CN107519192B - Application of cucurbitane tetracyclic triterpene compound in preparation of anti-renal fibrosis drugs - Google Patents
Application of cucurbitane tetracyclic triterpene compound in preparation of anti-renal fibrosis drugs Download PDFInfo
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- CN107519192B CN107519192B CN201610440793.8A CN201610440793A CN107519192B CN 107519192 B CN107519192 B CN 107519192B CN 201610440793 A CN201610440793 A CN 201610440793A CN 107519192 B CN107519192 B CN 107519192B
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Abstract
The invention belongs to the technical field of prevention and treatment of renal fibrosis, and relates to application of a cucurbitane tetracyclic triterpene compound in resisting renal fibrosis. The invention provides an application of cucurbitane tetracyclic triterpenoids in preparation of medicines and/or health-care products for preventing and/or treating renal fibrosis diseases. The invention discloses a new medical application of a cucurbitane tetracyclic triterpene compound, namely an application of the cucurbitane tetracyclic triterpene compound in preparing a medicament and/or a health-care product for preventing and/or treating renal fibrosis diseases. The compound provided by the invention is derived from natural plants, the original plants are widely distributed, the production cost is low, the prepared extract or monomer component has definite pharmacological action and small toxic and side effects, and the compound has wide application value.
Description
Technical Field
The invention belongs to the technical field of prevention and treatment of renal fibrosis, and relates to application of a cucurbitane tetracyclic triterpene compound in preparation of a medicament and/or a health-care product for preventing and/or treating renal fibrosis diseases.
Background
Renal fibrosis (including glomerular fibrosis, renal interstitial fibrosis, renal vascular fibrosis) is a common pathway for almost all renal diseases to progress to end-stage renal failure, is one of the major pathological manifestations of various chronic renal diseases, and is the final outcome of various glomerular, vascular and tubulointerstitial diseases themselves. Studies have shown that the development of renal fibrosis is progressive regardless of the etiology of renal disease, with glomerular fibrosis and renal interstitial fibrosis playing important roles in renal fibrosis.
The kidney is stimulated by various pathogenic factors such as trauma, infection, inflammation, blood circulation disorder, immune reaction and the like, so that the inherent cells of the kidney are damaged, and a large amount of collagen deposition and accumulation appear in the later stage, so that the kidney is gradually hardened to form scars until the kidney completely loses the function of the viscera. The process of fibrosis and sclerosis of cells in the kidney is also known as the process of kidney fibrosis. Renal fibrosis is characterized by abnormal deposition of extracellular matrix (ECM). The basic pathological reason of renal fibrosis is the over-activation of fibroblasts, and the inhibition of the over-activation of the fibroblasts can effectively inhibit the development of renal fibrosis.
At present, most of renal fibrosis treatment drugs have the problems of high toxicity, low safety, single pharmacological action and the like, and extracts or monomer compounds with pharmacological activity are obtained from natural plants, so that the potential drugs with high efficiency and low toxicity have important value. The cucurbitane-type triterpene glycoside compound is a main pharmacological component in momordica grosvenori and comprises Mogroside V (Mogridev), Mogroside IVe (Mogride IVe), Mogroside IIIe (Mogride IIIe), Mogroside II A2 (Mogride II A2), Mogroside III A1 (Mogride III A1), Mogroside IVa (Mogride eIVa), Mogroside VI (Mogride VI), siamenoside I (Siamenoside I), 11-O-Mogroside V (11-Oxomogride V) and the like. Mogrol is an aglycon of mogroside compounds and can be obtained by acid hydrolysis.
So far, no application report of cucurbitane tetracyclic triterpenoids in resisting renal fibrosis exists.
Disclosure of Invention
The invention discloses a new medical application of a cucurbitane tetracyclic triterpene compound, namely an application of the cucurbitane tetracyclic triterpene compound in preparing a medicament and/or a health-care product for preventing and/or treating renal fibrosis diseases.
The technical scheme of the invention is as follows:
application of cucurbitane tetracyclic triterpenoids in preparation of medicines and/or health products for preventing and/or treating renal fibrosis diseases.
The cucurbitane tetracyclic triterpenoid compound has a structural formula shown in a formula I, wherein R1 is hydroxyl or carbonyl, and R2, R3 and R4 are hydrogen or glycosyl; the glycosyl is hexapyranose, pentapyranose, hexafuranose, pentafuranose or their disaccharide, trisaccharide or tetrasaccharide.
