CN115645423B - Application of ginsenoside Re in preparing medicine for preventing or treating cholestatic liver diseases - Google Patents
Application of ginsenoside Re in preparing medicine for preventing or treating cholestatic liver diseases Download PDFInfo
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Abstract
The invention discloses application of ginsenoside Re (G-Re) in preparing medicines for preventing or treating cholestatic liver diseases, and a treatment effect and an action mechanism of the ginsenoside Re on cholestatic liver diseases are discussed by establishing an acute cholestatic hepatitis model of rats induced by phenyl isothiocyanate (APIT), and the result shows that the ginsenoside Re can relieve cholestatic liver disease symptoms, mainly shows that the ginsenoside Re can reduce serum ALT, ALP, tbil and gamma-GT levels, restore bile excretion amount and inhibit liver inflammatory factor expression level, and provides a novel medicine with definite curative effect and small side effect for clinically treating cholestatic liver diseases.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to application of ginsenoside Re in preparation of a medicine for preventing or treating cholestatic liver diseases.
Background
Cholestasis is a phenomenon in which bile acid accumulates in a large amount in hepatocytes and bile ducts due to formation and distribution of bile in the body. Cholestasis can lead to the occurrence of cholestatic liver disease. Cholestatic liver disease occurs because of complex causes, and viral infection, drugs, pregnancy, immunity, genetics, parenteral nutrition, etc. can cause intrahepatic cholestasis, such as less effective treatment, and may even progress to liver fibrosis, cirrhosis, liver failure, and liver tumors. Epidemiological evidence shows that the incidence rate of cholestatic hepatitis in China accounts for more than 10% of patients with chronic liver diseases. The incidence rate of cholestatic hepatitis in China accounts for more than 10% of patients with chronic liver diseases. Currently, the main clinical therapeutic drugs include ursodeoxycholic acid (UDCA), S-adenosylmethionine, cholestyramine, obeticholic acid, fibrates, etc., wherein UDCA is a first-line drug clinically recommended, and the main purpose is to improve clinical symptoms and liver injury caused by cholestasis. However, clinical efficacy is not yet satisfactory, about 30% of patients are ineffective against UDCA, and UDCA has slow onset, is more expensive, and is in urgent clinical demand for more effective drugs.
Ginsenoside Re (G-Re) is tetracyclic triterpene extracted from Notoginseng radix and Ginseng radix. At present, research reports that ginsenoside Re can relieve oxidative stress by up-regulating GPX4, so that 6-hydroxydopamine induced cell injury is relieved. Ginsenoside Re can also relieve LPS-induced systemic inflammation by inhibiting TLR4 pathway. Furthermore, ginsenoside Re has also been reported to reduce myocardial apoptosis following ischemia reperfusion by affecting Bcl-2 and Bax levels. In addition, ginsenoside Re can also regulate autophagy, inhibit JNK and NF- κB activation, and thereby reduce insulin. The ginsenoside Re has various biological activities such as anti-inflammatory, antioxidant and anti-apoptosis, and has remarkable effects in treating diabetes and cardiovascular diseases.
However, the therapeutic effect and mechanism of ginsenoside Re on cholestatic liver diseases have not been reported yet.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of ginsenoside Re in preparing a medicament for preventing or treating cholestatic liver diseases.
Preferably, the cholestatic liver disease according to the present invention is cholestatic hepatitis, more preferably acute cholestatic hepatitis induced by phenylisothiocyanate APIT.
The ginsenoside Re can be obtained by extracting and purifying ginseng or pseudo-ginseng, and can also be obtained by commercial purchase.
According to the invention, a rat acute cholestasis type hepatitis model is induced by phenyl isothiocyanate (APIT), and the result shows that ginsenoside Re has a remarkable inhibition effect on Tbil, ALT, ALP and gamma-GT activity increase caused by APIT induced cholestasis, and also has a remarkable improvement on inhibition of APIT induced hepatocyte injury, inflammatory cell infiltration and bile excretion, thus the ginsenoside Re has a good treatment effect on APIT induced cholestasis type hepatitis; and ginsenoside Re has remarkable inhibition effect on the increase of IL-1 beta, TNF-alpha and IL-6 mRNA level caused by APIT induced cholestasis, and also has remarkable improvement on the increase of protein levels of NOS, COX-2, IL-18 and NLRP3, which shows that the ginsenoside Re has good anti-inflammatory effect on APIT induced cholestasis hepatitis and provides more favorable pharmacodynamics basis for clinically treating cholestasis liver diseases.
