CN112316107B - Use of angiotensin (1-7) in pancreatic disorders - Google Patents
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Abstract
Use of angiotensin (1-7) in pancreatic disorders. The invention provides a composition for treating pancreatic diseases, which comprises angiotensin (1-7) and/or angiotensin (1-7) derivatives, and application of angiotensin (1-7) or angiotensin derivatives in preparation of drugs for treating pancreatic diseases. The composition can effectively reduce pathological damage of pancreas, inhibit abnormal secretion of pancreatin, inhibit autophagy of pancreatic acinar cells and relieve pancreatic microcirculation disturbance, so that the composition can be used as a novel medicine for treating, improving or relieving various pancreatic diseases.
Description
Technical Field
The invention relates to the field of medicine, in particular to application of angiotensin (1-7) in pancreatic diseases.
Background
The renin-angiotensin system (RAS), widely found in various systems of the body, participates in the regulation of normal vital activities through a series of molecular mechanisms. RAS maintains the balance of body's aqueous electrolytes and body fluids by regulating the functional activities of the kidneys and the cardiovascular system. After RAS is activated, decapeptide angiotensin I (AngI) is converted by Angiotensin Converting Enzyme (ACE) to octapeptide angiotensin ii (AngII), which binds to angiotensin type 1 receptor (AT 1R) and contracts blood vessels to raise blood pressure and maintain electrolyte and fluid balance through renal and central regulation. However, the overactivity of RAS induces inflammatory reaction, cellular hypertrophy and tissue fibrosis, which leads to pathophysiological changes of the body and finally corresponding disease manifestations. Ang-II can also be converted by ACE2 into the heptapeptide Ang (1-7) to exert a variety of effects.
The prior researches suggest that Ang (1-7) plays a biological effect antagonistic to AngII, and researchers continuously explore the molecular mechanism of Ang (1-7) and the action mechanism of Ang (1-7) in cardiovascular and nervous system diseases. ACE2, ang (1-7) and Mas constitute a new pathway of RAS, and are named as ACE2-Ang (1-7) -Mas axis at present. Our understanding of RAS has now changed greatly from the first. Initially we considered AngII to be the only bioactive component, but studies have now found a number of active molecules including AngIII, angIV, ang (1-7), ang (1-12), angA, which are all components of this system and contribute to the overall action of the RAS. It is currently acknowledged that the Ang (1-7) -Mas receptor axis is beneficial to central blood pressure regulation and plays a role in brain protection, and the enhancement of the activity of the axis can play a role in protecting the kidney and the cardiovascular system, and is a potential treatment target for kidney and cardiovascular diseases.
Ang (1-7) is widely present in hypothalamic supraoptic nucleus and paraventricular nucleus, and can affect the synthesis and release of other central neurotransmitters through bradykinin, nitric Oxide Synthase (NOS), cyclooxygenase (COX) and some signal pathways, thereby playing roles of dilating blood vessels, resisting arrhythmia, resisting inflammation and the like, and achieving the effect of protecting cardiovascular and central nervous systems. Angiotensin (1-7) has also been shown to be useful in the treatment of diseases such as tumors.
Although studies on Ang (1-7) are numerous, studies on the role Ang (1-7) plays in pancreatic disease are not yet comprehensive.
Disclosure of Invention
The invention creatively provides a new application of angiotensin (1-7) and derivatives thereof, namely reduction of pancreatic injury and slowing of disease course development in pancreatic diseases. The inventors have confirmed the reliability of the above effects through a large number of experimental data, thereby proposing a composition for treating pancreatic diseases, and the use of angiotensin (1-7) or its derivative for the preparation of a drug for treating pancreatic diseases. Hereinafter, the present invention will be described in detail.
According to one aspect of the present invention, there is provided a composition for treating pancreatic disorders, the composition comprising angiotensin (1-7) and/or angiotensin (1-7) derivatives. In one embodiment, the composition comprises only angiotensin (1-7). In another embodiment, the composition comprises only the angiotensin (1-7) derivative. In another embodiment, the composition comprises a combination of angiotensin (1-7) and angiotensin (1-7) derivatives. In any of the embodiments above, the composition further comprises a pharmaceutically acceptable agent.
