CN102526702A - Small peptide trefoil factor family 3 (TFF3) for curing metabolic syndrome - Google Patents
Small peptide trefoil factor family 3 (TFF3) for curing metabolic syndrome Download PDFInfo
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Abstract
The invention relates to small peptide trefoil factor family 3 (TFF3) for curing metabolic syndrome. Researches show that micromolecule-peptide TFF3 can cure relative diseases of the metabolic syndrome, can reduce blood sugar by adjusting relative glycometabolism genes in livers, can reduce content of triglyceride in the livers to improve fatty liver symptoms and is obvious in effects on improving tolerance of glucose and sensibility of insulin. Thus, the small peptide TFF3 can be used for improving blood sugar level of II type glycosuria patients, improve fatty liver symptoms and improve tolerance of glucose and sensibility of insulin, thereby curing metabolic syndromes of II type glycosuria, fatty liver, obesity, cardiovascular diseases and the like.
Description
Technical field
The present invention relates to the treatment field of metabolism related diseases.Particularly, the present invention relates to the purposes of little peptide TFF3 in treatment hyperglycemia, insulin resistant, fatty liver, obesity and cardiovascular associated metabolic disease.
Background technology
Metabolism syndrome is sent out well in modern civilization society; Many individualities show the risk factor of multiple cardiovascular disease simultaneously; Comprise metabolism obstacles of blood glucose (IFG, impaired glucose tolerance, type ii diabetes); Lipid metabolism unusual (rising of blood triglyceride concentration, the rising of VLDL concentration, HDL-C level reduce), hypertension, central obesity etc.
The sixties in 20th century impaired glucose tolerance and hypertension are called " rich syndrome ".1989 will be again the internal organs property obesity, impaired glucose tolerance, hypertriglyceridemia, hypertension on basis risk factor with the hyperinsulinemia, be summarised as " dead quartet " as coronary heart disease.1991 with this group metabolic cardiovascular disease syndrome called after " insulin resistance syndrome ".It is " four high one is low " (being hyperglycemia or impaired glucose tolerance, hypertriglyceridemia, hypertension, the reduction of HDL-C level) etc. that the metabolism syndrome of title is also arranged in addition.And report thinks that metabolism syndrome is a kind of state that multiple diseases such as hypertension, pathoglycemia, blood fat disorder and obesity are assembled, and directly causes the generation of diabetes, fatty liver and severe cardiovascular disease, and causes death in human body recently.
Metabolism syndrome is multiple with person in middle and old age, and U.S.'s investigation finds that crowd's prevalence is 23.7% more than 20 years old, and the sick investigation of China's Statistical is 14%-15%, and increases along with the increase at age.The whole world is died from cardiovascular and cerebrovascular disease and reach 1,550 ten thousand every year, accounts for nearly 30% of total death toll.China accounts for 1/5,2000 year China's city coronary heart disease death 71.3/10 ten thousand of world population, rural area 31.6/10 ten thousand; Die from about 3,500,000 people of cardiovascular diseases every year, according to estimating to suffer from the patient of metabolism syndrome; In following 7 years, it is dead because of metabolism syndrome that per 8 people just have 1 people, so metabolism syndrome is one of the serious public health issue of 21 century face of mankind; Its sickness rate cumulative year after year, the serious threat human health, and brought white elephant to the whole world.Think that at present metabolism syndrome is the risk factor of cardiovascular event, key link is an insulin resistant, and fatty liver is its root.Insulin resistant makes the decline of glucose utilization ability; Because reducing, glucose utilization causes that blood sugar level raises; Then the insulin compensatory increases; Show as hyperinsulinemia, can cause infection, heart change, cerebrovascular disease, renal failure, lose the sight of both eyes, lower limb gangrene etc. and become deadly major cause of morbidity.And, quicken atherosclerotic process through infringement to endothelial function.The individual endothelial function disturbance of insulin resistant shows as that adhesion factor increases, smooth muscle cell proliferation and vasodilation function reduction.These a series of changes are the key