CN102847140A - Application of gastrin in anion exchangers 2 - Google Patents
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- CN102847140A CN102847140A CN201210376849XA CN201210376849A CN102847140A CN 102847140 A CN102847140 A CN 102847140A CN 201210376849X A CN201210376849X A CN 201210376849XA CN 201210376849 A CN201210376849 A CN 201210376849A CN 102847140 A CN102847140 A CN 102847140A
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Abstract
The invention relates to application of gastrin in anion exchangers 2 in the medical field. The gastrin is used as modifier to be used for expressing the anion exchangers 2 and for preparing medicine for treating achlorhydria. The gastrin is used as the modifier of the anion exchangers 2, so that the traditional wrong ideas that increased secretion of gastric acid leads to the damage and repeated repairing of gastric mucosa and induces the gastric cancer, so that a great amount of proton pump inhibitors such as omeprazole are used for inhibiting the secretion of the gastric acid are remedied. The gastrin is used for appropriately promoting the secretion of the gastric acid and repairing the gastric mucosa so as to produce a beneficial effect for protecting the gastric mucosa; and at present no medicine for stimulating the secretion of the gastric acid is produced in the world, so that the gastrin has a good clinic application prospect.
Description
Technical field
The present invention relates to molecular biology, cytobiology, area of pharmacology, refer to that specifically gastrin is as the application of regulator in Kidney anion exchanger 2.
Background technology
Gastrin is called again gastrin, and its gene is positioned at chromosome g district No. 17, and length is 4.1kb, is a kind of important peptide class gut hormone, and it is mainly by the G emiocytosis of stomachus pyloricus mucosa.The To Gastrin Peptide Radioimmunoassay And class that human body produces is divided by length three kinds: what wherein activity was the highest is by the synthetic polypeptide of 17 aminoacid, claims little gastrin, and it is the principal mode of gastric antrum extract:
1.Gastrin-34 34 aminoacid are arranged, are called biggastrin;
2.Gastrin-17 17 aminoacid are arranged, are called littlegastrin;
3.Gastrin-14 14 aminoacid are arranged, be called minigastrin, and these 14 aminoacid just have whole physiologically actives.The biological value of human normal gastrin is: the Diagnostic Value of Fasting Serum gastrin is 20～160ng/L; To increase after the meal 2～3 times.
There has been in the market pentagastrin to be used for clinical diagnosis, but only be used for gastric analysis, it is not medicine for treatment, treatment for diseases such as chronic atrophic gastritis is confined to diet adjustment and traditional Chinese medical science conditioning more, can't reach the purpose for the treatment of both the principal and secondary aspects of a disease, such as " application of gastrin in suppressing gastrointestinal tumor " put down in writing among the Chinese patent literature CN101890157A, the document discloses the new application of gastrin in suppressing gastrointestinal tumor, be that gastric cancer target gene anion-exchange protein 1 interacts with tumor suppressor protein p16, bring out gastric cancer, and gastrin can suppress the expression of gastric cancer target gene AE1 and p16 effectively, thereby reaches the purpose for the treatment of gastric cancer.
Kidney anion exchanger 2 (AE2) exists in the brush border of people's kidney, intestinal, blood vessel, lung, bile duct epithelial cell, small intestinal mucosa pit cell, villus cell and early pregnancy fine hair, wherein expresses the abundantest with stomach AE2.In case the AE2 abnormal expression then can cause numerous pathological changes.AE2-/-mice, then showing as thin and weak, tooth can't eruption and severe growth retardation, and major part is died from weaning stage.In addition, this kind mice also shows achlorhydria.As seen, AE2 is the indispensable important component of body.