Formula I
Preferably, R1 in formula I is hydroxy.
Preferably, R4 in formula I is hydrogen.
Preferably, in formula I, R2 is hydrogen, R3 is hydrogen or a sugar group; more preferably, the glycosyl is hexose or a disaccharide group, a triglycosyl group or a tetrasaccharide group consisting of the hexose; more preferably, the glycosyl is the disaccharide or trisaccharide of a six carbon pyranose.
Preferably, in formula I, R2 is a glycosyl, R3 is hydrogen or glycosyl; more preferably, the glycosyl is hexose or a disaccharide group, a triglycosyl group or a tetrasaccharide group consisting of the hexose; more preferably, the glycosyl is the disaccharide or trisaccharide of a six carbon pyranose.
Further, the structural formula of the cucurbitane tetracyclic triterpenoid is as follows, and is Mogroside IIIe (formula II), Mogroside III A1 (formula III), Mogroside IVe (formula IV), Mogroside V (formula V), Mogroside II A2 (formula VI), Mogroside I E1 (formula VII), 11-oxidation-Mogroside V (formula VIII) or mogrol (formula IX):
formula II
Formula III
Formula IV
Formula V
Formula VI
Formula VII
Of the formula VIII
Formula IX.
More preferably, the cucurbitane tetracyclic triterpene compound has a structural formula II, IV or IX.
The cucurbitane tetracyclic triterpene compound is applied to preparation of medicines and/or health care products for preventing and/or treating renal fibrosis diseases, and the compound shown in the formula I and the composition thereof and other human acceptable pharmaceutical excipients are prepared into tablets, granules, decoction or capsules.
The cucurbitane tetracyclic triterpenoid is a medicine and/or health-care product for reducing the accumulation of collagen in renal interstitium.
The cucurbitane tetracyclic triterpene compound is a medicine and/or health care product for resisting renal fibrosis, and can reduce inflammation degree, inhibit collagen formation and inhibit renal histiocyte fibrosis.
Drawings
FIG. 1 shows kidney pathological microscopic observation results of experimental rats in high-dose group, pseudo-operation group, model group and positive control group of mogroside IIIe, mogroside IVe and mogrol.
Detailed Description
The cucurbitane tetracyclic triterpene compound shown in the formula I is applied to the preparation of medicines and/or health care products for preventing and/or treating renal fibrosis diseases; wherein R1 is hydroxy or carbonyl; r2, R3, R4 are hydrogen or glycosyl; the glycosyl is hexapyranose, pentapyranose, hexafuranose, pentafuranose, and disaccharide, trisaccharide, or tetrasaccharide composed of the above two.
Formula I
Preferably, R1 in formula I is hydroxy.
Preferably, R4 in formula I is hydrogen.
Preferably, in formula I, R2 is hydrogen, R3 is hydrogen or a sugar group; more preferably, the glycosyl is hexose or a disaccharide group, a triglycosyl group or a tetrasaccharide group consisting of the hexose; more preferably, the glycosyl is the disaccharide or trisaccharide of a six carbon pyranose.
Preferably, in formula I, R2 is a glycosyl, R3 is hydrogen or glycosyl; more preferably, the glycosyl is hexose or a disaccharide group, a triglycosyl group or a tetrasaccharide group consisting of the hexose; more preferably, the glycosyl is the disaccharide or trisaccharide of a six carbon pyranose.
Further, the mogroside compound is selected from one of the following compounds: mogroside IIIe (formula II), Mogroside III A1 (formula III), Mogroside IVe (formula IV), Mogroside V (formula V), Mogroside II A2 (formula VI), Mogroside I E1 (formula VII), 11-oxo-Mogroside V (formula VIII) or mogrol (formula IX):
formula II
Formula III
Formula IV
Formula V
Formula VI
Formula VII
Of the formula VIII or
Formula IX.
More preferably, the cucurbitane tetracyclic triterpene compound is mogroside IIIe (formula II), mogroside IVe (formula IV) or mogrol (formula IX).