factors that promote that atherosclerosis forms.Insulin resistant also causes the unbalance of blood coagulation and fibrinolytic state; Hypercoagulability appears: owing to Fibrinogen, plasminogen activator inhibitive factor 1 (PAI-1) level obviously increase; In case blood coagulation takes place in the body, and the patient can not normally start the fibrinolytic process, very easily causes the formation of thrombosis.It is another key character of metabolism syndrome that interior fat is piled up, and also is the main cause that causes insulin resistant.In the individuality that interior fat is piled up, the internal organs of at first getting involved are livers.When intrahepatic fat deposits when too much, can make that the liver tunicle expands, the ligaments of liver tractive, and cause that upper right abdomen has an intense pain or tenderness, heating, leukocytosis, ascites and lower limbs edema, electrolyte disturbance can be arranged as hanging down sodium, hypokalemia etc.During the fatty renal capsule follicular rupture, lipochondrion gets into blood also can cause brain, lung blood vessel fat embolism and sudden death; If when hepatocyte athero compressing sinus hepaticus or little bile duct; Portal venous flow and bile excretion are obstructed, and portal hypertension and cholestasis occur, and too much the deposition of free fatty can cause fatty liver; And can cause that liver enzyme level raises; Even the change of liver structure, and the fatty liver that causes might cause fat hepatitis, liver cirrhosis, even hepatocarcinoma.
Because the metabolism syndrome cause of disease is complicated, the medicine that uses clinically, great majority have shortcomings such as treatment inefficacy and untoward reaction.Originally discover that the little peptide of TFF3 can obviously improve the relevant symptoms of metabolism syndrome, and have no adverse reaction, possibly become effective new drug of treatment metabolism syndrome in future.
Summary of the invention
TFF3 is a kind of small-molecular peptides; The inventor discover this small-molecular peptides can through regulate the liver important gene relevant with carbohydrate metabolism for example GP6C, PEPCK, PGC-1 α have the function of blood sugar lowering, improve the fatty liver symptom thereby while TFF3 can regulate the content that liver lactone metabolism related gene reduces the interior three YOUGAN fat of liver.On the other hand TFF3 in diabetes model DB/DB Mus the glycolipid metabolism path through influencing a series of complicacies in the liver improve glucose tolerance and increase aspect the insulin sensitivity effect also fairly obvious; Therefore the little peptide of TFF3 can be used to improve the type ii diabetes blood glucose level in humans; Improve fatty liver; Improve the effect of glucose tolerance and increase insulin sensitivity aspect, thereby reach the disease of metabolism syndrome aspects such as treatment type ii diabetes, fatty liver, obesity, cardiovascular.
Kind people's TFF3 aminoacid sequence is following:
EEYVGLSANQCAVPAKDRVDCGYPHVTPKECNNRGCCFDSRIPGVPWCFKPLQEAECTF(SEQ?ID?No：1)。
Therefore, one aspect of the present invention relates to the purposes of little peptide TFF3 in the medicine of preparation treatment metabolism syndrome.
In the present invention, metabolism syndrome comprises fatty liver and obesity etc.
In the present invention, little peptide TFF3 can reduce the blood sugar concentration of hyperglycemic patients.
In the present invention, little peptide TFF3 can increase the sensitivity of insulin among the patient.
In the present invention, little peptide TFF3 can reduce the content of patient's liver tg.
In the present invention, thus little peptide TFF3 can be through reducing the mRNA expression treatment metabolism syndrome of liver glucose-6-phosphatase and/or phosphoenolpy ruvate carboxy kinase and/or PGC-1 α.
On the other hand, the invention still further relates to the purposes of little peptide TFF3 in the medicine of preparation treatment type ii diabetes.
Preferably, the medium and small peptide TFF3 of the present invention diabetes of being treated are insulin resistant type diabetes but not islet function damage type diabetes.
On the other hand; The invention still further relates to the purposes of little peptide TFF3 in the medicine of preparation treatment hyperglycemia relevant disease, described hyperglycemia relevant disease can be the infection, heart change, cerebrovascular disease, the renal failure that cause of hyperglycemia, lose the sight of both eyes, the lower limb gangrene.
