CN108066349B - Application of panax japonicus saponin IVa in preparing medicine for treating nephritis or renal fibrosis - Google Patents
Application of panax japonicus saponin IVa in preparing medicine for treating nephritis or renal fibrosis Download PDFInfo
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- CN108066349B CN108066349B CN201711487645.2A CN201711487645A CN108066349B CN 108066349 B CN108066349 B CN 108066349B CN 201711487645 A CN201711487645 A CN 201711487645A CN 108066349 B CN108066349 B CN 108066349B
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Abstract
The invention discloses a new application of panax japonicus saponin IVa in preparing a medicament for treating nephritis or renal fibrosis, the panax japonicus saponin IVa is an extract of aralia taibaiensis, and the inventor researches and discovers that the panax japonicus saponin IVa has a renal protection effect.
Description
Technical Field
The invention relates to a new application of panax japonicus saponin IVa in preventing and treating nephritis or renal fibrosis.
Background
Chronic Renal Failure (CRF) has become one of the major diseases affecting human health worldwide. Renal interstitial fibrosis is one of the traditional Chinese medicine pathological features of CRF. How to intervene in the development of renal interstitial fibrosis by using medicaments is the key point for preventing and treating CRF. Renal fibrosis is a must-pass pathway for CRF, a common pathway for the development of various renal diseases to end-stage renal disease. It is presently believed that the pathological changes in end-stage renal disease are irreversible and, therefore, it is critical to control the development of renal fibrosis. The pathogenesis of renal fibrosis is extremely complex, is a slow process of interaction among multiple links and multiple factors, and the main mechanisms comprise: inflammatory reaction, oxidative stress, apoptosis, myofibroblast activation and proliferation, unbalanced extracellular matrix synthesis and degradation, and the like.
The current clinical treatments for renal fibrosis mainly include: the treatment of primary diseases (such as obstructive nephropathy and the like), the elimination and intervention of related risk factors (such as infection, medicaments and the like) and the treatment aiming at pathogenesis (such as non-steroidal anti-inflammatory drugs and antihypertensive drugs). Although the above-mentioned treatment can have a certain therapeutic effect on renal fibrosis, the gradual progress of chronic kidney disease to the terminal stage cannot be completely prevented. Due to the complex pathogenesis and multiple involved factors of fibrotic diseases, a drug capable of resisting nephritis and renal fibrosis needs to be found.
Disclosure of Invention
The invention aims to provide a new application of panax japonicus saponin IVa, and the new application is that the panax japonicus saponin IVa is used for preparing a medicine for treating nephritis or renal fibrosis.
The invention is realized as follows:
application of panax japonicus saponin IVa shown in the following structural formula (I) in preparing a medicament for treating nephritis or renal fibrosis,
the above-mentioned medicine for treating renal fibrosis can be conventional capsule, tablet or pill.
The panax japonicus saponin IVa is prepared by the following method:
(1) adding 10 times of 80% ethanol into 20kg of Aralia taibaiensis powder, reflux-extracting at 80 deg.C for 60min for 3 times, filtering, mixing, concentrating, and recovering ethanol to obtain crude extract;
(2) dispersing the crude extract obtained in the step (1) by using distilled water, respectively extracting by using chloroform with 3 times of volume to remove fat-soluble impurities, extracting by using water-saturated n-butanol with 3 times of volume for 3 times, combining the extraction solutions for 3 times, recovering under reduced pressure at 60 ℃, and evaporating on a water bath at 60 ℃ to dryness;
(3) separating the n-butanol extract obtained in the step (2) by silica gel column chromatography, Sephadex LH-20 column chromatography, ODS reversed phase column chromatography, Lobar column chromatography and reversed phase HPLC preparation means to obtain panax japonicus saponin IVa;
(4) aralia taibaiensis saponin has a large molecular weight and a complex structure. Analyzing the structure of the separated saponin component by using spectral techniques such as 1D NMR (1H and 13C NMR), 2DNMR (DQCOSY, TOCSY, HMQC, HMBC, NOESY and ROESY) and MS (ESI-MS), and determining the planar and stereochemical structure by combining chemical means (acid hydrolysis, alkaline hydrolysis, enzymolysis, methylation, acetylation, etc.).
Aralia taibaiensis (A. taibaiensis)A ralia taibaiensisZ.Z. Wang et H.C. Zheng) is specially produced in Qinba mountainous areas and the rest veins of the midwest of China, the main chemical components of the Chinese and western medicine are triterpenoid saponin, aglycon is oleanolic acid and mainly exists in the form of glycoside, panax japonicus saponin IVa is an extract of aralia taibaiensis, and the inventor finds that the panax japonicus saponin IVa has a kidney protection effect through research.
