CN109908331A - Application of the Hexarelin in preparation protection ischemia-reperfusion injury of kidney drug/pharmaceutical composition - Google Patents
Application of the Hexarelin in preparation protection ischemia-reperfusion injury of kidney drug/pharmaceutical composition Download PDFInfo
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Abstract
The present invention proposes that a kind of Hexarelin is preparing the application in protection ischemia-reperfusion injury of kidney drug/pharmaceutical composition, belong to biomedicine field, the application is by proving a possibility that Hexarelin causes acute kidney injury protective effect to Ischemia and Reperfusion in vivo in Rats, and find that SFN gene expression amount significantly increases in renal ischemia/reperfusion injury model by data, SFN gene expression rises more obvious after Hexarelin is intervened, and apoptosis promotes gene Bax, Bad, caspase3 expression is lowered, to by inhibiting apoptosis to protect ischemia-reperfusion injury of kidney, and then pass through the possibility of molecular docking technical identification Hexarelin molecule and the 14-3-3 σ protein structure interaction encoded by the gene, to provide theoretical basis to widen the possible application range of Hexarelin.The present invention can be applied in the theoretical research and clinical application of ischemia-reperfusion injury of kidney, also provide theoretical basis to widen the possible application range of Hexarelin.
Description
Technical field
The invention belongs to biomedicine fields more particularly to a kind of Hexarelin in preparation protection renal ischemia/reperfusion injury damage
Application in vulnerary object/pharmaceutical composition.
Background technique
Acute kidney injury (Acute Kidney Injury, AKI) refers to causes detection of glomeruli filtration function to be dashed forward by a variety of causes
So (in 1-7d) and continue a series of clinical syndromes that (> for 24 hours) decline causes, is common in thrombosis of renal artery, kidney transplant, serious
Situations such as renal vascular diseases, shock, acute heart failure.Studies have shown that Renal proximal tubular epithelial cell is that renal ischemic fills again
Involvement most serious part when note damage occurs, is mainly shown as renal tubule atrophy, disappears, the apoptosis of proximal tubular epithelial cells,
Necrosis, fall off and Peritubular capillary reduce.Effective diagnosis and treatment of acute kidney injury process are blocked due to still lacking at present
Means, therefore it is clinically particularly important to prevent its occurrence and development.
There is Recent study discovery Growth Hormone Releasing Peptide analog the peripheral organ for not depending on growth hormone secretion to protect
Shield effect, Hexarelin is a kind of artificial synthesized Growth Hormone Releasing Peptide analog, compared with natural Ghrelin, synthesis
Stablize and application be convenient, have the characteristics that molecular mass small (only 887.47), it is oral effectively, toxicity is low, cheaper, consubstantiality
Inner growth hormone release peptide, which is compared, has more wide application prospect.But the research master of its peripheral organ's protective effect of current needle
Cardiac muscle, brain, skeletal muscle etc. are concentrated on, the effect in ischemia-reperfusion acute kidney injury is but rarely reported.In addition, acute kidney
Damage mechanism still lacks final conclusion, therefore still lacks strong evidence to its pharmaceutically-active research, and visits for pathogenesis
Study carefully acute kidney injury related drugs to be of great significance to clinic diagnosis.
Summary of the invention
The present invention proposes that a kind of Hexarelin is protected in ischemia-reperfusion injury of kidney drug/pharmaceutical composition in preparation
Using the application has carried out going deep into theoretical research to effect of the Hexarelin in ischemia-reperfusion acute kidney injury, from rat
Ischemia-reperfusion causes acute kidney injury model and molecular docking technology different angle to confirm that Hexarelin can be to Ischemia Reperfusion
The protective effect for infusing acute kidney injury, to provide theoretical basis to widen the possible application range of Hexarelin.
In order to achieve the above object, the present invention provides a kind of Hexarelins protects ischemia-reperfusion injury of kidney in preparation
Application in drug/pharmaceutical composition.
Preferably, the application is that Hexarelin passes through the Protein 14-3-3 σ acted on by SFN coding and significantly rises
The expression quantity of high SFN reduces the degree of ischemia-reperfusion injury of kidney.
Preferably, the application be Hexarelin by significantly increase SFN expression quantity, and then by with apoptosis precursor
The interaction of protein B AX, BAD carrys out regulating cell apoptosis, to reduce the degree of ischemia-reperfusion injury of kidney.
The present invention also provides a kind of Hexarelins for assessing and quantifying ischemical reperfusion injury and for monitoring
Purposes in the use of drug and any program of effect.
The present invention also provides a kind of drug/pharmaceutical composition, the drug/pharmaceutical composition includes being with Hexarelin
The drug of sole component, using Hexarelin as the drug of active pharmaceutical ingredient or containing the pharmaceutical preparations composition of Hexarelin.