The defined TFF3 of the present invention comprises monomer and dimeric forms; With and the homotype analog; The homotype analog can be different with natural TFF3 aminoacid sequence or glycosylation, acetylation, phosphorylation take place; But the carboxylated situation that waits the modification aminoacid sequence not change, perhaps the both exists.The aminoacid sequence of homotype analog comprise with natural TFF3 aminoacid sequence similarity degree at least 60%; Or similarity degree higher 70%; Or similarity degree higher 80%, or similarity degree higher 90%, or similarity degree higher 95% even 99%.
Preferably, the little peptide TFF3 among the present invention is:
A. aminoacid sequence is SEQ ID No:1, or
B. the aminoacid sequence in a is through replacing, lack or adding one or several aminoacid and active constant by a polypeptides derived.
Described in the above-mentioned b through replacing, lack or adding one or several aminoacid and the active constant sequence by a polypeptides derived can be following arbitrary polypeptide of sequence:
AEYVGLSANQCAVPAKDRVDCGYPHVTPKECNNRGCCFDSRIPGVPWCFKPLQET
ECTF(SEQ?ID?No：8)
YVGLSANQCAVPAKDRVDCGYPHVTPKECNNRGCCFDSRIPGVPWCFKPLQEAECTF(SEQ?ID?No：9)
ADEEYVGLSANQCAVPAKDRVDCGYPHVTPKECNNRGCCFDSRIPGVPWCFKPLQET(SEQ?ID?No：10)
Above-mentioned polypeptide of sequence can prepare through this polynucleotide sequence of expression vector expression through for example synthetic or according to aminoacid sequence design respective coding polynucleotide sequence and in the host.According to the present invention, the activity of prepared polypeptide can be passed through, and for example, detects the mRNA level of G6PC, PEPCK, PGC-1 α in the liver primary cell and confirms.
Description of drawings
Fig. 1: the mRNA level of TFF3 has descended 7.38 times than wild-type mice in the fat Mus of OB/OB.
Fig. 2: A crosses and expresses in the liver primary cell of the little peptide of TFF3, and the mRNA level of G6PC has descended 14.5 times than the GFP group; B crosses and expresses in the liver primary cell of the little peptide of TFF3, and the mRNA level of PEPCK has descended 6.7 times than the GFP group; C crosses and expresses in the liver primary cell of the little peptide of TFF3, and the mRNA level of PGC-1 α has descended 6.1 times than the GFP group.
Fig. 3: cross that content of triglyceride descends than the GFP group to some extent in the liver primary cell express the little peptide of TFF3.
Fig. 4: A, after hunger was pressed the dose ejection glucose of 1g/Kg after 16 hours, at 0 minute, 15 minutes, 30 minutes, 45 minutes, 60 minutes, detect blood glucose in the time of 90 minutes respectively, TFF3 can be good at increasing the sensitivity (n=5) of insulin; B detects glucose content in the serum, and the TFF3 group obviously reduces (n=5) than the blood glucose of GFP group; C, the horizontal TFF3 group of mRNA of injecting Ad-GFP and Ad-TFF3 adenovirus G6PC after 10 days respectively obviously reduces than the GFP group.
Fig. 5: A, after hunger was pressed the dose ejection glucose of 1g glucose/Kg body weight after 16 hours, at 0 minute, 15 minutes, 30 minutes, 45 minutes, 60 minutes, detect blood glucose in the time of 90 minutes respectively, TFF3 can improve the toleration (n=4) of glucose; B, the DB/DB Mus of injection TFF3 adenovirus after 5 days significantly decreases than the blood glucose of GFP group; After pressing the dose ejection insulin of 1U insulin/Kg body weight behind the hungry 6H, at 0 minute, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes time point detected blood glucose respectively, and TFF3 can increase the sensitivity of insulin.
