CN115252631A - Application of pseudo-ginseng extract in preparation of medicine for treating diabetic nephropathy - Google Patents
Application of pseudo-ginseng extract in preparation of medicine for treating diabetic nephropathy Download PDFInfo
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- CN115252631A CN115252631A CN202210725233.2A CN202210725233A CN115252631A CN 115252631 A CN115252631 A CN 115252631A CN 202210725233 A CN202210725233 A CN 202210725233A CN 115252631 A CN115252631 A CN 115252631A
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- notoginsenoside
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- diabetic nephropathy
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Abstract
The invention relates to the application of notoginseng extract in preparing medicine for treating diabetic nephropathy; the notoginsenoside Fc can improve proteinuria and renal histopathology, reduce renal tubular cell apoptosis, regulate the expression of PTEN/PDK1/Akt/mTOR pathway protein to reduce DN glomerulus and mitochondrial injury, reduce the generation of mitochondrial superoxide and reduce the loss of mitochondrial membrane potential; notoginsenoside Ft1 can improve insulin resistance, reduce the expression of insulin receptor signal pathway proteins p-IRS1/2, p-AKT and p-ERK1/2, can reduce the protein expression of AGO-1 in kidney tissues of two diabetic nephropathy model mice, inhibit insulin resistance by regulating AGO-1/TSP-1 pathway, improve metabolism and reduce DN kidney injury; notoginsenoside Fc and notoginsenoside Ft1 can be used for preparing medicine for treating diabetic nephropathy.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to application of a pseudo-ginseng extract in preparing a medicament for treating diabetic nephropathy.
Background
Diabetes is one of the most common chronic diseases in the world, and places a heavy burden on the whole society. Statistically, the prevalence of diabetes in the 20-79 year old population is about 10.5% (5.366 hundred million) in 2021, and increases to 12.2% (7.832 hundred million) by 2045 years. Diabetic Nephropathy (DN) is one of the common microvascular complications of Diabetes Mellitus (DM), and is also a main cause of Chronic Kidney Disease (CKD), and its progress to End-Stage Kidney Disease (ESRD) often occurs, and patients can only carry out dialysis treatment, which not only causes the pain of patients' bodies and soul, but also causes serious economic and social burden, and is one of the major public health problems at present. With the increasing incidence and prevalence of DN, the proportion of chronic kidney diseases associated with diabetes has exceeded the proportion of chronic kidney diseases associated with glomerulonephritis, and blood glucose and blood pressure management remains the main therapeutic strategy according to the KDIGO 2020 clinical practice guidelines, however, current DN treatment methods do not completely prevent disease progression, and therefore, the search for methods that effectively delay DN progression is imminent.
Pseudo-ginseng (Panax notoginseng) is a piece of treasure in traditional Chinese medicine, belongs to araliaceae herbaceous plants, and is recorded in Yu Long Yao Jie, the pseudo-ginseng has the effects of promoting blood circulation and removing blood stasis, and relieving swelling and pain, and can effectively relieve the symptoms of blood stasis; researches show that the active ingredients of pseudo-ginseng are mostly saponin substances, wherein the total Saponins (PNS) of pseudo-ginseng are the main ingredients in the saponin substances; however, the research on the prevention and treatment of DN by panax notoginseng is very little, and the action mechanism of panax notoginseng is not completely clear.
Therefore, the research on the effect of the panax notoginseng extract on diabetic nephropathy and the application of the panax notoginseng extract in preparing the medicine for treating diabetic nephropathy are urgently needed.
Disclosure of Invention
The invention aims to provide the application of a pseudo-ginseng extract in preparing a medicament for treating diabetic nephropathy, aiming at the defects in the prior art.
In order to achieve the purpose, the invention adopts the technical scheme that:
provides the application of the notoginseng extract in preparing the medicine for treating diabetic nephropathy.
Preferably, the notoginseng extract is notoginsenoside.
More preferably, the notoginsenoside is notoginsenoside Fc or/and notoginsenoside Ft1.
More preferably, the notoginsenoside Fc has a molecular formula of C58H98O26。
Preferably, the notoginsenoside Fc can reduce the level of tubular cell apoptosis.
Preferably, the notoginsenoside Fc can reduce the level of oxidative stress of HK-2 cells.
Preferably, the notoginsenoside Fc can improve the mitochondrial function of HK-2 cells.
Preferably, the notoginsenoside Fc delays the progression of diabetic nephropathy by improving renal function and structural abnormalities.
More preferably, the notoginsenoside Ft1 has a molecular formula of C47H80O17And a molecular weight of 917.13.
Preferably, the notoginsenoside Ft1 can reduce the expression level of AGO-1 in kidney tissues of DN mice.
Preferably, the notoginsenoside Ft1 improves insulin resistance in db/db mice.
Preferably, the notoginsenoside Ft1 improves high fat diet + streptozotocin (HFD/STZ) mouse insulin resistance.