Drawings
FIG. 1 is a bar graph of renal function indices for various groups of animals;
FIG. 2 is a bar graph of renal function indices for each group of animals;
FIG. 3 is a photomicrograph of HE stained sections of kidney tissue from each group of animals, including sham, model, low, medium, and high dose groups;
FIG. 4 is a photomicrograph of Masson stained sections of kidney tissue from each group of animals, including sham operated, model, low, medium, and high dose groups;
FIG. 5 is a bar graph of TGF- β 1-induced expression levels of MCP-1, TNF- α -6 inflammatory factors in NRK-49F cells.
Detailed Description
Example 1 (preparation of Panax japonicus Saponin IV a)
Extracting 20kg Aralia taibaiensis with 10 times of 80% ethanol under reflux for 3 times at 80 deg.C for 60min, and concentrating at 60 deg.C under reduced pressure to obtain crude extract with relative density of 1.01-1.05; dispersing the crude extract with distilled water, extracting with chloroform 1:3 (v/v) respectively to remove liposoluble impurities, extracting with water saturated n-butanol for 3 times (1:3, v/v), mixing the 3 times of extractive solutions, recovering under reduced pressure at 60 deg.C with rotary evaporator, and evaporating to dry on water bath at 60 deg.C. The n-butanol extract is separated by silica gel column chromatography, Sephadex LH-20 column chromatography, ODS reversed phase column chromatography, Lobar column chromatography, reversed phase HPLC preparation and other means. Carrying out structure analysis on separated saponin components by using spectral techniques such as 1D NMR (1H and 13C NMR), 2D NMR (DQCOSY, TOCSY, HMQC, HMBC, NOESY and ROESY) and MS (ESI-MS), and determining a planar and stereochemical structure by combining chemical means (acid hydrolysis, alkaline hydrolysis, enzymolysis, methylation, acetylation and the like) to obtain the compound panax japonicus saponin IVa.
Example 2 (Capsule)
Weighing 10mg of panax japonicus saponin IVa powder prepared in example 1, 50-100mg of starch and 50-70mg of microcrystalline cellulose, adding 70mg of dextrin, 70mg of lactose and 7mg of sodium carboxymethylcellulose, sieving with a 60-mesh sieve, uniformly mixing, preparing a soft material by using 85% ethanol as a wetting agent, sieving with a 40-mesh sieve, drying in an oven at 60 ℃ for 5 hours, grading with a 40-mesh sieve, and sieving with a 60-mesh sieve to remove fine powder to obtain 40-60-mesh granules. The critical relative humidity of the granule is below 78%, and size 1 capsule (0.50 ml) is selected for filling.
Example 3 (tablet)
The preparation method comprises the following steps of weighing the panax japonicus saponin IVa powder prepared in example 1, lactose, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate in a mass ratio of: 10: 25:83:6:0.8. Sieving the panax japonicus saponin IVa powder with a 100-mesh sieve, respectively sieving lactose, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate with a 60-mesh sieve, and respectively placing the obtained uniform powder in a clean container. Preparing the soft extract with 75% ethanol, granulating with 18-24 mesh sieve, drying at 60 deg.C for 2-4 hr, grading with 18-24 mesh sieve, adding silica gel micropowder and magnesium stearate, mixing, and tabletting to obtain tablet core.
Example 4 (pill)
The prescription for screening is as follows: medicine preparation: the mass ratio of the matrix is 1: 150, the mass ratio of PEG4000 to PEG6000 is 2: 1, the material temperature is 85 ℃, the dropping distance is 5cm, the cooling temperature is 10 ℃, and the condensate is vegetable oil. The panax japonicus saponin IVa prepared in the example 1 is precisely weighed according to the prescription amount and dissolved in a proper amount of purified water, and then the mixture of PEG4000 and PEG6000 is added and placed in a water bath kettle of a magnetic stirrer with the temperature of more than 80 ℃, and the mixture is heated and stirred until the mixture is completely melted and then uniformly mixed. Dripping into dripping pill device with dropper, controlling appropriate dripping speed to allow it to settle in condensate, cooling for molding, taking out dripping pill, removing coolant with filter paper, air drying, and selecting pill. And (5) obtaining the product.