In some embodiments, the angiotensin (1-7) derivative is a carboxy-terminal aminated and/or amino-terminal acylated derivative of angiotensin (1-7). Wherein, in one embodiment, the angiotensin (1-7) derivative is a carboxy-terminal aminated derivative of angiotensin (1-7). In another embodiment, the angiotensin (1-7) derivative is an amino-terminally acylated derivative of angiotensin (1-7). In another embodiment, the angiotensin (1-7) derivative is a carboxyl terminal aminated and amino terminal acylated derivative of angiotensin (1-7).
According to another aspect of the present invention, there is provided a composition for treating pancreatic disorders, the composition comprising a long-acting angiotensin (1-7).
In some embodiments, the long-acting angiotensin (1-7) has a half-life of 70-120 minutes.
According to another aspect of the present invention there is provided the use of angiotensin (1-7) or a derivative thereof in the manufacture of a medicament for the treatment of pancreatic disease. In one embodiment, the medicament is a medicament for reducing pancreatic injury. In another embodiment, the drug is a drug that inhibits the secretion of pancreatic enzymes. In another embodiment, the agent is an agent that inhibits pancreatic acinar cell autophagy, reducing pancreatic microcirculation disturbance. The above embodiments may be combined in any combination, i.e. the medicament is a medicament having any two or more of the effects of any of the three embodiments described above.
In some embodiments, the angiotensin (1-7) derivative in the above-described use is a carboxyl-terminal aminated and/or amino-terminal acylated derivative of angiotensin (1-7). Wherein, in one embodiment, the angiotensin (1-7) derivative is a carboxy-terminal aminated derivative of angiotensin (1-7). In another embodiment, the angiotensin (1-7) derivative is an amino-terminally acylated derivative of angiotensin (1-7). In another embodiment, the angiotensin (1-7) derivative is a carboxyl terminal aminated and amino terminal acylated derivative of angiotensin (1-7).
In some embodiments, the angiotensin (1-7) derivative in the above-described use is a long-acting angiotensin (1-7). In one embodiment, the long acting angiotensin (1-7) has a half-life of 70-120 minutes.
In some embodiments, the animal dose of angiotensin (1-7) or its derivatives for use as described above is 1-5 μ g/kg.
Drawings
FIG. 1 shows histopathological observation photographs of pancreas of mice of a control group, an AP group and an intervention group according to example 2 of the present invention;
FIG. 2 is a schematic diagram showing a comparison of pathological pancreatic tissue scores of mice in a control group, an AP group and an intervention group according to example 2 of the present invention;
FIG. 3 is a schematic diagram showing a comparison of pancreatic tissue pancreatin secretion amounts of mice in a control group, an AP group and an intervention group according to example 2 of the present invention;
FIG. 4 is a graph showing the comparison of pancreatic acinar cells of mice in the control group, AP group and intervention group according to example 2 of the present invention, including autophagy status (first row) and mitochondrial status of pancreatic microvascular endothelial cells (second row).
Detailed Description
The present invention will be described in further detail with reference to specific examples. It should be noted that these representative embodiments are only used for explaining and illustrating the technical solution of the present invention, and the present invention is not limited to these specific embodiments. Any combination, variation, and modification of the described embodiments, in accordance with the substance of the present invention, is within the scope of the claimed invention.
In order to make the present invention more understandable, definitions of some terms used in the present invention will be set forth in the present specification.
Pancreatic disease and its symptoms
Pancreatic disease is a general term for all diseases of the pancreas, including pancreatic congenital diseases, pancreatic injury diseases, pancreatic inflammatory diseases, pancreatic cystic changes, and pancreatic secretory tumors.
Acute pancreatitis and chronic pancreatitis can be caused by infection, overeating, hyperlipidemia, biliary calculus, biliary ascariasis, diverticulum beside duodenal papilla, trauma, operation, medicine, etc.; pancreatic injury may be caused by accidents, violence, high fall, etc.; genetic, stimulatory, genetic, environmental, etc. factors can induce tumors. In short, pancreatic diseases are of various kinds and have complicated and varied etiologies.
Congenital diseases of the pancreas include cyclic pancreas, ectopic pancreas, pancreatic segregation, and the like. The ring pancreas is the congenital anatomical abnormality caused by the embryonic development period, and pancreas tissues surround the descending part of duodenum circularly and can cause congenital duodenal obstruction; ectopic pancreas is a pancreatic tissue existing outside a normal pancreatic tissue, is located in the upper digestive tract, mainly comprises the parts of the stomach and duodenum, and mainly shows bleeding, obstruction, diverticulum, lumps and the like; pancreas separation means that the ventral pancreatic duct and the dorsal pancreatic duct of the pancreas cannot be fused and enter the duodenum, and the accessory pancreatic duct becomes the main excretion channel, mainly manifested as epigastric pain, radiating to the back and aggravating after eating.