Preferably, the notoginsenoside Ft1 improves the abnormal kidney function and structure of db/db mice and delays the progression of diabetic nephropathy.
Preferably, the notoginsenoside Ft1 improves the abnormal kidney function and structure of HFD/STZ mice and delays the progression of diabetic nephropathy.
Preferably, the medicament for treating diabetic nephropathy further comprises: one or more pharmaceutically acceptable adjuvants.
Preferably, the dosage form of the medicament for treating diabetic nephropathy comprises: decoction, pill, powder, paste, pellet, medicated wine, granule, oral liquid, capsule, tablet or injection.
Preferably, the administration route of the medicament for treating diabetic nephropathy comprises: oral administration, sublingual administration, intramuscular or subcutaneous administration or intravenous administration.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
in-vivo experiments are carried out on db/db mice and a diabetes and nephropathy model induced by high-fat diet and Streptozotocin (STZ), and the treatment effects of notoginsenoside Fc and notoginsenoside Ft1 on diabetes and nephropathy are discussed; the notoginsenoside Fc can improve proteinuria and renal histopathology, reduce renal tubular cell apoptosis, regulate the expression of PTEN/PDK1/Akt/mTOR pathway protein to reduce DN glomerulus and mitochondrial injury, and in vitro research further proves that the notoginsenoside Fc can reduce the generation of mitochondrial superoxide and reduce the loss of Mitochondrial Membrane Potential (MMP); notoginsenoside Ft1 can improve insulin resistance, reduce the expression of insulin receptor signal pathway proteins p-IRS1/2, p-AKT and p-ERK1/2, can down-regulate the protein expression of AGO-1 in kidney tissues of two diabetic nephropathy model mice, inhibit insulin resistance by regulating an AGO-1/TSP-1 pathway, improve metabolism and reduce DN kidney injury; notoginsenoside Fc and notoginsenoside Ft1 can be used for preparing medicine for treating diabetic nephropathy.
Drawings
FIG. 1 is a graph showing the effect of notoginsenoside Fc on the biochemical indicators of blood and urine of diabetic mice in example 1 of the present invention; wherein, FIG. 1A is a graph of a statistical analysis of urinary albumin/creatinine ratio (ACR) levels after 8 weeks of treatment; FIG. 1B is a graph of a statistical analysis of Blood Urea Nitrogen (BUN) levels after 8 weeks of treatment; FIG. 1C is a graph of statistical analysis of kidney weight to body weight ratio (KW/BW) levels after 8 weeks of treatment;
FIG. 2 is the effect of notoginsenoside Fc on kidney morphology in diabetic mice in example 1 of the present invention; wherein, fig. 2A is an HE staining picture of kidney tissues of each group of mice; FIG. 2B is a photograph of immunohistochemical staining of podocyte nephropathy protein (Nephrin) in kidney tissue of each group of mice; FIG. 2C is a semi-quantitative analysis of the change in Nephrin expression;
FIG. 3 shows the effect of notoginsenoside Fc on apoptosis in diabetic mouse podocyte in example 1 of the present invention; wherein, FIG. 3A is the Normal (Normal) group; FIG. 3B is a Model (Model) set; fig. 3C is the Losartan (Losartan) treatment group; fig. 3D is a Notoginsenoside Fc (notogenoside Fc) treatment group;
FIG. 4 is a fluorescent image of the mitochondrial ROS level of HK-2 cells in example 1 of the present invention;
FIG. 5 is a fluorescence image of the mitochondrial membrane potential level of HK-2 cells in example 1 of the present invention;
FIG. 6 shows the effect of notoginsenoside Fc in regulating PTEN/PDK1/Akt/mTOR signaling pathway in diabetic mice in example 1; wherein, FIG. 6A is an immunohistochemical staining picture of PTEN, PDK1, p-AKT and p-mTOR; FIG. 6B is a graph of the results of a semi-quantitative analysis of immunohistochemistry for PTEN; FIG. 6C is a graph showing the results of a semi-quantitative analysis of immunohistochemistry for PDK 1; FIG. 6D is a graph showing the results of a semi-quantitative analysis of immunohistochemistry for p-AKT; FIG. 6E is a graph showing the results of semi-quantitative analysis of immunohistochemistry for p-mTOR;
FIG. 7 is a graph showing the results of high AGO-1 expression in kidney tissues of diabetic mice in example 2 of the present invention; wherein, FIG. 7A shows the expression of AGO-1 protein; FIG. 7B is a semi-quantitative analysis of the expression of the AGO-1 protein in db/m and db/db mice; FIG. 7C is a semi-quantitative analysis of the AGO-1 protein expression of HFD/STZ mice; FIG. 7D is a photograph of immunohistochemical staining of AGO-1 protein;
FIG. 8 shows that notoginsenoside Ft1 significantly reduces the expression of AGO-1 in diabetic mouse kidney tissue in example 2 of the present invention; wherein, FIG. 8A shows the expression of AGO-1 protein; FIG. 8B is a photograph of immunohistochemical staining of AGO-1 protein;
