Application of triptophenolide in preparation of medicine for treating diabetic nephropathy

Abstract

The invention provides application of triptophenolide in preparation of a medicine for treating diabetic nephropathy, the structural formula of the triptophenolide is as shown in the specification, and # imgabs0 #. Experiments find that the triptophenolide has the effect of delaying the diabetic nephropathy of db / db mice, and a new method is provided for treating the diabetic nephropathy.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and relates to resorcinolone, specifically to the use of resorcinolone in preparing a medicine for treating diabetic nephropathy. Background Art

[0002] Diabetic Kidney Disease (DKD) is a chronic kidney disease caused by diabetes, mainly manifested by urine protein / creatinine ratio (UACR)>=30mg / g and / or estimated glomerular filtration rate (GFR)<60mL min -1 (1.73m 2 ) -1 , and lasts for more than 3 months. Microalbuminuria appears in the early stage, and as the disease progresses, persistent large amounts of proteinuria and hypertension appear, eventually developing into end-stage renal disease (ESRD).

[0003] As a source of clinical drugs, Chinese medicine monomers are widely recognized for their safety and effectiveness. Many studies have shown that Chinese medicine monomers have strong pharmacological effects, such as flavonoids have antioxidant, anti-inflammatory, cardiovascular and cerebrovascular softening, nerve protection, immune regulation and other effects, and alkaloids have multiple effects such as anti-pathogenic microorganisms, hypoglycemia, and hypolipidemic effects. Many Chinese medicines play an important role in the treatment of kidney disease, but their molecular targets and mechanisms of action have not yet been clarified. It is difficult to screen out the drugs with the most clear efficacy and the clearest mechanism of action from hundreds of compounds in Chinese medicine prescriptions to develop monomer drugs.

[0004] Therefore, it is of great significance to reduce the complexity of manual screening and verification of Chinese medicine monomers and to find the most potential monomer drugs for improving renal function, delaying the development of kidney disease and treating kidney disease. In-depth research on the therapeutic effect of Chinese medicine monomers on diabetic nephropathy to reveal their specific effects and pathway target mechanisms in the treatment of diabetic nephropathy can further provide a scientific basis for the development of Chinese medicine monomer drugs to treat kidney disease.

[0005] Diterpenes are a class of natural products containing isoprene structures. They are widely distributed in nature and have anti-inflammatory, anti-cancer, anti-malarial, and anti-microbial effects. In recent years, they have shown good application potential in the treatment of rheumatoid arthritis-related diseases. Rafenolactone is a diterpenoid compound extracted from plants such as Tripterygium wilfordii. Summary of the invention

[0006] In view of the above-mentioned technical problems in the prior art, the present invention provides the use of resorcinolone in the preparation of a drug for treating diabetic nephropathy. The use of resorcinolone in the preparation of a drug for treating diabetic nephropathy is intended to solve the technical problem that the drugs in the prior art are not effective in treating diabetic nephropathy.

[0007] The present invention provides the use of raphenol lactone in preparing a medicament for treating diabetic nephropathy. The structural formula of raphenol lactone is as follows:

[0008]

[0009] Specifically, the molecular formula of the raphenol lactone monomer compound of the present invention is: 20 H 24 O3, CAS: 74285-86-2.

[0010] The present invention predicts the therapeutic effect of raphenolide in diabetic nephropathy by detecting the fasting blood sugar, body weight and food intake of db / db mice, which is helpful to explore the mechanism of action for treating diabetic nephropathy and provides a new treatment plan for treating diabetic nephropathy. The present invention finds through experiments that raphenolide has the effect of delaying diabetic nephropathy in db / db mice, and provides a new method for treating diabetic nephropathy.

[0011] Compared with the existing technology, the present invention has positive and obvious technical effects, and has no obvious toxic and side effects. Compared with compound Chinese medicine, single Chinese medicine treatment has better controllability and efficacy evaluation. The use of Chinese medicine monomer resorcinolone to treat diabetic nephropathy has a wide source, low cost, good efficacy, and can be used for long-term treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It was shown that rapamycin improved fasting blood glucose, body weight, and food intake in mice with diabetic nephropathy.

[0013] Figure 2 Rafenolide was shown to reduce 24-hour urine volume in mice with diabetic nephropathy.

[0014] Figure 3 showed that rafenibactone reduced urine albumin and urine albumin / creatinine ratio in diabetic nephropathy mice.

[0015] Figure 4 Rafenolide was shown to reduce serum creatinine in diabetic nephropathy mice.

[0016] Figure 5 Rafenolide was shown to reduce urea nitrogen in mice with diabetic nephropathy.

[0017] Figure 6 PAS staining of glomeruli and tubules in mice with diabetic nephropathy is shown.

[0018] Figure 7 Rafenolide was shown to improve glomerulosclerosis in mice with diabetic nephropathy.

[0019] Figure 8 It was shown that rapamycin improved tubular basement membrane thickening and renal interstitial fibrosis in mice with diabetic nephropathy. DETAILED DESCRIPTION

[0020] Example 1 verified its therapeutic effect on diabetic nephropathy through animal model experiments.