The specific embodiment
Experiment material: carrier pGEM-T EASY, real-time quantitative PCR test kit are available from Promega company; PcDNA4/myc-His, TransScript II First-Strand cDNASynthesis SuperMix test kit, transfection reagent lipofectamine 2000 are available from Invitrogen company; PAdTrack-CMV and pAdEasy-1 are all available from Stratagene company; Various restriction endonucleases are all available from TAKARA company; All kinds of experimental animal models are available from Nanjing University's model animal institute; The steady bold and unconstrained type blood glucose monitoring system of OneTouch Ultra
and the blood sugar test paper that matches are available from Johson & Johnson.
Experimental program:
1. clone mice TFF3 gene:
Extract the dirty cell total rna of C57BL/6J Hepar Mus according to Invitrogen company's T rizol reagent description; Use TransScript II First-Strand cDNA Synthesis SuperMix test kit that total RNA reverse transcription of liver organization is become cDNA; With mouse liver cDNA is that template is carried out PCR (polymerase chain reaction), and design of primers does
F：5’-GAATTCCCACCATGGAGACC-3’
R：5’-CGAGAAATGTGCATTCTGTCT-3’
The PCR product is connected on the pGEM-T EASY carrier, and sequencing sequence is correct, obtains plasmid pGEM-T EASY-TFF3.
2. mice TFF3 crosses the structure of expression vector: with pGEM-T EASY-TFF3 template, design of primers does
F：5’-CGGAATTCCCACCATGGAGACC-3’
R：5’-ACATACTCGAGAAATGTGCATTCTGTCT-3’
The PCR product is used EcoRI and XholI double digestion respectively; Same with EcoRI and XholI double digestion pcDNA4/myc-His empty carrier; Both connect 16 ℃ and are transformed in the DH5 α escherichia coli after spending the night; Be applied on the LB flat board that contains amicillin resistance and cultivate, the clone of picking identifies that with EcoRI and XholI double digestion the positive colony that obtains is the pcDNA4-TFF3-myc-His expression plasmid.
3. the structure of mice TFF3 adenovirus and packing
With pGEM-T EASY-TFF3 is template, and design of primers does
F：5’-ACAGATCTCCACCATGGAGACCAGAGCCCTCTGG-3’
R：5’-ACCTCGAGTCACAGATCCTCTTCTGAGATGAGTTTTTGTTCAAATGTGCATTCTGTCT-3’
The PCR product is used Bgl II and XholI double digestion respectively; Same with Bgl II and XholI double digestion pAdTrack-CMV empty carrier; Both connect 16 ℃ and are transformed in the DH5 α escherichia coli after spending the night; Be applied on the LB flat board that contains amicillin resistance and cultivate, the picking clone identifies with Bgl II and XholI enzyme action and obtains positive colony pAdTrack-CMV-TFF3 plasmid.With pAdTrack-CMV-TFF3-myc with the PmeI linearization for enzyme restriction after with the pAdEasy-1 homologous recombination, if recombinate successfully, when identifying with the PacI enzyme action 30kb will appear, 4.5kb or 3kb band.The pAd-TFF3 plasmid that reorganization is successful is with PacI linearisation transfection 293A cell; The available fluorescence microscope in the left and right sides was to green fluorescence in 7-10 days; Collect cell during to the 30%-50% cell suspension; The centrifugal supernatant that goes of 50xg, deposition is resuspended among the PBS, and the liquid nitrogen multigelation is used for amplicon virus once more three times.To go up wheel virus and infect the 293A cell once more, cell suspension about about 50% is received cell after 24-48 hour, and it is the same to collect the cell step.The packing of mice TFF3 adenovirus is accomplished behind the amplicon virus 3 times, and the adenovirus that packing is accomplished can be used for cell experiment.Adopt the method purification packing of cesium chloride density gradient centrifugation to accomplish the TFF3 adenovirus.Adenovirus behind the purification can be used for zoopery.Injection system adopts the caudal vein injection, and ID is C57BL/6J Mus: 1x10
9Pfu; DB/DB Mus: 3x10
9Pfu.