FIG. 9 shows that notoginsenoside Ft1 improves insulin resistance in db/db mice in example 2 of the present invention; wherein, FIG. 9A is IPGTT levels; FIG. 9B is IPITT level; FIG. 9C is a graph comparing IPGTT-AUC for various groups of mice; FIG. 9D is a graph comparing IPITT-AUC for each group of mice; FIG. 9E is a graph comparing blood glucose levels in db/db groups of mice; FIG. 9F is a PAS staining picture; FIG. 9G is a Western blot image of TSP-1 protein expression; FIG. 9H is a Western blot image of p-IRS-1, p-ERK1/2, and p-AKT protein expression;
FIG. 10 shows that notoginsenoside Ft1 improves insulin resistance in HFD/STZ mice in example 2 of the present invention; wherein, FIG. 10A is IPGTT levels; FIG. 10B is the IPITT level; FIG. 10C is a graph comparing IPGTT-AUC for various groups of mice; FIG. 10D is a graph comparing IPITT-AUC for various groups of mice; FIG. 10E is a graph showing a comparison of blood glucose levels in STZ + HFD groups; FIG. 10F is a Western blot image of p-IRS-1, p-ERK1/2, and p-AKT protein expression;
FIG. 11 shows that notoginsenoside Ft1 improves kidney injury in db/db mice in example 2 of the present invention; wherein, figure 11A is ACR levels after 8 weeks of treatment; figure 11B is the blood urea nitrogen level after 8 weeks of treatment; figure 11C is the 24 hour urine volume level after 8 weeks of treatment; FIG. 11D is kidney weight to body weight ratio (KW/BW) levels after 8 weeks of treatment; FIG. 11E is an HE, masson stain image; FIG. 11F is an electron microscope image; FIG. 11G is a Western blot image of fibrosis-associated proteins α -SMA, vimentin;
figure 12A is ACR levels after 8 weeks of treatment in example 2 of the invention; figure 12B is blood urea nitrogen levels after 8 weeks of treatment; figure 12C is the 24 hour urine volume level after 8 weeks of treatment; figure 12D is kidney weight to body weight ratio (KW/BW) levels after 8 weeks of treatment.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive efforts based on the embodiments of the present invention, shall fall within the scope of protection of the present invention.
It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The invention is further described with reference to the following drawings and specific examples, which are not intended to be limiting.
Example 1
The embodiment provides application of notoginsenoside Fc in preparing a medicament for treating diabetic nephropathy.
1. Experimental materials and methods
1.1 preparation of the drug
Notoginsenoside Fc (HPLC purity more than 98%) was purchased from Anhui Jingke Co., ltd (Shanghai, china); losartan is available from merck; in animal experiments, the notoginsenoside Fc and the losartan are suspended in 0.5 percent methylcellulose solution and are administrated by intragastric administration; in cell experiments, notoginsenoside Fc is dissolved in DMSO to prepare mother liquor, and human renal proximal tubule epithelial cells (HK-2) are treated by diluting with culture medium.
1.2 animal experiments
The db/db mouse used in this example was purchased from an animal house of the sixth national hospital affiliated with Shanghai transportation university; experiments and operations thereof are in accordance with the regulations on the animal management for national laboratory and the rules on the implementation of the animal management for medical laboratory, and are approved by the animal ethics committee of the sixth national hospital affiliated to Shanghai university of transportation; male db/db diabetic mice (C57 BLKS/J-LepRdb/LepRdb) and littermate male db/m wild-type mice (C57 BLKS/J-LepRdb/+) 6 weeks old; 15 db/db mice and 5 db/m mice are raised in an SPF environment at a temperature of 18-29 ℃ and a relative humidity of 40-70%, and are given standard clean diet and water;
db/m mice were considered as a control group (Con), and db/db mice were randomly divided into 5 groups:
(1) Model group: gavage with an equal volume of 0.5% sodium carboxymethylcellulose solution;
(2) Losartan group (Losartan): after the losartan is suspended in 0.5 percent sodium carboxymethylcellulose solution, the losartan is intragastrically infused according to the dose of 10 mg/kg/d;
(3) Notoginsenoside Fc low dose group: suspending notoginsenoside Fc in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 2.5 mg/kg/d;
(4) Notoginsenoside Fc medium dose groups: suspending notoginsenoside Fc in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 5 mg/kg/d;
(3) Notoginsenoside Fc high dose group: suspending notoginsenoside Fc in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 10 mg/kg/d;
body weight was monitored weekly and dosed according to the above schedule for 8 weeks.
