CN103417523B - Application of L-glutamine to preparation of drug for treating high homocysteine - Google Patents
Application of L-glutamine to preparation of drug for treating high homocysteine Download PDFInfo
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- CN103417523B CN103417523B CN201310309033.XA CN201310309033A CN103417523B CN 103417523 B CN103417523 B CN 103417523B CN 201310309033 A CN201310309033 A CN 201310309033A CN 103417523 B CN103417523 B CN 103417523B
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Abstract
The invention discloses an application of L-glutamine to the preparation of a drug for treating high homocysteine, and relates to the technical field of medical drugs. The drug is a common amino acid, and has the following advantages when used for treating homocysteine compared with the universal drug clinically and frequently used for treating homocysteinemia: firstly, the curative effect, particularly the effect of directly reducing homocysteine in serum is remarkable; secondly, the safety is high, and no toxic and side effects exist; thirdly, economical load of patients can be reduced as the drug is obviously cheaper compared with the effective drugs frequently used or reported in the market at present; fourthly, the drug can be combined with other drugs for treatment as a compound preparation; fifthly, the drug can directly reduce the content of homocysteine in blood while remarkably reducing inflammatory reaction, thereby improving the oxidation resistance of the organism.
Description
Technical field
The present invention relates to a kind of novelty teabag of L-glutaminate, the particularly L-glutaminate novel medical use in preparation treatment hyperhomocysteinemiainjury medicine, belong to medical art.
Background technology
Homocysteine (High homocysteine, HHcy) mass formed by blood stasis is homocysteine (homocysteine, Hcy) a kind of metabolic disease formed is raised in blood, HHcy mass formed by blood stasis is the risk factor of various diseases, generally speaking, homocysteine level raises and cardiovascular disease mortality prediction can be made to increase by 4 ~ 6 times, there is research display, then 60% is increased when the total Hcy level of blood plasma often raises 5umol/L risk of coronary heart disease male, women then increases by 80%, and severe plasma homocysteine mostly occurs the crowd with Other diseases, particularly diabetes, coronary atherosclerosis, alzheimer disease, apoplexy, the diseases such as venous thrombosis, these patient's plasma homocysteine levels are apparently higher than normal person.Past has the shortage of research display patient vitB12, vitB6 to be cause a key factor of hyperhomocysteinemiainjury, but by finding the research of numerous case, there is most of patient after supplementary vitB12, vitB6, homocysteine content does not in blood have any change, this prompting is also completely not bright and clear about HHcy pathogenesis, and the new tool finding effective prevention and therapy hyperhomocysteinemiainjury is very necessary.
L-glutaminate (L-Glutamine, L-Gln), formal name used at school: 2-amino-5-carboxyl pentanamide is the coded amino acid in protein synthesis, in vivo can by convert glucose.L-Gln is the required nutrient substance of intestinal mucosa cellular metabolism, plays a very important role (Li, Nan to the integrity maintaining intestinal mucosal epithelial structure; Ma, Liya; Liu, Xueyan; Shaw, Lynn; Calzi, Sergio Li; Grant, Maria B; Neu, Jose.Arginyl-Glutamine Dipeptide orDocosahexaenoic Acid Attenuates Hyperoxia-induced Small Intestinal Injury in NeonatalMice [J] .Journal ofPediatric Gastroenterology & Nutrition.2012,54 (4): 499-504).Glutamine is one of important sources of reduced glutathion in body, plays immunoregulatory effect in body.Glutamine is that lymphocytic emiocytosis, propagation and function thereof remain necessary, glutamine also can as the precursor of Nucleic acid and the energy simultaneously, glutamine can impel mitosis and the differentiation and proliferation of lymphocyte, macrophage, increases the generation of cytokine TNF, IL-1 etc. and the mRNA synthesis of phospholipid.The ratio of CD4/CD8 in the total lymphocyte count providing exogenous glutamine obviously can increase critical patient, T lymphocyte and circulation, the immunologic function of enhancing body.Glutamine can also improve the oxidation resistance of body in addition; supplement glutamine; by keeping and increase the deposit of the GSH in histiocyte; improve antioxidant ability of organism; stabilizing cell membrane and protein structure; the function of the vitals such as protection liver, lung, intestinal and immunocyte, maintains the normal function of kidney, pancreas, gallbladder and liver.Glutamine has positive role in promotion protein metabolism.Glutamine can suppress inflammatory mediator to discharge, and alleviates Systemic stress response degree, shortens the hospital stays.Glutamine or a few can the release of growth promoting effects hormone one of aminoacid (one, Ting Han, Xiuli Li, Donglian Cai, Yan Zhong, Lingyun Chen, ShanhanGeng, Shaojun Yin.Effect of glutamine on apoptosis of intestinal epithelial cells of severe acutepancreatitis rats receiving nutritional support in different ways [J] .Int J Clin Exp Pathol.2013, 6 (3): 503-509. bis-, Claire Boutry, Hideki Matsumoto, C é cile Bos, Christophe Moinard, Luc Cynober, Yulong Yin, Daniel Tom é, Frangois Blachier.Decreased glutamate, glutamine and citrullineconcentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutaminesupplementation:a primary intestinal defect? [J] .Amino Acids.2012, 43 (4): 1485-1498.).In recent years, lot of domestic and foreign expert finds that glutamine can increase the content of GLP-1 in blood of human body, with the increase of glutamine oral dose, in blood, GLP-1 secretion increases, when the amount of fasting insulin does not increase, fasting glucose is declined, insulin sensitivity increases, glycolated hemoglobin declines, thus reach reduction blood glucose, increase insulin sensitivity, reduce effect (the Jerry R Greenfield of insulin resistant, I Sadaf Farooqi, Julia M Keogh.Oral glutamineincreases circulating glucagon-like peptide1glucagon, and insulin concentrations in lean, obese, andtype2diabetic subjects.The American Journal of Clinical Nutrition, 2009, 106 (13): 106-113), at home and abroad all do not report about the relation of glutamine and hyperhomocysteinemiainjury at present.