The cucurbitane tetracyclic triterpene compound is applied to preparation of medicaments and/or health care products for preventing and/or treating renal fibrosis diseases, and the compounds shown in the formula I and the composition thereof and other human acceptable pharmaceutical excipients are prepared into tablets, granules, decoction or capsules.
The medicine and/or health care product is a medicine and/or health care product for reducing collagen accumulation in renal interstitium.
The medicine and/or health care product can reduce the degree of inflammation, inhibit the formation of collagen and inhibit the renal tissue cell fibrosis and is a medicine and/or health care product for resisting renal fibrosis.
The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.
The invention takes mogroside IIIe, mogroside IVe and mogrol as examples to verify partial pharmacodynamic tests and results of the mogroside compounds in resisting renal fibrosis diseases.
The preparation of mogroside IIIe, mogroside IVe and mogrol of the invention:
the mogroside V content in the total mogroside extracted from natural fructus Siraitiae Grosvenorii is the highest, the total mogroside is hydrolyzed by β -glucosidase, and extracts containing different mogroside component ratios can be obtained according to the enzymolysis time.
The mogroside IIIe is obtained by separating commercially available fructus Siraitiae Grosvenorii extract with macroporous resin, and separating with high pressure reversed phase preparative chromatography to obtain product with purity of above 95%, or by preparing mogroside IV with Chinese patent 2010105610299, hydrolyzing commercially available fructus Siraitiae Grosvenorii extract with β -glucosidase, separating with macroporous resin, and separating with high pressure reversed phase preparative chromatography to obtain product with purity of above 95%.
The mogroside IVe is obtained by separating commercially available fructus Siraitiae Grosvenorii extract with macroporous resin, and separating with high pressure reversed phase preparative chromatography, and has purity of above 95%, or referring to the method for preparing mogroside IV in Chinese patent 2010105610299, hydrolyzing commercially available fructus Siraitiae Grosvenorii extract with β -glucosidase, separating with macroporous resin, and separating with high pressure reversed phase preparative chromatography, and has purity of above 95%.
The mogrol is prepared from commercially available fructus Siraitiae Grosvenorii extract by hydrolyzing with 5% sulfuric acid, and purifying with silica gel. The purity is more than 95 percent.
Example 1 Effect of cucurbitane-type tetracyclic triterpene Compounds on renal fibrosis model rats
Rat renal interstitial TGF- β 1, SGK1 and CTGF are expression factors of renal fibrosis, the expression level of the factors is increased, namely the development of the renal fibrosis is indicated, apoptosis is an autonomous cell clearing process triggered by physiological or pathological signals and has close relation with renal fibrosis, Bcl-2 is a protooncogene and can inhibit apoptosis, Bax has the effect of promoting apoptosis, the level of Bcl-2 is up-regulated, the level of Bax is down-regulated, namely the apoptosis process of the renal cell is improved, in addition, a large amount of accumulation of interstitial collagen is also an important factor causing the renal fibrosis, and the invention selects a rat renal interstitial fibrosis animal model with ligation and replication of a unilateral ureter for activity evaluation, and the model is an ideal model for evaluating a renal fibrosis treatment method at present.
