CN101361962A - New use of thymosin alpha1 - Google Patents
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- CN101361962A CN101361962A CNA2008100719122A CN200810071912A CN101361962A CN 101361962 A CN101361962 A CN 101361962A CN A2008100719122 A CNA2008100719122 A CN A2008100719122A CN 200810071912 A CN200810071912 A CN 200810071912A CN 101361962 A CN101361962 A CN 101361962A
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Abstract
The invention discloses a new application of thymosin Alpha 1, which relates to the thymosin Alpha 1 and provides a new application of the thymosin Alpha 1. The thymosin Alpha 1 is used for preparing diabetes medicines. By the verification of animal experiments, the thymosin Alpha 1 can not only slow down the weight increase of a mouse, lower the normal fasting blood sugar of the mouse and obviously enhance the sugar tolerance of the mouse, but also prevent STZ from inducing the occurrence of diabetes of the mouse; besides, the thymosin Alpha 1 also plays an important role in protecting the structure of islet cells and the secretion level of insulin. The thymosin Alpha 1 can be used for maintaining normal glycometabolism and protecting the structure and functions of islet cells; by adopting the method of taking the thymosin Alpha 1 orally, the effect of obviously slowing down weight increase can be realized; therefore, the thymosin Alpha 1 can be applied to preparing drugs for preventing diabetes from occurring and treating diabetes and clinical practice.
Description
Technical field
The present invention relates to thymosin (Thymosin α 1, T α 1), especially relate to a kind of new purposes of thymosin.
Background technology
The clinical practice of thymosin starts from 20th century the mid-1970s, its topmost contribution is to the thymus dependent treatment of diseases, because it is for the immunoreactivity of keeping PID, autoimmune disease and cancer patient, stimulate the lymphocytic activity of its specificity to play main effect, therefore be widely used in diseases such as therapy system lupus erythematosus, Behcet's syndrome, rheumatoid arthritis, severe infection, bronchial asthma, acute, chronic hepatitis and tumor.In addition, because human wearing out reflects the atrophy of thymic tissue and the depletion of function significantly, thymosin can be postponed the appearance of some Senile disease, and therefore using the thymosin defying age also has extremely wide prospect.
Along with going deep into of research, people have turned to research emphasis the single peptide in the thymosin, in the hope of finding more effective clinical treatment medicine.Document shows that prophymosin-alpha (prothymosin α, ProT α) and T α 1 are the focuses in prothymosin research.
NH
2-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-COOH。
Thymosin is to extract the also Acid polypeptide of purification biologically active from thymus the 5th component (TF5), as immunostimulant, can regulate immune many links, comprise activation NK cell, T cell, monokaryon and macrophage, can also stimulate the proliferation and differentiation of myeloid element; Wherein most importantly to the adjusting of T cell differentiation.Be mainly used in infectious disease such as treatment hepatitis B, hepatitis C now, malignant tumor such as nonsmall-cell lung cancer, melanoma, hepatocarcinoma, gastric cancer, autoimmune disease,, systemic lupus erythematosus (sle) unable etc., and the treatment of immunodeficiency as rheumatoid arthritis, serious symptom.
