CN103505720A - Application of apolipoprotein A-I in preparation of medicine used for preventing and treating liver disease metabolic syndrome - Google Patents
Application of apolipoprotein A-I in preparation of medicine used for preventing and treating liver disease metabolic syndrome Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and relates to an application of apolipoprotein A-I in preparation of a medicine used for preventing and treating liver disease metabolic syndrome, wherein the liver disease metabolic syndrome is fatty liver caused by obesity, hyperlipidaemia and type 2 diabetes factors but not alcohol. Results of a high fat diet fatty liver model test show that the apolipoprotein A-I can obviously reduce liver index, liver lipid content and malondialdehyde (MDA) content of NAFLD (non alcoholic fatty liver disease) animals; activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in blood serum and liver can be improved, and activity of inducible nitric oxide synthase (iNOS) is reduced; expression of SOD, GPx and catalase CAT mRNA in the liver can be obviously up-regulated, so that the apolipoprotein A-I has an obvious antioxidation effect; the apolipoprotein A-I can be further prepared into an antioxidant medicine and used for preventing and treating diseases related to oxidative stress regulating enzyme, especially used for preventing and treating the liver disease metabolic syndrome and complications thereof.
Description
Technical field
The invention belongs to medical technical field, relate to the new medical use of apolipoprotein A-1 (apolipoprotein A-I, apoA-I) based on antioxidation, be specifically related to the purposes of apolipoprotein A-1 in preparation prevention and treatment hepatopathy metabolism syndrome medicine.
Background technology
Studies show that, NAFLD(hereinafter referred to as: be hepatopathy metabolism syndrome) a kind of without excessive drinking history, but the similar alcohol fatty liver of pathological change (AFLD), take hepatic cell fattydegeneration and lipid and store up the clinical pathology syndrome as feature.Its spectrum of disease comprises the pathological processes such as simple fatty liver, fat hepatitis (NASH), fatty liver fibrosis and fatty cirrhosis.The generation of NAFLD, development relate to the many factors such as heredity, environment and life style; Its risk factor comprises obesity, hyperlipemia, insulin resistant (IR), type 2 diabetes mellitus etc., is the ingredient of metabolism syndrome.According to statistics, the prevalence of China's fatty liver in population is 15%～19%, is modal hepatic disease, and the prevalence of NAFLD in total crowd reaches 20% (15%～39%).Have report to point out, NAFLD can bring out or increase the weight of multiple complications as hypertension, diabetes, liver cirrhosis, hepatocarcinoma etc., and the mankind's health and lives in serious threat.
The pathogenesis of NAFLD is complicated, and this research field obtains the most general approval for the two-hit theory of its proposition at present.This theory proposes, and hitting is first Liver fatty deposition, and the second strike that plays most critical effect is oxidative stress and lipid peroxidation.Oxidative stress refers to that the generation of reactive oxide (ROS) in hepatocyte and effect thereof surpass antioxidant system removing ability, and ROS can bring out lipid peroxidation, finally causes hepar damnification to form NAFLD.As can be seen here, have antioxidation medicine will prevention and treatment NAFLD field play a significant role.
Prior art discloses high density lipoprotein (high density lipoprotein, HDL) be lipoprotein important in blood plasma, mainly participate in the antiport of cholesterol, by the cholesterol transport of the outer cell of liver to liver, and transformed and remove, thereby there is study of anti-atherogenic effect.Studies show that, human apolipoprotein A-I (apolipoprotein A-I, ApoA-I) be the major apolipoprotein of HDL, the main executive of HDL function, at the transhipment of cholesterol, metabolism, atherosclerosis, antiinflammatory, antiviral and suppress to play an important role in tissue injury that Acute Phase inflammatory reaction causes, it has become one of emphasis in lipid metabolism research at present.ApoA-I antioxidation, its machine-processed correlational study and the impact of NAFLD be have not been reported, therefore, the present invention plans the medicine that its exploitation becomes prevention and treatment NAFLD.
Summary of the invention
The object of the invention is to provide the new medical use of apoA-I based on antioxidation, is specifically related to the purposes of apolipoprotein A-1 in preparation prevention and treatment hepatopathy metabolism syndrome medicine.Relate in particular to the new purposes aspect its other pathological changes of liver that cause at prevention and treatment NAFLD and complication thereof, oxidative stress.