Preferably, as needed can contain pharmaceutically acceptable carrier, wherein Hexarelin as pharmaceutical activity at
Point, shared weight percent can be 0.1-99.9% in the formulation.
Preferably, the dosage form of the drug/pharmaceutical composition is selected from tablet, capsule, oral solution, mouth containing agent, particle
Any one in agent, electuary, pill, powder, pulvis, solution and injection.
Compared with prior art, the advantages and positive effects of the present invention are:
This project intervenes the research of Ischemia and Reperfusion in vivo in Rats model by Hexarelin to estimate it to people's acute kidney injury
Protective effect, it was demonstrated that Hexarelin to people's ischemia-reperfusion cause acute kidney injury protective effect a possibility that.Pass through data point
Analysis discovery gene SFN is significantly increased in renal ischemia/reperfusion injury model, and the dry prognostic gene SFN expression of Hexarelin rises more
Obviously.Further pass through molecular docking technical identification Hexarelin molecule and gene coded protein 14-3-3 σ structure phase interaction
Possibility, to provide theoretical basis to widen the possible application range of the drug, be vast acute kidney injury patient with
Carry out Gospel.
Detailed description of the invention
Fig. 1 is the schematic diagram that serum creatinine is expressed after Hexarelin provided by the embodiment of the present invention is intervened；
Fig. 2 is the schematic diagram that urea nitrogen is expressed after Hexarelin provided by the embodiment of the present invention is intervened；
Fig. 3 is the schematic diagram that KIM-1 is expressed after Hexarelin provided by the embodiment of the present invention is intervened；
Fig. 4 is that injury of kidney degree mitigates after Hexarelin provided by the embodiment of the present invention is intervened, wherein A: normal group；
B: sham-operation group；C: acute kidney injury (AKI) group；D: acute kidney injury (HEX+AKI) group after Hexarelin；E: after physiological saline
Acute kidney injury (Saline+AKI) group；
Fig. 5 is Hexarelin structural schematic diagram provided by the embodiment of the present invention；
Fig. 6 is Hexarelin molecular docking figure provided by the embodiment of the present invention；
Fig. 7 is that Hexarelin raises the table of SFN in ischemia-reperfusion acute kidney injury provided by the embodiment of the present invention
Up to improvement renal function schematic diagram；
Fig. 8 is that apoptosis promotees after Hexarelin intervention in ischemia-reperfusion acute kidney injury provided by the embodiment of the present invention
It is expressed into gene caspase3 and lowers schematic diagram；
Fig. 9 is that apoptosis promotees after Hexarelin intervention in ischemia-reperfusion acute kidney injury provided by the embodiment of the present invention
It is expressed into gene Bax and lowers schematic diagram；
Figure 10 be the embodiment of the present invention provided by ischemia-reperfusion acute kidney injury Hexarelin intervene after apoptosis
Gene Bad expression is promoted to lower schematic diagram.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
Technical staff's every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The pretreatment of 1 Hexarelin of embodiment
8 week old are chosen, healthy SPF grades of the male SD rat 30 of weight 250-300g is raised in the isolation cage of independent air-feeding
In tool, temperature is controlled in 21 DEG C ± 2 DEG C, and relative humidity is controlled in 50% ± 15%, daily cycle 12h, normal diet.At random
5 groups are divided into, respectively normal group, sham-operation group, acute kidney injury (AKI) group, acute kidney injury (HEX+ after Hexarelin
AKI) acute kidney injury (Saline+AKI) group after group, physiological saline, every group each 6.Administration group and saline control group are big
Mouse models to be started to give drug-treated in a manner of being injected intraperitoneally for first 7 days, according to experimental group, Hex+AKI group and Saline+
AKI group gives Hexarelin (dosage is 100 μ g/kg.d) respectively and isometric physiological saline, Hexarelin dosage determine ginseng
Examine the past experimental study.
Embodiment 2 establishes rat kidney Ischemia-Reperfusion Injury Model
Rat pre-operative anxiety 12h, free water, preoperative weighing, after yellow Jackets (30mg/kg) intraperitoneal injection of anesthesia
Along the positive split shed of abdomen, each layer in abdominal cavity, the kidney base of a fruit on the left of careful separation are successively separated, and is closed with micro-arterial clamp folder, observes kidney
Color moment bleaches, and same operation is taken in opposite side, and blood vessel clip is unclamped after 50min, and kidney becomes red then ischemic again from atropurpureus
It is perfused successfully, layer-by-layer suture closes abdominal cavity, and warming fluid infusion is paid attention in art, restores normal diet after rat revival.It leaves and takes afterwards for 24 hours
Rat kidney tissue and new blood carry out next experiment.Sham-operation (sham) group except not folder close the kidney base of a fruit processing in addition to,
Remaining operation is identical.
