CN116870068A - Application of shinyleaf yellowhorn leaf in preparation of medicine for preventing and treating hyperuricemia nephropathy - Google Patents
Application of shinyleaf yellowhorn leaf in preparation of medicine for preventing and treating hyperuricemia nephropathy Download PDFInfo
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- CN116870068A CN116870068A CN202310981674.3A CN202310981674A CN116870068A CN 116870068 A CN116870068 A CN 116870068A CN 202310981674 A CN202310981674 A CN 202310981674A CN 116870068 A CN116870068 A CN 116870068A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
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- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Physical Education & Sports Medicine (AREA)
- Microbiology (AREA)
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- Biotechnology (AREA)
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- Urology & Nephrology (AREA)
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Abstract
The invention relates to application of shinyleaf yellowhorn leaf in preparing a medicament for preventing and treating hyperuricemia nephropathy. The results show that: the shinyleaf yellowhorn leaf can reduce serum uric acid, creatinine, urea nitrogen, liver XOD activity and serum KIM-1 concentration of a rat with hyperuricemia nephropathy, inhibit phosphorylation of PI3K/AKT signal pathway protein PI3K, AKT, mTOR in the kidney of the rat, down regulate uric acid transporter GLUT9 and URAT1 and up regulate ABCG2, down regulate expression of ECM related proteins Collagen I, MMP2 and MMP9, and has the action mechanism that the uric acid transporter is regulated through PI3K/AKT signal pathway to maintain in vivo uric acid balance, improve the fibrosis degree of the kidney and fuse and repair tubular epithelial cell mitochondrial lesions, thereby playing a role in kidney protection.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of shinyleaf yellowhorn leaves in preparation of medicines or health-care products for preventing or treating hyperuricemia and renal injury.
Background
Xanthoceras sorbifolia She Yuanyu xanthoceras sorbifolia BungeXanthoceras sorbifoliumBunge), which was originally found in the "salvage materia medica" (in 1406 of the official unit), is used for treating complications of hyperuricemia and nephropathy such as arteriosclerosis, hyperlipidemia, hypertension, chronic hepatitis and rheumatism. According to the records of Chinese herbal medicine assembly, shinyleaf yellowhorn leaves are sweet in taste and flat, dispel wind-damp and can be used for treating rheumatic arthritis after being decocted into paste. The Chinese medicine 'arthralgia syndrome' includes rheumatic arthritis, and gout is also included in the category. The "Huangdi's internal channel, su and Bi Lun" describes the cause of arthralgia syndrome, i.e., the "cause of arthralgia" due to deficiency of five zang organs. Meanwhile, the "Ji Shi Sheng Fangzhu Bi men-Wu Bi Lun Ji (treating of arthralgia) also discloses that bone arthralgia is a disease, kidney should be treated, its bone should be serious, pain and distention should be caused, and ancient prescriptions emphasize important roles of kidney in the pathogenesis of arthralgia syndrome. The leading cause of gouty arthritis is hyperuricemia, which is the same as hyperuricemia nephropathy, i.e. the pathogenesis of both is similar. Therefore, the pathogenesis of rheumatic arthritis and hyperuricemia nephropathy may accord with the traditional Chinese medicine theory of simultaneous treatment of different diseases.
The shinyleaf yellowhorn leaf is rich in compounds such as quercetin, epicatechin, quercitrin, luteolin, apigenin, rutin and the like, and proved to be capable of treating hyperuricemia, so that a sufficient theoretical basis is provided for prevention and treatment of hyperuricemia nephropathy by the shinyleaf yellowhorn leaf.
Nevertheless, the inhibiting effect of shinyleaf yellowhorn leaf on uric acid and even the protecting effect of shinyleaf yellowhorn leaf on hyperuricemia nephropathy have not been reported yet.
Disclosure of Invention
Application of shinyleaf yellowhorn leaf extract in preparing medicine or health care product for preventing or treating hyperuricemia nephropathy; the hyperuricemia nephropathy comprises tubular interstitial fibrosis, glomerulosclerosis, kidney hypertrophy, proteinuria and the like, and the typical treatment is that the shinyleaf yellowhorn leaf ethanol extract can reduce the fibrosis degree of damaged kidneys.
The shinyleaf yellowhorn leaf is used as the sole component for preparing the medicine or health care product for preventing or treating hyperuricemia nephropathy; the hyperuricemia nephropathy comprises tubular interstitial fibrosis, glomerulosclerosis, kidney hypertrophy, proteinuria and the like, and the typical treatment is that the shinyleaf yellowhorn leaf ethanol extract can reduce the fibrosis degree of damaged kidneys.
The application of shinyleaf yellowhorn leaf in preparing medicine or health product for reducing serum uric acid, creatinine and uric acid nitrogen.
The application of xanthoceras sorbifolia leaf in preparing medicine or health product for reducing liver Xanthine Oxidase (XOD) activity is provided.
The application of shinyleaf yellowhorn leaf in preparing medicine or health product for reducing serum KIM-1 concentration.
Application of shinyleaf yellowhorn leaf in preparing medicine or health product for inhibiting PI3K/AKT signal path phosphorylation.
The application of shinyleaf yellowhorn leaf in preparing medicine or health care product for reducing GLUT9, URAT1, collagen I, MMP2 and MMP9 protein expression is provided.
Application of shinyleaf yellowhorn leaf in preparing medicine or health product for raising ABCG2 protein expression.
Application of shinyleaf yellowhorn leaf in preparing medicine or health product for inhibiting ECM formation is provided.
Application of shinyleaf yellowhorn leaf in preparing medicine or health product for improving intracellular mitochondrial lesions is provided.
