CN104096218A - Application of recombinant human cytoglobin in preparation of drugs treating hyperlipidemia and atherosclerosis - Google Patents
Application of recombinant human cytoglobin in preparation of drugs treating hyperlipidemia and atherosclerosis Download PDFInfo
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Abstract
The invention discloses application of recombinant human cytoglobin (rhCYGB) in preparation of drugs treating hyperlipidemia and atherosclerosis. A hyperlipidemia rat model and an atherosclerosis rat model are respectively established by the inventor, and subcutaneous injection of rhCYGB is carried out for treatment. Experimental results show that the rhCYGB drug is non-toxic, compared with a model control group, the rhCYGB treatment group has significant improvement, the four items of blood lipid test are significantly decreased than those of a model group, and the four items of blood lipid test of a polysaccharide sulfate treatment group are significantly higher than normal, thus rhCYGB has better efficacy than polysaccharide sulfate in treatment of hyperlipidemia caused by high fat diet. In the atherosclerosis rat model, compared with the model group, the four items of blood lipid test of the treatment group are also significantly reduced, and atherosclerotic plaques also obviously decreased. Therefore, treatment of hyperlipidemia and atherosclerosis by the recombinant human cytoglobin has the advantages of low toxicity, safety and effectiveness.
Description
Technical field
The present invention relates to the new purposes of recombination human source cytoglobin, the particularly application of recombination human source cytoglobin in preparation treatment hyperlipidemia and atherosclerosis medicine.
Background technology
According to relevant, hyperlipemia and atherosclerotic generation and develop closely related.The main harm of hyperlipidemia is to cause atherosclerosis, and then causes numerous relevant diseases, and wherein modal a kind of mortality disease is exactly coronary heart disease.The concurrent angina pectoris of atherosclerosis, myocardial infarction, apoplexy, renal insufficiency, hemiplegia etc. are often the major causes of death of middle-older patient.A lot of doctors think that effective treatment hyperlipidemia is very beneficial for the generation that prevention of arterial is atherosis.
Hyperlipemia shows as lipid metabolism or running makes one or more lipid contents in blood plasma higher than normal value extremely.About the diagnostic criteria of hyperlipemia, the current internal and international unified method that there is no.Previously think total cholesterol density of blood plasma >5.17mmol/L(200mg/dl) can be decided to be hypercholesterolemia, plasma triglyceride concentration >2.3mmol/L(200mg/dl) be hypertriglyceridemia.A large amount of feed high fat diets, smoke, lack exercise, stress, inherited genetic factors etc. can cause hyperlipidemia, the high lipid food of wherein taking food is in a large number a key factor of hyperlipidemia.According to statistics, China's patients with dyslipidemia, up to 1.6 hundred million, has 2,500 ten thousand people to suffer from hypertension and hyperlipemia in 35 years old above crowd simultaneously.Therefore, be correctly familiar with hyperlipidemia, diagnose in time and treat, significant.
Normal person's blood fat mainly comprises cholesterol (or claiming T-CHOL TC) and triglyceride, in blood circulation, exists with non-free state, becomes the such macromole transport of lipoprotein with protein binding.Main lipoprotein is divided into Chylomicron, extra-low density (front-β) lipoprotein (VLDL), low-density (β-) lipoprotein (LDL) and high density (a-) lipoprotein (HDL), and these albumen are allo.Hyperlipemia is often hyperlipoproteinemia (hyperlipoproteinemia), shows as hypercholesterolemia, hypertriglyceridemia or both have concurrently, is divided into clinically two classes: 1. constitutional, and rare, belong to heritability disorders of lipid metabolism disease; 2. Secondary cases, is common in high fat diet, smokes, drinks, controls bad diabetes, hypothyroidism, nephrotic syndrome, biliary obstruction etc.There is multiple hypothesis in its pathogeny: someone thinks ldl receptor function reduction, and LDL removes barriers; Someone think by VLDL produce too much or removing obstacles and VLDL be transformed into LDL too much due to ldl receptor remove ineffective.Because hyperlipemia is a kind of chronic disease, and existing hyperlipemia animal model generally adopts the chyle gavage of high fat, stimulation to animal body is large, simultaneously, gavage is large to the stimulation of animal, causes animal psychentonia, and nervous system and the hormonal system of animal are under some influence, there is larger difference with the Diet hyperlipemia that true development forms in the animal model obtaining, this has brought impact to a certain degree also to the drug screening of Diet hyperlipemia.