Pancreatic injury diseases include pancreatic contusion, laceration, and pancreatic rupture, and depending on the degree of injury, there may be abdominal pain, which may be radiating to the back and shoulder, accompanied by nausea, vomiting, etc., and manifested as abdominal tenderness, rebound pain, and muscular tension.
Inflammatory diseases of the pancreas, such as acute pancreatitis, are manifested by abdominal pain, abdominal distension, fever, dyspepsia, organ dysfunction, etc., and when Carlen's syndrome (Cullen) and Gray-Turner's syndrome (Grey-Turner) appear, the disease is serious, and simultaneously water, electrolyte and acid-base balance disorder exist, and blood urine amylase is obviously increased. Chronic pancreatitis is often manifested as abdominal pain, abdominal distension, diarrhea, upper gastrointestinal discomfort, emaciation, elevated blood sugar, jaundice, abdominal mass, etc.
The cystic lesions of pancreas comprise true cyst of pancreas, false cyst of pancreas, cystic tumor of pancreas, etc. The congenital true cyst is congenital pathological change of pancreas, cystic fibrosis, multiple cyst, enterogenous cyst, isolated cyst, etc. Acquired true cysts are mostly distal pancreatic ducts caused by pancreatic duct obstruction, cystic expansion of acinus and retention cysts caused by pancreatic fluid retention. Pancreatic pseudocyst is a complication secondary to acute pancreatitis, chronic pancreatitis, and pancreatic injury. The pancreatic cystic tumors include serous cystadenoma, mucinous cystadenoma and mucinous cystadenocarcinoma.
Pancreatic secretory tumors include pancreatic exocrine tumors and pancreatic endocrine tumors. Among them, the exocrine pancreatic tumor is mainly pancreatic cancer, and is manifested by abdominal pain (mostly dull pain), abdominal distension, anorexia, progressive emaciation, jaundice, etc. Pancreatic endocrine tumor: is a tumor mainly formed by a certain cell in pancreatic islet, such as insulinoma, gastrinoma, somatostatin tumor, pancreatic polypeptinoma, glucagonoma, etc.
"pancreatic disease" as used in the context of the present invention includes, but is not limited to, the types and symptoms of pancreatic disease described above. In some embodiments, the pancreatic disorder of the invention is manifested by one or more of the following symptoms:
(1) (iii) pancreatic injury;
(2) Excessive secretion of pancreatin;
(3) Pancreatic acinar cell autophagy;
(4) Pancreatic microcirculation disturbance.
In one embodiment according to the invention, the pancreatic disease is a pancreatic congenital disease, such as a ring pancreas, an ectopic pancreas or a pancreatic isolate. In another embodiment according to the present invention, the pancreatic disorder is a pancreatic injury disorder, such as a pancreatic contusion, laceration or pancreatic rupture. In another embodiment according to the invention, the pancreatic disease is an inflammatory disease of the pancreas, for example acute pancreatitis or chronic pancreatitis. In another embodiment according to the invention, the pancreatic disease is a cystic lesion of the pancreas, for example a true cyst of the pancreas, a pseudocyst of the pancreas, or a cystic tumor of the pancreas. In another embodiment according to the invention, the pancreatic disease is a pancreatic secretory tumor, for example a pancreatic exocrine tumor or a pancreatic endocrine tumor. The compositions for treating pancreatic disorders provided by the present invention can be used for the treatment, amelioration, or amelioration of any one or more of the pancreatic disorders in any of the embodiments described above.
The terms "treating pancreatic disease", "treatment of pancreatic disease", "treatment, amelioration or palliation of pancreatic disease" and the like as used herein mean achieving one or more of the following effects:
(1) Reducing pancreatic injury;
(2) Inhibiting the secretion of pancreatin;
(3) Inhibiting pancreatic acinar cell autophagy;
(4) Alleviating microcirculatory disturbance of the pancreas;
(5) Slow down or block the progression of the disease.