Test method 1
1.1 materials and reagents
Mogroside IIIe, mogroside IVe, mogrol (made by the method provided by the invention), benazepril (Beijing Nowa pharmacy Co., Ltd.), rabbit anti-rat TGF- β1CTGF polyclonal antibodies and SABC kits; rabbit anti-rat SGK1 polyclonal antibody (Up state, usa); rat Bcl-2 protein polyclonal antibody, rat Bax polyclonal antibody, rat apoptosis in-situ detection kit, immunohistochemical SP kit and DAB kit (doctor Ded bioengineering Co.); the other reagents are analytically pure or molecular biology grade; benazepril, manufactured by Beijing Nowa pharmaceutical Limited; hydroxyproline (HYP) kit (tokyo bio corporation); fibronectin (FN) kit (shanghai bio-products institute); ML11 biomicroscope (Olympus corporation); full-automatic quantitative plotting enzyme-labeling instrument (Model ELx 808, Bio-Tek indications)
1.2 test methods
Clean adult male rats 90 with a body mass of 200 ± 20 g were randomly divided into 9 groups: a sham operation group, a model group, a control group (30 mg/kg, benazepril), a mogroside IIIe high dose group (50 mg/kg, mogroside IIIe-H), a mogroside IIIe low dose group (10 mg/kg, mogroside IIIe-L), a mogroside IVe high dose group (50 mg/kg, mogroside IVe-H), a mogroside IVe low dose group (10 mg/kg, mogroside IVe-L), a mogrol high dose group (50 mg/kg, mogrol-H), a mogrol base dose group (10 mg/kg, mogrol-L), 10 rats in each group, the model group rats were anesthetized with 4% chloral hydrate (1 ml/100 g) by intraperitoneal injection, the right side was recumbent, the hair was shaved, the left side was covered with a conventional sterilized towel, and about 0.5 cm below the dorsal rib was selected as an incision, after the skin is incised to the peritoneum once, the kidney and the ureter are dissociated, the left ureter is lifted by using a tissue clamp to take the middle section, the middle section is clamped by using a hemostatic clamp, the ureter is cut after the two sections of the left ureter are respectively ligated by silk threads, then the skin is continuously sutured, and the animal is fed with normal diet and drinking water. The sham group only opened the abdomen and left ureter was isolated, but ligation and clipping were not performed. All rats were post-operatively intramuscular with penicillin (10U/d, 5 consecutive days). The sham operation group and the model group were administered 1 ml of physiological saline by gavage every day, and the control group and the test drug group were administered 2 days before the operation in the above-mentioned dose for 2 weeks. After the end of dosing, 5 rats in each group were sacrificed at random, bled and assayed for Fibronectin (FN) according to fibronectin assay instructions. The left kidney was taken, half was soaked in 4% formaldehyde solution for pathology and immunohistochemistry examination, and the other half was quick frozen in a-75 ℃ freezer for future use. Another 5 rats in each group were sacrificed and the left kidneys were removed for examination of the kidneys Bcl-2, Bax and measurement of hydroxyproline.
2 index Observation and detection
2.1 pathological examination of the Kidney organs
Pathological changes of the kidney are observed by naked eyes, the left kidney tissue is fixed by 4 percent formaldehyde solution, conventional HE staining is carried out, and pathological conditions of the rat kidney tissue are observed under a light microscope.
2.2 Kidney TGF- β1Detection of SGK1 and CTGF
Detecting TGF- β in renal interstitium according to SABC kit instruction1SGK1, expression of CTGF. Selecting high power lens field (x 500) of tubulointerstitial region without glomerulus, analyzing brown signal in the field by using immunohistochemical analysis software system, and calculating kidney tissue TG of each group of ratsAverage positive expression rates of F- β 1, SGK1, and CTGF.
2.3 detection of Kidney Bcl-2, Bax
According to the specification of a rat Bcl-2 and Bax kit, Bcl-2 and Bax stained cells in the section are respectively observed under a light microscope visual field (50 multiplied by 10), and the cells with brown particles are positive cells. The mean gray levels of the kidneys Bcl-2 and Bax of the rats in each group were compared.
2.4 Kidney hydroxyproline and fibronectin detection
After the experiment, the rats were sacrificed for blood removal and Fibronectin (FN) was determined according to the fibronectin determination instructions. The left kidney was left after repeated lavage with saline and kidney tissues were fixed with 4% paraformaldehyde buffer. Cutting a proper amount of kidney tissues, and determining the content of hydroxyproline according to the determination instruction of a hydroxyproline kit.
All data from this experiment were processed using SPSS 14.0 statistical software. The measured data are expressed by mean +/-standard deviation, the difference between groups is compared by adopting a t test, and the difference with P <0.05 has statistical significance.
3 results of the experiment
3.1 Observation of Kidney pathologies
The kidney of the rat in the sham operation group is normal in size and shape, is reddish brown, has smooth surface, is not tense in coating luster, is free from adhesion, has clear nephron, and is free from dilatation or inflammatory cell infiltration. The model group rat has enlarged kidney volume, pale color, cystic sensation, tense envelope, adhesive envelope in a few areas, obvious renal tubule expansion, and a large amount of inflammatory cells infiltrated into interstitium, and is in an obvious fibrosis state. The positive drug control group and the high-dose group of the mogroside IIIe, the mogroside IVe and the mogrol are used for experimental rats, the kidneys of the rats are slightly enlarged and basically normal in color, but the rats are lighter than those in a pseudo operation group, the renal tubules of the rats are slightly dilated, inflammatory cells are slightly infiltrated, only obvious fibrotic lesions exist, and compared with a model group, the rats have obvious morphological improvement and obvious difference with the model group. The low dose groups of mogroside IIIe, mogroside IVe and mogrol were slightly less effective, the kidneys were enlarged and the color was light, and the differences were not particularly obvious compared with the model group (FIG. 1).