1.3 urine and blood Biochemical index detection
Collecting urine from the metabolism cage, centrifuging the urine at 3500rpm at 4 deg.C for 15 min, and measuring urine albumin and urine creatinine in urine supernatant with a full-automatic biochemical analyzer; calculating urinary albumin excretion using urinary albumin/creatinine ratio (ACR);
blood was collected from abdominal aorta, allowed to stand for 30 minutes or more, centrifuged at 3500rpm at 4 ℃ for 15 minutes, and blood Glucose (GLU) and Blood Urea Nitrogen (BUN) of blood supernatant were measured with a fully automatic biochemical analyzer.
1.4 pathological examination of Kidney tissue
Staining 4 μm sections of paraffin-embedded kidney tissue with Hematoxylin and Eosin (HE), drying at 65 ℃ for 30 minutes, and then deparaffinizing with xylene 2 times for 10 minutes each; rehydrating with 100% ethanol (I), 100% ethanol (II), 95% ethanol, 90% ethanol, 80% ethanol and deionized water sequentially for 10 min each time, and finally staining the slices with HE solution.
1.5 immunohistochemical detection
Immunohistochemical detection was performed on 4 μm paraffin-embedded kidney tissue; dewaxing and rehydrating the slices, boiling in citrate buffer to extract the antigen, and slicing the slices to 0.3% H2O2Blocking for 15 minutes, blocking for 1 hour with 5% BSA; nephrin, PTEN, PDK1, p-AKT and p-mTOR primary antibody were incubated overnight at 4 ℃, after which the sections were incubated with secondary antibodies for 1 hour at 37 ℃, and finally, the sections were counterstained with diaminobenzidine and hematoxylin before micrographs were collected using an optical microscope, all of which were analyzed by ImageJ software.
1.6 detection of apoptosis by immunofluorescence and TUNEL method
Putting the white mouse kidney tissue slices into a 60 ℃ oven for 2 hours to melt paraffin; sequentially carrying out dewaxing, 4% paraformaldehyde fixing, antigen repairing, 0.3% Triton (Triton X-100) membrane rupture and punching, TUNEL marking and dyeing, 5% BSA sealing, hatching a first antibody, hatching a fluorescent second antibody in a dark place and dyeing by using a light-shading DAPI dye, then sucking excess liquid by using water-absorbing filter paper, dropwise adding an anti-fluorescent quenching sealing piece, slowly covering tissues by using a cover glass for sealing, then fixing the cover glass by using transparent nail polish, and placing in a ventilation cabinet for drying for 30 minutes; and finally, observing by using a fluorescence microscope, shooting, and keeping out of the sun at room temperature.
1.7 cell culture
Human renal proximal tubular epithelial cells (HK-2) were placed in DMEM medium containing 10% fetal bovine serum and 1% double antibody at 5% CO2Culturing at 37 deg.C;
HK-2 cells in the logarithmic growth phase were selected and randomly divided into 6 groups:
(1) Normal glucose control group (Con): culturing the cells in a culture medium containing 5.5mmol/L glucose;
(2) High osmotic pressure group (HM): culturing the cells in a culture medium containing 5.5mmol/L glucose and 24.5mmol/L mannitol;
(3) High sugar group (HG): culturing the cells in a culture medium containing 30mmol/L glucose;
(4) Notoginsenoside Fc-L group: culturing the cells in a culture medium containing 30mmol/L glucose and 10 mu mol/L notoginsenoside Fc;
(5) Notoginsenoside Fc-M group: culturing the cells in a culture medium containing 30mmol/L glucose and 15 mu mol/L notoginsenoside Fc;
(6) Notoginsenoside Fc-H group: culturing the cells in a culture medium containing 30mmol/L glucose and 20 mu mol/L notoginsenoside Fc;
dissolving notoginsenoside Fc in DMSO to obtain mother solution, diluting with culture medium, and treating for 48 hr.
1.8 live cell imaging
MitoSOX Red is a fluorescent probe specifically targeting living cell mitochondria, has cell membrane permeability, can be quickly and selectively combined with mitochondria, and is oxidized by superoxide to generate Red fluorescence once entering the mitochondria; mitochondrial superoxide production was measured using the MitoSOX Red mitochondrial superoxide indicator, and Mitochondrial Membrane Potential (MMP) levels were detected by JC-1 detection kit.
1.9 statistical analysis
Data were analyzed using GraphPad Prism 8, all expressed as mean ± Standard Deviation (SD), and differences between groups were statistically significant using one-way analysis of variance (ANOVA), with P <0.05 as the difference.
2. Results of the experiment
2.1 Effect of notoginsenoside Fc on blood and urine biochemical indexes of diabetic mice
Compared with rats in a control group, the ACR level of diabetic mice is obviously increased, but both notoginsenoside Fc and losartan can obviously reduce the ACR level of diabetic rats after 8 weeks of treatment (figure 1A); both the notoginsenoside Fc and losartan groups significantly reduced blood urea nitrogen levels compared to the diabetes model group (fig. 1B); the kidney weight/body weight ratio of db/db mice was significantly higher than that of normal db/m mice, and both notoginsenoside Fc and losartan reduced the kidney weight/body weight ratio of diabetic rats after 8 weeks of treatment (fig. 1C).