Research both at home and abroad (2, Rubin LA, Kurman CC, Friez ME, et al.Soluble interleukin receptorsare released from activated human lymphoid cellin vitro.J Immun, 1985,135:3172; 3, Sun Yongliang. soluble il-II receptor and infectious disease. foreign medical science epidemiology lemology volume, 1991,18:34) all find, SIL-2R is a kind of important immunosuppressive substance, the similar blocking factor of its effect, increasing of its level is many with the decline of NK cytoactive and the minimizing of cd4 cell, and may reflect that organism immune response descends and the order of severity of the state of an illness.Thymosin be by the synthetic general name with hormonelike active polypeptides matter different of thymic epithelial cell with excretory multiple biochemical property (4, Zhang Fuguang, Liu Dianxin. thymus and thymosin progress. foreign medical science immunology fascicle, 1996,19:187).With healthy calf thymus is the injection liquid of thymic peptide alpha 1 that raw material contains various active polypeptide such as extrasin alpha, mainly act on the differentiation of T lymphocyte, growth and sophisticated each stage, thereby the effect of cellular immune function is regulated in performance, can strengthen simultaneously the NK cell phagocytic activity (5, Muzzioli M, Mocchegiani E, Bressani N, et al.In vitrorestoration by thymulinof Nk activity of cells from old mice.Int J Immunopharma Col, 1992,14:57).Cai Wenwei etc. (6, Cai Wenwei, Lu Ping, Zhu Jian. clinical health care for the middle and old aged, 2002,5 (2): 90-91) and Wang Zhaohai (7, clinical lung section magazine, 2004,9 (4): 357-358) adopt thymosin to strengthen diabetes and diabetes merging lunger's cellular immune function, obtain certain curative effect.The proof thymosin has positive effect aspect human body immunity improving function and the adjusting body immunity.
The major reason and the autoimmune disease of type i diabetes are closely related, wherein mainly be because beta Cell of islet is subjected to the attack of autoimmune cell, cause antigen-exposed, cause that immune system further reacts, make beta Cell of islet lose in a large number, normal secretion of insulin is affected, and blood sugar increasing forms diabetic symptom.Streptozotocin (STZ) is used widely in type i diabetes model preparation, and rat is under the disposable ejection situation of 50mg/kg and can the modeling success, and mice then reaches the modeling purpose after the injection at same dose through 5 times continuously substantially.Think that at present the mechanism of action of STZ is by making body produce excessive N O, attack and destroy beta Cell of islet, cause that pancreatic island cell antigen exposes, activation immunity of organism mechanism, thereby a large amount of macrophages enter the damage of islet cells aggravation islet cells, cause insulin secretion to reduce at last, cause that blood glucose increases, and brings out diabetes.Inductive mouse thymus atrophy, the obvious enlargement of kidney, and the serum oxidation resistance significantly descends.
In recent years, the cause of disease of diabetes and study of pathogenesis show the generation of oxidative stress and diabetes and develop closely related (8, Cao Wenbin etc., the antioxidation micronutrient is prevented and treated the progress of diabetes, Changchun University of Traditional Chinese Medicine's journal, 2006,22 (2): 73-74), in order to prevent developing of diabetes, people have the natural anti-reflecting oxide of preventing and treating the diabetes effect to some and have carried out systematic research, find that they interrupt the vicious cycle that oxidation invasion and attack cause the beta Cell of islet infringement by expressing different mechanism with the effect link, thereby provide a new strategy for natural anti-oxidation treatment diabetes.
Liu Renhai etc. (9, Liu Renhai, etc. change thymosin gene Synechococcus Antioxidation Effects, Chinese Journal of Marine Drugs, 2002.2:4-7; 10, Liu Renhai, Deng. oral commentaries on classics thymosin gene Synechococcus is to the research of mouse T cell subgroup effect, Xiamen University's journal (natural science edition), 2003,4:517-520) proved that respectively commentaries on classics thymosin gene Synechococcus has significant effect aspect antioxidation and the adjusting mouse T cell subgroup, can significantly improve healthy mice CD3, CD4 subgroup level improves body CD4/CD8 ratio.Further specifying thymosin is a kind of effective immunostimulant.