The hyperuricemia nephropathy includes tubular interstitial fibrosis (literature support), glomerulosclerosis (literature support), renal hypertrophy (literature support), proteinuria and the like (literature support), and typical treatment refers to reducing the degree of fibrosis of damaged kidneys. The medicine or health product is in the form of oral administration, injection, mucosa administration, transdermal administration, etc. The medicine or health product is tablet, capsule, granule, oral liquid, patch or gel.
In order to deeply discover the medicinal value and action mechanism of the shinyleaf yellowhorn leaf, the inventor uses a liquid chromatography-time-of-flight mass spectrometer to identify the ingredients of the shinyleaf yellowhorn leaf, and predicts the target points of the ingredients and the hyperuricemia nephropathy through network pharmacology, and the result shows that the PI3K/AKT signal path is the main signal path of the shinyleaf yellowhorn leaf for preventing or treating the hyperuricemia nephropathy. The shinyleaf yellowhorn leaf can reduce the serum UA, CRE, BUN and liver XOD activity and serum KIM-1 concentration of the rat with hyperuricemia nephropathy, and has the effect of preventing or treating the hyperuricemia nephropathy. The shinyleaf yellowhorn leaf can down regulate the expression of p-PI3K, p-AKT, p-mTOR, GLUT9, URAT1, collagen I, MMP2 and MMP9 of the kidney of the rat with hyperuricemia nephropathy, and up regulate the expression of ABCG 2. The shinyleaf yellowhorn leaf can regulate uric acid transporter to maintain the in vivo uric acid balance of the rat with hyperuricemia nephropathy through a PI3K/AKT signal channel, improve the fibrosis degree of the kidney, and fuse and repair the mitochondrial lesions of the tubular epithelial cells, thereby playing a role in preventing or treating the hyperuricemia nephropathy. In conclusion, the shinyleaf yellowhorn leaf has great potential in the field of developing medicaments or health-care products for preventing or treating hyperuricemia nephropathy, and is worthy of further research and development.
Drawings
Fig. 1 EX alleviates the HN progression core target PPI network;
figure 2 EX eases molecular docking of HN-progressing core compounds to core target AKT 1;
FIG. 3 effects of EX on HN rat SUA, CRE, BUN, liver XOD, serum KIM-1 changes: in comparison with the normal group, ## ， ### respectively representP<0.01，P<0.001; in comparison with the set of models, * ， ** ， *** respectively representP<0.05，P<0.01，P<0.001; wherein A: effects of EX on HN rat SUA, B: effects of EX on HN rat serum CRE, C: effect of EX on HN rat serum BUN, D: EX effect on HN rat liver XOD, E: influence of EX on HN rat serum KIM-1 changes;
FIG. 4 EX effect on HN rat kidneys ABCG2, URAT1 and GLUT9 (western blot): in comparison with the normal group, # ， ## respectively representP<0.05，P<0.01; in comparison with the set of models, * representation ofP<0.05；
Fig. 5 EX effect on HN rat kidneys ABCG2 and GLUT9 (immunohistochemistry): in comparison with the normal group, ## representation ofP<0.01；In comparison with the set of models, * representation ofP<0.05；
FIG. 6 EX effect on HN rat kidney p-PI3K, p-AKT, p-mTOR: in comparison with the normal group, # ， ## respectively representP<0.05，P<0.01; in comparison with the set of models, * ， *** representation ofP<0.05，P<0.001；
FIG. 7 EX effect on HN rat kidney Collagen I, MMP9 and MMP2 (western blot): in comparison with the normal group, # ， ## ， ### respectively representP<0.05，P<0.01，P<0.001; in comparison with the set of models, * ， ** respectively representP<0.05，P<0.01；
FIG. 8 EX effect on HN rat kidney Collagen I and MMP2 (immunohistochemistry): in comparison with the normal group, ## ， ### respectively representP<0.01，P<0.001; in comparison with the set of models, * ， ** respectively representP<0.05，P<0.01；
Fig. 9 HN rat kidney Masson trichromatic staining and transmission electron microscopy photographs: in comparison with the normal group, ### representation ofP<0.001; in comparison with the set of models, ** respectively representP<0.01; the transmission electron microscope photo is taken by Hitachi HT7700 transmission electron microscope under 13000 times of visual field; wherein A: HN rat kidney Masson trichromatic stained sections, B: HN rat kidney transmission electron microscope photograph.
Detailed Description
The invention is described below by means of specific embodiments. The technical means used in the present invention are methods well known to those skilled in the art unless specifically stated. Further, the embodiments should be construed as illustrative, and not limiting the scope of the invention, which is defined solely by the claims. Various changes or modifications to the materials ingredients and amounts used in these embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The raw materials and reagents used in the invention are all commercially available.
1 identification of the composition of ethanol extract of shinyleaf yellowhorn leaf
1.1 Experimental materials
1.1.1 Experimental reagent
Ethanol (MIEuro chemical reagent Co., ltd.) in Tianjin, methanol, formic acid, and acetonitrile (Siemens technology Co., ltd.).
1.1.2 Experimental instrument
The ultra-high performance liquid chromatography system is combined with a mass spectrometer (AB SCIEX company in the United states), a rotary evaporator (BUCHI company in Switzerland), a one-ten-thousandth balance (Metrehler company in Switzerland), a freeze dryer (Semer Feishmania science and technology Co., ltd.), an SHB-III circulating water type multipurpose vacuum pump (Henan China's Instrument Co., ltd.), an MH-20000 adjustable electric heating jacket (Shanghai Asia Biochemical instruments Co., ltd.), an electronic balance (Shanghai precision science and technology Co., ltd.), a pipettor (Semer Feishmania science and technology Co., ltd.), an ultrapure water system (Semer Feishmania technology Co., ltd.), an electrothermal constant temperature blast drying oven (Shanghai Qiao Feng Co., ltd.), an electrothermal constant temperature water bath pot (Beijing Changan An science and ultrasonic cleaner (Shanghai analysis ultrasonic instruments Co., ltd.).