Example 5 (Effect test)
Wild type, male C57BL/6, 18-20g, adapted feeding for one week, randomly divided into sham operation group, model group, low dose group, medium dose group, high dose group, each group consisting of 8 rats. In addition to the sham group, four groups of left-sided ureteral ligations (UUO) constructed renal fibrosis models. Before the operation, the operation is not performed for 12 hours, water is not forbidden, 3.5% chloral hydrate (350 mg/kg) is used for intraperitoneal injection and anesthesia, the patient is fixed on an operation plate in a prone position, skin is prepared under the right rib of the back, the field skin is subjected to conventional iodophor disinfection operation, the side of the right side of the spine is 0.5cm, a longitudinal incision is made along the edge of the rib, skin muscles are cut layer by layer, the right ureter is exposed and separated, the operation field is ligated twice by 4-0 suture line, the bleeding phenomenon in the operation field is observed, and subcutaneous tissues and the skin are sutured. The sham operation group only dissociates the ureter, not ligates, and the rest of the operation is the same. Gavage starting half an hour after intervention group of panax japonicus saponins IVa 10 mg/kg/d, 20 mg/kg/d and 40 mg/kg/d for 14 consecutive days. Sham surgery and model groups were gavaged with an equal volume of solvent, and each group of mice was sacrificed on day 14 post-surgery as required. On day 14 after the successful model creation, each group of mice was sacrificed and bilateral kidney tissue samples were collected, respectively. The mice were anesthetized with 3.5% chloral hydrate (350 mg/kg) by intraperitoneal injection and fixed. Collecting blood with carotid artery of blood taking needle, 1ml each time, centrifuging and reserving. The chest cavity and the abdominal cavity are dissected layer by layer at the midline position of the abdomen, and the heart and the kidneys at two sides are exposed. The right atrium is cut open by the ophthalmic scissors, the perfusion needle penetrates into the left ventricle and is fixed, the perfusion needle is perfused by precooled physiological saline (about 200 ml), and after the whole color of the bilateral kidney is whitened, the bilateral kidney is immediately cut off and is immersed into the precooled physiological saline. After fat tissues and kidney envelopes are rapidly removed, longitudinal incisions are respectively performed on bilateral kidneys for half-cutting, then a part of kidneys are placed in a refrigerator at the temperature of-80 ℃ for immunofluorescence detection, after a part of kidney tissues are immediately put into liquid nitrogen, the kidney tissues are stored in the refrigerator at the temperature of-80 ℃ for Western Blotting and PCR detection, and a part of kidney tissues are immersed in 10% formalin for fixation and used for optical microscopy.
First, the influence of chikusetsusaponin IVa on renal function of UUO rat renal fibrosis
Serum samples of each group of rats are taken, and the serum creatinine content in the rat serum is detected according to the serum creatinine kit instruction (Nanjing institute of bioengineering). Taking urine of each group of mice, and determining the content of urea nitrogen and urine protein according to the operation of the urea nitrogen and urine protein kit (Nanjing institute of bioengineering). The results (tables 1-3, FIG. 1) show that: the model group has significant difference compared with the sham operation group (p<0.01), the low, medium and high dose administration groups can obviously reduce the expression of serum creatinine, urea nitrogen and urine volume of kidney fibrosis of UUO mice (p<0.01), which shows that the panax japonicus saponin IVa has a certain protective effect on the damaged kidney.
Secondly, the influence of chikusetsusaponin IVa on kidney fibrosis renal index of UUO rats
3.5 percent chloral hydrate is injected into the abdominal cavity of each group of mice for anesthesia, the separated mouse kidney tissues are taken out for weighing, and the ratio of the left kidney of the kidney to the body weight is calculated. The results (tables 4-5, FIG. 2) show that: the renal index of the model group was significantly different from that of the blank group (p<0.01); the middle and high dose administration groups can obviously reduce the left kidney index and the expression of urine protein (p<0.01); the panax japonicus saponin IVa is prompted to have a certain inhibition effect on renal fibrosis caused by a UUO model.
And thirdly, the influence of the chikusetsusaponin IVa on the inflammatory reaction of the kidney tissue after the unilateral ureteral obstruction and the renal fibrosis.