Prothymosin former (prothymosin) has 28 identical peptides of N end with thymosin, its total length is 108～110 aminoacid, it has the effect of adjustment immunologic function the experiment in vivo and vitro proof, can make too drastic immunologic function downward modulation, avoid the generation of autoimmune disease, simultaneously, research (11 recently, Malicet, C., Dagorn, J.C., Neira, j.l.and Iovanna, J.L.P8 and prothymosin alpha:unity is strenthe.Cell cycle, 2006,5 (8): 829-830) also show, ProT α and apoptosis factor P8 can form complex, play the inhibition apoptosis jointly, promote fissional function.In addition; research (12 recently; Mallo; G.V.; Fiedler; F., Calvo, E.L.; Ortiz; E.M., Vasseur, et al.cloningand expression on the rat p8 cDNA; a new gene pancreas during the acute phase of pancreatitis; pancreas development, and regeneration, and which promostes celluar production.J.Biol.Chem.1997; 272 (51): 32360-32369) also prove; P8 can stimulate insulin β cell propagation, therefore, infers that ProT α not only can protect islet cells to avoid the attack of autoimmune cell; can promote simultaneously the division of islet cells, thereby increase the secretion of insulin function.As far back as the Tabata eighties in 20th century, T (13, Tabata, T., Kinoshita, Y., Fujin, S., Hato, F., et al.pretection by thymosin fraction 5 from streptozotocin induce diabetes in mice.Cellular and molecular biology 1989,35 (2): 121-127) adopt the put up a resistance generation of the inductive diabetes of STZ of the peptide gland factor that is separated to from the thymus of pig, certain effect is arranged, but used be the complex that contains multiple composition.
Summary of the invention
The object of the present invention is to provide a kind of new purposes of thymosin.
Thymosin of the present invention is used to prepare diabetes medicament.
Confirm that by zoopery thymosin not only can slow down the increase of mice body weight, reduce the normal mouse fasting blood sugar, obviously strengthen the carbohydrate tolerance effect of mice, and can resist the generation of STZ inducing mouse diabetes; Has important function for protection islet cells structure and secretion of insulin level in addition.Thymosin of the present invention can be used for keeping normal carbohydrate metabolism, protection islet cells 26S Proteasome Structure and Function; By the method for oral thymosin, can also obviously slow down the effect of weight increase, so thymosin can be in the medicine and the application clinically of generation of preparation prevent diabetes and treatment diabetes.
Adopting Zadaxin (Italy matches hundred victory products, the 1.6mg/ bottle) is experiment material, and selecting kunming mice and C57BL/6 is laboratory animal, by oral and two kinds of administrations of subcutaneous injection, can verify the above-mentioned physiological function of thymosin.
The experimental technique of a kind of new purposes of thymosin of the present invention may further comprise the steps:
1) by oral and two approach of subcutaneous injection thymosin is pressed 10 a μ g/ dosed administration;
2) claimed the mice body weight every 5 days;
3) survey mice fasting glucose and carry out the carbohydrate tolerance experiment after 14 days;
4) the mice part of oral administration is catched and killed, and strips mice body fat (perirenal fat and genitals fat), weighs.Calculate total fat weight (equaling perirenal fat weight and genitals fat weight sum) and fat/body ratio and [equal (total fat weight/body weight * 100);
5) mice another part of oral administration, disposable celiac injection STZ presses 100mg/kg dosage, after the injection, surveys blood glucose once in per 10 days certainly;
6) subcutaneous injection thymosin in advance, after 14 days, mice once a day, is pressed 50mg/kg dosage through lumbar injection STZ, continuous 4 days, inject STZ certainly after, surveyed blood glucose in per 5～10 days.Get blood system from serum after 30 days, adopt the insulin detection kit to detect serum insulin levels;
7) the hypodermic while of thymosin, mice once a day, is pressed 50mg/kg dosage through lumbar injection STZ, continuous 4 days, inject STZ certainly after, surveyed blood glucose in per 5～10 days.
By testing in the animal body, prove that thymosin has the generation of the inductive diabetes of good opposing STZ, the influence that shows good opposing diabetes-induced factor, and possessing the function that strengthens the carbohydrate tolerance effect.In addition; through oral discovery; thymosin can; obviously slow down the effect of weight increase speed; check discovery by dissecting, perirenal fat weight and genitals fat weight are obviously low than matched group in its body, prove that this albumen is fat in minimizing; have important protective effect in the generation of opposing diabetes, lay the foundation for developing diabetes genetic engineering potential drug from now on.