In some embodiments according to the invention, in vitro and in vivo assays may be employed to assess the effect of the composition or components thereof for treating pancreatic disease. In one embodiment, the extent of pancreatic injury can be assessed by observation of pancreatic histopathology, e.g., by comparing the pancreatic histopathological score of a subject ingesting a composition or component thereof for treating pancreatic disease according to the present invention to a control group to assess the effect of the composition or component thereof on reducing pancreatic injury. In one embodiment, the effect on the amount of pancreatic enzymes secreted can be evaluated by detecting the amount of pancreatic enzymes secreted, for example, by comparing the amount of pancreatic enzymes secreted per unit volume of pancreatic tissue in a subject who has ingested the composition for treating pancreatic diseases of the present invention or a component thereof with that in a control group. In one embodiment, the effect on pancreatic acinar cell autophagy can be evaluated by microscopic observation of pancreatic acinar cells, for example, by observing by electron microscopy and comparing the size, morphology, number of pancreatic acinar cells of a subject ingesting the composition for treating pancreatic disease or a component thereof of the present invention with those of a control group to evaluate the effect of the composition or a component thereof on inhibiting pancreatic acinar cell autophagy and reducing pancreatic microcirculation disturbance.
The "subject" as defined above may refer to an animal, a human, or a cell, tissue, which has been administered.
Angiotensin (1-7) and derivatives thereof
Angiotensin is a polypeptide of the renin-angiotensin system. The circulating renin-angiotensin system (RAS) has a clear role in the balance of circulation. Local tissue-based RAS is also present in the body, for example in the lungs, which may play a role in the body's injury and repair response. Naturally occurring angiotensin (1-7) is a linear polypeptide with the amino acid sequence Asp-Arg-Val-Tyr-Ile-His-Pro. In the renin-angiotensin system, the vasodilating activity of angiotensin (1-7) and the vasoconstricting activity of angiotensin II cancel each other out. Angiotensin (1-7) is an endogenous ligand of the Mas receptor. The Mas receptor is a G protein-coupled receptor comprising seven transmembrane regions.
Angiotensin (1-7) or its derivatives suitable for use in the present invention include naturally occurring angiotensin (1-7) and functional equivalents or modified derivatives thereof. The functional equivalent of naturally-occurring angiotensin (1-7) according to the present invention refers to any peptide having the same amino acid sequence as naturally-occurring angiotensin (1-7) and retaining substantially the same or similar activity as naturally-occurring angiotensin (1-7). The terms "peptide" and "polypeptide" are used interchangeably herein.
In some embodiments, the angiotensin (1-7) derivatives suitable for use in the present invention are derivatives that are modified by one or more modifications on the angiotensin (1-7) polypeptide to increase protease resistance, serum stability and/or bioavailability. In some embodiments, suitable modifications are selected from amination, acylation, glycosylation, biotinylation, pegylation, D-amino acid and/or unnatural amino acid substitution, and/or peptide cyclization.
In some embodiments, the angiotensin (1-7) derivative is a carboxy-terminal aminated and/or amino-terminal acylated derivative of angiotensin (1-7). Wherein, in one embodiment, the angiotensin (1-7) derivative is a carboxyl terminal aminated derivative of angiotensin (1-7), and the structure is shown in formula (I). In another embodiment, the angiotensin (1-7) derivative is an amino-terminally acylated derivative of angiotensin (1-7), having the structure shown in formula (II). In another embodiment, the angiotensin (1-7) derivative is a carboxyl terminal aminated and amino terminal acylated derivative of angiotensin (1-7), as shown in formula (III).
In the above formulae (I), (II) and (III), R 1 And R 2 Each independently hydrogen, alkyl (e.g. C) 1 -C 6 Alkyl) or aralkyl.
In some embodiments, R 1 And R 2 Each independently is hydrogen or C 1 -C 4 An alkyl group. In other embodiments, R 1 And R 2 Each independently hydrogen, methyl, ethyl or propyl. In other embodiments, R 1 And R 2 Each independently hydrogen or methyl. In one embodiment, R 1 And R 2 And is also hydrogen. In another embodiment, R 1 And R 2 And is also methyl. In another embodiment, R 1 Is hydrogen, R 2 Is a methyl group. In another embodiment, R 1 Is methyl, R 2 Is hydrogen.