The present invention proposes the mechanism of apoA-I antioxidation, and find that apoA-I has the effect of prevention and treatment NAFLD, provides the new medical use of apoA-I.
ApoA-I described in the present invention obtains according to prior art separated and gene engineering expression in human serum.The present invention selects laboratory animal New Zealand white rabbit, it is carried out to high lipid food nursing and set up fatty liver model, is divided at random NAFLD model group, apoA-I(20mg/kg/w) group and apoA-I(40mg/kg/w); Pharmaceutical intervention is carried out in high fat diet simultaneously, the frequency that gives animal subject apolipoprotein A-1 in embodiments of the invention is on every Mondays to 2 times, dosage is each 5mg-80mg/kg body weight, after 20 weeks, leave and take serum and hepatic tissue for researching and analysing the antioxidation mechanism of apoA-I and its in the effect aspect prevention and treatment fatty liver and described hepatopathy metabolism syndrome;
Result demonstration, apoA-I can significantly reduce the content of hepatic injury degree, liver index, liver lipid content and the liver malonaldehyde MDA of NAFLD rabbit; Can improve the vigor of SOD and GPx in serum and liver, reduce the vigor of iNOS simultaneously; The expression that can obviously raise SOD in liver, GPx and CAT mRNA, has obvious antioxidation.
Apolipoprotein A-1 of the present invention can further be made anti-oxidation medicine, for regulating prevention and the treatment of the disease that oxidative stress enzyme is as relevant in SOD, GPx, iNOS and CAT, in particular for prevention and treatment NAFLD(hepatopathy metabolism syndrome) and complication, and the disease relevant to oxidative stress related enzyme activity is as hepatitis, hepatic fibrosis, hepatocarcinoma etc.
NAFLD described in the present invention is especially by factors such as obesity, hyperlipemia, type 2 diabetes mellitus but not the fatty liver that ethanol causes.
The present invention has carried out fatty liver model experiment:
The impact of 1.apoA-I on the damage of NAFLD rabbit liver
Getting hepatic tissue section carries out the rear micro-Microscopic observation of HE dyeing and takes pictures.Result demonstration, normal rabbit liver regulating liver-QI leaflet structure is complete; The consistent and boundary of hepatocyte size, and to surrounding, be streak, radial proper alignment centered by central vein.Cell cytoplasm is abundant, sinus hepaticus queueing discipline, and portal area is clear.In model group hepatocyte kytoplasm, be full of the circular fat differing in size in a large number and drip, lobules of liver structure is unclear, liver rope arrangement disorder, and most of hepatocyte is steatosis, visible point-like necrosis region and inflammatory cell infiltration therebetween, part of hepatocytes is balloon sample and becomes.ApoA-I administration group hepatocyte injury all obtains inhibition in various degree, and apoA-I (40mg/kg/w) group therapeutic effect is more obvious.Illustrate that apoA-I can improve the rabbit liver damage that high fat diet causes.
The impact of 2.apoA-I on NAFLD Hepar Leporis seu Oryctolagi index
To after rabbit conventional treatment, get liver and weigh, calculate liver coefficient (liver quality/weight).Result shows to be compared with model group, and the liver coefficient of apoA-I administration group rabbit all reduces (P < 0.05), with apoA-I(40mg/kg/w) the liver coefficient of group reduces the most obvious.Illustrate that apoA-I can improve the rabbit liver damage that high fat diet causes.
The impact of 3.apoA-I on NAFLD rabbit liver lipid content
In liver, accumulating of lipid is guide's factor that NAFLD forms.Adopt lipid content detection kit to measure lipid content in NAFLD rabbit liver.Result demonstration, compares with model group animal, and in apoA-I administration group Hepar Leporis seu Oryctolagi tissue homogenate, the content of TC, TG, LDL-C obviously reduces; Contrary, HDL-C content raises to some extent, but there was no significant difference.And apoA-I (40mg/kg/w) group effect is more obvious.Illustrate that apoA-I can reduce the degree of injury of liver by reducing the content of TC, TG, LDL-C in liver of laboratory animal.