Description of drawings
Fig. 1 is the influence of oral thymosin to the mice body weight.In Fig. 1, abscissa is a natural law (d) after the oral medicine, and vertical coordinate is mice body weight (g);-◆-be matched group ,-■-be the thymosin group.
Fig. 2 induces the diabetic mice effect for oral thymosin (10d) opposing STZ.In Fig. 2, abscissa is a natural law (d) behind the injection STZ, and vertical coordinate is blood glucose value (mmol/L);-◆-be matched group ,-■-be the thymosin group; Compare P＜0.05, significant difference with matched group; Compare with matched group, P＜0.01, difference is extremely remarkable.
Fig. 3 is that the subcutaneous injection thymosin is to strengthening the effect of mice carbohydrate tolerance effect.In Fig. 3, abscissa is respectively 1: matched group, 2: thymosin group, vertical coordinate are area under curve.
Fig. 4 is subcutaneous thymosin (injecting in advance 14 days) is induced diabetes to mice opposing STZ effect.In Fig. 4, abscissa is injection streptozotocin (STZ) back natural law (d), and vertical coordinate is blood glucose value (mmol/L);-◆-be the citric acid group ,-■-be the thymosin group.
Fig. 5 is the influence of thymosin to serum insulin levels.In Fig. 5, abscissa is T α 1, and control, vertical coordinate are Pg/mL; Compare with matched group, P＜0.01 difference is extremely remarkable.
Fig. 6 induces the effect (thymosin and STZ inject simultaneously) of diabetes to mice opposing STZ for subcutaneous thymosin.In Fig. 6, abscissa is natural law (d), and vertical coordinate is blood glucose value (mmol/L);-◆-be the citric acid group ,-■-be the thymosin group.
The specific embodiment
Following examples will the present invention is further illustrated in conjunction with the accompanying drawings.
The materials and methods that embodiment adopted is described as follows.
1. experiment is drawn materials and main biological reagent
Experimental animal is the C57BL/6 mice, and (20 ± 2) g is male age in 6-7 week, the SPF level, and 60 of mices are provided by Shanghai Slac Experimental Animal Co., Ltd., the quality certification number: SCXK (Shanghai) 200320003.Single cage is fed, 18～25 ℃ of room temperatures, and relative temperature 50%～80%, illumination every day 12h freely ingests, drinks water.
Streptozotocin (streptozotocin STZ, SIGMA.USA), lot number 053K1569; Citric acid (Chengdu letter He Huagongshijichang), lot number: 20040821.Insulin test kit (west, Shanghai Tang bio tech ltd).Blood-sugar detecting instrument is the Llifscan of Johson ﹠ Johnson product and supporting detection reagent paper.
2. 40 mices are equally divided into 2 groups, 20 every group, 1 group of oral route feed thymosin is organized in contrast with the equal volume normal saline for one group.Continuous 10 days, during weighed once in per 5 days, oral thymosin the results are shown in Table 1 and Fig. 1 to the influence of mice body weight.
Table 1
*: compare P＜0.05, significant difference with matched group;
*: compare with matched group, P＜0.01 difference is extremely remarkable
5d, 10d survey fasting glucose.Continuous oral thymosin 5d, the mice fasting blood sugar the results are shown in Table 2 behind the 10d.
Table 2
*: compare P＜0.05 with matched group
After the experiment in the 20th day, each group is got 10 respectively, strips mice body fat (perirenal fat and genitals fat), weighs.Calculate total fat weight (equaling perirenal fat weight and genitals fat weight sum) and fat/body ratio and [equal (total fat weight/body weight * 100).Oral thymosin the results are shown in Table 3 to the influence of mice fat weight.