Current do not have the specific medicament for the treatment of HHcy mass formed by blood stasis in clinical, prevent for many risk factors, it is the fundamental measure reducing this sick sickness rate, the measure of clinical middle treatment HHcy mass formed by blood stasis mainly contains 3 aspects: 1, apply antioxidant, such as ginkgo agent, injection Vitamin B_6, beta-carotene, superoxide dismutase (SOD) etc., 2, folic acid is applied, vitamin B6, B12 etc. promote the medicine of homocysteine metabolism, 3, application anti-inflammatory preparation, and as aspirin, indometacin etc.In above Therapeutic Method, antioxidant and anti-inflammatory drugs mainly pure play prevention and delay disease occur and develop effect, and apply folic acid, vitamin B6, B12 three and apply together, the content of HHcy in blood can be reduced, but the diversity of individuality is obvious, and some patient is invalid; The present invention's application Glutamine HHcy mass formed by blood stasis, compared to medicine conventional in clinical, with the obvious advantage, be mainly manifested in the content that not only significantly can reduce homocysteine in blood, also significantly can reduce rat inflammation reaction simultaneously, improve oxidation resistance, every equal significant effective of rat after treatment simultaneously, these are that the three major types medicine of stating above can not be compared.
Summary of the invention
The object of this invention is to provide a kind of novelty teabag of L-glutaminate, i.e. the application of L-glutaminate in preparation treatment HHcy mass formed by blood stasis medicine.
The novelty teabag of L-glutaminate of the present invention, being novel drugs L-glutaminate being used as treatment HHcy mass formed by blood stasis, is namely medicine main component with L-glutaminate, the application in this disease for the treatment of HHcy mass formed by blood stasis.
The main component (or effective ingredient) of the medicine for the treatment of HHcy mass formed by blood stasis of the present invention is L-glutaminate, one or more pharmaceutically acceptable adjuvants can also be added, to improve drug absorption effect or to be convenient to take, as made capsule or pill, powder, tablet, granule, oral liquid and injection etc.
The present invention can add comprise the common filler of pharmaceutical field, diluent, binding agent, absorption enhancer when preparing treatment HHcy mass formed by blood stasis medicine, and the adjuvants such as stabilizing agent are taken, and can also add flavouring agent and sweeting agent etc. if desired.
The invention provides a kind of novelty teabag of L-glutaminate, namely the application in preparation treatment hyperhomocysteinemiainjury medicine, results of animal: the average content of (1) HHcy group rat homocysteine is that 16.43 ± 6.28 μm of ol/L are significantly higher than normal group (5.24 ± 1.17 μm of ol/L), (glutamine solution gavage is given after with L-glutaminate treatment, every day 2 times, each 0.5g/kg rat body weight) content that significantly can reduce homocysteine in rat blood (is finally reduced to 7.74 ± 1.17 μm of ol/Lg/ml, the ratio reduced is up to 53%), even indivedual rat is also better than blank group, blood vitamin B12 obviously raises (model control group 550+203pmol/L, L-GLn treatment group 7904 ± 43pmol/L, blank group 990 ± 188pmol/L) compared to model group, in rat body, folate level almost returns to normal level (model control group 18.5+14.3nmoL/L, L-GLn treatment group 34.7 ± 4.3nmoL/L, blank group 39.6+7.8nmoL/L), (2) Rats with Hyperhomocysteinemia model is accepting after L-GLn treats 8 weeks, and the related inflammatory factors such as IL-6, IL-1, NF-kB, CRP are significantly improved, (3) Rats with Hyperhomocysteinemia model is accepting after L-GLn treats 8 weeks, and the oxidative and anti-oxidative ability that SOD, MDA, GSH, T-AOC etc. are relevant significantly returns to normal level, (4) two kinds of key enzyme CBS and MTHFR of rat homocysteine metabolism obtain obvious improvement, and by above the results show, glutamine may be used for hyperhomocysteinemiainjury and therapeutic equivalence is remarkable.