1.1.3 Xanthoceras sorbifolia leaf sample
The shinyleaf yellowhorn leaf is collected from the red peak city of the inner Mongolian autonomous region 9 in 2020, and is identified as shinyleaf yellowhorn of the soapberry family plant by the professor LihuiXanthoceras sorbifoliumBune).
1.2 Experimental method
1.2.1 Preparation of shinyleaf yellowhorn leaf ethanol extract
Pulverizing dried xanthoceras sorbifolia leaf, sieving with 40 mesh sieve, reflux extracting 1.5kg with 10 times of 70% ethanol water solution for 2 h, and filtering to obtain filtrate. Repeating the above steps for two times, mixing filtrates, vacuum filtering, rotary evaporating under reduced pressure to obtain extract, volatilizing on water bath, and lyophilizing to obtain lyophilized powder.
1.2.2 LC-MS analysis
1.2.2.1 Sample pretreatment
Dissolving the ethanol Extract (EX) of the shinyleaf yellowhorn leaf in methanol, diluting to 2.5 mg/mL, and filtering with a 0.22 μm filter membrane to obtain an EX sample.
1.2.2.2 Chromatographic conditions
The column was a Acquity UPLC HSS T column (100 mm×2.1mm i.d.,1.8 μm particle size, waters, USA) with a dose of 5 μl. Flow rate 0.3 mL/min, chromatographic separation procedure: 0-40 min,5-95% B (A: 0.1% formic acid water; B: acetonitrile).
1.2.2.3 Mass spectrometry conditions
After UPLC separation, the effluent was further examined by X500-R Q-TOF system (AB SCIEX, USA) equipped with a 500℃ESI source. In ESI +/- In the collection mode, the voltage at which the ion spray voltage floats was kept at 5500V, respectively. The scanning range is 100-1500Da. The nebulizer gas, assist gas, and curtain gas pressures were maintained at 50psi, and 30psi, respectively, during the 0.25s integration time during MS acquisition. The declustering voltage (DP) was set to ±80V, and the Collision Energy (CE) was set to ±10V. During the 0.25s accumulation time during TOF MS/MS acquisition, DP was set to 80V and CE was set to 10V. The obtained MS and MS/MS data were analytically characterized by AB Sciex OS software. When the quality deviation number is less than 5 and the forward matching score, the reverse matching score and the integrated score value with the database are all greater than 70, the component is identified.
1.3 Experimental results
The shinyleaf yellowhorn leaves are extracted by 70% ethanol, concentrated and freeze-dried to obtain 330g of dry powder, and the extraction rate is 22%. Samples were analyzed by the X500R QTOF system, a total of 32 chemical components were characterized (table 1).
TABLE 1 LC-MS analysis and identification results
2. Network pharmacology research on treating hyperuricemia nephropathy by shinyleaf yellowhorn leaf ethanol extract
2.1 Network pharmacology research method
2.1.1 Collecting and screening targets of shinyleaf yellowhorn leaf ethanol extract
Target prediction is carried out on the 32 identified chemical components by using a Pharmmap platform, the target prediction quantity is set to be 300, other data are selected to be default values, a UniProt database is utilized, species are limited to be "homosapiens", the target names of the chemical components are converted to be gene names, and repeated targets are removed.
2.1.2 Confirmation of shinyleaf yellowhorn leaf ethanol extract and hyperuricemia kidney disease intersection target
The target information of the diseases is searched and collected in databases such as GeneCards, GEO, TTD, disGeNET, durgbank, OMIM, pharmgkb by taking Hyperuricemia and Hyperuricemia nephropathy as keywords, and the target names of the diseases are converted into gene names by using UniProt and species definition as homosapiens. Drawing a wien diagram of a disease target and a shinyleaf yellowhorn leaf related target through JVEnn.
2.1.3 Kyoto gene and genome encyclopedia (KEGG) pathway enrichment analysis and Gene Ontology (GO) biological function analysis
Inputting the intersection target point of the disease and the shinyleaf yellowhorn leaf into Metascape, selecting 'homo sapiens', running data, respectively performing KEGG and GO analysis, and finally realizing visualization through microbiological message drawing.
2.1.4 Construction of protein-protein interaction (PPI) networks and core target screening
Entering an intersection target point of the disease and shinyleaf yellowhorn leaf components into a STRING database, selecting 'multiple proteins', setting a species 'homo sapiens', and setting the rest as default, constructing a PPI network for deleting free targets, and importing the result into a Cytoscape 3.7.1 for network topology analysis and realizing visualization.
2.1.5 Molecular docking
And selecting a compound with the chemical component, namely the target point and the signal path network with the intermediate value of 10, and carrying out a molecular docking experiment on a core target point AKT1 in the PPI network through AutoDockTools and Pymol software.
2.2 Experimental results
2.2.1 Screening of shinyleaf yellowhorn leaf ethanol extract target points
Target prediction was performed using the Pharmmapper platform according to 32 chemical components in table 1, gene name conversion was performed using Uniprot database, and 425 potential targets were obtained in total by integration and deduplication.
2.2.2 Screening of shinyleaf yellowhorn leaf ethanol extract and hyperuricemia kidney disease intersection target
And searching and collecting targets of related diseases by each large database, merging and de-duplicating, and converting the targets of the diseases into gene names to obtain 5495 potential targets. And drawing a target Wen diagram to obtain 251 intersection targets of 32 chemical component prediction targets and disease targets.