2.2 Effect of notoginsenoside Fc on Kidney morphology in diabetic mice
Histologically, HE staining showed that diabetic mice had significant mesangial matrix deposition, tubular dilation and tubular vacuolar degeneration, and both notoginsenoside Fc and losartan significantly improved these pathological changes (fig. 2A); the level of Nephrin in the kidney of the mice in the Model group is reduced compared with that in the control group (Normal), which indicates that the adhesion level is reduced; compared with the Model group, the renal Nephrin levels of the Losartan (Losartan) treatment group and the Notoginsenoside Fc (Notogenoside Fc) treatment group are relatively increased, which indicates that the adhesion levels are increased (fig. 2B-C); the results show that the notoginsenoside Fc improves the abnormality of the kidney morphology of the diabetic rat.
2.3 Effect of notoginsenoside Fc on apoptosis of diabetic mouse foot cells
In order to explore the influence of notoginsenoside Fc on the apoptosis level of kidney podocytes of db/db diabetic mice, carrying out immunofluorescence detection of WT 1 and TUNEL on frozen sections of mouse kidneys, and observing the apoptosis level of the kidney podocytes of each group of mice under a fluorescence microscope; the results are shown in FIGS. 3A-D, where the level of apoptosis in the kidney paw is increased in the Model (Model) group mice compared to the Normal (Normal) group; the level of renal podocyte apoptosis was reduced in mice in the Losartan (Losartan) treated group and Notoginsenoside Fc (notogenoside Fc) treated group compared to the Model group.
2.4 Effect of notoginsenoside Fc on mitochondrial oxidative stress level of HK-2 cells under hyperglycosemia
The high sugar significantly increases the mitochondrial superoxide production of HK-2 cells, and after the treatment of notoginsenoside Fc, the mitochondrial superoxide production was reduced.
2.5 Effect of notoginsenoside Fc on HK-2 cell mitochondrial membrane potential levels under hyperglycosemia
When the mitochondrial membrane potential in the cell is high, JC-1 forms an aggregate in a mitochondrial matrix and can generate red fluorescence, and conversely, when the potential is lower, JC-1 is a monomer and can emit green fluorescence because the JC-1 cannot aggregate; as shown in FIG. 5, hyperglycemia resulted in the loss of mitochondrial membrane potential in HK-2 cells, while notoginsenoside Fc reversed mitochondrial membrane depolarization, suggesting that notoginsenoside Fc could restore mitochondrial function in HK-2 cells under hyperglycemic conditions.
2.6 Regulation of the PTEN/PDK1/Akt/mTOR Signaling pathway by notoginsenoside Fc in diabetic mice
As shown in fig. 6A-E, renal PTEN levels were decreased in the Model (Model) group mice compared to the Normal (Normal) group; compared with the Model group, the renal PTEN level of the Losartan (Losartan) treatment group is relatively increased compared with the Notoginsenoside Fc (Notogenoside Fc) treatment group; the mice in the Model group (Model) had elevated renal PDK1, p-AKT and p-mTOR levels compared to the Normal group (Normal); compared with the Model group, the Losartan (Losartan) treatment group and Notoginsenoside Fc (Notogenoside Fc) treatment group have the kidney PDK1, p-AKT and p-mTOR levels reduced.
Example 2
The embodiment provides application of notoginsenoside Ft1 in preparing a medicament for treating diabetic nephropathy.
1. Experimental materials and methods
1.1 preparation of the drug
Notoginsenoside Ft1 (HPLC purity more than 98%) was purchased from Jing Jie biology, inc. of Anhui; losartan is available from merck; streptozotocin (STZ) was purchased from Sigma-Aldrich; in animal experiments, notoginsenoside Ft1 and losartan are suspended in 0.5% methylcellulose solution and are administrated by intragastric administration.