4.C57BL/6J the separation in liver former generation:
Separate liver and spread Mus tail collagen to culture dish earlier before former generation, ultraviolet is sterilized more than 2 hours.Use the dosage anesthetized mice of 0.3% amobarbital sodium according to the 0.15ml/10g body weight.Elder generation is the U font then and cuts off skin with ethanol wiping skin degerming before dissecting mice, opens the abdominal cavity.Separate postcava, make a call to a false knot, by locating to insert catheter cannula down, fixedly (suggestion is made a call to two knots in case anti-avulsion falls to false knot at false knot.Fixing earlier first knot down before killing second knot).Withdraw from sleeve pipe, inlying catheter.Inject heparin 0.2-0.3ml immediately.Open the thoracic cavity then immediately, the ligation superior vena cava is also cut off portal vein.Slowly injected perfusate I 2-3 minute to inferior caval conduit.Take by weighing 0.015g type i collagen enzyme and be dissolved in the perfusate II (collagenase final concentration 0.05%) of 37 ℃ of preheatings of 30ml, mixing.In the conductive pipe slowly injection perfusate II 5 minutes to liver occur chapping or blister after liver is transferred to 75cm
2Big ware.Tear Glisson's capsule, add 1640 culture medium.Remove big piece of tissue with tweezers, use 400 mesh filter screens screening hepatocyte (the liquid drippage that carefully will not contain piece of tissue).Left standstill 5 minutes, what settle down then is hepatocyte.Contain a large amount of antibacterials in the supernatant liquid, siphon away supernatant liquid (directly do not fall supernatant liquid, otherwise loss cell is a lot) with rifle, stay small amount of liquid with cell transfer to the 50ml centrifuge tube.Use 1641 culture medium to clean cell, centrifugal 2 minutes of 50xg abandons supernatant liquid, repeats 2-3 time.Use trypan blue living cell counting number (the viable count ratio should reach more than 70% just can reach requirement of experiment) then, 100% inoculating cell is in the previous culture dish of spreading Mus tail collagen.
5. each item index detects:
The real-time quantitative PCR appearance detects the mRNA level, and reaction condition is 95 ℃ 10 minutes, 95 ℃ 30 seconds, 57 ℃ 30 seconds, 72 ℃ 30 seconds (seizure fluorescent values), circulates 45 times, and makes solubility curve.DAS is provided by IQ5 real-time quantitative PCR appearance.
Indexs such as triglyceride detect and are accomplished by BJ Union Hospital.
Experimental result:
1. in the fat Mus of OB/OB, the horizontal significance of the mRNA of TFF3 descends, and is about 7.38 times, explains that the decline of the little peptide of TFF3 possibly have close ties (Fig. 1) with obesity.
2. to the isolated liver primary cell of C57BL/6J, add respectively and can cross the adenovirus after 24 hours hungry 6 hours of expressing GFP and TFF3, and continue with dexamethasone (Dexamethasone) and 6 hours post processing cells of Forskolin (Forskolin) processing.The result finds expressing in the liver primary cell of the little peptide of TFF3 excessively; (GFP) compares with matched group; The important gene that glyconeogenesis is correlated with is G-6-Pase (G6PC) for example, phosphoenolpy ruvate carboxy kinase (PEPCK), and the mRNA level of peroxisome Proliferator-activated receptor γ co-activation factor 1 α (PGC-1 α) has descended 14.5 times respectively; Doubly, 6.7 6.1 times (Fig. 2).
3. at the isolated liver primary cell of C57BL/6J; Add respectively and can cross 30 hours post processing cells of adenovirus of expressing GFP and TFF3; Use triglyceride (Triglyceride) test kit to measure TG content and find, cross the liver primary cell TG content of expressing the little peptide of TFF3 and obviously organize descend to some extent (Fig. 3) than GPF.