Normal Gastric pH reference value is 0.8～1.8; Empty stomach gastric juice free acid: 0～30U; Total acidity: 10～50U; Basal gastric acid secretion amount (BAO): 1.92～5.88mmol/h; Maximum gastric acid output (MAO): 3～23mmol/h (women is lower slightly); Peak gastric acid output (PAO): 12.23～28.97mmol/h.The diagnostic criteria of achlorhydria: pH3.5～7.0 are low acid, and pH7.0 is anacidity.The cause of disease of achlorhydria: psychentonia, heating, autonomic nervous dysfunction etc., can cause the factor of sympathetic nerve neural excitation, temporarily gastric acid secretion inhibiting causes gastric acid to reduce.Irritable food and medicine long-term taking have diet and the medicine of intense stimulus to gastric mucosa, directly act on gastric mucosa such as strong tea, spirits, pungent or salicylic acid salt medicine and cause gastric acid secretion to reduce.The diseases such as atrophic gastritis, gastric cancer, pernicious anemia can cause that gastric acid obviously reduces or shortage.The anti-stream of duodenal juice, the phospholipid in the pancreatic juice can dissolve mucus with bile and pancreas digestive enzyme, and destroys gastric mucosal barrier, impels H+ and pepsin back diffusion to enter mucosa, causes damage.The change of immune factor immunologic function can cause that atrophic gastritis causes gastric acid secretion to reduce.Behind the gastrectomy, can cause that also gastric acid secretion reduces.Acid heat or without gastric acid, this is because there being anti-gastrin antibody to have event for Hypothyroidism 50% Stomach in Patients, and diabetics can cause achlorhydria often with immunodeficiency.
Having the omeprazole of employing to carry out the inhibition of sour pump in the parietal cell in the prior art, is a kind of alkalescence material, suppresses H
+/ K
+ -The activity of ATP enzyme (proton pump).This inhibitory action that gastric acid is formed is dosage correlation, and highly suppresses basal gastric acid secretion and zest gastric acid secretion.Human vein gives omeprazole can reduce rapidly Acidity in the stomach, average decline 90% in 24 hours.Helicobacter pylori is the principal element that causes gastritis.Helicobacter pylori and gastric acid are the principal element that causes peptic ulcer together.But omeprazole and antibiotic share eradicate helicobacter pylori, this with rapid relief of symptoms, the gastric mucosa repair rate is high and long-term remission peptic ulcer disease is relevant, and so has reduced the complication such as gastrointestinal hemorrhage.
Gastric acid reduces due to the proton pump inhibitor, can increase the quantity of normal flora in the gastrointestinal tract, may increase such as salmonella and campylobacter infection gastrointestinal danger.Because omeprazole can affect digestive function in gastric acid inhibitory, cause the malaise symptoms such as abdominal distention, even atrophic gastritis occurs, affect patients ' life quality, waiting a moment property atrophic gastritis and achlorhydria occur relevant with gastric cancer.
Summary of the invention
The present invention is directed to the prior art above shortcomings, the application of a kind of gastrin in Kidney anion exchanger 2 proposed, with its regulator as anion-exchange protein, corrected wrong views in the past: think that namely gastric acid secretion increases gastric mucosal lesion caused by gastric and repeatedly reparation, and bring out thus gastric cancer, so the proton pump inhibitors such as extensive application omeprazole are with gastric acid secretion inhibiting.Promote in right amount the secretion of gastric acid and the beneficial effect that gastric mucosa reparation produces the protection gastric mucosa by gastrin, the medicine that not can be used in gastric acid secretion at present comes out, and under this background, gastrin has good potential applicability in clinical practice.
The present invention is achieved by the following technical solutions:
The present invention relates to the application of a kind of gastrin in Kidney anion exchanger 2, be about to gastrin is used for Kidney anion exchanger 2 (AE2) as regulator expression.
Described application further comprises: be used for promoting that intracellular ion transport is active.
Described promotion adopts 10
-10-10
-6The gastrin of mol/L is cultivated or the subcutaneous injection gastrin realizes.
Described incubation time is 24 hours-30 days.
Described application further comprises: for the preparation of the medicine for the treatment of achlorhydria.
Described achlorhydria includes but not limited to chronic gastritis.
Described medicine is used for gastric acid secretion.
Key of the present invention is that gastrin promotes ion exchange by regulating AE2 albumen, stimulates the secretion of gastric acid, has gastric mucosal protective effect for achlorhydria patient (especially gastritis, gastric cancer cause achlorhydria patient).
The present invention provides foundation for gastrin is applied to achlorhydria, will bring for the patient of achlorhydria new hope.
Description of drawings
[0001] Fig. 1 is that gastrin stimulates the Mouse Stomach mucosa to thicken schematic diagram among the embodiment.
[0001] Fig. 2 is that gastrin is protected Mouse Stomach mucosa schematic diagram by the AE2 effect among the embodiment.
[0001] Fig. 3 is the expression schematic diagram that gastrin stimulates mice AE2 among the embodiment.