The detection of 3 renal function of embodiment
3.1 rat model serum creatinines, urea nitrogen detection
Rat inferior caval vein is collected in serum tube after taking blood, room temperature stand 1h, supercentrifuge with 3000rpm revolving speed from
Heart 15min leaves and takes 200ul upper serum, detects serum creatinine, urea nitrogen in automatic biochemistry analyzer picric acid method.
The detection of 3.2 rat model KIM-1mRNA
3.2.1mRNA extracting
Rat kidney Ischemia-Reperfusion Injury Model is successfully established rear every rat and leaves and takes 10mg left kidney tissue, with
Trizol method extracts total tissue RNA, that is, 1ml Trizol/ sample is added when collecting sample, is fully ground rear every sample and is added 200
μ l chloroform/ml Trizol mixes manually, and in standing 3min on ice, latter 4 DEG C, 12000rpm is centrifuged 15min, carefully draws supernatant
It to being added in the EP pipe of 400 μ l isopropanols, mixing again, stands after 10min 4 DEG C, 12000rpm is centrifuged 10min, supernatant is abandoned,
It is added after addition 75% ethyl alcohol of 1ml/sample washing RNA and RNA is dissolved without enzyme water, and is dense with spectrophotometer detection RNA
Degree.
3.2.2 reverse transcription, real-time fluorescence quantitative PCR
It is carried out according to after TAKARA Reverse Transcriptase kit (RR037a) specification reverse transcription synthesis cDNA by template of cDNA
Real-time fluorescence quantitative PCR detection.Reaction condition are as follows: 95 DEG C of 30s*1 circulations；95 DEG C of 5s, 60 DEG C of 40s, 40* circulation, solubility curve
It is set as 55 DEG C of 30s, 95 DEG C of 30s, the primer sequence used in experiment is as follows:
| Gene | Forward Primer | Reverse Primer |
| β-Actin | TCGACAGTCAGCCGCATCTT | GAGTTAAAAGCAGCCCTGGTG |
| KIM-1 | TCCACACATGTACCAACATCAA | GTCACAGTGCCATTCCAGTC |
Note: data analysis uses 2-△△CTMethod, P < 0.05 think that result is statistically significant.
The results show that compared with Normal group (control), sham-operation group (sham) serum creatinine becomes without obvious such as Fig. 1
Change, and is that acute kidney injury group (AKI) rat serum creatinine significantly increases (P < 0.05) after ischemical reperfusion injury；With physiological saline
Pretreated group (Saline+AKI) compares, and Hexarelin pretreated group acute kidney injury serum creatinine significantly reduces (P < 0.05).
Likewise, as shown in Figure 2,3, compared with Normal group, sham-operation group urea nitrogen, albuminuria molecule -1 (KIM-1) are equal
Without significant change, acute kidney injury group is then significantly increased, and Hexarelin pretreated group is compared with physiological saline pretreated group urea nitrogen
Significant decrease (P < 0,05), KIM-1 level are also substantially reduced, therefore Hexarelin pretreatment can obviously reduce acute kidney injury
Generation.
Embodiment 4HE dyes microscopic observation renal histopathology and changes
After renal tissue is fixed through 4% paraformaldehyde, graded ethanol is dehydrated, dimethylbenzene is transparent and paraffin embedding, with slice
Machine-cut is at 5 μm of slabs.Hematoxylin-eosin (HE) dyeing is carried out after dewaxing, aquation, assesses kidney under microscope after taking pictures
Dirty degree of impairment.Tubular damage is defined as: expansion occurs in renal tubule, brush border disappears, epithelial cell shedding.Every nephridial tissue is cut
Skin marrow intersection selects 5 nonoverlapping high power field of view areas (200 mesh) to carry out shooting and by two professions to piece under the microscope
Kidney internist carries out read tablet.
If Fig. 4 HE coloration result is shown, A: normal group；B: sham-operation (Sham) group, the no significant difference compared with normal group；
C:AKI group, tubular ectasia, brush border are lost, and cast is formed, and cell infiltration, red blood cell diffuse in renal interstitial；D: sea sand is auspicious
Acute kidney injury (HEX+AKI) group after woods, compared with C, E group, tubule dilatation mitigates, and cast is reduced, and cell infiltration area subtracts
Few, renal damage degree is substantially reduced；E: acute kidney injury (Saline+AKI) group after physiological saline pretreatment, with AKI group
No significant difference, to further prove that Hexarelin pretreatment can significantly mitigate the generation of acute kidney injury.