2.2.3 KEGG pathway enrichment analysis and GO biological function analysis
2.2.3.1 KEGG enrichment analysis
A total of 212 KEGG entries were obtained, and after conversion of the LogP value to P value, the KEGG pathways of 20 before the P value were plotted as bar graphs in the microbial message. The results show that the shinyleaf yellowhorn leaf plays a role in preventing or treating Hyperuricemia Nephropathy (HN) and has the main signal paths of hsa05200: pathways in cancer, hsa05205: proteoglycans in cancer, hsa04151:PI3K-Akt signaling pathway, hsa04010: MAPK signaling pathway, hsa04014: ras signaling pathway, hsa 05215:Protate cancer, hsa01522: endocrine resistance, hsa04068: foxO signaling pathway, hsa05208: chemical carcinogenesis-reactive oxygenspecies, hsa04015:rap 1:1 signaling pathway, hsa04926: relaxin signaling pathway, hsa04917: prolactin signaling pathway, hsa04933:AGE-RAGE signaling pathway in diabetic complications, hsa05161:hepatitis B, hsa04915: estrogen signaling pathway, hsa05207: chemical carcinogenesis-receptor activation, hsa01521: EGFR tyrosine kinase inhibitor resistance, hsa04140:autophagy-an, hsa 04510:Focus addition, and hsa05210: colorectal cancer. Component-target-signal pathway visualization analysis was performed by Cytoscape 3.7.1 software, and the network consisted of 303 nodes and 5194 edges. Topology analysis is carried out on the Network by using 'Network analysis', the depth of the relevant node is in direct proportion to the degree value, and the compounds at the first 10 positions of the degree value are linoleic acid, luteolin, procyanidine B2, quercetin, epicatechin (EC), quercetin, liquidus acid, colchicoside, african, betulinic acid respectively.
2.2.3.2 GO analysis
1979 BP entries, 99 CC entries, 218 MF entries are obtained. And drawing a GO analysis bar chart by taking the first 10 bits of target enrichment. The results show that BP is mainly involved in hormone response (response to hormone), cellular response to hormone stimulus (cellular response to hormonestimulus), kinase activity regulation (regulation of kinase activity), positive regulation of phosphorylation (positive regulation of phosphorylation), protein phosphorylation (protein phosphorylation), enzyme-linked receptor protein signaling pathway (enzyme-linked receptor protein signaling pathway), positive regulation of cell migration (positiveregulation of cell migration), positive regulation of cell movement (positive regulation of cell motility), positive regulation of movement (positiveregulation of locomotion), response to bacteria (response to bacterium), etc.; CC is mainly related to the capsule cavity (vesiclelumen), secretory granule cavity (secretory granule lumen), cytoplasmic vesicle cavity (cytoplasmic vesicle lumen), extracellular matrix (extracellular matrix), external encapsulation structure (external encapsulating structure), focal adhesion (focal adhesion), cell matrix junction (cell-subtletjunction), perinuclear region of the cytoplasm (perinuclear region of cytoplasm), fylline-1-rich granule (ficolin-1-rich granule), hormone receptor complex (receptor complex), etc.; MF is mainly associated with kinase activity (kinase activity), phosphotransferase activity, alcohol group receptor (phosphotransferase activity, alcoholgroup as acceptor), protein kinase activity (protein kinase activity), amino acid kinase binding protein (kinase binding), peptidase activity (peptidase activity), protein domain specific binding (proteindomain specific binding), calmodulin binding protein kinase (protein kinase binding), protein homodimer activity (protein homodimerization activity), oxidoreductase (oxidoreductase activity), endopeptidase activity (endopeptidase).
2.2.4 Construction of PPI network and core target screening
Entering the intersection targets (251) into a STRING database, selecting 'multiple proteins', setting the species as 'homosapiens', deleting the free targets, and constructing the PPI network. And directly importing the output data in the tsv format into Cytoscape 3.7.1 software to complete data analysis, wherein the selection of the core target point is based on the size of the scale value, and the condition is more than 2 times of median (figure 1). Wherein the nodes represent proteins (43), each edge represents a protein interaction relationship (652), and the average degree of the nodes is 64.23. The degree value is based on the number of lines connected to each node, and the importance of each node is analyzed on the premise. The node degree value in the visualized picture is represented by color and area, and the larger and deeper the node is, the more important the node is. Targets at the top 10 th position of the degree value are ALB, AKT1, EGFR, SRC, MMP9, HSP90AA1, CASP3, IGF1, HRAS and ESR1 respectively.
2.2.5 Molecular docking experiments
Inhibition of activation of AKT phosphorylation has been reported to reduce renal ECM deposition. Through KEGG enrichment analysis, the PI3K/AKT signal pathway is a key pathway for relieving HN progress of shinyleaf yellowhorn leaves, AKT1 is a core target point of the pathway, the HN process is relieved by high-level ginseng shinyleaf yellowhorn leaves, and the former ten core compounds in a chemical component-target point-signal pathway network are combined and subjected to molecular butt joint verification one by one. The results show that the screened core components have good affinity with AKT 1. Visualization of the docking results was done by Pymol 3.7.3 (fig. 2).