The impact of 4.apoA-I on MDA content in NAFLD rabbit liver
Oxidative stress causes lipid peroxidation, and they finally cause hepar damnification.Lipid peroxidation product is evaluated the sign of oxidative stress and level of lipid as MDA can be used as.Adopt the content of MDA in MDA reagent box for detecting content NAFLD rabbit liver.Result shows, compares with model group, and in the liver of apoA-I administration group rabbit, MDA content all decreases, with apoA-I(40mg/kg/w) group reduces the most obvious.Illustrate that apoA-I can carry out the liver protecting by reducing the levels of peroxide of lipid in liver of laboratory animal.
5.apoA-I on SOD, GPx in NAFLD rabbit anteserum and liver and iNOS enzyme activity affect SOD and GPx is two kinds of important antioxidases, can be to anti-oxidation stress.And iNOS can promote a kind of generation with the material NO that increases the weight of oxidative stress effect.Therefore increase the enzyme activity of SOD and GPx, the enzyme activity that simultaneously reduces iNOS will be conducive to anti-oxidation stress.The vigor of SOD, GPx and iNOS enzyme in employing enzyme activity determination kit measurement NAFLD rabbit anteserum and hepatic tissue.Result demonstration, compares with model group, and in apoA-I administration group rabbit anteserum and liver, SOD and GPx enzyme activity all rise; On the contrary, iNOS enzyme activity declines, with apoA-I(40mg/kg/w) group effect is the most obvious.Illustrate that apoA-I can increase the vigor of SOD and GPx enzyme in laboratory animal serum, suppress the vigor of iNOS enzyme simultaneously, with this, improve the antioxidant levels in serum and liver, for illustrating the antioxidation mechanism of apoA-I, provide possible research target spot.
The impact of 6.apoA-I on SOD, GPx in NAFLD rabbit liver and CAT mrna expression
SOD, GPx and CAT are all important antioxidases, can be to anti-oxidation stress.The present invention adopts real-time fluorescence quantitative PCR to detect the expression of three kinds of enzyme mRNA in NAFLD rabbit liver.Result shows, compares with model group, and in apoA-I administration group rabbit liver, three kinds of enzyme mrna expression levels all rise, with apoA-I(40mg/kg/w) group expression rises the most obvious.Illustrate that apoA-I can improve the antioxidant levels of liver by the expression of SOD, GPx and CATmRNA in rise liver of laboratory animal, provide possible research target spot for illustrating the antioxidation mechanism of apoA-I.
The invention has the advantages that, research is found and proves that apoA-I can significantly reduce the content of the hepatic injury degree of NAFLD rabbit, liver index, liver lipid content and liver malonaldehyde MDA by experiment; Can improve the vigor of SOD and GPx in serum and liver, reduce the vigor of iNOS simultaneously; The expression that can obviously raise SOD in liver, GPx and CAT mRNA, has obvious antioxidation, can further make anti-oxidation medicine, for prevention and treatment NAFLD(hepatopathy metabolism syndrome) and complication.
Accompanying drawing explanation
Fig. 1 is the impact of apoA-I on NAFLD Hepar Leporis seu Oryctolagi index, compares * P < 0.05 with model group.
Fig. 2 is the impact of apoA-I on NAFLD rabbit liver lipid (TC, TG, LDL-C and HDL-C) content, compares * P < 0.05 with model group.
Fig. 3 is the impact of apoA-I on NAFLD rabbit liver MDA content, compares with model group, and * P < 0.05,, * * P < 0.01.
Fig. 4 is the impact of apoA-I on SOD, GPx in NAFLD rabbit anteserum and liver and iNOS enzyme activity,
Wherein, A is SOD vigor in serum, and B is GPx vigor in serum, and C is iNOS vigor in serum, and D is SOD in liver, and E is GPx vigor in liver, and F is iNOS vigor in liver;
Compare with model group, * P < 0.05,, * * P < 0.01.
Fig. 5 is the impact of apoA-I on SOD, GPx in NAFLD rabbit liver and CAT mrna expression,
Wherein, A is SOD mrna expression, and B is GPx mrna expression, and C is CAT mrna expression;
Compare with model group, * P < 0.05,, * * P < 0.01.