[0002] Fig. 4 is the expression schematic diagram that gastrin promotes AE2 in the cell among the embodiment.
[0003] Fig. 5 is that gastrin promotes the ion transport schematic diagram among the embodiment.
[0004] Fig. 6 is the expression schematic diagram that gastrin is regulated AE2 among the embodiment by cholecystokinin B receptor (CCKBR).
[0005] Fig. 7 is gastrin gastric acid secretion schematic diagram among the embodiment.
The specific embodiment
[0006] below embodiments of the invention are elaborated, the present embodiment is implemented under take technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
[0007] (1) gastrin stimulates the Mouse Stomach mucosa to thicken
[0008] utilize Writhing test to make up the chronic atrophic gastritis animal model: to get 50 of the female C57BL/6 mices of adult healthy, be divided at random the experimental group matched group, experimental group gives ammonia (0.05%～0.1%), adopts mouth medication to replace the mice drinking water; Ethanol (40%), biweekly one, four on an empty stomach gavages once, each 8ml/kg; NaTDC (20mmol/L), single-revolution gavage every day once, each 8ml/kg.It is drinking water that matched group gives distilled water, and normal saline replaces NaTDC, ethanol gavage, each 8ml/kg.
[0009] chemistry modelization is after four months, and the gastrin group gives subcutaneous injection gastrin (0.4mg/ml), and every day twice, (gastrin concentration approximately 10 in the blood for each 2mg/kg
-7Mol/L); Successive administration 30 days.Paraffin section, HE dyeing by the full stomach of sample are observed and are found: utilize Writhing test successfully to make up the chronic atrophic gastritis animal model, gastrin can be treated chronic atrophic gastritis, alleviate the gastric mucosa atrophy symptom, by measuring Mouse Gastric Mucous Membrane thickness under the mirror, the gastric mucosa of finding gastrin Therapy group mice obviously thickens (Figure 1A) with respect to matched group, finds that through statistical analysis the Mouse Gastric Mucous Membrane thickness of gastrin Therapy group and matched group has significant difference (Figure 1B).
[0010] (2) gastrin is by AE2 effect protection Mouse Stomach mucosa.
[0011] dyeing shows normal gastric mucosa to model mice gastric tissue HE, positive distribute (brown) of visible significantly AE2 in the parietal cell cell membrane of secreting gastric acid and endochylema, (Fig. 2 A and B); HE dyeing shows that gastric tissue is the chronic atrophic gastritis performance, the atrophy of part body of gland, and single arrow shows that the body of gland intestinalization is obvious, AE2 expresses negative, and double-head arrow shows relatively normal oxyntic gland body, AE2 expresses positive (Fig. 2 C and D); HE dyeing shows the atrophy of gastric mucosa body of gland, and asterisk shows obvious cell infiltration performance, prompting stomach lining inflammation significant reaction, but owing to given 10
-7After the mol/L gastrin was interfered, the gastric mucosa body of gland is the AE2 albumen of expressed in abundance (Fig. 2 E and F) still.
[0012] (3) gastrin stimulates the expression of mice AE2.
[0013] repeats Writhing test and make up chronic atrophic gastritis animal model model, the gastrin that gives variable concentrations is processed, get the Mouse Stomach tissue and carry out paraffin embedding, section, carry out the detection that AE2 expresses with immunohistochemical method, discovery is with respect to the matched group that gives normal saline, in blood 10
-10, 10
-9, 10
-8, 10
-6Under the gastrin effect of mol/L concentration, all the expression of visible AE2 increases (Fig. 3).
[0014] (4) gastrin promotes the expression of AE2.
[0015] SGC7901 cell line is with containing 10
-10, 10
-9, 10
-8, 10
-7, 10
-6The culture fluid of the gastrin of five kinds of variable concentrations of mol/L was cultivated 24 hours, extracted albumen and carried out western blot detection, and along with the increase of gastrin concentration, AE2 expresses raise (Fig. 4 A).In the animal experiment, the C57 mice is divided into four groups at random, give respectively normal saline, gastrin, gastrin and DIDS, the DIDS intravenous injection is after 15 minutes, AE2mRNA and the protein expression of injection gastrin group mice all obviously raise, and the blocker of AE2 can suppress the facilitation (Fig. 4 B) that gastrin is expressed AE2.
[0016] (5) gastrin promotes ion transport.