3 research on mechanism of action of shinyleaf yellowhorn leaf ethanol extract on treating hyperuricemia nephropathy
3.1 Experimental materials
3.1.1 Experimental reagent
Potassium oxazinate (Sigma-Aldrich), adenine, allopurinol (Shanghai Michelin Biotechnology Co., ltd.), uric Acid (UA), creatinine (Cr), urea nitrogen (BUN), xanthine Oxidase (XOD) test Kit (Nanjing Biotechnology Industry), rat KIM-1/HAVCR1 ELISA Kit, GLUT9, URAT1, MMP2, MMP9, mTOR, p-mTOR, GAPDH (Wohan Sanying Biotechnology Co., ltd.), p-PI3K p (Cell Signaling Technology), PI3Kp85 (Hangzhou Hua Ann Biotechnology Co., ltd.), collagen I, ABCG2, AKT, p-AKT (Abcam, UK), RIPA buffer, PVDF membrane, BCA protein assay Kit, beyoECL Star (super-sensitive ECL chemiluminescent Kit), horseradish peroxidase-labeled goat anti-rabbit IgG (h+l), horseradish peroxidase-labeled goat anti-mouse IgG (h+l), wash, skimmed milk powder, TEMED (shanghai bi yun biotechnology ltd), reagents markers (sammer femto technology ltd), SDS-PAGE gel preparation Kit, masson trichromatic staining Kit, universal SP detection Kit, TBST (ph 8.0, 10 x), tris-glycine transfer buffer (ph 8.3, 10 x), 5 x Tris-glycine electrophoresis buffer (beijing soyaku technologies ltd).
3.1.2 Experimental instrument
Microplate reader (TECAN, switzerland), vertical electrophoresis apparatus, gel imaging system (Bio-Rad Co., USA), constant temperature shaker (Shanghai know Chu instruments Co., ltd.), transmission electron microscope (Hitachi, japan).
3.1.3 Experimental animal
Male SD rats 24 (180+ -20 g), supplied by Liaoning Changsheng Biotechnology Co., ltd., laboratory animal license number SCXK 2020-0001.
3.2 Experimental method
3.2.1 Grouping and molding drug delivery
Male SD rats were placed in a barrier environment at 25.+ -. 1 ℃ and humidity of 50.+ -. 10% and light/dark cycled for 12 hours. Rats eat and drink water freely. One week after adaptation to the barrier environment, rats were randomly divided into 4 groups, a normal control group (NC), a model group (HN), an allopurinol group (AP, 30 mg/kg/d BW) and a dose group (EX, 3.3 g/kg/d BW), 6 each. Each of the remaining groups was gastrected (i.g) with the exception of the normal group, with a mixed solution of adenine (0.1 g/kg BW) and PO (1.5 g/kg BW) at 8:00 am for 5 consecutive weeks. EX (3.3 g/kg BW) was given to the dosing group, AP (30 mg/kg BW) was given to the positive group, and ddH was given to the NC group and HN group at 18:00 PM each day 2 O. The lavage volume was 10 ml/kg BW. Rats were anesthetized on day 35 of the experiment. Blood sampling of abdominal aorta, separating serum, and separating liver and kidneySeparating on ice plate, fixing part of kidney with 4% paraformaldehyde, and performing Maron trichromatic staining and immunohistochemistry. 1mm is taken 3 Kidneys containing a portion of the renal cortex and the outer medulla were subjected to standardized Transmission Electron Microscopy (TEM). The remaining kidneys and livers were stored in liquid nitrogen for subsequent XOD kit, western blot analysis.
3.2.2 Hyperuricemia nephropathy rat serum UA, CRE, BUN, liver XOD activity and serum KIM-1 assay
The assay was performed according to the procedure of commercial kits.
3.2.3 Rat kidney Western blot analysis of hyperuricemia nephropathy
The kidney tissues were immersed in RIPA buffer, transferred together to ice bath, and subjected to lysis treatment for 30min. The supernatant was collected by centrifugation at 13500r/min for 15 minutes at 4 ℃. The BCA kit was used to determine the concentration of each treated kidney tissue protein.
Various concentrations of the required separation gel and concentration gel were prepared according to the instructions of the SDS-PAGE kit. Protein samples were added to the wells and 3.5 μl markers were added to each outer well for labeling. Placing the gel plate added with the sample into an electrophoresis apparatus, concentrating gel at 55V for 30min to enable the protein to be positioned at the top of the separation gel boundary, and adjusting voltage to 75V to enable the protein to run to the bottom of the separation gel.
The electrophoresis was stopped and the gel was cut to a suitable size. Spreading the soaked sponge and filter paper on a black panel of an electric transfer jacket, placing the sponge on the lower filter paper, and placing the gel on the filter paper. Firstly, cutting a PVDF film into gel size by scissors, then putting the PVDF film into methanol for shaking for 1min for activation, finally taking out the film, covering the film on the gel, then spreading filter paper and sponge, and finally clamping an electric transfer jacket, wherein the whole process needs to keep the infiltration of transfer film liquid, and drying or bubble generation is avoided.
The electrotransfer nip was placed in a transfer tank and the transfer tank was placed in a water bath with ice added, the voltage was kept constant at 75V and the transfer time was 2 hours. In room temperature environment, the cut PVDF film is soaked in 5% skimmed milk powder and sealed on a horizontal shaker for 1 hour.
The blocked PVDF membrane is washed by TBST to remove the milk powder particles. PVDF was cut into appropriate bands according to the size of the target protein, placed in primary antibodies and incubated overnight at 4 ℃.
The next day, TBST was used to wash the membrane 3 times for 10min each. PVDF membranes were placed in the corresponding secondary antibody solutions and incubated for 1 hour at 37 ℃. The membrane was washed 3 times with TBST, each wash lasting 10min.
The strips were developed by dropping ECL luminophoric solution and developed using a Bio-Rad gel imaging system. Drops were developed using ECL luminophores to the corresponding positions of the strips and accurate gel photographs were taken by a Bio-Rad gel imaging system.