The specific embodiment
Model animal experimental model:
1, male New Zealand rabbit, in 8 week age, body weight is provided by Fudan University's Experimental Animal Center for 1.9-2.3kg().Give standard feed 120g/kg and high lipid food (additionally adding 1.0% cholesterol in standard feed) 30g/kg every day.Animal is divided into model group at random, apoA-1(20mg/kg/w) group and apoA-1(40mg/kg/w) group, every group of 12 rabbits.Once, AS model group animal is normal saline 5ml to auricular vein injectable drug weekly, and apoA-1 administration treated animal is the medicine 5ml of variable concentrations (20 or 40mg/kg body weight), weighs weekly.20 weeks post processing animals, heart extracting blood 6～7ml measures for index of correlation.Take liver heavy, and leave and take two parts of liver specimens, portion is fixed on 10% formaldehyde 24h makes tissue slice above, and another part detects for index of correlation.Laboratory animal is produced and use procedure all meets relevant laws and regulations regulation.
2, prepare serum and liver tissue homogenate
The fresh blood obtaining after laboratory animal is processed 3000 leaves heart 10min in 37 ℃ after standing 1 hour, gets supernatant.
Prepare 10% liver tissue homogenate:
1. take the frozen liver organization 200mg in-80 ℃ and be placed in 2mLEP pipe, fully shred (ice bath operation);
2. add 300 μ μ L normal saline, and add the special-purpose steel ball of a tissue refiner, be placed in tissue refiner 60HZ homogenate 60s;
3. add again 1500 μ L normal saline to mix 60HZ homogenate 30s in tissue refiner;
4. 4 ℃, the centrifugal 15min of 4000r, gets supernatant and is 10% liver tissue homogenate liquid.
Jiang10% liver tissue homogenate normal saline dilution, obtains 1%He5% liver tissue homogenate.
Experimental technique: perusal liver color substantially, glossiness, surface flatness, volume etc., and compare sense of touch.
Experimental result: normal rabbit liver answers color vivid, glossy, is bronzing.In this experiment, the liver surface of hyperlipidemia model group rabbit is coarse, is sallow, canescence, and surface and tangent plane are tactile greasy feeling, and volume has obvious enlargement; Each group that gives apoA-I all has improvement to a certain degree compared with hyperlipidemia model group, with apoA-I(40mg/kg/w) group alleviates the most obvious.Illustrate that apoA-I can improve the rabbit liver damage that high fat diet causes.
Embodiment 2 hepatic tissue HE dyeing observation experiments
Experimental technique: get liver organization routine paraffin wax embedded section
1. dyeing procedure dewaxing: each 10min → aquation of dimethylbenzene I, II: use successively gradient ethanol 100%, 95%, 80%, 70% each 1min of ethanol, distilled water flushing 5min * 2 time → haematoxylin dyeing 10min, washing → 2% hydrochloride alcohol differentiation 15-30s → flowing water rinses 10min → Yihong dyeing 2min → use successively gradient alcohol dehydration, 80%, each lmin of 95% ethanol, 100% ethanol 5min * 2 time → transparent: dimethylbenzene 5min neutral gum mounting.
2. research contents: variation the film making of light Microscopic observation aortic tissue (inner membrance, middle film, foam cell etc.).
Experimental result: normal rabbit liver regulating liver-QI leaflet structure is complete; The consistent and boundary of hepatocyte size, and to surrounding, be streak, radial proper alignment centered by central vein.1～2 core rounded or similar round is positioned at cell central authorities, and kytoplasm is abundant, sinus hepaticus queueing discipline, and portal area is clear.In model group hepatocyte kytoplasm, be full of the circular fat differing in size in a large number and drip, lobules of liver structure is unclear, liver rope arrangement disorder, and most of hepatocyte is steatosis, visible point-like necrosis region and inflammatory cell infiltration therebetween, part of hepatocytes is balloon sample and becomes.ApoA-I administration group hepatocyte injury all obtains inhibition in various degree, and apoA-I (40mg/kg/w) group therapeutic effect is more obvious.Illustrate that apoA-I can improve the rabbit liver damage that high fat diet causes.
Embodiment 3 liver assessment of indices experiments
Experimental technique: weigh in before rabbit is put to death, put to death rear sharp separation liver and weigh, calculate liver coefficient (liver quality/weight).
Experimental result: liver coefficient is the percentage ratio of animal livers weight and body weight.In this experiment, compare with model group, the liver coefficient of apoA-I administration group rabbit all reduces (P < 0.05), with apoA-I(40mg/kg/w) the liver coefficient of group reduces the most obvious.Illustrate that apoA-I can improve the rabbit liver damage that high fat diet causes, as shown in Figure 1.