The invention also provides a medicine for preventing or treating cholestatic liver diseases, which comprises effective content of ginsenoside Re and a pharmaceutically acceptable carrier. The medicament for preventing or treating cholestatic liver diseases can be prepared into a proper dosage form by a conventional method in the field. Preferably, the dosage form of the medicament is tablets, capsules, powder, injection, powder, syrup, pills, mixture or granules.
Such pharmaceutically acceptable carriers include, but are not limited to, fillers, disintegrants, sweeteners, lubricants, suspending agents, preservatives, binders and the like, in amounts conventional in the art.
Compared with the prior art, the invention has the following excellent effects:
the invention provides a new application of ginsenoside Re in preparing medicines for preventing or treating cholestatic liver diseases, and a treatment effect and an action mechanism of the ginsenoside Re on cholestatic liver diseases are discussed by establishing A Phenyl Isothiocyanate (APIT) induced rat acute cholestatic hepatitis model.
Drawings
FIG. 1 shows the effect of ginsenoside Re on pathological changes in cholestatic rats.
Detailed Description
The present invention will be further illustrated by the following examples, which are not intended to limit the scope of the invention.
The reagents or reagents used in the examples of the present invention are as follows:
ginsenoside Re (lot number: S27142, available from Shanghai Seiyaku Biotechnology Co., ltd.);
ursodeoxycholic acid (lot number: s25093, available from Shanghai Seiyaku Biotechnology Co., ltd.);
the dosage of ginsenoside Re is 5mg/kg, 10mg/kg, 20mg/kg, and the dosage is 20ml/kg.
The ginsenoside Re is in solid powder form, and the application method of the ginsenoside Re comprises the following steps: dissolving in DMSO of 1% of the total volume, shaking for dissolving, and adding distilled water to obtain 0.25 mg/ml, 0.5 mg/ml, 1 mg/ml, and 2 mg/ml solution.
Acute cholestatic liver disease is induced by phenylisothiocyanate (APIT) (liquid, 1.13g per 1 ml) diluted to 110mg/kg with olive oil.
Ursodeoxycholic acid is used as a positive medicine group, the dosage is 50 mg/kg, the ursodeoxycholic acid is dissolved in DMSO of which the total volume is 1%, and distilled water is added to prepare a solution of 2.5 mg/ml after shaking and full dissolution.
The following experimental examples demonstrate the technical effects of the present invention.
Example 1: protection of ginsenoside Re in cholestatic liver diseases
1. Experimental materials
Clean-class male SD rats, 200+ -20+ -g weight, were housed in plastic cages and fed with free diet and drinking water for 7 days, and were acclimatized.
2. Experimental method
The experimental example uses phenyl isothiocyanate (APIT) to establish a rat acute intrahepatic cholestasis type hepatitis model, and researches the therapeutic effect of ginsenoside Re on the model rat.
2.1 Experimental grouping
The rats were randomly divided into a normal control group, a model group, ursodeoxycholic acid positive drug group, ginsenoside Re 5mg/kg drug group, ginsenoside Re10 mg/kg drug group and ginsenoside Re20 mg/kg drug group.
2.2 methods of administration
The positive drug group and the drug administration group are subjected to gastric lavage administration according to the dosage of 20ml/kg, normal control group and model group are given with physiological saline with the same volume once daily, administration is carried out for 6 days, after 6 days of the lavage, other groups of rats are subjected to gastric lavage administration of 110mg/kg of APIT except the normal control group, and after 8 hours of the administration of APIT, all rats are subjected to biliary excretion test to determine the bile flow rate for 2 hours; then, the abdominal aorta was bled to prepare serum, and left She Ganzang was fixed in 10% formaldehyde solution for later use.