Atherosclerosis (atherosclerosis, AS) be most important one common in arteriosclerotic angiopathy, be characterized in getting involved arterial disease from inner membrance, generally first have that lipid and compound saccharide gather, hemorrhage and thrombosis, proliferation of fibrous tissue and calcinosis, and have medial transformation gradually and calcification, pathological changes is often involved elasticity and large medium muscular artery, be enough to obstructing arterial chamber once develop into, the tissue that this tremulous pulse is supplied or organ are by ischemia or necrosis.Because the lipid outward appearance of gathering at endarterium is yellow medicated porridge sample, be therefore called atherosclerosis.Atherosclerosis is disease occurred frequently at western developed country.Along with the change of Chinese people's living standard raising and dietary habit, this disease also becomes the disease occurred frequently of China.Optionally have an electro-cardiogram clinically, the internal organs scannings such as radioactive nucleus wish, brain, kidney, ultrasonic examination by Doppler's method, and selective angiography etc., just can make tentative diagnosis.Current atherosclerotic conventional therapy is exactly: reasonable diet, appropriate exercise Drug therapy in addition.
According to the investigation of WHO, because the difference at sex, heredity, age, hyperlipidemia and atherosclerosis all do not have very reliable and effective therapeutic scheme at present.In view of Chinese medicine ingredients complexity, preparation technology is not mature enough stable, and the side effect of Western medicine is obvious, develops the effective anti-curing hyperlipemia of real safety non-toxic and atherosclerotic medicine, is a research that has very much realistic meaning and use value.
Cytoglobin (cytoglobin) is the intrinsic protective protein of human body, and body is had no side effect.Cytoglobin is found in rat HSC by Kawada etc. at first, it expresses obviously in the liver fibrosis sternzellen (HSC) of thioacetamide stress-inducing increases, thereby be originally named as HSC activate associated protein (Stellate cell activation-associated protein, STAP).Protein sequencing shows that it belongs to the hexa-coordinate albumen (Hexacoordinate globin super-family) that a new class contains haemachrome, is one of four kinds of globulin (Globin) in mammal.Further research finds that STAP does not exist only in HSC, is also prevalent in the mechanocyte of the multiple organ-tissue of the mankind and kidney and pancreas, thereby is unified to be called cytoglobin (Cytoglobin, Cygb).Cytoglobin is made up of 190 amino acid residues, and molecular weight is 21.4kD, is positioned chromosome 17q25.Current research shows that Cygb has effect and the EC 1.14.12.17 function of the effect of peroxidase, active oxygen scavenger, on gene, there is conservative histanoxia response element (HRE), its 3 ' UTR also contains the mRNA stabilization signal (HIPBS) of histanoxia induction simultaneously, can ensure expression and the stability of Cygb gene in the time of histanoxia.Various stress situation under during as ischemia, oxidative stress and fibrosis, Cygb expresses increase.The same with other members of globulin family, Cygb has the damage that Cell protection is avoided oxidative stress, in body and experiment in vitro show that the exogenous expression rhCygb that crosses can protect hepatic stellate cell avoid oxidative stress damage and suppress it and break up to fibroblast-like cell.There is not so far reported in literature people ortet albumen to have and improve or treatment hyperlipemia and atherosclerotic effect.
Because mankind Cygb and rat Cygb have 97% homology in gene order, therefore the present invention adopts cytoglobin (recombination human source cytoglobin, the rhCygb) albumen that derives from people to carry out the treatment experiment of rat model.
Summary of the invention
The object of the present invention is to provide recombination human source cytoglobin (rhCygb) in the application of preparing in Cardiovarscular medicine, described cardiovascular disease is preferably hyperlipidemia, atherosclerosis.
Inventor sets up respectively hyperlipemia rat model and atherosclerotic rat model, and by subcutaneous injection, rhCYGB treats.Experimental result shows, rhCYGB medicine avirulence, compared with model control group, rhCYGB treatment group is significantly improved, its four items of blood lipid tests obviously reduces compared with model group, and algae diesteras treatment group four items of blood lipid tests is apparently higher than normally, therefore the hyperlipidemia that rhCYGB treatment high fat diet causes is better than propylene glycol alginate sodium sulfate drug effect.In atherosclerotic rat model, treatment group is compared with model control group, and its four items of blood lipid tests also has obvious minimizing, and atherosclerotic plaque also has obvious minimizing.Thereby adopt recombination human source cytoglobin treatment hyperlipidemia and atherosclerosis to there is low toxicity, safe and effective advantage.