1.2 animal experiments
The db/m mice and db/db mice used in the embodiment are purchased from Nanjing university model animal institute, and are bred in SPF animal house (temperature: 26 ℃, humidity: 55% -60%) of animal experiment center of the college of medicine of the university, and the animal experiment operation conforms to the regulation of animal experiment ethics committee;
mice were randomized into 6 groups (n = 8/group), db/m mice served as control group, db/db mice were randomized into 5 groups (n = 8/group):
(1) Model group: gavage with an equal volume of 0.5% sodium carboxymethylcellulose solution;
(2) Losartan positive control group: after the losartan is suspended in 0.5 percent sodium carboxymethylcellulose solution, the losartan is intragastrically infused according to the dose of 20 mg/kg/d;
(3) Notoginsenoside Ft1 low dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 2.5 mg/kg/d;
(4) Notoginsenoside Ft1 medium dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 5 mg/kg/d;
(5) Notoginsenoside Ft1 high dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 10 mg/kg/d;
body weight was monitored weekly and dosed as above for 8 weeks;
the C57 mice used in the example were purchased from Nanjing university model animal institute, and were bred in SPF-level animal house (temperature: 26 ℃, humidity: 55% -60%) of animal laboratory center of college of medicine of Compound denier university, and the animal experiment operations were in accordance with the regulations of animal experiment ethics committee; adaptively feeding 4-week-old mice for 1 week, feeding high fat diet, 8 weeks later, fasting for 12h, performing intraperitoneal injection of STZ (40 mg/kg/d), preparing STZ with sterile 0.1mol/L citric acid-sodium citrate buffer solution, and sterilizing injection part with alcohol for 5 days;
under the condition of free drinking and eating, the normal blood sugar is measured for 1 time before molding; after STZ administration, observing the animal state every day, weighing 1 time every day, and taking mice with fasting plasma glucose of more than 16.7mmol/L and less than 2 times of blood glucose of a control group to enter into formal experiments;
mice were randomized into 6 groups (n = 8/group), normal mice served as control groups, and diabetic mice were randomized into 5 groups (n = 8/group):
(1) Model group: gavage with an equal volume of 0.5% sodium carboxymethylcellulose solution;
(2) Losartan positive control group: after the losartan is suspended in 0.5 percent sodium carboxymethylcellulose solution, the losartan is intragastrically infused according to the dose of 20 mg/kg/d;
(3) Notoginsenoside Ft1 low dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 10 mg/kg/d;
(4) Notoginsenoside Ft1 medium dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 20 mg/kg/d;
(5) Notoginsenoside Ft1 high dose group: suspending notoginsenoside Ft1 in 0.5% sodium carboxymethylcellulose solution, and performing intragastric administration at a dose of 30 mg/kg/d;
body weight was monitored weekly and dosed according to the above schedule for 8 weeks.
1.3 urine and blood Biochemical index detection
Collecting urine from a mouse metabolism cage, centrifuging the urine at 4 ℃ at 3500rpm for 15 minutes, and detecting urine microalbumin and urine creatinine in the urine supernatant by using a urine microalbumin enzyme-linked immunosorbent assay kit and a creatinine kit; calculating urinary albumin excretion using urinary albumin/creatinine ratio (ACR);
blood was drawn through the orbit, allowed to stand for more than 30 minutes, centrifuged at 4500rpm for 30 minutes at 4 ℃, and blood creatinine and blood urea nitrogen were detected by creatinine and urea nitrogen kits.
1.4 pathological examination of Kidney tissue
Paraffin-embedded 4 μm sections of kidney tissue were stained with Hematoxylin and Eosin (HE), masson (Masson) and periodic acid-schiff (PAS), dried at 65 ℃ for 30 minutes, the sections were deparaffinized in xylene 2 times for 10 minutes each, rehydrated sequentially with 100% ethanol (I), 100% ethanol (II), 95% ethanol, 90% ethanol, 80% ethanol and deionized water for 10 minutes each, and then the sections were stained with HE, masson and PAS, 20 pictures were randomly collected, quantified by two blind researchers, and the percentage of mesangial matrix occupying each glomerulus was calculated.
1.5 Electron microscopy
Observing glomeruli and podocyte Foot Processes (FP) by adopting a transmission electron microscope;
the renal cortex was fixed with 2% glutaraldehyde and stained with uranyl acetate and lead citrate.
1.6 immunohistochemical detection
Immunohistochemical detection was performed on 4 μm paraffin-embedded kidney tissue;
dewaxing and rehydrating the slices, and boiling in citrate buffer to extract the antigen; 0.3% for slicing2O2Blocking for 15 minutes, blocking for 1 hour with 5% BSA; AGO-1 primary antibody was incubated overnight at 4 ℃ followed by incubation of the sections with secondary antibodies for 1 hour at 37 ℃ and finally, the sections were counterstained with diaminobenzidine and hematoxylin and micrographs were collected using an optical microscope and all micrographs were analyzed by ImageJ software.
1.7 Western blot immunoassay (Western blot):
western blot detection of renal tissue and cell AGO-1, TSP-1, p-IRS1/2, p-AKT, p-ERK1/2, p-NF kappa B p protein levels.
1.8 inflammatory factor detection
The expression of IL-1 beta, IL-6, IL-18 and TNF-alpha in serum and kidney tissues is detected by an ELISA detection kit.
1.9 statistical analysis:
all data measurements in this example are expressed as Mean ± standard error (Mean ± SEM); differences between groups were evaluated using t-test (two sample comparisons, obeying normal distribution and satisfying the homogeneity of variance test) or one-way anova (multiple group sample comparisons, obeying normal distribution and satisfying the homogeneity of variance test), which was processed using GraphPad Prism6 (GraphPad Software, usa) statistical Software, with P <0.05 being statistically significantly different.