3. Experimental data detection and processing
3.1 detection index
3.1.1 serum index determination
After the abdominal aorta of the rat takes blood, the blood sample is kept at room temperature for more than 30min, centrifuged at 3000 rpm for 10 min, and then the supernatant is taken to obtain a serum sample. The serum levels of glutamic pyruvic transaminase (ALT), alkaline phosphatase (ALP), total serum bilirubin (Tbil), and glutamyltransferase (gamma-GT) were then assayed in each group, following the kit instructions.
3.1.2 histopathological observations of liver
Rat livers were fixed with 10% neutral formaldehyde, paraffin embedded, 4-5 μm sections, xylene dewaxed, gradient ethanol dehydrated, conventional HE stained, ethanol dehydrated, xylene transparent, resin mounted and observed using a microscope.
3.1.3 biliary excretion experiments
The rats were anesthetized by intraperitoneal injection of uratam 1 g/kg, cannulated by common bile duct, and bile was collected on ice with a centrifuge tube pre-weighed and added with KH2PO4 of 1mol/L and 100. Mu.L.
3.2 statistical analysis
SPSS 26.0 software is adopted for data processing, and a statistical method selects single-factor analysis of variance.
4. Experimental results
The effect of ginsenoside Re on the biochemical index of serum of cholestatic rats is shown in Table 1, the effect on bile excretion is shown in Table 2, and the effect on liver histopathological changes of cholestatic rats is shown in FIG. 1.
TABLE 1 influence of ginsenoside Re on the biochemical index of cholestatic rat serum
# indicates that P < 0.01 compared to the normal control group,
* Represents P < 0.01 compared to the model control group, and represents P < 0.05 compared to the model control group.
TABLE 2 influence of ginsenoside Re on bile excretion of cholestatic rats
# # indicates that P < 0.001 compared to the normal control group,
* Represents P < 0.001 compared to the model control group, and represents P < 0.05 compared to the model control group.
Elevated Tbil, ALP and gamma-GT activity are serological markers of intrahepatic cholestasis, ALT is a serological marker of reactive liver function. As can be seen from tables 1 and 2, the model groups Tbil, ALP, γ -GT and ALT activity were significantly increased, and bile excretion was significantly reduced; as can be seen from fig. 1, the model group showed inflammatory infiltration and hepatocyte necrosis; indicating that the model modeling of the acute intrahepatic cholestasis type hepatitis of the rat is successful.
It is also clear from tables 1 and 2 that ursodeoxycholic acid and ginsenoside Re have remarkable inhibitory effect on increase of Tbil, ALT, ALP and gamma-GT activity caused by APIT-induced cholestasis, and remarkably improve inhibition of APIT-induced hepatocyte injury, inflammatory cell infiltration and bile excretion.
5. Conclusion of the experiment
Ginsenoside Re has good therapeutic effect on cholestatic hepatitis induced by APIT.
Example 2: influence of ginsenoside Re on inflammation index in cholestatic liver disease
1. Experimental materials
Clean-class male SD rats, 200+ -20+ -g weight, were housed in plastic cages and fed with free diet and drinking water for 7 days, and were acclimatized.
2. Experimental method
The experimental example uses phenyl isothiocyanate (APIT) to establish a rat acute intrahepatic cholestasis type hepatitis model, and researches the therapeutic effect of ginsenoside Re on the model rat.
2.1 Experimental grouping
The rats were randomly divided into a normal control group, a model group, ursodeoxycholic acid positive drug group, ginsenoside Re10 mg/kg drug group, ginsenoside Re20 mg/kg drug group and ginsenoside Re 40mg/kg drug group.
2.2 methods of administration
The administration group and the yang administration group are administrated by lavage according to the dosage of 20ml/kg, normal control group and model group are administrated with physiological saline with the same volume once daily, administration is carried out for 6 days, rats in the other groups are administrated by lavage for 110mg/kg except for the normal control group after 6 days of administration, all rats are sacrificed after 8 hours of administration of APIT, liver is taken, residual blood on the surface is washed by physiological saline, and the residual blood is wiped clean by filter paper and stored at-80 ℃ for standby.