Although angiotensin (1-7) polypeptides are effective for biological activity in vitro, the in vivo effectiveness of the polypeptides may be reduced by the presence of proteases. Angiotensin (1-7) has a very short half-life in circulation in the body, approximately only 3-15 minutes, influenced by hydrolysis by Angiotensin Converting Enzyme (ACE), neutral Endopeptidase (NEP), aminopeptidase (APs). Due to the rapid hydrolysis in vivo, only a small amount of angiotensin (1-7) polypeptide can reach the lesion to exert its effect when administered in vivo. In this inefficient mode of action, repeated dosing can only be used to achieve the desired therapeutic effect, and increasing the dose results in more side effects. In view of this, it is often more advantageous to use angiotensin (1-7) polypeptides modified to reduce the effects of hydrolysis in vivo. The derivative of the angiotensin (1-7) provided by the invention is a modifier of the angiotensin (1-7), the derivative retains the structural characteristics of the biological activity required by the original generation of the angiotensin (1-7), but has the advantage of being not easy to be broken and hydrolyzed by Angiotensin Converting Enzyme (ACE), neutral Endopeptidase (NEP) and Aminopeptidase (APs), and the half-life period in vivo can reach 70-120 minutes. The angiotensin (1-7) derivative provided by the invention can be used as a long-acting angiotensin (1-7) preparation to improve the treatment effect, reduce the administration dosage and reduce the side effect of the medicament.
The angiotensin (1-7) or its derivative according to the present invention may be present as a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" as used herein refers to salts which retain the desired activity of the polypeptide or equivalent compound but preferably do not adversely affect the activity of the polypeptide or other components of the system in which it is used. Examples of such salts are acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like. Salts may also be formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, ascorbic, benzoic, tannic, pamoic, alginic, polyglutamic acids and the like. The salts formed using cationic materials can use the conjugate bases of these inorganic and organic acids. Salts may also be formed using polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, or organic cations formed by N, N' -dibenzylethylenediamine or ethylenediamine, or combinations thereof (e.g., zinc tannate salts). Non-toxic, physiologically acceptable salts are preferred.
The present invention provides a composition for treating pancreatic diseases, comprising the angiotensin (1-7) and/or angiotensin (1-7) derivatives described above. In one embodiment, the composition comprises only angiotensin (1-7). In another embodiment, the composition comprises only the angiotensin (1-7) derivative. In another embodiment, the composition comprises a combination of angiotensin (1-7) and angiotensin (1-7) derivatives. The pharmaceutical composition comprising angiotensin (1-7) may be in the form of a solution, capsule, tablet, emulsion, suppository, gel, powder sustained release dosage form, and the like. In any of the embodiments above, the composition further comprises a pharmaceutically acceptable agent.
Pharmaceutically acceptable agents that can be incorporated into the compositions include absorption enhancers, excipients, pH adjusting and buffering agents, tonicity adjusting agents, preservatives, stabilizers, antioxidants, surfactants, thickening agents, lubricants, dispersing agents, flavoring agents, coloring agents, and wetting agents.
Excipients suitable for use in the present invention include water, glucose, sucrose, lactose, ethylene glycol, ethanol, glycerol monostearate, gelatin, starch, chalk, sodium stearate, malt, sodium chloride and the like.
Fillers or binders suitable for use in the present invention include acacia, alginic acid, calcium phosphate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, dextrin, dextrates, sucrose, methylcellulose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium metabisulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch, and zein. In some embodiments, the filler or binder is microcrystalline cellulose.
Disintegrants suitable for use in the invention include alginic acid, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, disodium metabisulfite, disodium edetate, disodium Ethylenediaminetetraacetate (EDTA) -crosslinked polyvinylpyrrolidone, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose.
Lubricants suitable for use in the present invention include calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium fumarate stearate, stearic acid, talc and zinc stearate, glyceryl behenate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, sodium benzoate/acetate, DL-leucine and the like.
Silicon flow rate modifiers suitable for use in the present invention include colloidal silica, magnesium aluminum silicate, and guar gum. Another most preferred silicon flow rate modifier is silica.
Stabilizers suitable for use in the present invention include acacia, albumin, polyvinyl alcohol, alginic acid, bentonite, dicalcium phosphate, carboxymethylcellulose, hydroxypropylcellulose, colloidal silicon dioxide, cyclodextrin, glyceryl monostearate, hydroxypropylmethylcellulose, magnesium trisilicate, magnesium aluminum silicate, propylene glycol alginate, sodium alginate, carnauba wax, xanthan gum, starch, stearate, stearic acid, glyceryl monostearate, and stearyl alcohol.
