阅读说明：本技术 一种寡肽在制备治疗或预防肾缺血再灌注损伤的药物中的应用 (A kind of application of oligopeptides in the drug that preparation treats or prevents renal ischemic reperfusion injury ) 是由 刘吉华 戴文玲 李姗姗 于 2019-09-27 设计创作，主要内容包括：本发明提供了一种寡肽在制备治疗或预防肾缺血再灌注损伤的药物中的应用。其中所述寡肽序列为SEQ ID No.1所示的氨基酸序列的寡肽,或者为该寡肽所述寡肽的氨基酸经过一个或几个氨基酸残基的取代和/或缺失和/或添加得到的具有相同功能的寡肽。在肾脏缺血再灌注小鼠模型中,所述寡肽能够明显缓解小鼠肾脏缺血再灌注损伤；显著降低肾脏缺血再灌注模型小鼠血清中的肌酐和尿素氮水平,有效改善肾脏缺血再灌注模型小鼠肾脏病理损伤。本发明的寡肽可以用于制备预防和治疗肾脏缺血再灌注损伤的治疗药物。(The present invention provides a kind of application of oligopeptides in the drug that preparation treats or prevents renal ischemic reperfusion injury.Wherein the oligopeptide sequence is the oligopeptides of amino acid sequence shown in SEQ ID No.1, or is substitution and/or deletion and/or addition obtained with the same function oligopeptides of the amino acid by one or several amino acid residues of oligopeptides described in the oligopeptides.In renal ischemia/reperfusion injury mouse model, the oligopeptides can be relieved mouse kidney ischemical reperfusion injury；The creatinine and urea nitrogen levels in renal ischemia/reperfusion injury model mice serum are significantly reduced, the damage of renal ischemia/reperfusion injury model mice Pathological is effectively improved.Oligopeptides of the invention can be used for preparing the therapeutic agent for preventing and treating ischemia-reperfusion injury of kidney.)

1. a kind of oligopeptides treats or prevents the application in renal ischemic reperfusion injury drug in preparation, which is characterized in that the widow Peptide is a1) or a2):

It a1 is) oligopeptides of amino acid sequence shown in SEQ ID No.1；

A2) amino acid for the a1) oligopeptides passes through the substitution and/or deletion and/or addition of one or several amino acid residues Obtained oligopeptides with the same function.

2. oligopeptides according to claim 1 treats or prevents the application in renal ischemic reperfusion injury drug in preparation, Be characterized in that: the oligopeptides increases the hexapeptide of an amino acid for the a1) oligopeptides.

3. oligopeptides according to claim 1 treats or prevents the application in renal ischemic reperfusion injury drug in preparation, Be characterized in that: the oligopeptides is the oligopeptides of amino acid sequence shown in SEQ ID No.2.

4. any oligopeptides treats or prevents in renal ischemic reperfusion injury drug in preparation according to claim 1~3 Using, it is characterised in that: the drug is made of the oligopeptides and pharmaceutically acceptable carrier.

5. oligopeptides according to claim 4 treats or prevents the application in renal ischemic reperfusion injury drug in preparation, Be characterized in that: the pharmaceutically acceptable carrier is diluent, carrier or excipient.

6. oligopeptides according to claim 4 treats or prevents the application in renal ischemic reperfusion injury drug in preparation, Be characterized in that: the drug is ejection preparation or oral preparation.

Technical field

The present invention relates to a kind of applications of oligopeptides more particularly to a kind of oligopeptides to treat or prevent Ischemia-reperfusion Injury in preparation Application in the drug of damage.

Background technique

Ischemia-reperfusion injury of kidney (renal ischemia reperfusion injury, RIRI) refers in kidney group Knitting renal function after restoring hemoperfusion on the basis of ischemic cannot be restored, notably occur more thoroughly, irreversibly kidney The common pathologic, physiologic phenomenon of one kind of dirty damage or acute renal failure.It is common in kidney transplantation operation, kidney trauma operation, body Situations such as combined use of ESWL lithotrity is one of the main reason for leading to acute renal failure.Ischemia-reperfusion injury of kidney is also Kidney underlying diseases can further be deteriorated, delay treatment cycle, the death rate of patient has been significantly greatly increased.Its disease incidence height and prognosis Bad, mechanism of action not yet illustrates completely, there is no special effective intervening measure at present.It is found that prevention or treatment kidney lack The drug of blood reperfusion injury has important clinical meaning.