The experiment of embodiment 4 liver lipids (TC, TG, LDL-C and HDL-C) assay
Experimental technique: adopt lipid content detection kit to measure the content of TC, TG, LDL-C and HDL-C in 10% liver tissue homogenate.Experimental principle and process reference reagent box description.
Experimental result: compare with model group animal, in apoA-I administration group Hepar Leporis seu Oryctolagi tissue homogenate, the content of TC, TG, LDL-C all decreases; ApoA-I(20mg/kg/w) the horizontal there was no significant difference of the reduction of TC, TG, LDL-C in group, apoA-I(40mg/kg/w) group TC, TG, LDL-C content significantly reduce (P < 0.05).Contrary, to compare with model group animal, in apoA-I administration group rabbit liver, HDL-C content all raises to some extent, but there was no significant difference.Illustrate that apoA-I can reduce the degree of injury of liver by reducing the content of TC, TG, LDL-C in liver of laboratory animal, as shown in Figure 2.
Embodiment 5 hepatic lipid peroxidation product MDA assay experiments
Experimental technique: adopt MDA reagent box for detecting content to measure the content of MDA in 10% liver tissue homogenate.Experimental principle and process reference reagent box description.
Experimental result: compare with model group in this experiment, in the liver of apoA-I administration group rabbit, MDA content all decreases, with apoA-I(40mg/kg/w) group reduces the most obvious.Illustrate that apoA-I can reduce the levels of peroxide of lipid in liver of laboratory animal, as shown in Figure 3.
SOD, GPx and the experiment of iNOS enzyme activity determination in embodiment 6 serum
Experimental technique: the vigor of SOD, GPx and iNOS enzyme in employing SOD, GPx and iNOS enzyme activity determination kit measurement serum.Experimental principle and process reference reagent box description.
Experimental result: compare with model group in this experiment, in apoA-I administration group rabbit anteserum, SOD and GPx enzyme activity all rise; On the contrary, iNOS enzyme activity declines, with apoA-I(40mg/kg/w) group effect is the most obvious.Illustrate that apoA-I can increase the vigor of SOD and GPx enzyme in laboratory animal serum, suppress the vigor of iNOS enzyme simultaneously, with this, improve the antioxidant levels in serum, as shown in Fig. 4 (A-C).
SOD, GPx and the experiment of iNOS enzyme activity determination in embodiment 7 livers
Experimental technique: adopt SOD, GPx and iNOS enzyme activity determination test kit, get 1%,5%He 10% liver tissue homogenate, be respectively used to the mensuration of SOD in liver, GPx and iNOS enzyme activity.Experimental principle and process reference reagent box description.
Experimental result: compare with model group in this experiment, in apoA-I administration group rabbit liver, SOD and GPx enzyme activity all rise; On the contrary, iNOS enzyme activity declines, with apoA-I(40mg/kg/w) group effect is the most obvious.Illustrate that apoA-I can increase the vigor of SOD and GPx enzyme in liver of laboratory animal, suppress the vigor of iNOS enzyme simultaneously, with this, improve the antioxidant levels of liver, as shown in Fig. 4 (D-F).
SOD, GPx and CAT mrna expression level determination experiment in embodiment 8 livers
Experimental technique:
1) the total RNA extraction-Trizol of experimental rabbit liver organization method
(1) take out the experimental rabbit aorta 50mg that is stored in-80 ℃ of cryogenic refrigerators, move in EP pipe, shred.Add 200 μ lTrizol and steel balls, on Potter-Elvehjem Tissue Grinders, make homogenate, adding 800 μ lTrizol homogenate on Potter-Elvehjem Tissue Grinders again.
(2) homogenate room temperature is placed 5-30 minute, then with every lmlTrizol liquid, adds the ratio of 0.2ml to add chloroform, covers tightly centrifuge tube, with hands, acutely sways centrifuge tube 15 seconds, and room temperature is placed 2-3 minute.
(3) 4 ℃, centrifugal 15 minutes of 12000rpm.
(4) get upper strata water and (note not drawing any intermediate layer material) in the EP pipe of the 1.5ml of a new RNase-free, the ratio that adds 0.5ml isopropyl alcohol in every lmlTrizol liquid adds isopropyl alcohol, puts upside down mix homogeneously, and room temperature is placed 10 minutes.