5 bioinformatics molecular docking of embodiment
From PubChem compound database (https: //www.ncbi.nlm.nih.gov/gds/) and SWISS-
Stratifin is obtained respectively in MODEL database (https: //swissmodel.expasy.org/repository/)
The three-dimensional structure of (SFN, 14-3-3 σ) albumen tertiary structure and Hexarelin carries out albumen and sea sand using Autodock software
Molecular docking between Rayleigh calculates, and can be carried out analysis to the combination between gained Hexarelin and selected albumen.As a result
It was found that Hexarelin is stablized with the 14-3-3 σ protein binding encoded by SFN gene, in conjunction with that can be -8.51, as seen in figs. 5-6.
14-3-3- σ is a member in transcription factor 14-3-3 family, can be by interacting with proapoptotic protein BAX, BAD etc.
Regulating cell apoptosis, main mechanism are that BAX can be isolated in the rush apoptosis that BAX is blocked in cytoplasm by 14-3-3 σ
Effect.In addition, can also by with BAD zygotic induction BAD conformational change, to inhibit the apoptosis-promoting effect of BAD.The study find that
SFN expression quantity is significantly raised in acute kidney injury.
6 real-time fluorescence quantitative PCR of embodiment
Rat kidney Ischemia-Reperfusion Injury Model leaves and takes renal tissue after being successfully established, in method pair similar to the above
The expression quantity of SFN is detected.
Used primer is as follows in experiment:
| Gene | Forward Primer | Reverse Primer |
| β-Actin | TCGACAGTCAGCCGCATCTT | GAGTTAAAAGCAGCCCTGGTG |
| SFN | AGGATGAGTTCTGAACGTCGAAA | GGGGAAGTGGCAACTGATGA |
| Caspase3 | GGAGGATGAGTGACGAGTTTGTG | ATCCCACCAGGACTGGAAGAC |
| BAX | TGGCAGCTGACATGTTTTCTG | TCCCGGAGGAAGTCCAATG |
| BAD | TGAGGAAGATGAAGGGATGGA | CGAGGAAGTCCCTTGAAGGAA |
For real-time quantitative PCR the results show that compared with normal group and sham-operation group, acute kidney injury group SFN expression quantity is significant
Rise, and compared with control group, after Hexarelin pretreatment, SFN expression rising is more obvious, as shown in Figure 7.And same control group
It compares, apoptotic proteins Caspase3, rush antiapoptotic factors BAX, BAD significantly reduce (P < 0.05) (as schemed after Hexarelin pretreatment
Shown in 8- Figure 10).
Claims (7)
1. application of the Hexarelin in preparation protection ischemia-reperfusion injury of kidney drug/pharmaceutical composition.
2. application as described in claim 1, which is characterized in that the application is Hexarelin by acting on by SFN gene
The 14-3-3 σ albumen of coding simultaneously increases the expression quantity of 14-3-3 σ albumen significantly to reduce the journey of ischemia-reperfusion injury of kidney
Degree.
3. application as claimed in claim 2, which is characterized in that the application is Hexarelin by significantly increasing 14-3-3 σ
The expression quantity of albumen and then by interacting with proapoptotic protein BAX, BAD come regulating cell apoptosis, is lacked with reducing kidney
The degree of blood reperfusion injury.
4. Hexarelin is in times of use and effect for assessing and quantifying ischemical reperfusion injury and for monitoring drug
Purposes in what program.
5. drug/pharmaceutical composition, which is characterized in that the drug/pharmaceutical composition includes using Hexarelin as sole component
Drug, using Hexarelin as the drug of active pharmaceutical ingredient or containing the pharmaceutical preparations composition of Hexarelin.
6. drug/pharmaceutical composition as claimed in claim 5, which is characterized in that as needed can be acceptable containing drug
Carrier, wherein Hexarelin is as active pharmaceutical ingredient, and shared weight percent can be 0.1-99.9% in the formulation.
7. drug/pharmaceutical composition as claimed in claim 5, which is characterized in that the dosage form of the drug/pharmaceutical composition is selected
From any in tablet, capsule, oral solution, mouth containing agent, granule, electuary, pill, powder, pulvis, solution and injection
It is a kind of.
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Cited By (1)
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| CN112076309A (en) * | 2020-07-27 | 2020-12-15 | 南通大学 | Application of cyclic erythropoietin-derived peptide in kidney injury and cyclosporin A injury protection |
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2019
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| EP1354597A2 (en) * | 2001-01-03 | 2003-10-22 | Centro De Ingenieria Genetica Y Biotecnologia (Cigb) | Pharmaceutical combination for the treatment of tissue damage owing to an arterial irrigation defect |
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| CN112076309A (en) * | 2020-07-27 | 2020-12-15 | 南通大学 | Application of cyclic erythropoietin-derived peptide in kidney injury and cyclosporin A injury protection |
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