The pathologic process of RIRI is a complicated cascade reaction, is currently known main pathomechanism and is related to aoxidizing Stress, calcium overload, cell autophagy, apoptosis and ischemic, inflammation damnification, immune system activation etc..Nephridial tissue is in Ischemia Reperfusion A large amount of active oxygen (reactive oxygen species, ROS) can be generated during note, be more than the Scavenging activity of body, ROS leads to cell oxidative damage due to it easily reacts with various eucaryotic cell structure ingredients.Intracellular Ca²⁺Raising can swash Ca-dependent protease living, intracellular protein of degrading, also leads to the generation of calcium pyrophosphate complex compound and the formation of uric acid and activity The generation of oxygen, and promote the generation of inflammation；Mitochondrial calcium overload will lead to mitochondria permeability transition pore (mitochondrial Permeablity transition pore, MPT) opening, the opening of MPT is one in process of cell death crucial thing Part eventually leads to the damage of nephridial tissue and the decline of renal function.RIRI often with a series of inflammation damnifications, is mainly shown as white Cell aggregation simultaneously passes through wall of micrangium, infiltrates surrounding tissue, at the same with liquid in microvascular dysfunction and local organization and Protein gathers.The accumulation of ischemic stage metabolite, histocyte fragment etc. can trigger acute inflammatory reaction, kidney parenchyma and Resident leucocyte secretes a variety of chemotactic factor (CF)s and cell factor, these inflammatory mediators, intracellular adhesion molecule -1 (ICM-1) and Palatelet-selectin recruits leukocyte infiltration to ischemic tissue again, then leads to leucocyte and endothelial cell Interaction enhanced, thus Promote endothelial cell damage, swelling, hinders blood flow.These inflammatory mediators also mediate monocyte, neutrophil cell, T In the migration of kidney, the leucocyte of infiltration can further increase chemotactic factor (CF) and thin for cell, inflammatory Dendritic Cells and NKT cell The secretion of intracellular cytokine induces inflammatory reaction.Inflammatory cell infiltration is the pass of RIRI pathogenesis and tubulointerstitial injury progress Key process.Urea nitrogen (BUN), creatinine (Scr) are that clinically evaluation renal function common counter, BUN are that vivo protein metabolism produces Object, Scr are the itrogenous organic substances that muscle metabolism generates, both metabolites are excreted through kidney, and blood level depends on In glomerular filtration ability, if kidney substantial damage, glomerular filtration rate decline drops to after critical point that BUN, Scr will in blood It increases.Therefore renal function changes after BUN, Scr can be used for evaluating ischemia-reperfusion injury of kidney.

However, still not knowing starting at present and promoting the detailed process of inflammation.The integrated mechanism of RIRI is extremely complex, is related to Interaction between different molecular approach, pathogenesis do not illustrate completely yet so far, and treatment method does not also have breakthrough, clinical On there is no the specific medicament of prevention and treatment renal ischemic reperfusion injury, existing therapeutic scheme is to give anti-inflammatory drug and enhancing is immune mostly The problems such as drug, use for a long time can generate drug resistance, systemic effect, and since RIRI disease incidence is high and prognosis is poor, mesh It is preceding still to lack highly effective means of prevention, it is mostly to give antioxidant or anti-inflammatory agent etc. when preceding or generation occurs for RIRI to subtract Few damage to kidney such as inflammatory reaction and Apoptosis.Thus exploitation has weight to the protection drug of ischemia-reperfusion injury of kidney The clinical meaning and value wanted.

It is Xm-Leu-Asn-Leu-Tyr- that patent 110128506A (publication date 2019-08-16), which discloses amino acid sequence, The oligopeptides of Yn, the application are to disclose the amino acid of the oligopeptides and the oligopeptides on this basis by one or several ammonia The oligopeptides that the substitution and/or deletion and/or addition of base acid residue obtain treats or prevents renal ischemic reperfusion injury in preparation Purposes in drug.