(5) 4 ℃, centrifugal 10 minutes of 12000rpm, is RNA in EP tube edges and bottom precipitation after centrifugal.
(6) abandoning supernatant, adds at least ratio of lml to add 75% ethanol of processing through DEPC in every lml Trizol liquid, and vortex mixes, rinsing RNA.
(7) 4 ℃, centrifugal 5 minutes of 7500rpm.
(8) abandoning supernatant, room temperature or vacuum drying 5-30 minute.
(9) RNA is dissolved in DEPC treated water 50 μ l, in 55 ℃-60 ℃, hatches and to dissolve RNA, precipitate for 5-10 minute, it is standby that packing is stored in-80 ℃ of refrigerators.
2) real-time fluorescence quantitative RT-PCR amplification target DNA fragment
(1) reverse transcription reaction---adopt two-step method (20 μ l system), reaction system is as follows:
The first step:
Mix, centrifugal, be placed in PCR instrument, 65 ℃, 5min, ice bath is cooling immediately, and recentrifuge is placed on ice.
Second step:
Mix, centrifugal, be placed in PCR instrument, 25 ℃, 10min; 50 ℃, 15min; 85 ℃, 5min, cessation reaction.After the packing of reverse transcription product in-80 ℃ of preservations.
(2) real-time fluorescence quantitative PCR reaction (25 μ l system), reaction system is as follows:
(3) PCR reaction condition (two step TRAP programs)
Experimental result: compare with model group in this experiment, in apoA-I administration group rabbit liver, SOD, GPx and CAT mrna expression level all rise, with apoA-I(40mg/kg/w) group expression rises the most obvious.Illustrate that apoA-I can improve the antioxidant levels of liver by the expression of SOD, GPx and CAT mRNA in rise liver of laboratory animal, as shown in Figure 5.
The statistical analysis of experimental result of the present invention: measurement result all adopts mean ± standard error (X ± SEM) to represent.All statistical informations are all used the analysis of SPSS11.5 statistical software, two samples relatively adopt t check, a plurality of samples relatively adopt post hoe tests LSD one factor analysis of variance (analysis of variance, ANOVO), experimental data indicates significant difference with P < 0.05.
Embodiment 9 apoAI In Vitro Anti hepatitis B effects
Experiment material and method
In vitro cell model: by prior art, the HepG2 cell of hepatitis B virus (HBV) transfection, i.e. HepG22.2.15 cell.
Mtt assay detects the toxicity of sample to cell.
Euzymelinked immunosorbent assay (ELISA) (EIA) detects the inhibitory action of sample to HBsAg and HBeAg.
Positive drug contrast: lamivudine (3TC).Result demonstration, apoAI is external has inhibitory action to HBsAg and HBeAg, as shown in table 1.
Table 1ApoAI In Vitro Anti hepatitis B effect
Claims (6)
1. apolipoprotein A-1 prevents and treats the purposes in hepatopathy metabolism syndrome medicine in preparation.
2. by purposes claimed in claim 1, it is characterized in that, described hepatopathy metabolism syndrome is the disease that oxidative stress related enzyme activity is relevant, and described oxidative stress relevant enzyme comprises SOD, GPx, iNOS and CAT.
3. by purposes claimed in claim 2, it is characterized in that, the disease that described oxidative stress related enzyme activity is relevant also comprises hepatitis, hepatic fibrosis or hepatocarcinoma.
4. by purposes claimed in claim 1, it is characterized in that, described hepatopathy metabolism syndrome is by obesity, hyperlipemia, type 2 diabetes mellitus factor but not the fatty liver that ethanol causes.
5. by purposes claimed in claim 1, it is characterized in that, described medicine reduces liver index; Reduce liver lipid content; Reduce hepatic lipid peroxidation product MDA content; The vigor of SOD and GPx in raising serum and liver, the vigor of inhibition iNOS; The expression of SOD, GPx and CAT mRNA in raising liver.
6. by purposes claimed in claim 1, it is characterized in that, described drug dose is: the frequency that gives animal subject apolipoprotein A-1 is on every Mondays to 2 times, and dosage is each 5mg-80mg/kg body weight.
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| 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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