2. Results
2.1 high expression of AGO-1 in diabetic mouse Kidney tissue
By western blot detection, it was found that AGO-1 expression was significantly increased in kidney tissues of diabetic mice as compared to db/m mice and normal control C57 mice (FIGS. 7A-C); immunohistochemistry results also showed high expression of AGO-1 in kidney tissue of db/db mice (FIG. 7D).
2.2 notoginsenoside Ft1 significantly reduced diabetic mouse Kidney tissue AGO-1 expression
Through western blot detection, AGO-1 expression in kidney tissues of diabetic mice treated with notoginsenoside Ft1 for 8 weeks was significantly reduced compared to diabetic mice (FIG. 8A); immunohistochemistry results also showed that notoginsenoside Ft1 could significantly reduce renal tissue AGO-1 high expression (fig. 8B).
2.3 notoginsenoside Ft1 improves insulin resistance in db/db mice
As shown in fig. 9A-E, after 30min of intraperitoneal injection of glucose, the blood glucose levels rapidly increased to a peak value and then gradually decreased; the blood sugar of the model mouse IPGTT level is obviously higher than that of the normal group (P < 0.05) at 30-120 minutes (IPGTT-AUC is also obviously increased than that of the normal group (P < 0.05), and the IPGTT level and the IPGTT-AUC are lower than those of the model group (P < 0.05) at 30-120 minutes after the intervention of notoginsenoside Ft 1; the blood sugar value of db/db mice is obviously increased (P < 0.05) at 30-120 minutes and IPITT-AUC also shows an increasing trend (P < 0.05) compared with the normal group observed after the intraperitoneal injection of insulin; compared with the model group, the notoginsenoside Ft1 treatment group can reduce the blood sugar level (P < 0.05) and IPITT-AUC (P < 0.01) at 30-120 minutes, and the notoginsenoside Ft1 can regulate IPGTT and IPITT levels of db/db mice and enhance peripheral insulin sensitivity; the notoginsenoside Ft1 can obviously reduce the blood sugar level after being treated for 8 weeks, and the treatment effect of the low-dose notoginsenoside Ft1 has no obvious difference, but is also reduced to a certain extent; PAS staining of the kidney of the diabetic mouse shows that notoginsenoside Ft1 can significantly reduce renal glycogen deposition (fig. 9F); thrombin-sensitive protein-1 (TSP-1) is a potent anti-angiogenic factor that inhibits angiogenesis by preventing endothelial cell stimulation in response to various angiogenic factors, AGO-1 reduces insulin sensitivity by activating TSP-1 expression, indicating that notoginsenoside Ft1 significantly reduces TSP-1 expression levels in kidney tissue of db/db mice (FIG. 9G); the western blot further proves that compared with the model group mice, the expression of insulin signaling pathway-related proteins p-IRS-1, p-ERK1/2 and p-AKT in the kidney tissues of the diabetic nephropathy mice treated by notoginsenoside Ft1 is remarkably increased, which indicates that the fusion protein activates insulin-related signaling (FIG. 9H).
2.4 notoginsenoside Ft1 improves HFD/STZ mouse insulin resistance
As shown in fig. 10A-E, after each group of mice is intraperitoneally injected with glucose for 30min, the blood glucose level rapidly rises to reach a peak value, and then gradually decreases, the blood glucose level of model group mice IPGTT is significantly higher than that of normal group (P < 0.05) at 30-120 min, IPGTT-AUC is also significantly increased than that of normal group (P < 0.05), and the IPGTT level and IPGTT-AUC are lower than those of model group (P < 0.05) at 30-120 min after intervention of notoginsenoside Ft 1; the blood sugar value of the mouse IPITT level of the model group is obviously increased (P < 0.05) at 30-120 minutes compared with the normal group after the intraperitoneal injection of the insulin, and the IPITT-AUC also shows an increasing trend (P < 0.05); compared with the model group, the notoginsenoside Ft1 treatment group can reduce the blood sugar level (P < 0.05) and IPITT-AUC (P < 0.01) at 30-120 minutes, and the notoginsenoside Ft1 can regulate the IPGTT and IPITT levels of HFD/STZ mice and enhance the peripheral insulin sensitivity; the notoginsenoside Ft1 can obviously reduce the blood sugar level after being treated for 8 weeks, and the treatment effect of the low-dose notoginsenoside Ft1 has no obvious difference, but is also reduced to a certain extent; western blot further proves that compared with model mice, the expression of insulin signaling pathway-related proteins p-IRS-1, p-ERK1/2 and p-AKT is significantly increased in kidney tissues of diabetic nephropathy mice treated with notoginsenoside Ft1, indicating activation of insulin-related signaling by the fusion protein (fig. 10F).