Compared with treatment fatty liver medicament conventional clinically at present, medicine of the present invention has the following advantages: (1) is evident in efficacy; (2) safety is high, owing to being a kind of common aminoacid, almost non-toxic side effect.(3) cheap, the financial burden of patient can be alleviated.(4) this medicine also can reduce inflammatory reaction in blood direct reduction in blood while content of homocysteine, improves the oxidation resistance of body.(5) evident in efficacy, useful to each individuality, the suitability is wide.
Because the application of Glutamine hyperhomocysteinemiainjury belongs to Late Cambrian; therefore; no matter be that L-glutaminate uses as monomer medicine, still utilize L-glutaminate to coordinate other medicines to make the application of reagent compound, all in protection scope of the present invention as main component.
Accompanying drawing explanation
Fig. 1 is content of homocysteine comparative result schematic diagram in the rat blood serum after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury;
Fig. 2 be L-glutaminate of the present invention treatment hyperhomocysteinemiainjury after rat blood serum Folic Acid and vitamin B
12comparision contents result schematic diagram, wherein A is folate content; B is vitamin B
12content;
Fig. 3 is rat blood serum oxidability index S OD, MDA result of variations figure after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury, and wherein A is SOD result; B is GSH result;
Fig. 4 is the result of variations figure of rat blood serum oxidability index GSH after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury, T-AOC, and wherein A is MDA result; B is T-AOC result;
Fig. 5 is the change schematic diagram of rat portions inflammatory factor IL-6, IL-1 after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury in rat blood serum, and wherein A is IL-1 result; B is IL-6 result;
Fig. 6 is the variation diagram of rat portions inflammatory factor NF-kB, CRP after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury in rat blood serum, and wherein A is NF-kB result; B is CRP result;
Fig. 7 is that after L-glutaminate of the present invention treatment hyperhomocysteinemiainjury, the western of rat CBS, MTHFR albumen expresses schematic diagram;
Detailed description of the invention
Below by embodiment, the present invention is described in further detail, but content of the present invention is not limited thereto, method operating all according to a conventional method if no special instructions in the present embodiment, agents useful for same employing conventional reagent if no special instructions or the reagent configured according to a conventional method.
Homocysteine, folic acid, vitamin B in rat blood serum after embodiment 1:L-Glutamine hyperhomocysteinemiainjury
12determination study
The laboratory animal adopted in experiment is SD rat, and rat is male, and body weight is 180-200g, is provided by Kunming Medical University's Experimental Animal Center, and rat adopts 12, large cage, and 6 isolated rearings of little cage, raise as conventional feed, free diet and drinking-water.
The medicine adopted in experiment is for L-glutaminate for Amada Co., Ltd. provides, and modeling medicine methionine is purchased from Beijing Ding Guo biotech company; Detect rat homocysteine, folic acid, vitamin B
12bio-Swamp company is purchased from etc. the Elisa test kit of index.
40 rats are divided into blank (CON) to organize 13 at random, model comparison (HFD) organizes 13, L-glutaminate group 14, CON group gives normal feedstuff and feeds, HFD group, L-Gln group give normal diet+methionine solution gavage feed (feeding volume of the every day of methionine be every morning once, the each 1g of every kg rat, with the dilution of 10mi water during nursing).After feeding 12 weeks, often organize and get two rats execution, get serum to do index of correlation inspection (methionine stops nursing after 1 week, in Serological testing blood, content of homocysteine is that 15.00 μm of more than ol/L confirm modeling success), after confirming that model is successfully established, L-Gln group gives one day secondary, each 0.5g/kg rat body weight L-glutaminate gavage and treats, and HFD group gives the distilled water gavage treatment of equivalent, a blank group still feeding normal feedstuff, the treatment phase is 8 weeks.
With rat homocysteine, folic acid, vitamin B
12relevant Elisa test kit detects content of homocysteine, folic acid, vitamin B in rat blood serum
12content, can find out from Fig. 1 and Fig. 2: L-Gln treatment group is compared with model group, and in serum, content of homocysteine obviously reduces, through inspection treatment after p value be less than 0.05; L-Gln treatment group folic acid and vitamin B
12compared with model group, after inspection treatment, p value is also less than 0.05; The results show: Glutamine HHcy mass formed by blood stasis significantly can reduce the content of Hcy in serum, improves serum Folic Acid and vitamin B simultaneously
12content, thus reach the effect directly reducing Hcy in blood.