Brief description of the drawings
Fig. 1 is the rat liver pathological observation result of rhCygb treatment group and Polysaccharide sulfate in treatment group.
Fig. 2 is the rat liver pathological observation result of model control group and Normal group.
Fig. 3 is rat artery specimen pathological observation result.
Detailed description of the invention
one, hyperlipemia rat model test
1, animal modeling:
50 of clean level healthy adult male SD rats that are 200～250g by body weight are divided into 2 groups by complete random method, 10 of Normal groups, 40 of modeling groups.
Normal group: the plain particles of throwing something and feeding feedstuff, freely ingest, average every day every approximately 20 grams of left and right.
Model group: (high lipid food is the free formula of laboratory to the high lipid food of throwing something and feeding, and is made by Nanfang Medical Univ's Experimental Animal Center: 85% normal feedstuff, 4% cholesterol, 10% Adeps Sus domestica, 0.2% propylthiouracil, 0.5% cholate), freely ingest, average every day every approximately 20 grams of left and right.Modeling 4 weeks.
40 modeling group rats, after modeling in 4 weeks success, are chosen at random 10 and adopt tail vein blood sampling to measure four items of blood lipid tests, and measurement result confirms modeling success.
2, animals administer:
40 modeling group rats are divided into 3mg/kg rhCygb treatment group (8), 6mg/kg rhCygb treatment group (8), 9mg/kg rhCygb treatment group (8), positive drug (propylene glycol alginate sodium sulfate) treatment group (8), model control group (8) at random.
Normal group: the plain particles of always throwing something and feeding feedstuff.
Model control group: continue the high lipid food of throwing something and feeding at experimental session.
RhCygb treatment group: after modeling success, give respectively the dosage subcutaneous injection of rhCygb 3mg/kg, 6mg/kg, 9mg/kg, 1 times/day, treat altogether 1 month.Continue at experimental session the high lipid food of throwing something and feeding.
Polysaccharide sulfate in treatment group: after modeling success, give propylene glycol alginate sodium sulfate 9mg/kg.d dosage subcutaneous injection, 1 times/day, treat altogether 1 month.Continue to feed high lipid food at experimental session.
Each treated animal is kept quite at experimental session Animal House, natural lighting, 25 DEG C of left and right of temperature.
3, acute toxicity test:
Cygb is enorganic protective protein, substantially body is had no side effect.The acute toxicity tests also shows: in one day, give mouse stomach rhCygb 500.0mg/kg, and Continuous Observation seven days, mice general status is good, and none death illustrates rhCygb low toxicity, safety.
4, drug effect result:
(1) observation of animal ordinary circumstance
Normally, fur is clean and tidy for rats in normal control group feed, growth, and hair color is moist, and the irritant reaction of environment is rapid to external world, without dead.During modeling, modeling group appetite declines, lethargy, and the not whole and dark and gloomy tarnish of later stage fur, food-intake and amount of drinking water are obviously less than Normal group, and body weight gain is slow.
During treatment, rhCygb treatment group food-intake is cumulative many, reacts gradually sensitive, and activity before increases.Polysaccharide sulfate in treatment group symptom is slightly improved, but improves obviously not as good as rhCygb treatment group.During treatment, without rats death.
Conclusion: recombination human source cytoglobin medicine avirulence.
(2) detection of four of rat fats
Blood lipid level comparison between each group, one factor analysis of variance the results are shown in Table 1.
The impact of table 1 rhCYGB on four of rat fats (
± s)
With Normal group comparison:
ap<0.05; With model control group comparison:
bp<0.05; With the comparison of Polysaccharide sulfate in treatment group:
cp<0.05; A:3mg/kg rhCygb treatment group; B:6mg/kg rhCygb treatment group; C:9mg/kg rhCygb treatment group; D: Polysaccharide sulfate in treatment group; E: model control group; F: Normal group.
