CN104548066A - New application of novel peptide with hypoglycemic activity - Google Patents
New application of novel peptide with hypoglycemic activity Download PDFInfo
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- CN104548066A CN104548066A CN201510030228.XA CN201510030228A CN104548066A CN 104548066 A CN104548066 A CN 104548066A CN 201510030228 A CN201510030228 A CN 201510030228A CN 104548066 A CN104548066 A CN 104548066A
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Abstract
The invention relates to a new application of a novel peptide with hypoglycemic activity, and belongs to the technical field of bio-pharmacy. An STZ-induced diabetes mouse animal model is built; the therapeutic action of a novel peptide O-IA-2(5)-P2 is investigated; the activity of xanthine oxidase in the mouse can be significantly inhibited by the O-IA-2(5)-P2; the serum uric acid level is significantly reduced; meanwhile, the content of glutathione in diabetes mouse bodies, the activity of superoxide dismutase and catalase in the mouse bodies and the total antioxidant capacity are significantly improved; and the content of malonaldehyde and hydrogen peroxide is significantly reduced, so that the novel peptide O-IA-2(5)-P2 is expected to further develop medicines for preventing and treating diabetic complications, such as diabetic nephropathy, atherosclerosis, alzheimer disease and gout, which are related to diabetes oxidative stress and uric acid increase and/or xanthine oxidase activity reduction.
Description
Technical field
The present invention relates to a kind of novelty teabag of new type of peptides, particularly relate to new type of peptides O-IA-2 (5)-P2 in antioxidation, the effect suppressed in xanthine oxidase activity, reduction serum uric acid level, and contain the pharmaceutical preparation of this new type of peptides and derivant or analog, the present invention relates to pharmacy and medical science association area.
Background technology
Diabetes (Diabetes) be due to insulin definitely or relative deficiency and the disorderly syndrome of a kind of generalized metabolic that causes, be after tumor, cardiovascular and cerebrovascular disease, occupy the chronic disease of the 3rd.To the year two thousand twenty, global diabetics total amount will reach 300,000,000 people, and the diabetics wherein living in the developing country such as India, China accounts for 75%.The harm that diabetes are brought nearly all comes from diabetic complication, such as diabetic nephropathy, diabetic neuropathy and diabetictrunk angiopathy etc.
Had report uric acid relevant with diabetes and diabetic nephropathy, urate deposition can cause renal tubular interstitium inflammation, Fibrotic increase in renal tubulointerstitial, and urate also causes obstructive kidney by participating in urate calculus formation.Urate crystal also can produce independent pro-inflammatory effect, and then causes inflammation and tissue injury.
Current research is thought, the oxidative stress that high sugar causes is the pathogenetic key link of chronic complicating diseases of diabetes, in the sugared situation of height, the electronics showed increased that mitochondrial electron transport chain produces, produce too much reactive oxygen species (ROS), make cell be in the unbalance stress state of oxidative and anti-oxidative.Large quantity research finds, the excessive ROS produced in oxidative stress and oxidative stress process is the important promoting factor that atherosclerosis occurs.Excessive ROS can cause lipid peroxidation, the metabolite hydrogen peroxide produced in lipid peroxidation process can coup injury endotheliocyte, increase adhesiveness and the activity of neutrophilic granulocyte, increase the sensitivity of platelet aggregation, cause or promote atherosclerotic lesions process.A large amount of evidences also shows the earliest events that oxidative stress is not only senile dementia (AD), all can observe significant oxidative stress phenomenon and strengthen with course advancement in AD each phase.Also there are some researches show, oxidative stress plays an important role in the developing of diabetic nephropathy, and many factors result in the gathering of the ROS of nephridial tissue, and ROS assembles and mediated developing of diabetic nephropathy by many approach.
In diabetes oxidative system and antioxidant system unbalance be minimizing due to polyphenoils (as glutathion, superoxide dismutase, catalase) concentration, glucose, lipid peroxidation that oxidizing substance (hydrogen peroxide, malonaldehyde) concentration increase causes, when extent of peroxidation exceeds the removing of oxide, body internal oxidition system and antioxidant system unbalance, tend to oxidation, cause neutrophilic granulocyte inflammatory infiltration, protease secretion increases, produce a large amount of oxidation intermediates, thus cause tissue injury.Except classical polyphenoils is as except catalase (CAT), superoxide dismutase (SOD), glutathion (GSH) etc., organize hydrogen peroxide (H
2o
2), malonaldehyde (MDA) and total antioxidant capacity (T-AOC) receive publicity as antioxidation, oxidative stress index in tissue, just day by day also as one for the treatment of correlative diseases or the method alleviating disease.