[0021] The mice (db / db mice) used in this experiment were purchased from Saiye Biotechnology Co., Ltd. The db / db type 2 diabetic mice were gavaged for 12 consecutive weeks (W0-W12). Mice with fasting blood glucose>=16.7mmol / L were selected for inclusion in the study. When significant proteinuria occurred, the mice were randomly divided into a control group (NC), a model group (DN), and a rapamycin treatment group (DN+TP). Rapamycin was dissolved in a solution with a mass percentage concentration of 0.5% sodium carboxymethylcellulose (CMC-Na) and gavaged at a dose of 80mg / kg once a day for 12 weeks. The control group and the model group were given an equal amount of 0.5% sodium carboxymethylcellulose. During the administration process, the weight and blood glucose of the mice were tested every two weeks, and random urine of the mice was collected once. After the administration, the mice were anesthetized with a mass percentage concentration of 0.1% sodium pentobarbital, and blood and kidney tissue were collected.

[0022] The fasting blood glucose of mice was tested regularly by blood glucose meter. In order to evaluate the effect of raphenolide on the renal function of diabetic nephropathy mice, the urine albumin and urine creatinine levels of each group of animals were detected by kit, and the urine albumin to urine creatinine ratio (UACR), blood creatinine (Cr), and blood urea nitrogen (BUN) levels were calculated. Pathological changes in the structure of renal tissue are the direct cause of decreased renal function. In order to detect the effect of raphenolide on renal pathological changes, the pathological changes of mouse renal tissue were observed by PAS staining and transmission electron microscopy.

[0023] Experimental Results

[0024] 1. Rafenolactone has no significant effect on improving blood sugar, body weight, food intake and water intake of diabetic nephropathy mice

[0025] In this study, the blood glucose level of diabetic mice treated for 12 weeks was Figure 1 -a), weight ( Figure 1 -b) 24h food intake ( Figure 1 -c) Water intake ( Figure 1 -d) decreased compared with the model group, but there was no significant difference and it was not statistically significant.

[0026] 2. Rafenolactone can reduce urine volume in diabetic nephropathy mice

[0027] Polydipsia and polyuria are complications of hyperglycemia. When blood sugar concentration exceeds a certain level, the glucose filtered through the glomerulus exceeds the reabsorption capacity of the renal tubules, causing osmotic diuresis. Rafenoxalide can alleviate the symptoms of osmotic diuresis to a certain extent, such as Figure 2 ,.

[0028] 3. Rafenoxalide improves the renal function and renal pathological changes in diabetic nephropathy mice.

[0029] Persistent microalbuminuria is one of the characteristics of diabetic nephropathy and is closely related to progressive kidney damage. Therefore, effectively reducing urinary albumin levels in the early and middle stages is one of the goals of traditional Chinese medicine in the development of new drugs for diabetic nephropathy. This study observed that compared with the control group, the blood sugar and body weight of diabetic nephropathy mice were significantly increased, accompanied by a significant increase in UACR, indicating that diabetic nephropathy mice had obvious proteinuria.

[0030] After 12 weeks of treatment with rapamycin, the urinary albumin ( Figure 3 -a) and UACRUACR( Figure 3 -b) were significantly reduced.

[0031] In addition, this study also found that the decrease in serum creatinine and urine albumin content in diabetic nephropathy mice was correlated with the increase in urine creatinine (Cr) and urea nitrogen (BUN). Therefore, it can be inferred that raphenolide can promote the excretion of urea nitrogen and creatinine, thereby reducing blood sugar in diabetic mice and improving symptoms caused by albuminuria and high serum creatinine, such as Figure 4 , 5.

[0032] 4. Rafenolactone reduces glomerular inflammation in mice

[0033] Inflammation and glomerular sclerosis are key pathological features in the development of diabetic nephropathy. Sustained inflammatory response is a key factor leading to various types of renal damage. In recent years, anti-inflammatory therapy has received increasing attention in the study of diabetic nephropathy. Compared with the model group, the basement membrane thickening in the treatment group was significantly reduced, and the proliferation of mesangial cells, endothelial cells and epithelial cells in the kidney tubules was reduced. Figure 6 , indicating that renal phenol lactone can reduce the glomerular inflammatory response in mice with diabetic nephropathy.

[0034] 5. Rafenolactone improves glomerular sclerosis symptoms in diabetic nephropathy mice

[0035] Glomerular sclerosis in the renal tissue of diabetic nephropathy mice and the replacement of glomerular cells by fibrous tissue are one of the glomerular pathological characteristics of diabetic nephropathy and are an important cause of impaired renal filtration function. Figure 7 Compared with the model group (DKD), the TP group showed significantly reduced glomerular sclerosis, indicating that TP can delay the development of diabetic nephropathy by reducing glomerular sclerosis in diabetic nephropathy mice.

[0036] 6. Rafenolactone can improve the symptoms of renal interstitial fibrosis in diabetic nephropathy mice

[0037] The thickening of the tubular basement membrane, widening of the interstitial area, and tubular atrophy in the renal tissue of diabetic nephropathy mice are typical characteristics of the renal tubules in diabetic nephropathy. These changes can lead to tubular dysfunction and affect the filtration and excretion function of the kidney. In the group treated with rapamycin, the thickening of the tubular basement membrane was significantly reduced, indicating that rapamycin can slow down the progression of renal interstitial fibrosis in diabetic nephropathy mice. Figure 8 .

Claims

1. Use of raphenol lactone in the preparation of a drug for treating diabetic nephropathy. The structural formula of raphenol lactone is shown below:

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