3.2 TGF- β in Kidney1Expression of SGK1 and CTGF
The experimental result shows that the renal interstitium of the rats in the sham operation group basically does not have the expression of the fibrosis expression factors of TGF- β 1, SGK1 and CTGF, in the model group, the fibrosis degree is obvious, the TGF- β 1, SGK1 and CTGF are expressed in a large quantity, in the rat kidney of the low-dose mogroside IIIe, mogroside IVe and mogrol experiment group, the expression levels of TGF- β 1, SGK1 and CTGF are reduced compared with the model group, but the statistical difference (P > 0.05) does not exist, in the positive drug control group and the rat kidney of the high-dose mogroside IIIe, mogroside IVe and mogrol experiment group, the expression levels of TGF- β 1, SGK1 and CTGF are remarkably reduced, compared with the model group, the statistical difference (P < 0.01) is remarkable, and the statistical result shows that the secretion of the TGF-891, the mogroside IVe and the mogrol resistance factors can be inhibited, and have a certain fibrosis resistance effect according to the dosage (Table 1).
TABLE 1 Effect of different cucurbitane tetracyclic triterpenoids on TGF- β 1, SGK1, CTGF expression (area percentage, n =10, x. + -. s)
| Group of | TGF-β1 | SGK1 | CTGF |
| Artificial operation group | 2.15±0.58 | 5.08±1.69 | 4.25±1.03 |
| Model set | 13.55±1.87## | 16.72±2.83## | 11.38±1.29## |
| Benazepril group | 6.98±0.87** | 8.91±1.74** | 6.28±1.16** |
| Mogroside IIIe-H | 6.81±1.12** | 8.74±1.65** | 6.39±1.02** |
| Mogroside IIIe-L | 11.87±0.97 | 14.55±2.18 | 9.64±1.27 |
| Mogroside IVe-H | 7.12±0.86** | 9.15±1.27** | 6.13±1.08** |
| Mogroside IVe-L | 10.76±1.18 | 13.58±1.92 | 9.22±1.14 |
| mogrol-H | 6.59±0.89** | 8.73±1.28** | 6.44±1.16** |
| mogrol-L | 11.35±1.21 | 13.76±1.88 | 9.48±1.22 |
Comparison with sham group##P is less than 0.01, compared with the model group**P＜0.01。
3.3 comparison of Bcl-2 and Bax expression levels in Kidney
The mean gray values of Bcl-2 and Bax in the rat kidneys of the model group and the low-dose mogroside IIIe, mogroside IVe and mogrol experimental group are both obviously increased, and compared with the sham-operated group, the statistical difference is obvious (P is less than 0.01). Compared with the model group, the experimental group of low-dose mogroside IIIe, mogroside IVe and mogrol has higher Bcl-2 expression level and lower Bax expression level, but has no obvious statistical difference. The average gray value of Bcl-2 in the rat kidney of the positive drug and high-dose mogroside IIIe, mogroside IVe and mogrol experimental group is obviously increased compared with that of the model group, the average gray value of Bax is obviously reduced compared with that of the model group, and both the positive drug and the high-dose mogroside IIIe, the high-dose mogroside IVe and the mogrol experimental group have statistical difference (P < 0.05). The statistical data show that mogroside IIIe, mogroside IVe and mogrol can up-regulate Bcl-2 level to a certain extent and down-regulate Bax level, improve apoptosis, relieve renal fibrosis degree and have certain dosage dependence (Table 2).