The left kidney tissue of each group of mice was sectioned and half fixed in 10% formalin solution, and HE staining and Masson staining were performed, respectively, and the results (fig. 3 to 4) showed that: in the HE stained section, kidney tissues of each UUO group showed obvious interstitial inflammation and fibrosis, obviously enlarged interstitial space of kidney, inflammatory cell infiltration, glomerular telangiectasia, tubular necrosis and gradual atrophy. After treatment with different doses of panax japonicus saponin IVa, the damage degree of the kidney tissues of UUO rats can be improved, and the treatment is most obvious in high dose. Masson staining showed no proliferation of collagen fibers in the sham group and the tubular basement membrane was clearly visible. In the UUO group, a great deal of collagen staining of kidney tissues can be seen, collagen fibers are obviously increased in renal interstitium, and interstitial fiber tissues are formed in a bundle-shaped and reticular hyperplasia manner. After different doses of panax japonicus saponin IVa are given for treatment, the renal fibrosis degree of kidney tissues of UUO rats is reduced, and the fact that the panax japonicus saponin IVa can effectively improve renal interstitial fibrosis generated after renal tissue obstruction is prompted.
Fourth, the influence of chikusetsusaponin IVa on the expression of NRK-49F cell inflammatory factor induced by TGF- β 1
Cells were discarded cell culture medium and rinsed with cold PBSOnce. Pancreatin digestive juice is at 37 deg.C for 1-2 min. The pancreatin was neutralized by adding complete medium at 1000rpm for 6min and the supernatant was discarded. The blood cell count plates were counted and plated in 96 well plates at 1X10 per well4And (4) cells. Then placed at 37 ℃ in 5% CO2Culturing in a cell culture box for 24h, pretreating cells with 20, 40 and 80 μ g/ml chikusetsusaponin IVa solution for 1h, treating with TGF- β 1 (10ng/ml) for 24h, collecting cell culture supernatant, and using monocyte chemotactic factor-1 (MCP-1) ELISA kit (America R-1)&D) Human tumor necrosis factor- α (TNF- α) ELISA kit (U.S. R)&D) And human interleukin-6 (IL-6) ELISA kit (US R)&D) The concentrations of MCP-1, TNF- α and IL-6 in the cell sap were measured separately, and the results (Table 6-8, FIG. 5) showed that MCP-1 and TNF- α -6 were significantly increased in the model group (see Table 6-8, FIG. 5)p<0.01), the low, medium and high dose groups of the chikusetsusaponin IVa can obviously inhibit the rising of the MCP-1, TNF- α and IL-6 levels of cells induced by TGF- β 1 (the formula is shown in the specification)p<0.01) has no influence on normal cells, and shows that the chikusetsusaponin IVa can effectively inhibit the expression of inflammatory factors.
Claims (3)
1. Application of panax japonicus saponin IVa shown in structural formula (I) in preparing medicine for treating nephritis or renal fibrosis,
（I）。
2. use according to claim 1, characterized in that: the medicine for treating renal fibrosis is a conventional capsule, tablet or pill.
3. Use according to claim 1 or 2, characterized in that: the panax japonicus saponin IVa is prepared by the following method:
(1) adding 10 times of 80% ethanol into 20kg of Aralia taibaiensis powder, reflux-extracting at 80 deg.C for 60min for 3 times, filtering, mixing, concentrating, and recovering ethanol to obtain crude extract;
(2) dispersing the crude extract obtained in the step (1) by using distilled water, respectively extracting by using chloroform with 3 times of volume to remove fat-soluble impurities, extracting by using water-saturated n-butanol with 3 times of volume for 3 times, combining the extraction solutions for 3 times, recovering under reduced pressure at 60 ℃, and evaporating on a water bath at 60 ℃ to dryness;
(3) and (3) separating the n-butanol extract obtained in the step (2) by using silica gel column chromatography, Sephadex LH-20 column chromatography, ODS reversed-phase column chromatography, Lobar column chromatography and reversed-phase HPLC preparation means to obtain panax japonicus IV a.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102824355A (en) * | 2012-08-22 | 2012-12-19 | 中国人民解放军第四军医大学 | Use of panax japonicus saponin IV a in preparation of alpha-glycosidase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824355A (en) * | 2012-08-22 | 2012-12-19 | 中国人民解放军第四军医大学 | Use of panax japonicus saponin IV a in preparation of alpha-glycosidase inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| Inhibitory effects of Chikusetsusaponin IVa on lipopolysaccharide-induced pro-inflammatory responses in THP-1 cells;H Wang, et al.;《International Journal of Immunopathology and Pharmacology》;20151231;第28卷(第3期);308-317 * |
| 竹节参皂苷IVa及其衍生物的药理活性及作用机制研究进展;吴忻晶 等;《中国药房》;20181231;第29卷(第18期);2560-2564 * |
| 补肾益气类方药对慢性肾脏病中IL-6干预作用的研究进展;盖丰丰 等;《中国中西医结合肾病杂志》;20120430;第13卷(第4期);366-367 * |
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