Xanthine oxidase can the last two steps of catalysis purine metabolism process, hypoxanthine is oxidized to xanthine and then xanthine oxidase is turned to uric acid, when urate deposition is in renal tubulointerstitial, renal tubular interstitium inflammation, Fibrotic increase can be caused, and urate also causes obstructive kidney by participating in urate calculus formation, by suppressing xanthine oxidase, hypoxanthine can be blocked and be oxidized to xanthine, xanthine oxidase turns to the path of uric acid, effective reduction serum uric acid level, developing of control diabetic nephropathy.Suppress xanthine oxidase can also reduce ROS in body, hydrogen peroxide and superoxide anion etc. simultaneously.
New type of peptides O-IA-2 (5)-P2 mentality of designing is: utilize B cell Antigen Epitope Prediction software and on-line prediction instrument, xanthine oxidase B cell antigen epi-position is predicted, select a line style B epi-position RLEPYKKKNPS, with a linear epitope FEYQD of islet cells specific antigen-insulin associated protein (IA-2) membrane-proximal region JM2, two B epi-positions are connected with Gly and are inserted in the P2 nitrogen end of P277.
Summary of the invention
Goal of the invention:
The object of this invention is to provide new type of peptides O-IA-2 (5)-P2 or be that the preparation of effective ingredient is prevented and treated diabetes oxidative stress in preparation and raised relevant diabetic complication as the novelty teabag in diabetic nephropathy, atherosclerosis, senile dementia and gout with uric acid with O-IA-2 (5)-P2.
Technical scheme:
Announced new type of peptides O-IA-2 (5)-P2, aminoacid sequence is shown in SEQ ID NO:1.
Described new type of peptides and containing above-mentioned amino acid whose sequence or by amino acid modified, replace the aminoacid sequence that obtains and to comprise application in diabetic nephropathy, senile dementia, atherosclerosis and gout at control diabetic complication
The described pharmaceutical composition containing new type of peptides, is characterized in that new type of peptides and one or more pharmaceutically acceptable adjuvant, pharmaceutically active substance or pharmaceutically acceptable carriers.
The described preparation that is effective ingredient with new type of peptides O-IA-2 (5)-P2 is injection, slow releasing agent, subdermal implants, tablet, powder, granule, capsule or oral liquid containing O-IA-2 (5)-P2.
Described adjuvant is filler, diluent, excipient etc.Such as include but not limited to: lactose, sucrose, glucose, starch, cellulose family (as carboxymethyl cellulose, hydroxypropyl methylcellulose etc.), ethylene glycol, Oleum Glycines, Oleum sesami, ethanol, physiological saline solution, sterilized water etc.
Described pharmaceutical carrier is heat shock protein HSP60/65, asparaginase, asparaginase-TTP, asparaginase-TTP-CETPC, and pharmaceutically active substance is insulin, GLP-1 and analog thereof, Exendin-4 and analog, sulphanylureas, biguanides; Wherein sulphanylureas comprises glibenclamide, gliclazide, Mick pancreas, Ge Liebo urea, gram sugar profit, gliquidone, gliquidone, Gliguidone, glipizide; Described biguanides comprises phenformin, metformin, buformin.
Described compositions comprises the application in diabetic nephropathy, senile dementia, atherosclerosis and gout at control diabetic complication.
Experiment of the present invention proves, new type of peptides O-IA-2 (5)-P2 can significantly suppress xanthine oxidase activity in Mice Body, remarkable reduction serum uric acid level, simultaneously after new type of peptides O-IA-2 (5)-P2 treats, in diabetic mice glutathion inside content, Mice Body, superoxide dismutase, catalase activity and total antioxidant capacity also significantly rise, and malonaldehyde negative control compared with content of hydrogen peroxide significantly declines.Therefore, new type of peptides O-IA-2 (5)-P2 is expected to be developed further into as raising relevant diabetic complication as the medicine of diabetic nephropathy, atherosclerosis, senile dementia and gout for the preparation of preventing and treating diabetes oxidative stress with uric acid.
Accompanying drawing explanation
Fig. 1 O-IA-2 (5)-P2 is on the impact of diabetic mice serum xanthin oxydase activity (figure A) and uric acid level (scheming B)
Fig. 2 O-IA-2 (5)-P2 stress the impact (oxidative stress index of correlation: glutathione content (figure A), catalase activity (figure B), total antioxidant capacity (figure C), mda content (figure D), superoxide dismutase activity (figure E), content of hydrogen peroxide (figure F)) of index of correlation on diabetic mice serum oxidative.