2.5 notoginsenoside Ft1 can improve kidney injury of db/db mouse
Significantly reduced ACR levels were achieved following treatment with notoginsenoside Ft1 in db/db mice with significantly lower blood urea nitrogen and 24 hour urine levels than untreated db/db mice (fig. 11A-B); the mouse kidney index refers to the ratio of the bilateral kidney mass of the mouse to the weight of the mouse, the reaction is the relative weight change of the kidney, the data shows that the kidney index of the diabetic nephropathy mouse is obviously increased compared with a control group, the kidney index of the diabetic mouse can be obviously reduced after 8 weeks of treatment by the notoginsenoside Ft1 (fig. 11C-D), the HE result shows that the mesangial cell proliferation and the matrix of the diabetic nephropathy mouse are obviously increased, and the pathological damage of the kidney of the db/db mouse is obviously reduced after 8 weeks of treatment by the notoginsenoside Ft1 (fig. 11E); electron microscope detection shows that compared with untreated diabetic nephropathy mice, the thickening degree of glomerular basement membrane of the diabetic nephropathy mice treated by notoginsenoside Ft1 is reduced, the podocyte foot process fusion degree is obviously improved (fig. 11F), masson staining is carried out on mouse kidney tissues, collagen deposition in db/db mouse kidney tissues is increased, and the collagen deposition level of the diabetic mice can be obviously improved after treatment by notoginsenoside Ft1 (fig. 11E); the western blot result and quantitative statistical analysis thereof further indicate that notoginsenoside Ft1 can reduce the expression levels of fibrosis-associated proteins alpha-SMA and Vimentin in kidney tissues of diabetic nephropathy mice (FIG. 11G).
2.6 notoginsenoside Ft1 can improve HFD/STZ mouse kidney injury
After the administration of notoginsenoside Ft1 treatment in HFD/STZ mice, ACR levels could be significantly reduced (fig. 12A), with significantly lower blood urea nitrogen and 24 hour urine volume than untreated HFD/STZ mice (fig. 12B-C); the data show a significant increase in renal index in diabetic nephropathy mice compared to the control group; and the renal index of diabetic mice was significantly reduced after 8 weeks of treatment with notoginsenoside Ft1 (FIG. 12D).
In conclusion, the therapeutic effect of notoginsenoside Fc and notoginsenoside Ft1 on diabetic nephropathy is discussed through in vivo experiments on db/db mice and a diabetic nephropathy model induced by high fat diet and Streptozotocin (STZ); the notoginsenoside Fc can improve proteinuria and renal histopathology, reduce renal tubular cell apoptosis, regulate the expression of PTEN/PDK1/Akt/mTOR pathway protein to reduce DN glomerulus and mitochondrial injury, and in vitro research further proves that the notoginsenoside Fc can reduce the generation of mitochondrial superoxide and reduce the loss of Mitochondrial Membrane Potential (MMP); notoginsenoside Ft1 can improve insulin resistance, reduce the expression of insulin receptor signal pathway proteins p-IRS1/2, p-AKT and p-ERK1/2, can reduce the protein expression of AGO-1 in kidney tissues of two diabetic nephropathy model mice, inhibit insulin resistance by regulating AGO-1/TSP-1 pathway, improve metabolism and reduce DN kidney injury; notoginsenoside Fc and notoginsenoside Ft1 can be used for preparing medicine for treating diabetic nephropathy.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
Claims (8)
1. Application of Notoginseng radix extract in preparing medicine for treating diabetic nephropathy is provided.
2. The use of claim 1, wherein the notoginseng extract is notoginsenoside.
3. The use of claim 2, wherein the notoginsenoside is notoginsenoside Fc or/and notoginsenoside Ft1.
4. The use according to claim 3, wherein the notoginsenoside Fc has the molecular formula C58H98O26。
5. The use according to claim 3, wherein the notoginsenoside Ft1 has a molecular formula of C47H80O17Molecular weight is 917.13.
6. The use of claim 1, wherein the medicament for treating diabetic nephropathy further comprises: one or more pharmaceutically acceptable adjuvants.
7. The use according to claim 1, wherein the medicament for the treatment of diabetic nephropathy is in a dosage form comprising: decoction, pill, powder, paste, pellet, medicated wine, granule, oral liquid, capsule, tablet or injection.
8. The use according to claim 1, wherein the route of administration of the medicament for the treatment of diabetic nephropathy comprises: oral administration, sublingual administration, intramuscular or subcutaneous administration or intravenous administration.
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| CN108014118A (en) * | 2017-12-25 | 2018-05-11 | 上海中医药大学 | A kind of purposes of notoginsenoside Ft1 |
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| CN108014118A (en) * | 2017-12-25 | 2018-05-11 | 上海中医药大学 | A kind of purposes of notoginsenoside Ft1 |
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