Summary of the invention

Goal of the invention: the first object of the present invention is to provide a kind of oligopeptides, and the second object of the present invention is to provide institute State application of the oligopeptides in the drug that preparation treats or prevents renal ischemic reperfusion injury.

To achieve the above object, technical scheme is as follows:

The present invention provides a kind of oligopeptides and treats or prevents the application in renal ischemic reperfusion injury drug, the widow in preparation Peptide is a1) or a2):

It a1 is) oligopeptides of amino acid sequence shown in SEQ ID No.1；

A2) be a1) amino acid of the oligopeptides by the substitution of one or several amino acid residues and/or missing and/or Add obtained oligopeptides with the same function.

Wherein, the oligopeptides of amino acid sequence shown in above-mentioned SEQ ID No.1 is Leu-Asn-Leu-Tyr-Pro.

Preferably, the oligopeptides increases the hexapeptide of an amino acid for the a1) oligopeptides.

Preferably, the oligopeptides is the oligopeptides of amino acid sequence shown in SEQ ID No.2.That is the amino acid of the oligopeptides Sequence is Leu-Asn-Leu-Tyr-Pro-Tyr.

Preferably, the drug is made of the oligopeptides and pharmaceutically acceptable carrier.It is described pharmaceutically acceptable Carrier, it may have certain physiological activity, but the addition of the ingredient will not change aforementioned pharmaceutical compositions in disease treatment Leading position in journey, and auxiliary effect is only played, these auxiliary effects are only the utilization to the ingredient known activity, are The usual adjuvant treatment modality of field of medicaments.If above-mentioned complementary ingredient is used cooperatively with pharmaceutical composition of the present invention, still It should belong to the scope of protection of the invention.

Preferably, the pharmaceutically acceptable carrier is diluent, carrier or excipient.

Further, the drug is ejection preparation or oral preparation.

The utility model has the advantages that the present invention, which closes the mouse bilateral renal kidney base of a fruit by folder, establishes renal ischemic reperfusion injury model, apply Oligopeptides drug treatment, the extremely significant downward model mice serum creatinine of energy and urea nitrogen levels, Pathological slice display oligopeptides energy Model mice renal tubule large area coagulation necrosis and institutional framework is significantly inhibited to destroy, significantly reduce in renal tissue inflammation because Sub- TNF-α, IL-1 β and IL-10 are horizontal.Show that oligopeptides there is good prevention and treatment to make ischemia-reperfusion injury of kidney With.

Detailed description of the invention

Fig. 1 is influence of the LP-5 to renal ischemia/reperfusion injury model mice blood serum Bun, BUN content.A. mice serum creatinine (Scr) content；B. mice serum urea nitrogen (BUN) content.###, p < 0.001vs.sham；* *, p < 0.001vs.model；n =10

Fig. 2 is LP-5 to TNF-α, the content of IL-1 β and IL-10 in renal ischemia/reperfusion injury model mice renal tissue It influences.A. in kidney of mouse TNF-α content；B. in kidney of mouse IL-1 β content；C. IL-10 in kidney of mouse Content.###, p < 0.001vs.sham；* *, p < 0.001；*, p < 0.01vs.model；N=10

Fig. 3 is influence (HE dyeing) of the LP-5 to renal ischemia/reperfusion injury model mice renal tissue form

Fig. 4 is LP-6 to renal ischemia/reperfusion injury model mice blood serum Bun, BUN assay result.A. mice serum flesh Acid anhydride (Scr) content；B. mice serum urea nitrogen (BUN) content.###, p < 0.001vs.sham；* *, p < 0.001vs.model； N=10

Fig. 5 is that LP-6 measures TNF-α, containing for IL-1 β and IL-10 in renal ischemia/reperfusion injury model mice renal tissue Determine result.A. in kidney of mouse TNF-α content；B. in kidney of mouse IL-1 β content；C. IL- in kidney of mouse 10 content.###, p < 0.001vs.sham；* *, p < 0.001；*, p < 0.01vs.model；N=10

Fig. 6 is influence (HE dyeing) of the LP-6 to renal ischemia/reperfusion injury model mice renal tissue form

Specific embodiment

The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.