Table 3
*: compare with matched group, P＜0.01 difference is extremely remarkable
Residue experimental mice disposable celiac injection STZ presses 100mg/kg dosage, after the injection, surveys blood glucose once in per 10 days certainly.Matched group gives the citrate buffer solution of equal volume.Detect the same experimental group of step.Oral thymosin (10d) opposing STZ induces the diabetic mice effectiveness results to see Table 4 and Fig. 2.
Table 4
*: compare P＜0.05, significant difference with matched group;
*: compare with matched group, P＜0.01 difference is extremely remarkable
3. 20 mices are equally divided into 2 groups, 10 every group, 1 group of subcutaneous route is given thymosin, organizes in contrast with the equal volume citrate buffer solution for one group.Continuous 14 days, during weighed once in per 5 days, carried out the carbohydrate tolerance experiment on the 14th day, then lumbar injection STZ continuously once a day, press 50mg/kg dosage, continuous 4 days, inject STZ certainly after, every 5-10 days survey body weight and blood glucose are surveyed 5 times.Subcutaneous injection thymosin (continuous 14 days) the results are shown in Table 5 and Fig. 3 to what strengthen the effect of mice carbohydrate tolerance, and subcutaneous thymosin (injecting in advance 14 days) induces the effect of diabetes to see Table 6 and Fig. 4 to mice opposing STZ.
Table 5
*: compare P＜0.05, significant difference with matched group
Table 6
*: compare P＜0.05, significant difference with matched group;
*: compare with matched group, P＜0.01 difference is extremely remarkable
Posterior orbit was got blood in 30 days, and separation of serum is put-20 ℃ of refrigerators, adopted the ELISA method to detect wherein insulin level, and thymosin the results are shown in Figure 5 to the influence of serum insulin levels.
4. 20 mices are equally divided into 2 groups, 10 every group, 1 group of subcutaneous route is given thymosin, organizes in contrast with the equal volume citrate buffer solution for one group.Lumbar injection STZ in the time of administration once a day, presses 50mg/kg dosage, continuous 4 days, inject STZ certainly after, surveyed body weight and blood glucose, and surveyed 5 times in per 5 days.The subcutaneous injection thymosin induces the effect (T α 1 and STZ inject simultaneously) of diabetes to the results are shown in Table 7 and Fig. 6 to mice opposing STZ.
Table 7
*: compare P＜0.05, significant difference with matched group;
*: compare with matched group, P＜0.01 difference is extremely remarkable
The carbohydrate tolerance experiment is calculated as follows:
AUC＝0.25×(BS?value?at?0?hour+4×BS?value?at?0.5?hours+3×BS?value?at?2?hours)。
This is tested all data and carries out analyzing and processing by SPSS (version 13.0, SPSS Inc.) software.
Thymosin is that ProT α N holds preceding 28 peptides, studies show that it possesses same biological activity.Thymic peptide-5 also shows as the effective ingredient of thymosin and the function of similar blood sugar regulation of other thymic factor and protection islets of langerhans, and therefore, the present invention proves the theoretical foundation that thymosin has science in the prevention and the function aspect the treatment of diabetes.
Claims (1)
1. thymosin is used to prepare diabetes medicament.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2476789A (en) * | 2009-11-10 | 2011-07-13 | Gl Holdings Inc Bv | Use of thymosin for treatment of type 2 diabetes |
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| US4444757A (en) * | 1981-11-16 | 1984-04-24 | Research Corporation | Use of thymosin as an anti-diabetes and anti-hypertensive disease agent |
| US6197751B1 (en) * | 1997-11-10 | 2001-03-06 | The United States Of America As Represented By The Department Of Health And Human Services | Thymosin α1 promotes tissue repair, angiogenesis and cell migration |
| CN100342909C (en) * | 2005-05-11 | 2007-10-17 | 北京双鹭药业股份有限公司 | Thymosin alpha-1 aqua prepn and its prepn process and application |
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| GB2476789A (en) * | 2009-11-10 | 2011-07-13 | Gl Holdings Inc Bv | Use of thymosin for treatment of type 2 diabetes |
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