Detailed description of the invention
Experimental technique in following embodiment, if no special instructions, is conventional method.The condition that used kit is all advised according to the manufacturer that manufactures a product is carried out.
The pharmacodynamic evaluation of embodiment 1, new type of peptides O-IA-2 (5)-P2
1, the foundation of diabetic mouse model
Adopt low dose of continuous several times lumbar injection streptozotocin (STZ) induced diabetes model.4 week age, male C57BL/6J (was purchased from Yangzhou University's comparative medicine center, credit number: SCXR (Soviet Union) 2012-0004), preparing STZ concentration with 0.1M pH4.4 citrate buffer is 7.5mg/mL, by 50mg/kg dosage lumbar injection, once a day, continuous injection 5 days, measures fasting blood sugar in the 7th, 14 day after STZ with inject for the last time, with fasting blood sugar double >=11.1mmol/L is for one-tenth mould standard.
2, immunization ways
36 diabetic mices are divided into 3 groups at random, often organize 12, be respectively placebo group (group of solvents, negative control group), P277 group (positive controls, sequence is shown in SEQ ID NO:2), O-IA-2 (5)-P2 group (sequence is shown in SEQ ID NO:1).Administration group administration concentration is 1.2mg/mL, and dosage is 100 μ g//times, i.e. 100 μ L; Negative control group: 100 μ L oil preparationes/only/time.Method for preparation of drug is that 1.2mg polypeptide drugs+48mg mannitol is dissolved in 1.2mL 20%Lipofundin Extemporaneous and becomes oil preparation.After model success, (after final injection STZ, the 7th, 14 day blood glucose >=11.1mmol/L is as the criterion) starts to carry out animal immune, and in this, as initial first week, Per-Hop behavior 1 time afterwards, amounts to 5 times, then respectively at immunity in the 7th, 9,11,13 week 4 times.
3, new type of peptides O-IA-2 (5)-P2 diabetic mice uric acid level that streptozotocin is induced and xanthine oxidase activity impact
After last administration one week, get blood, separation of serum.Measure serum uric acid level and xanthine oxidase activity, concrete operation step all illustrates according to test kit and carries out.
Data represent with meansigma methods ± SD value, and carry out statistical procedures with SPSS 17.0 software, each group difference compares employing independent samples t test.* P < 0.05, * * P < 0.01 compared with group of solvents; Compared with P277 group, #P < 0.05, ##P < 0.01.
Active and the serum uric acid level by kit measurement serum xanthin oxydase, result as shown in Figure 1, compare with positive controls with group of solvents, new type of peptides O-IA-2 (5)-P2 significantly can suppress xanthine oxidase activity (P < 0.05) (Figure 1A), significantly reduces the level (P < 0.05) (Figure 1B) of serum uric acid.
4, new type of peptides O-IA-2 (5)-P2 is on the impact of the diabetic mice oxidative stress index of correlation that streptozotocin is induced
After last administration one week, get blood, separation of serum, kit measurement Serum glutathione content, total antioxidant capacity, catalase activity, superoxide dismutase activity, content of hydrogen peroxide, level of lipid adopts micro-Mda test kit to detect.
Data represent with meansigma methods ± SD value, and carry out statistical procedures with SPSS 17.0 software, each group difference compares employing independent samples t test.* P < 0.05, * * P < 0.01 compared with group of solvents; Compared with P277 group, #P < 0.05, ##P < 0.01.
As shown in Figure 2, diabetic mice is after giving O-IA-2 (5)-P2 treatment, Serum glutathione content significantly raises to compare with positive controls with group of solvents all to be had significant difference (P < 0.05) (Fig. 2 A), activity of catalase compare group of solvents also significantly decline (P < 0.05) (Fig. 2 B), soluble transferring receptor and group of solvents and positive controls all exist pole significant difference (P < 0.01) (Fig. 2 C), Serum MDA content is compared group of solvents and positive controls and also significantly to be declined (P < 0.05) (Fig. 2 D).Simultaneously, O-IA-2 (5)-P2 treatment group mice, serum superoxide dismutases content also significantly rises, have pole significant difference (P < 0.01) (Fig. 2 E) with solvent, and have significant difference (P < 0.05) between positive control, serum content of hydrogen peroxide comparatively group of solvents significantly declines (P < 0.01) (Fig. 2 F).