[0017] with the SGC7901 cell with 10
-7The mol/L gastrin was cultivated 24 hours, and pH value is down to 7.22 ± 0.25 by 7.86 ± 0.30 in its cell, and the rate of change of per minute pH value (dpHi/dt) increases to 0.23 ± 0.066 per minute by 0.091 ± 0.031 per minute.Illustrated that gastrin has promoted intracellular ion transport active (Fig. 5).
[0018] (6) gastrin is regulated the expression of AE2 by cholecystokinin B receptor (CCKBR):
[0019] designs and make up the SSKBR interference carrier and verify its effectiveness, select the carrier of interference effect the best to carry out follow-up test (seeing that Fig. 6 A is left).Select interference carrier transfection SGC7901 cell No. 1, extract albumen and carry out western blot analysis, visible AE2 expresses and reduces (seeing that Fig. 6 A is right), illustrates that CCKBR has mediated the effect of gastrin rise AE2.In addition, SGC7901 processes through the blocker proglumide of the CCKBR of variable concentrations, and AE2 expresses and presents the performance (Fig. 6 B) of successively decreasing successively, confirms that further gastrin passes through cholecystokinin B regulation AE2.
[0020] (7) gastrin gastric acid secretion
[0021] SGC7901 cell line was cultivated 8,10,12,24 hours with the culture fluid that contains gastrin, and intracellular ph value prolongs in time and successively decreases, and proves that it has the effect of gastric acid secretion (Fig. 7 A).The C57 mice is divided into four groups, give respectively normal saline, gastrin, gastrin and DIDS, DIDS intravenous injection, measure the gastric acid secretion situation after 15 minutes, the result shows, gastrin has stimulated the secretion of gastric acid, and DIDS makes gastrin be suppressed (Fig. 7 B) to the secretory action of gastric acid by the function that suppresses AE2.
[0022] specific implementation:
Cell culture and processing:
The SGC7901 cell is available from typical case's culture collection committee of Chinese Academy of Sciences cell bank, and the DMEM culture fluid with containing 10% hyclone at 37 ℃, contains 5%CO
2The condition of air under cultivate.When testing, cell is with 2-5x10
5The density inoculation of individual/mL, gastrin or the AE2 protein-specific inhibitor DIDS (Sigma) of adding prescribed concentration.
Immunoblotting
With the cell of processing SDS cracking, the extraction whole protein is for subsequent use, the SDS-polyacrylamide gel of preparation 10%, the protein of before this cracking is added respectively in the loading hole, and beginning electrophoresis, after electrophoresis finishes, with albumen by electrotransfer (AmershamBioscience, UK) to nitrocellulose membrane.After nitrocellulose membrane sealed with the skim milk that contains 5%, the primary antibodie and corresponding two of hatching respectively AE2 resisted.Use most horseradish peroxidase (CellSignaling, MA, U.S.A) according to the operation instruction detection signal.All experiments all repeat three times at least.
The detection of ion exchange activity
HEK-293T cell and the cell that uses DIDS to process according to respective concentration with gastrin, gastrin+DIDS, separately are seeded in respectively on the culture dish of 35mm, and the culture fluid that does not contain serum that contained 2 μ MBCECF-AM with 1mL after washing with the culture fluid that does not contain serum was hatched 20 minutes at 37 ℃.Then wash twice with the culture fluid that does not contain serum, again with the Ringer ' s buffer (5mMglucose, 5mMpotassiumgluconate, 1mMcalciumgluconate, the 1mMMgSO that contain Cl-
4, 2.5mMNaH
2PO
4, 25mMNaHCO
3, 10mMHepes, pH7.4) and lucifuge hatched 20 minutes.In culture dish to different cell climbing sheets respectively with the Ringer ' s buffer that contains 140mMNaCl with contain the perfusion that carries out that the Ringer ' s buffer of 140mMsodiumgluconate replaces.With being equipped with NIKONTE2000EMicroscope, HAMAMATSUIRCCDJVCcolorvideomonitor, the ion imaging instrument of DAD-8VCPP8pinchvalve perfusion system (excitation wavelength 440and490nm, emission wavelength 528.7nm) obtains and records fluorescent image.Then with high what nigericin method by proofreading and correct to obtain the pH curve in four pH value 6.5,7.0,7.5 and 8.0 fluorescence intensity.At the intracellular Cl of single HEK293T
-/ HC0
3 -Exchange activity passes through Cl
-Ooze out and again infiltrate the time cause change with pH curve the linear correlation and obtain.