3.2.4 Renal transmission electron microscope analysis of hyperuricemia nephropathy rat
The sample volume of each group was about 1mm 3 Comprises a portion of the renal cortex and the outer medulla, and is washed with PBS until no blood stain is present. The samples were transferred to EP tubes containing 2.5% glutaraldehyde and left to stand overnight at 4 ℃. The next day, the fixed tissue was washed 3 times with PBS for 5 minutes each. The tissue was then transferred to 1% osmium tetroxide for another 2 hours and finally the fixed tissue was washed 3 times with PBS for 10 minutes each. Dehydrating by using ethanol and acetone with gradient concentration, and infiltrating and embedding the tissue by using Epon 812 embedding liquid; and preparing ultrathin slices by using an ultrathin slicer, respectively adopting uranyl acetate and lead citrate double-dyeing, and finally observing and photographing by using a transmission electron microscope.
3.2.5 Rat kidney masson trichromatic staining for hyperuricemia nephropathy
The sections were conventionally dewaxed to water. The Weigert iron hematoxylin staining solution was stained at 37℃for 5min.
The acid ethanol differentiated solution is differentiated for 5-15s and washed with water. Masson's bluing dye solution was allowed to act for 5min and then washed with distilled water for 1min. The ponceau dyeing liquid is dyed for 5-10min. Washing with weak acid for 1min (ratio of weak acid to distilled water 1:2). The sections were washed with phosphomolybdic acid for 2min. Washing with weak acid for 1min. The sections were stained in aniline blue staining solution for 2min. Then, the mixture was washed in a weak acid solution for 1min. Quick dehydration treatment is carried out, and the materials are soaked in 95% ethanol for 3s and then soaked in absolute ethanol for 5s (3 times). The sample was immersed in xylene for 2min for transparency treatment and repeated 3 times, with a neutral resin seal. The images were observed and photographed using a Nikon CI-S microscope.
3.2.6 Rat kidney immunohistochemical analysis of hyperuricemia nephropathy
The sections were dewaxed conventionally to water (tertiary xylenes, tertiary ethanol). Inactivation of endogenous enzymes requires the use of 3% H at room temperature 2 O 2 Soaking for 5min. After which it was washed 3 times with distilled water. The slices after the inactivation treatment are completely placed in a 0.01mol/L sodium citrate buffer solution (PH 6.0), the electric furnace is automatically powered off after the temperature reaches 100 ℃, and the heating is continued after the setting for 10min by using a timer, and the process is repeated for 3 times. Then, after waiting for the temperature of the sections to decrease, the sections were washed 2 times with PBS (pH 7.2-7.6). And dripping the sealing liquid at room temperature for 20min. And (5) removing redundant liquid. GLUT9 (1:500), ABCG2 (1:400), collagen I (1:500) and MMP2 (1:100) were diluted in proportion with the dilution. The primary antibody was added dropwise to the sample and placed in an incubator at constant temperature of 4℃overnight. Then washed 3 times with PBS (pH 7.4) for 2min each. The secondary antibody was added dropwise to the sample and incubated at 37 ℃ for 30min. PBS (pH 7.4) was washed 3 times/2 min. streptavidin-POD was added dropwise at 37℃for 30min. PBS (pH 7.4) was washed 4 times/5 min. DAB color development liquid is dripped at room temperature, the duration of the reaction system is controlled under a mirror, and the optimal color development time range is 5-30 minutes. The reaction was then stopped by washing with distilled water. Counterstaining with hematoxylin, slicing, dewatering, transparent treating and sealing. Finally, nikon CI-S microscopy was used for observation and photographing.
3.2.7 Statistical analysis
The experimental data are processed by using GraphPadprism 8.0.2 software through Image J software analysis, and differences among groups are compared by using T test or single factor variance analysis, so that the result is statistically significantP<0.05). Data are presented as mean ± standard deviation, each sample being independently subjected to 3 replicates.
3.3 Experimental results
3.3.1 Effect of shinyleaf yellowhorn leaf ethanol extract on HN rat serum UA, CRE, BUN, liver XOD Activity and serum KIM-1 concentration
As shown in fig. 3A, the SUA level of HN group significantly increased compared to NC groupHigh%P<0.01 AP and EX treatment significantly reduced SUA levelsP<0.01). CRE and BUN are also important indicators reflecting kidney damage. The CRE and BUN levels of HN group are obviously increasedP<0.001, fig. 3B-C). AP and EX treatment obviously inhibits the rise of CRE and BUN of HN ratsP<0.05 orP<0.01 EX is shown to be effective in ameliorating kidney injury in HN rats, which acts similarly to AP. The key enzyme XOD is closely related to the production of UA. As shown in FIG. 3D, the level of XOD in the liver of HN group was significantly increased as compared to the control group [ ]P<0.001). AP and EX can obviously reduce the level of XOD in liverP<0.001 Indicating that the effect of shinyleaf yellowhorn leaf in reducing SUA is closely related to the inhibition of XOD activity. KIM-1 can rapidly and accurately reflect the injury and recovery process of various kidney diseases, and is an important detection index of early kidney injury, as shown in figure 3E, compared with NC group, HN group serum KIM-1 level is obviously increasedP<0.001 AP and EX treatment significantly reduced the level of KIM-1 in serumP<0.05 Indicated that shinyleaf yellowhorn leaf can alleviate the kidney injury degree caused by hyperuricemia, and the kidney injury is mainly represented by tubular interstitial fibrosis.