4.C57BL/6J zoopery
Glucose tolerance experiment is given the C57BL/6J injectable dextrose monohydrate of hunger after 16 hours according to the dosage of 1g glucose/Kg body weight; Detect the C57 Mus of change of blood sugar situation discovery injection Ad-TFF3 and after 15 minutes, organize faster that blood glucose descends, explain that TFF3 can increase the sensitivity of insulin (the A figure among Fig. 4) than GFP.
Glucose content in the C57 Mus serum that injection Ad-GFP and Ad-TFF3 adenovirus detected after 10 days finds that TFF3 has the function (the B figure among Fig. 4) of tangible blood sugar lowering.
Injection Ad-GFP and Ad-TFF3 adenovirus detect G6PC in the liver organization after 10 days mRNA level finds that the mRNA level of G6PC is organized than GFP and descended 3.9 times, from molecular level the function of polysaccharide (C Fig. 4 schemes) of TFF3 has been described.
5. diabetes model DB/DB Mus zoopery:
Glucose tolerance experiment is given the DB/DB Mus injectable dextrose monohydrate of hunger after 16 hours according to the dosage of 1g glucose/Kg body weight; The DB/DB Mus blood glucose rate of climb in the unit interval that detects after the change of blood sugar situation is found injection Ad-TFF3 in different time points is slower than the GFP group; Faster than the former level of GFP group blood sugar recovery after 45 minutes, prove that thus the little peptide of TFF3 can reduce the toleration of glucose (the A figure among Fig. 5).
Insulin resistance experiment (ITT) is given the DB/DB Mus insulin injection of hunger after 6 hours according to the dosage of 1U insulin/Kg body weight; Detect the change of blood sugar situation in different time points; DB/DB Mus behind data show injection Ad-TFF3 blood glucose decrease speed in the unit interval is faster than the GFP group; Especially more obvious time point blood glucose decline in 15 minutes, prove that thus the little peptide of TFF3 can increase the sensitivity of insulin (the B figure among Fig. 5).
Claims (9)
1. the purposes of little peptide TFF3 in the medicine of preparation treatment metabolism syndrome.
2. the purposes of little peptide TFF3 according to claim 1 in the medicine of preparation treatment metabolism syndrome, wherein metabolism syndrome comprises fatty liver, obesity.
3. the purposes of little peptide TFF3 according to claim 1 in the medicine of preparation treatment metabolism syndrome, its medium and small peptide TFF3 reduces patient's blood sugar concentration.
4. the purposes of little peptide TFF3 according to claim 1 in the medicine of preparation treatment metabolism syndrome, its medium and small peptide TFF3 increases the sensitivity of patient's insulin.
5. the purposes of little peptide TFF3 according to claim 1 in the medicine of preparation treatment metabolism syndrome, its medium and small peptide TFF3 reduces patient's liver content of triglyceride.
6. the purposes of little peptide TFF3 according to claim 1 in the medicine of preparation treatment metabolism syndrome, its medium and small peptide TFF3 reduces the mRNA expression of patient's liver G-6-Pase and/or phosphoenolpy ruvate carboxy kinase and/or PGC-1 α.
7. the purposes of little peptide TFF3 in the medicine of preparation treatment type ii diabetes.
8. the purposes of little peptide TFF3 according to claim 7 in the medicine of preparation treatment type ii diabetes, wherein said diabetes are insulin resistant type diabetes but not islet function damage type diabetes.
9. according to each described purposes among the claim 1-8, wherein said little peptide TFF3 is:
A. aminoacid sequence is SEQ ID No:1, or
B. the aminoacid sequence in a is through replacing, lack or adding one or several aminoacid and active constant by a polypeptides derived.
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Cited By (1)
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| CN111053889A (en) * | 2019-12-23 | 2020-04-24 | 上海中医药大学附属龙华医院 | Application of trefoil factor 3 and trefoil factor 3 expression promoter in preparation of medicine for preventing and treating liver injury |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111053889A (en) * | 2019-12-23 | 2020-04-24 | 上海中医药大学附属龙华医院 | Application of trefoil factor 3 and trefoil factor 3 expression promoter in preparation of medicine for preventing and treating liver injury |
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Application publication date: 20120704 |