As shown in Table 1, between each group, four items of blood lipid tests level does not equate entirely, has significant difference.Multiple comparisons Bonferroni method assay and Normal group comparison between group, model control group TC, TG, LDLC are significantly higher than Normal group, and more obviously (P=0.000) of TC rising, and HDLC no difference of science of statistics (P=0345); Polysaccharide sulfate in treatment group TC, TG, LDLC, HDLC and Normal group comparison, have significant difference (P=0.000); 9mg/kg rhCygb treatment group TG and the equal no difference of science of statistics of Normal group (P=0.121), and TC, LDLC, HDLC and Normal group have significant difference (P=0.000), there were significant differences for TC, TG, LDLC, HDLC and model control group (P=0.000); 6mg/kg rhCygb treatment group TC, TG, LDLC, HDLC and Normal group, model control group all have significant difference (P=0.000); 3mg/kg rhCygb treatment group TC, TG, LDLC and Normal group, model control group all has significant difference (P=0.000), and HDLC Normal group, the equal no difference of science of statistics of model control group (with model control group P=0.858, with Normal group P=1.000).
Conclusion: injection 9mg/kg rhCygb can effectively reduce rat hyperlipidemia, and lipid-lowering effect is more obvious compared with propylene glycol alginate sodium sulfate.
(3) rat liver pathological observation
Rat liver pathological observation result is as shown in Figure 1 and Figure 2: in Fig. 1, Fig. 2, and A:3mg/kg rhCygb treatment group; B:6mg/kg rhCygb treatment group, C:9mg/kg rhCygb treatment group; D: Polysaccharide sulfate in treatment group; E: model control group; F: Normal group; Wherein, A1～F1 is low power lens photo: × 100; A2～F2 be in times mirror photo: × 200, length of the scale is 500 μ m.
Fig. 1,2 results show, rats in normal control group liver peplos is smooth complete, and surface color is dark red, and smoothness is tender, good springiness, and clear-cut margin, the sense of tangent plane fine grained, without greasy feeling.Model group rat liver volume obviously increases, and is lark, peplos anxiety, rough surface, the obvious greasy feeling of tangent plane.Liver tissue slices, the HE observation of dyeing, Normal group lobules of liver structural integrity, hepatocyte is polygon, and cell boundary is clear, and core circle, is positioned at cell central authorities, fat-free degeneration.Model group hepatocyte volume increases, and has the circular cavity differing in size in cytoplasm, clear-cut margin, and several little cavitys are fused to large cavity, and liver cell nuclear is squeezed a cytotropic side by large cavity, and header region, with inflammatory cell infiltration, shows as severe steatosis.
6mg/kg rhCygb treatment group and 9mg/kg rhCygb treatment group liver compared with normal matched group are slightly large, but less than normal than Polysaccharide sulfate in treatment group, and most of color is dark red, moist, and tangent plane is without greasy feeling.Liver tissue slices, the HE observation of dyeing, Normal group hepatocyte lobules of liver clear in structure, hepatocyte radially distributes towards periphery centered by central vein.
Conclusion: compared with model control group, rhCygb treatment group is significantly improved, and its fat drop obviously reduces compared with model group, liver rope marshalling.Polysaccharide sulfate in treatment group still has obvious steatosis, slight hepatic cell swelling.The fatty liver of rhCygb treatment hyperlipidemia secondary is better than propylene glycol alginate sodium sulfate drug effect.
two, atherosclerotic rat model test
1, animal grouping:
The SD rat of male SD rat and high blood lipid model is from same batch.Totally 41 of rats, are divided into 2 groups by complete random method, 8 of Normal groups, 33 of modeling groups.
The Normal group plain particles feedstuff of throwing something and feeding, freely ingests, average every day every approximately 20 grams of left and right.
The modeling group high lipid food (with the same formula of high lipid food in hyperlipemia rat model) of throwing something and feeding, freely ingests, average every day every approximately 20 grams of left and right, and on the basis of high fat diet, lumbar injection vitamin D3, totally 70 ten thousand IU/Kg, divide 4 times, every injection in two days once.Modeling 4 weeks.
33 modeling group rats, after modeling in 4 weeks success, are chosen 1 pathological section that does ventral aorta HE dyeing at random, and pathological examination confirms modeling success; 32 rats are divided into 4mg/kg rhCygb treatment group (8), 9mg/kg rhCygb treatment group (8), positive drug (propylene glycol alginate sodium sulfate) treatment group (8), model control group (8) at random.
, animals administer:
Normal group: the plain particles of always throwing something and feeding feedstuff.
Model control group: continue the high lipid food of throwing something and feeding at experimental session.
RhCygb treatment group: after modeling success, give respectively the dosage subcutaneous injection of rhCygb 4mg/kg, 9mg/kg, 1 times/day, treat altogether 1 month.Continue at experimental session the high lipid food of throwing something and feeding.
