly.
Dose: 2 times on the one, one time 1.
Embodiment 3, protect the liver the preparation of ejection preparation
Proportioning raw materials: MnSODm 200 mg, sodium chloride 850mg, tween 1 mL, water for injection adds to 100 mL.
Preparation technology: in the preparation container, add the water for injection of recipe quantity 80 %, add MnSODm 200 mg and sodium chloride and tween, stirring is dissolved it fully, filters, and embedding, 100 ℃ of sterilization 30 min are promptly.Specification 2 mg:1mL
Dosage: 2 times on the one, one time 1.
Embodiment 4, protect the liver the preparation of drop pill
Proportioning raw materials: MnSODm 200 mg, PEG 6000 1800mL
Preparation technology: get PEG 6000 and in oil bath, be heated to about 135 ℃, add MnSODm fine powder 200 mg, constantly stir and make whole fusions, filtered while hot is put in the reservoir, 135 ℃ of insulations down, be respectively the dropper titration of 9.0mm, 9.8mm with the inside and outside footpath of the mouth of pipe, drip 80/min of speed, splash in the liquid paraffin liquid coolant that contains 43% kerosene, be condensed into ball, wash ball with liquid paraffin, to there not being the kerosene flavor, inhaling with writing paper made from bamboo and remove adherent liquid paraffin, promptly.
Dose: 2 times on the one, one time 1.
Claims (3)
1. the application of manganese superoxide dismutase analogies in the preparation hepatic.
2. the application of manganese superoxide dismutase analogies in the preparation hepatic according to claim 1, it is characterized in that: with the manganese superoxide dismutase analogies is active component, technology and adjuvant are prepared into the acceptable preparation of pharmaceutics routinely.
3. as the application of manganese superoxide dismutase analogies as described in the claim 2 in the preparation hepatic, it is characterized in that: described preparation is granule, capsule, drop pill, injection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105949793A (en) * | 2016-05-31 | 2016-09-21 | 西北师范大学 | Preparation of compound obtained through combining soybean protein chitosan microspheres with amino acid metal complex and application as antioxidant |
| CN107823635A (en) * | 2017-11-29 | 2018-03-23 | 杭州睿道医药科技有限公司 | The application of manganese type high stability superoxide dismutase |
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| CN1513988A (en) * | 2003-07-09 | 2004-07-21 | 王建英 | Production method of corn superoxide dismutase multienzyme |
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| CN105949793A (en) * | 2016-05-31 | 2016-09-21 | 西北师范大学 | Preparation of compound obtained through combining soybean protein chitosan microspheres with amino acid metal complex and application as antioxidant |
| CN107823635A (en) * | 2017-11-29 | 2018-03-23 | 杭州睿道医药科技有限公司 | The application of manganese type high stability superoxide dismutase |
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