3. Experimental data detection and processing
3.1 detection index
3.1.1 RT-qPCR detection of expression level of inflammatory factor mRNA
Taking rat liver tissue of 50-100 mg, adding 1mLTRIzol, repeatedly extracting with a 1mL injector until the mixture is uniformly suspended, sequentially adding chloroform, isopropanol and 75% alcohol, respectively centrifuging at 12000 rpm and 4 ℃ to obtain an RNA sample, measuring the concentration of the RNA by using an ultraviolet spectrophotometry instrument, configuring a reverse transcription system according to the requirements of the specification, and preparing a cDNA sample on the reverse transcription instrument. According to the specification, a PCR reaction system (DEPC water 2 mu L, mix mu L, upstream and downstream primers 1 mu L, cDNA mu L) is configured.
The PCR amplification reaction conditions were: pre-denaturation at 95℃for 30 s, denaturation at 95℃for 10 s, annealing at 60℃for 30 s,40 cycles. The study uses a relative quantification method, using 2- ΔΔct analysis data.
3.1.2
3.2 statistical analysis
SPSS 26.0 software is adopted for data processing, and a statistical method selects single-factor analysis of variance.
4. Experimental results
The effect of ginsenoside Re on IL-1 beta, IL-6 and TNF-alpha mRNA levels in cholestatic rat liver is shown in Table 3 and the effect on inflammatory protein levels in cholestatic rat liver is shown in Table 4.
TABLE 3 Effect of ginsenoside Re on IL-1 beta, IL-6 and TNF-alpha mRNA levels in cholestatic rat liver
# # indicates that P < 0.001 compared to the normal control group, # indicates that P < 0.05 compared to the normal control group,
* P < 0.001 is shown as compared to the model control group, P < 0.01 is shown as compared to the model control group, and P < 0.05 is shown as compared to the model control group.
TABLE 4 influence of ginsenoside Re on the inflammatory protein levels in cholestatic rat liver
# indicates that P < 0.01 compared to the normal control group, # indicates that P < 0.05 compared to the normal control group,
* Represents P < 0.001 compared to the model control group, and represents P < 0.05 compared to the model control group.
NLRP3 is a key regulator involved in inflammatory responses, COX-2 and iNOS are two important inflammatory proteins, and IL-18, IL-1β, TNF- α and IL-6 are pro-inflammatory factors, all of which can be involved in the development and amplification of inflammatory responses. As can be seen from tables 3 and 4, the levels of IL-1β, TNF- α and IL-6 mRNA were significantly increased in the model group, and the levels of iNOS, COX-2, IL-18 and NLRP3 proteins were significantly increased, indicating an increased inflammatory level in the acute intrahepatic cholestatic hepatitis model in rats.
It is also clear from tables 3 and 4 that ursodeoxycholic acid and ginsenoside Re have remarkable inhibitory effect on increase of IL-1β, TNF- α and IL-6 mRNA levels caused by cholestasis induced by APIT, and remarkably improve protein levels of NOS, COX-2, IL-18 and NLRP 3.
5. Conclusion of the experiment
Ginsenoside Re has good anti-inflammatory effect on cholestatic hepatitis induced by APIT.
Claims (3)
1. Use of ginsenoside Re as the sole active ingredient in the manufacture of a medicament for preventing or treating cholestatic liver disease, which is acute cholestatic hepatitis induced by phenylisothiocyanate APIT; the ginsenoside Re can reduce the levels of serum ALT, ALP, tbil and gamma-GT, restore bile excretion, and inhibit the expression level of liver inflammatory factors.
2. The use according to claim 1, wherein the medicament comprises an effective amount of ginsenoside Re and a pharmaceutically acceptable carrier.
3. The use according to claim 2, wherein the medicament is in the form of a tablet, capsule, powder, injection, powder, syrup, pill, mixture or granule.
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| JP4719465B2 (en) * | 2002-09-04 | 2011-07-06 | ディーエスエム アイピー アセッツ ビー．ブイ． | A nutritional and therapeutic composition comprising an insulin sensitivity enhancer and a peptide fraction |
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| JPH1099094A (en) * | 1996-09-25 | 1998-04-21 | Happy World:Kk | Production of ginseng saponin metabolites |
| CN101721598A (en) * | 2008-10-22 | 2010-06-09 | 维康力(国际)有限公司 | Traditional Chinese medicine composition for treating liver diseases and preparation method and use thereof |
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