Gastric acidity determination:
The C57 mice is divided into four groups, gives respectively normal saline, single gastrin, gastrin and DIDS common, single DIDS intravenous injection, carries out the test of gastric acid secretion situation after 15 minutes.
Interpretation of result:
Because there is the cascade enlarge-effect in gastrin effect in vivo, therefore relative gastric carcinoma cell lines, namely show effect in short time, cultivated 8,10,12,24 hours with the culture fluid that contains gastrin in people's gastric cancer SGC7901 cell line, extract albumen and carry out the westernblot detection, the result shows that the expression of AE2 obviously raises.
In animal experiment, the C57 mice is divided into four groups, gives respectively normal saline, 10
-10To 10
-6Common, the single DIDS intravenous injection of the single gastrin of mol/L, gastrin and DIDS, after 15 minutes, AE2mRNA and the protein expression of injection gastrin group mice all obviously raise, and the blocker DIDS of AE2 can suppress the facilitation that gastrin is expressed AE2.
With the SGC7901 cell with 10
-7The gastrin of mol/L was cultivated in 24 hours, and its intracellular ph value is down to 7.22 ± 0.25 by 7.86 ± 0.30, and the rate of change of per minute pH value (dpHi/dt) increases to 0.23 ± 0.066 per minute by 0.091 ± 0.031 per minute.Illustrate that gastrin has promoted intracellular ion transport active.
Gastrin is regulated the expression of AE2 by cholecystokinin B receptor (CCKBR): design and structure are for the interference carrier of SSKBR, transfection SGC7901 cell, extract albumen and carry out the westernblot analysis, as seen AE2 expresses and reduces (seeing on Fig. 3), SGC7901 processes through the blocker proglumide of the CCKBR of variable concentrations, and AE2 expresses and presents the performance of successively decreasing successively.
The C57 mice is divided into four groups, gives respectively normal saline, 10
-10To 10
-6Common, the single DIDS intravenous injection of the single gastrin of mol/L, gastrin and DIDS, carry out the test of gastric acid secretion situation after 15 minutes, measure the gastric acid secretion situation of mice, the result shows, gastrin has stimulated the secretion of gastric acid, and DIDS is by the effect (seeing on Fig. 3) of the function blocking gastrin gastric acid secretion of inhibition AE2.SGC7901 cell line was cultivated 8,10,12,24 hours with the culture fluid that contains gastrin, and intracellular ph value constantly descends.
Claims (7)
1. the application of gastrin in Kidney anion exchanger 2 is characterized in that, gastrin is used for the expression of Kidney anion exchanger 2 as regulator.
2. the application of gastrin in Kidney anion exchanger 2 is characterized in that, is used for promoting that intracellular ion transport is active.
3. application according to claim 2 is characterized in that, described promotion adopts 10
-10-10
-6The gastrin of mol/L is cultivated or the subcutaneous injection gastrin realizes.
4. application according to claim 3 is characterized in that, described incubation time is 24 hours-30 days.
5. the application of a gastrin is characterized in that, for the preparation of the medicine for the treatment of achlorhydria.
6. application according to claim 5 is characterized in that, described achlorhydria includes but not limited to chronic gastritis.
7. application according to claim 5 is characterized in that, described medicine is used for gastric acid secretion.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101890157A (en) * | 2009-05-22 | 2010-11-24 | 上海交通大学医学院 | Application of gastrin in inhibiting gastrointestinal tumor tumors |
-
2012
- 2012-09-28 CN CN201210376849XA patent/CN102847140A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101890157A (en) * | 2009-05-22 | 2010-11-24 | 上海交通大学医学院 | Application of gastrin in inhibiting gastrointestinal tumor tumors |
Non-Patent Citations (3)
| Title |
|---|
| LING-JUN SONG ET AL: "Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK", 《J MOL MED》, vol. 90, no. 6, 30 June 2012 (2012-06-30) * |
| 吴静 等: "胃酸分泌的调节", 《胃肠病学》, vol. 17, no. 3, 25 March 2012 (2012-03-25) * |
| 赵雷: "胃泌素抑制胃癌细胞增殖机制的研究", 《万方数据知识服务平台》, 30 March 2012 (2012-03-30) * |
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Application publication date: 20130102 |