After embodiment 2:L-Glutamine hyperhomocysteinemiainjury, in rat blood serum, oxidation resistance index contains quantifier elimination
The animal adopted in this experiment is identical with embodiment 1 with experimental drug, detects the test kit of the indexs such as SOD, MDA, GSH, T-AOC purchased from Nanjing Bioengineering Research Institute.
In this experiment, rat modeling and Therapeutic Method are identical with the method adopted in embodiment 1.
Rat blood serum SOD, MDA, GSH, T-AOC tetra-indexs are detected with corresponding reagent box.
L-Gln treatment group, compared with model group, obtains obvious improvement, and four index p < 0.05 after inspection treatment, illustrate that Glutamine HHcy mass formed by blood stasis significantly can improve Antioxidation Ability of Rats, can find out from Fig. 3 and Fig. 4:
SOD: model control group 33.6+18.6U/mgprot, L-GLn treatment group 70.65+19.34U/mgprot, blank group 92.67 ± 23.34U/mgprot; MDA: model control group 3.15 ± 1.30nmol/mgprot, L-GLn treatment group 1.67 ± 1.22nmol/mgprot, blank group 1.02 ± 0.86nmol/mgprot; GSH: model control group 0.98 ± 1.03mmol/L, L-GLn treatment group 3.70 ± 1.23mmol/L, blank group 4.6 ± 0.84mmol/L; T-AOC: model control group 7.5 ± 5.6u/L, L-GLn treatment group 14.7 ± 4.3u/L, blank group 19.6+4.8u/L.
Embodiment 3: the research that glutamine affects the inflammatory factor of HHcy mass formed by blood stasis
The animal adopted in experiment is identical with embodiment 1 with experimental drug, detects the Elisa test kits such as rat IL-6, IL-1, NF-kB, CRP inflammatory factor and is purchased from Bio-Swamp company.
In experiment, rat modeling is identical with the method that adopts in embodiment 1 with treatment.
Rat blood serum IL-6, IL-1, NF-kB, CRP tetra-indexs are detected with corresponding reagent box.Find that L-Gln treatment group is compared with model group, four indexs all take an evident turn for the better (IL-6: model control group 1640 ± 424pg/ml, L-GLn treatment group 1255 ± 315pg/ml, blank group 813 ± 234pg/ml; IL-1: model control group 518 ± 186pg/ml, L-GLn treatment group 325 ± 193pg/ml, blank group 243 ± 574pg/ml; NF-kB: model control group 404 ± 136umol/g, L-GLn treatment group 137 ± 82umol/g, blank group 94 ± 27umol/g; CRP; Model control group 423 ± 116pg/ml, L-GLn treatment group 227 ± 45pg/ml, blank group 183 ± 49pg/ml), prompting: L-Gln significantly can reduce HHcy mass formed by blood stasis Organism of Rats inflammatory reaction, after inspection treatment, four group p values are all less than 0.05, refer to Fig. 5 and Fig. 6.
Embodiment 4: glutamine is tested the expression of Rats with Hyperhomocysteinemia CBS, MTHFR albumen
The animal adopted in experiment is identical with embodiment 1 with experimental drug, and CBS, MTHFR and β-actin one anti antibody of employing is purchased from Santa company, and two anti antibodys are purchased from company of Zhong Shan Golden Bridge.
In experiment, rat modeling and Therapeutic Method are identical with the method adopted in embodiment 1.
CBS is detected with Western, the expression of MTHFR albumen, method is as follows: get liver organization histiocyte lysate capable and make homogenate, BCA method measures protein content, get each sample 80tg and carry out SDS-PAGE electrophoresis, half-dried robin by protein delivery to pvdf membrane, polyclone primary antibodie is added respectively after 2h closed by the skim milk of 5%, 4 DEG C are spent the night, add corresponding HRP labelling after washing film two anti-hatch, washing after and ECL luminescence reagent react, exposure is developed a film, with the gray value of each band of Image J computed in software after scanogram, standard control is carried out using β-actin as internal reference, often group experiment repetition 3 times.After rat treatment, Glutamine group is compared with model group, and the expression of CBS, MTHFR almost returns to the level of normal value, and P < 0.05, the results are shown in Figure 7.
Claims (1)
- The application of 1.L-glutamine in preparation treatment hyperhomocysteinemiainjury medicine.
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| Title |
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| Effects of Various Amino Acids on Methionine-Induced Hyperhomocysteinemia in Rats;Shin-ichiro Fukada et al;《Biosci.Biotechnol.Biochem.》;20080707;第72卷(第7期);1940-1943 * |
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