TABLE 2 Effect of different cucurbitane tetracyclic triterpenoids on Bcl-2, Bax expression (grey values)
| Group of | Bcl-2 | Bax |
| Artificial operation group | 75.16±3.12 | 135.74±5.21 |
| Model set | 158.66±5.37# | 201.38±6.15# |
| Benazepril group | 215.73±6.55* | 156.71±6.49* |
| Mogroside IIIe-H | 221.87±6.89* | 152.33±8.12* |
| Mogroside IIIe-L | 168.75±4.83 | 186.35±7.26 |
| Mogroside IVe-H | 218.61±7.23* | 149.82±6.87* |
| Mogroside IVe-L | 165.37±5.28 | 180.29±7.15 |
| mogrol-H | 225.69±7.06* | 145.78±6.88* |
| mogrol-L | 166.32±6.37 | 182.18±6.55 |
Comparison with sham group#P is less than 0.05, compared with the model group*P＜0.05。
3.4 measurement of hydroxyproline content in Kidney and fibronectin content in vivo
The content of rat renal Hydroxyproline (HYP) and the content of Fibronectin (FN) in the model group are obviously improved, which indicates that the model building is successful. The hydroxyproline and fibronectin in the kidney of rats in the low-dose mogroside IIIe, mogroside IVe and mogrol experimental group are reduced to a certain extent, but the low-dose mogroside IVe and mogrol experimental group has no significant statistical difference compared with the model group. The contents of hydroxyproline and fibronectin in the rat kidney in the positive drug control group, the high-dose mogroside IIIe, mogroside IVe and mogrol experimental group are all obviously reduced, and the positive drug control group has obvious difference compared with the model group. The above complaints show that the mogroside IIIe, the mogroside IVe and the mogrol can reduce the content of hydroxyproline and fibronectin in vivo, reduce the accumulation of collagen and relieve the symptoms of renal fibrosis, have a certain effect of resisting the renal fibrosis and have certain dosage tolerance.
TABLE 3 Effect of different cucurbitane tetracyclic triterpenoids on HYP, FN content
| Group of | HYP(μg/g) | FN(mg/L) |
| Artificial operation group | 328 | 6.7 |
| Model set | 744# | 28.5## |
| Benazepril group | 536* | 17.8* |
| Mogroside IIIe-H | 517* | 17.3* |
| Mogroside IIIe-L | 689 | 25.7 |
| Mogroside IVe-H | 489* | 16.5* |
| Mogroside IVe-L | 712 | 23.9 |
| mogrol-H | 506* | 18.2* |
| mogrol-L | 693 | 24.9 |
Comparison with sham group#P is less than 0.05, compared with the model group*P＜0.05。
The experiments show that the mogroside IIIe, the mogroside IVe and the mogrol can effectively inhibit the expression of fibrosis factors TGF- β 1, SGK1 and CTGF, reduce the expression of hydroxyproline and fibronectin, can also regulate the expression levels of Bcl-2 and Bax to inhibit the apoptosis of kidney cells, and further relieve the renal fibrosis lesion from multiple angles.
Claims (3)
1. The cucurbitane tetracyclic triterpene compound is used for preparing a medicament for preventing and/or treating renal fibrosis diseases, and the cucurbitane tetracyclic triterpene compound is:
the formula II,
The formula IV,
Or
2. The use of the cucurbitane tetracyclic triterpene compound according to claim 1 in the preparation of a medicament for preventing and/or treating renal fibrosis diseases, wherein the cucurbitane tetracyclic triterpene compound is prepared into tablets, granules, decoction or capsules together with other pharmaceutically acceptable excipients for a human body.
3. The use of the cucurbitane tetracyclic triterpene compound according to claim 1 or 2 for preparing a medicament for preventing and/or treating a renal fibrosis disease, wherein the cucurbitane tetracyclic triterpene compound is a medicament for reducing collagen accumulation amount in renal interstitium; or the cucurbitane tetracyclic triterpene compound is a medicine capable of reducing the expression of a fibrosis factor and inhibiting the renal cell apoptosis and resisting the renal fibrosis.
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Non-Patent Citations (3)
| Title |
|---|
| 中医药对TGF-β 1调控作用的研究进展;宋雅芳等;《上海中医药杂志》;20040131;摘要 * |
| 罗汉果总苷的微生物转化研究;司鹏鹏;《中国优秀硕士学位论文全文数据库农业科技辑》;20111231;摘要，第1-2页和图1，第15页第1段 * |
| 罗汉果甜苷对肝星状细胞HSC-T6 增殖及肝纤维化相关基因的影响;王勤等;《中草药》;20130228;摘要，第332页左栏第2段，第334页左栏第3段 * |
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