According to the above results, show: new type of peptides O-IA-2 (5)-P2 significantly can suppress xanthine oxidase activity, the level (P < 0.05) of remarkable reduction serum uric acid, simultaneously after new type of peptides O-IA-2 (5)-P2 treats, in diabetic mice glutathion inside content, Mice Body, superoxide dismutase, catalase activity and total antioxidant capacity also significantly rise, and malonaldehyde negative control compared with content of hydrogen peroxide significantly declines.Therefore, new type of peptides O-IA-2 (5)-P2 is expected to be developed further into as reducing relevant diabetic complication as the medicine of diabetic nephropathy, atherosclerosis, senile dementia and gout for the preparation of preventing and treating diabetes oxidative stress with uric acid rising and/or xanthine oxidase activity.
Claims (7)
1. announced new type of peptides O-IA-2 (5)-P2, aminoacid sequence is shown in SEQ ID NO:1.
2. peptide according to claim 1 and containing above-mentioned amino acid whose sequence or by amino acid modified, replace the aminoacid sequence that obtains and to comprise application in diabetic nephropathy, senile dementia, atherosclerosis and gout at control diabetic complication.
3. the pharmaceutical composition of new type of peptides according to claim 1, is characterized in that, comprises the new type of peptides described in claim 1 and one or more pharmaceutically acceptable adjuvant, pharmaceutically active substance or pharmaceutically acceptable carriers.
4. compositions according to claim 3, is characterized in that: the described preparation that is effective ingredient with new type of peptides O-IA-2 (5)-P2 is injection, slow releasing agent, subdermal implants, tablet, powder, granule, capsule or oral liquid containing O-IA-2 (5)-P2.
5. adjuvant according to claim 3 is filler, diluent, excipient etc.Such as include but not limited to: lactose, sucrose, glucose, starch, cellulose family (as carboxymethyl cellulose, hydroxypropyl methylcellulose etc.), ethylene glycol, Oleum Glycines, Oleum sesami, ethanol, physiological saline solution, sterilized water etc.
6. pharmaceutical carrier according to claim 3 is heat shock protein HSP60/65, asparaginase-TTP, asparaginase-TTP-CETPC, and pharmaceutically active substance is insulin, GLP-1 and analog thereof, Exendin-4 and analog, sulphanylureas, biguanides; Wherein sulphanylureas comprises glibenclamide, gliclazide, Mick pancreas, Ge Liebo urea, gram sugar profit, gliquidone, gliquidone, Gliguidone, glipizide; Described biguanides comprises phenformin, metformin, buformin.
7. compositions according to claim 3 comprises the application in diabetic nephropathy, senile dementia, atherosclerosis and gout at control diabetic complication.
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| CN201510030228.XA CN104548066A (en) | 2015-01-19 | 2015-01-19 | New application of novel peptide with hypoglycemic activity |
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| CN201510030228.XA CN104548066A (en) | 2015-01-19 | 2015-01-19 | New application of novel peptide with hypoglycemic activity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108715601A (en) * | 2018-05-24 | 2018-10-30 | 华南理工大学 | It is a kind of while there is polypeptides that are anti-oxidant and inhibiting 42 aggregation properties of A β and its application and the gene that encodes the polypeptide |
| CN109970863A (en) * | 2017-12-28 | 2019-07-05 | 南京零一生物科技有限公司 | A kind of bifunctional polypeptides and application thereof with hypoglycemic and immunoregulation effect |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101677999A (en) * | 2006-11-13 | 2010-03-24 | 塔普医药产品公司 | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| CN102633873A (en) * | 2012-05-09 | 2012-08-15 | 中国药科大学 | Novel peptide, applications and preparation method thereof |
| CN103265636A (en) * | 2013-05-23 | 2013-08-28 | 中国药科大学 | Novel peptide with hypoglycemic effect |
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2015
- 2015-01-19 CN CN201510030228.XA patent/CN104548066A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101677999A (en) * | 2006-11-13 | 2010-03-24 | 塔普医药产品公司 | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| CN102633873A (en) * | 2012-05-09 | 2012-08-15 | 中国药科大学 | Novel peptide, applications and preparation method thereof |
| CN103265636A (en) * | 2013-05-23 | 2013-08-28 | 中国药科大学 | Novel peptide with hypoglycemic effect |
Non-Patent Citations (1)
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| 黎莉 等: "中草药来源的黄嘌呤氧化酶抑制剂的研究进展", 《中药材》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109970863A (en) * | 2017-12-28 | 2019-07-05 | 南京零一生物科技有限公司 | A kind of bifunctional polypeptides and application thereof with hypoglycemic and immunoregulation effect |
| CN108715601A (en) * | 2018-05-24 | 2018-10-30 | 华南理工大学 | It is a kind of while there is polypeptides that are anti-oxidant and inhibiting 42 aggregation properties of A β and its application and the gene that encodes the polypeptide |
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Application publication date: 20150429 |