Table 2 EX effects on HN rat SUA, CRE, BUN, liver XOD, serum KIM-1 changes (n=6,' x.+ -. S)
Note that: ## ， ### respectively represent the significance compared with the normal groupP<0.01，P<0.001； * ， ** ， *** Respectively represent the significance compared with HN groupP<0.05，P<0.01，P<0.001。
3.3.2 Effect of shinyleaf yellowhorn leaf ethanol extract on HN rat kidney uric acid transporter GLUT9, URAT1 and ABCG2
As shown in FIG. 4, the expression levels of UTAT1 and GLUT9 were significantly increased in HN group rats compared to NC group ratsP<0.01，P<0.05 AP and EX treatment significantly reduced protein expression of UTAT1 and GLUT9P<0.05 ABCG2 in HN rat kidneyExpression in viscera is obviously reducedP<0.01 AP and EX treatment significantly increased ABCG2 expression @P<0.05). Meanwhile, as shown in fig. 5, the immunohistochemical experiment proves that compared with the NC group rats, the area of the positive region expressed by the GLUT9 of the kidney of the HN group rats is obviously increased [ ]P<0.01 AP and EX treatment both significantly reduced the positive area of GLUT9 expressionP<0.05 The positive area of the expression of ABCG2 in HN rat kidney is obviously reducedP<0.01 AP and EX treatment significantly increased positive area for ABCG2 expressionP<0.05)。
3.3.3 Effect of shinyleaf yellowhorn leaf ethanol extract on HN rat kidney PI3K/AKT signaling pathway
As shown in FIG. 6, compared with the NC group rats, the HN group rats have significantly increased expression levels of p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTORP<0.01，P<0.05，P<0.05 AP treatment significantly reduced p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR protein expressionP<0.05，P<0.001，P<0.05 EX treatment significantly reduces expression of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR expression levelsP<0.05)。
3.3.4 Influence of ethanol extract of shinyleaf yellowhorn leaf on HN rat kidney fibrosis degree
As shown in FIG. 7, the expression levels of Collagen I, MMP9 and MMP2 in the kidney of HN group rats are obviously increased compared with that of NC groupP<0.001，P<0.01，P<0.05 AP treatment significantly reduced protein expression of Collagen I, MMP9, MMP2P<0.05 EX treatment can also obviously reduce protein expression of Collagen I, MMP9 and MMP2P<0.01，P<0.05，P<0.05). Meanwhile, as shown in FIG. 8, the immunohistochemical experiment proves that compared with the NC group rats, the area of the positive region expressed by the kidney Collagen I of the HN group rats is obviously increased [ ], the area of the positive region expressed by the kidney Collagen I of the HN group rats is obviously increasedP<0.01 AP and EX treatment both significantly reduced positive area of Collagen I expressionP<0.05 The positive area of MMP2 expressed in HN rat kidney is obviously increasedP<0.001 AP and EX treatment significantly inhibited MMP2 expressionP<0.05，P<0.01). Trichromatic staining of masson showed (fig. 9A), kidney presence in HN ratsECM protein deposition and severe renal interstitial fibrosis improved by EX treatmentP<0.01 While AP treatment has a trend of improvement, but has no statistical significance drivingup-P>0.05). As shown in fig. 9B, the morphology of the tubular epithelial cells of NC group was complete, the nucleus was clearly visible, the plasma membrane bulge structure was complete, the mitochondria were abundant, the mitochondrial cristae was clear, and the basement membrane was complete. The HN group can be seen to have unclear renal tubular epithelial cell nuclear membrane structure, the plasma membrane bulge is dissolved and shed, a large amount of lysosomes can be seen in cells, mitochondria are swollen, and the basement membrane is thickened. The epithelial cells of the renal tubules of the AP group are complete in morphology, the nuclei are clearly visible, and the nuclei are slightly swollen, the cristae is broken, the vacuoles are renatured and the endoplasmic reticulum is expanded. The tubular epithelial cells of the EX group have complete morphology, and slightly drop plasma membranes and swell mitochondria, and compared with the HN group, the mitochondrial morphology is obviously improved. These results indicate that mitochondrial homeostasis of HN rat tubular epithelial cells can be maintained following AP and EX intervention.
4. Discussion of the invention
HN is a kidney disease caused by hyperuricemia-induced tubular interstitial fibrosis, ultimately leading to end-stage kidney disease. Although people pay more attention to hyperuricemia, the corresponding research on HN is rare, and the corresponding therapeutic drugs are only symptomatic drugs of HUA. Our studies found that shinyleaf yellowhorn leaf prevention or treatment of HN is a multi-target, multi-pathway complex process and determined that PI3K/AKT signaling pathway might be a key signaling pathway for shinyleaf yellowhorn leaf prevention or treatment of HN. And it is clear that AKT1 is a core target of shinyleaf yellowhorn leaf for relieving HN progression, and AKT expression is related to kidney diseases, and inhibiting AKT phosphorylation can relieve ECM process. Accordingly, we selected the top ten compounds of the "drug-target-pathway" network with linoleic acid, luteolin, procyanidin B2, quercetin, epicatechin (EC), quercitrin, lulutaric acid, colchicoside, aftoside, betulinic acid for molecular docking with the core target AKT 1. The results show that AKT1 and the compounds have better binding capacity, which indicates that the shinyleaf yellowhorn leaf cooperates with each active ingredient to act on a core target point in the process of preventing or treating HN, so that the activation of PI3K/AKT signal channels is limited to regulate and control the expression of HN related proteins.