EXAMPLE 1 preparation of Long-acting Ang (1-7)
The synthesis of Ang (1-7) polypeptide was performed using standard Fmoc solid phase synthesis. Adding MBHA amino resin to perform amino protection at the Ang (1-7) C end. At the end of the synthesis reaction, acetic anhydride, DIEA and DCM were added for N-terminal protection. Column chromatography purification, HPLCThe purity was confirmed. Spectral characterization confirmed structure. To give Ang (1-7) derivatives as shown in formula (III) above, wherein R 1 Is hydrogen, R 2 Is methyl.
Example 2 animal experiments
C57BL/6 mice were divided into a control group, an Acute Pancreatitis (AP) group, and an intervention group. The CAE combined with LPS is injected into the abdominal cavity of a C57BL mouse to induce an Acute Pancreatitis (AP) model, an angiotensin Ang (1-7) intervention group is injected into tail veins with long-acting Ang (1-7) of 3 mu g/kg immediately after molding, and a control group is injected with equal volume of normal saline at the same time point. Three groups of mice were sacrificed at the same time (6 h after successful molding) and their pancreatic tissues were taken.
(1) And (3) pathological scoring:
the pathological pancreatic tissue score of the mice in the intervention group was significantly lower than that of the AP group (see FIGS. 1 and 2), indicating that the pancreatic tissue damage of the mice in the intervention group was less severe.
(2) Pancreatic enzyme secretion:
the pancreatic enzyme secretion of the intervention group is lower than that of the AP group (see figure 3), which shows that the long-acting Ang (1-7) can obviously inhibit the pancreatic enzyme secretion amount and slow down the course of disease.
(3) Electron microscope: observing pancreatic acinar cells of three groups of mice under an electron microscope, wherein autophagy vesicles appear in AP cells, and autophagy of an intervention group is reduced; the endothelial cell mitochondria of the pancreatic microvascular cavity of the AP mouse obviously swell, and the mitochondria of the intervention group has low damage degree. It shows that long-acting Ang (1-7) inhibits autophagy of pancreatic acinar cells when AP is applied, relieves pancreatic microcirculation disturbance, and blocks disease development (see figure 4).
Claims (2)
1. The application of the angiotensin (1-7) derivative in the preparation of the medicine for treating pancreatic diseases, wherein the medicine is the medicine for inhibiting the secretion of pancreatin, the structure of the angiotensin (1-7) derivative is shown as the formula (III),
wherein R is 1 Is hydrogen, R 2 Is methyl, and
wherein the angiotensin (1-7) derivative is used for inhibiting pancreatin secretion.
2. Use according to claim 1, characterized in that the animal dose of angiotensin (1-7) derivative is 1-5 μ g/kg.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2163259A1 (en) * | 2008-09-12 | 2010-03-17 | Charité-Universitätsmedizin Berlin (Charité) | Use of an Ang-(1-7) receptor agonist in acute lung injury |
| CN106535920A (en) * | 2014-07-21 | 2017-03-22 | 代表亚利桑那大学的亚利桑那校董会 | Ang-(1-7) derviative oligopeptides and methods for using and producing the same |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2163259A1 (en) * | 2008-09-12 | 2010-03-17 | Charité-Universitätsmedizin Berlin (Charité) | Use of an Ang-(1-7) receptor agonist in acute lung injury |
| CN106535920A (en) * | 2014-07-21 | 2017-03-22 | 代表亚利桑那大学的亚利桑那校董会 | Ang-(1-7) derviative oligopeptides and methods for using and producing the same |
Non-Patent Citations (3)
| Title |
|---|
| Angiotensin-（1-7）attenuates caerulein-induced pencreatic acinar cell apoptosis;LIJIAN CUI等;《MOLECULAR MEDICINE REPORTS》;20171231;第16卷;全文 * |
| 急性胰腺炎的研究进展;张芬等;《现代生物医学进展》;20160531;第16卷(第15期);摘要，第4.1-4.4节 * |
| 血管紧张素1-7对雨蛙素诱导的胰腺腺泡细胞Toll 样受体4 /核因子－κB 通路的影响;王艳等;《临床肝胆病杂志》;20161130;第32卷(第11期);第2147页左栏第1段，讨论部分 * |
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