Polysaccharide sulfate in treatment group: after modeling success, give propylene glycol alginate sodium sulfate 9mg/kg dosage subcutaneous injection, 1 times/day, treat altogether 1 month.Continue to feed high lipid food at experimental session.
Each treated animal is kept quite at experimental session Animal House, natural lighting, 25 DEG C of left and right of temperature.
, drug effect result:
(1) observation of animal ordinary circumstance
Normally, fur is clean and tidy for rats in normal control group feed, growth, and hair color is moist, and the irritant reaction of environment is rapid to external world, without dead.During modeling, modeling group appetite declines, lethargy, and the not whole and dark and gloomy tarnish of later stage fur, food-intake and amount of drinking water are obviously less than Normal group, and body weight gain is slow.
During treatment, rhCygb treatment group food-intake is cumulative many, reacts gradually sensitive, and activity before increases.Polysaccharide sulfate in treatment group symptom is slightly improved, but improves obviously not as good as rhCygb treatment group.During treatment, without rats death.
Conclusion: recombination human source cytoglobin medicine avirulence.
(2) detection of four of rat fats
Blood lipid level comparison between each group, one factor analysis of variance the results are shown in Table 2.
The impact of table 2 rhCYGB on four of rat fats (
± s)
With Normal group comparison:
ap<0.05; With model control group comparison:
bp<0.05; With the comparison of Polysaccharide sulfate in treatment group:
cp<0.05; A:4mg/kg rhCygb treatment group; B:9mg/kg rhCygb treatment group; C: Polysaccharide sulfate in treatment group; D: model control group; E: Normal group.
As shown in Table 2, between each group, four items of blood lipid tests level does not equate entirely, has significant difference.Multiple comparisons Bonferroni method assay and Normal group comparison between group, model control group TC, TG, LDLC are significantly higher than Normal group, and HDLC no difference of science of statistics (P=0.379); Polysaccharide sulfate in treatment group TC, TG, LDLC, HDLC and Normal group comparison, have significant difference (P=0.000); 9mg/kg rhCygb treatment group TC, TG, LDLC, HDLC and Normal group have significant difference (P=0.000), and there were significant differences for TC, TG, LDLC, HDLC and model control group (P=0.000); 4mg/kg rhCygb treatment group TC, TG, LDLC, all have significant difference (P=0.000) with Normal group, model control group, HDLC and normal group are without significant difference (P=1.000); Conclusion: 9mg/kg rhCYGB can effectively reduce rat hyperlipidemia, and lipid-lowering effect is more obvious compared with propylene glycol alginate sodium sulfate.
(2) rat artery specimen pathological observation
Rat artery specimen pathological observation result is as shown in Figure 3: in Fig. 3, and A:4mg/kg rhCygb treatment group; B:9mg/kg rhCygb treatment group, C: Polysaccharide sulfate in treatment group; D: model control group; E: Normal group; Wherein, A1～E1 is low power lens photo: × 100; A2～E2 be in times mirror photo: × 200, length of the scale is 500 μ m.
Fig. 3 result shows, rats in normal control group ventral aorta blood vessel wall thickness homogeneous, and monolayer endothelium is met personally in chamber, marshalling homogeneous, core is justified empurple greatly; Inner membrance has endotheliocyte that monolayer is complete and a small amount of extracellular matrix to form, and has no smooth muscle cell, inside and outside elastic plate complete display, media thickness homogeneous.Model group rat aorta blood vessel wall variable thickness, interior membrane portions comes off, and forms foam cell, and middle level elastic plate ruptures and has a large amount of calcifications.The inner membrance of the ventral aorta of 4mg/kg rhCygb treatment group and 9mg/kgrhCygb treatment group is imperfect, has a small amount of foam cell to form, but less than normal than Polysaccharide sulfate in treatment group; Middle level elastic membrane is without obviously destroying and calcification.
Conclusion: compared with model control group, rhCygb treatment group is significantly improved, its inner membrance foam cell obviously reduces and obviously medial calcification of nothing.Polysaccharide sulfate in treatment group foam cell is more, and middle level elastic membrane fiber alignment is mixed and disorderly.RhCygb treatment atherosclerosis is better than propylene glycol alginate sodium sulfate drug effect.
Claims (3)
1. recombination human source cytoglobin is in the application of preparing in Cardiovarscular medicine.
2. the application of recombination human source cytoglobin in preparation treatment hyperlipidemia.
3. the application of recombination human source cytoglobin in preparation treatment atherosclerosis medicine.
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