The PI3K/AKT signal path is mainly involved in the regulation and control of the processes of cell proliferation, differentiation, apoptosis and the like. Upon extracellular stimulation, PI3K phosphorylates phosphatidylinositol 4, 5-biphosphate (PIP 2) to phosphatidylinositol 3,4, 5-triphosphate (PIP 3). PIP3 produced further induces translocation of AKT plasma membrane and activates AKT under catalysis of phosphoinositide dependent kinase-1 (PDK 1). AKT after activation acts by modulating downstream signaling molecules such as mTOR. Gao Tangshui is reported to induce the production of activated AKT by rat kidney cells NRK-52E and phosphorylate mTOR, and to participate in the epithelial-to-mesenchymal transition (EMT) of NRK-52E cells, exacerbating kidney fibrosis. The metabolic process of UA in vivo includes four steps of filtration, resorption, secretion and post-secretory resorption. In addition to the filtration without the involvement of a transporter, other metabolic processes of UA require the action of a UA transporter. GLUT9 and URAT1 play an important role in UA reabsorption, and inhibition of GLUT9 and URAT1 activity may be effective in inhibiting UA reabsorption. Deletion of ABCG2 has been reported to result in an increase in SUA concentration. Prolonged UA contact causes damage to HK-2 cells, stimulates kidney fibroblasts to produce excess extracellular matrix (ECM) protein, and activates PI3K/AKT signaling pathways to mediate GLUT9 and URAT1 overexpression, exacerbating UA reabsorption, ultimately leading to HN. The PI3K/AKT signaling pathway is thought to be a coactive pathway for a variety of fibrogenic factors. Once this pathway is activated, overexpression of ECM modifications, such as Collagen I and MMP 2/9, etc., will be promoted, leading to an exacerbation of tubular interstitial fibrosis, ultimately leading to end stage renal disease.
To better understand the effect of shinyleaf yellowhorn leaf, we established a mouse HUA model by injecting PO intraperitoneally at a dose of 300 mg/kg BW, and the effective dose of EX to treat HUA was determined by the biochemical index of HUA. Then, an HN rat model is constructed by adenine (0.1 g/kg BW) and PO (15 g/kg BW) combined lavage, and a body surface conversion formula is adopted to determine that the EX lavage dosage of the rat is 3.3g/kg BW. Following drug intervention in the HN rat model, EX was found to significantly reduce SUA by inhibiting XOD activity in the liver and blocking purine metabolism, similar to the effect of XOD inhibitor AP. CRE, BUN and KIM-1 are important biomarkers of kidney function. Both AP and EX interventions can down regulate the expression of HN rat kidney injury biomarkers, confirming that EX and AP can play a certain kidney protection role while controlling SUA level.
The subject study showed that the phosphorylation level of PI3K, AKT and mTOR protein was up-regulated in HN rat kidney, suggesting that PI3K/AKT signaling pathway is activated. Meanwhile, uric acid transporter GLUT9 and URAT1 mediated by PI3K/AKT signal channels are over-expressed, and the expression of ABCG2 is down-regulated, so that the accumulation of UA in HN rats is aggravated. Whereas EX and AP intervention can down-regulate PI3K, AKT and mTOR protein phosphorylation levels, reduce URAT1 and GLUT9 protein expression, and up-regulate ABCG2 protein expression. The EX and the AP can regulate and control the HN rat kidney ABCG2 pathway to increase UA transportation and GLUT9 and URAT1 pathways to inhibit UA resorption by inhibiting the activation degree of PI3K/AKT signal pathway, thereby promoting UA excretion and further reducing SUA level. PI3K/AKT signaling pathways are associated with the progression of a variety of kidney diseases, limiting activation of the pathway core protein AKT can reduce the extent of tubular epithelial cell EMT, reduce ECM protein deposition, and alleviate various kidney diseases caused by fibrosis. Accordingly, we demonstrate through Western blot, immunohistochemistry and masson trichromatic staining that Collagen formation and ECM protein deposition can be reduced by downregulating expression of Collagen I, MMP2 and MMP9 in HN rat kidney after EX intervention, which indicates that shinyleaf yellowhorn leaf ethanol extract can reduce kidney fibrosis degree, thereby playing a role in kidney protection. In addition to maintaining cellular energy supply, mitochondria play a role in other ways. The mitochondria content in the kidneys is very high, next to the heart. Thus, mitochondrial dysfunction will also lead to exacerbation of kidney fibrosis. In transmission electron microscopy of HN rat kidney, we found that large amounts of lysosomes were visible in HN rat tubular epithelial cells with severe mitochondrial swelling, mitochondrial cristae disappearance, etc. pathological changes. After EX and AP intervention, the morphology of the tubular epithelial cells is restored to be complete, and the pathological changes such as mitochondrial swelling and the like are obviously improved. The EX is suggested to be capable of relieving part of mitochondrial pathological changes and converting into fusion repair, so that the effect of relieving HN progression is achieved. Network pharmacology and in vivo experiments prove that the shinyleaf yellowhorn leaves limit the activation of the shinyleaf yellowhorn leaves through targeting PI3K/AKT signal channels, so that the expression of HN related proteins is effectively regulated and controlled, and the kidney protection effect of the shinyleaf yellowhorn leaves is exerted.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While those obvious variations or modifications which come within the spirit of the invention remain within the scope of the invention.
Claims (2)
1. Application of shinyleaf yellowhorn leaf extract in preparing medicine or health care product for preventing or treating hyperuricemia nephropathy; the hyperuricemia nephropathy includes tubular interstitial fibrosis, glomerular hyperfiltration or early stage of renal hypertrophy or glomerulosclerosis.
2. The shinyleaf yellowhorn leaf is used as the sole component for preparing the medicine or health care product for preventing or treating hyperuricemia nephropathy; the hyperuricemia nephropathy includes tubular interstitial fibrosis, glomerular hyperfiltration or early stage of renal hypertrophy or glomerulosclerosis.
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