CN116098932A - Swertia pseudochinensis extract for improving cholestatic liver injury and application thereof - Google Patents
Swertia pseudochinensis extract for improving cholestatic liver injury and application thereof Download PDFInfo
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Abstract
The invention relates to the field of biomedicine simulation, and discloses a swertia pseudochinensis extract for improving cholestatic liver injury and application thereof. Proved by an intrahepatic cholestasis rat model, the swertia davidiana extract has an obvious effect of improving intrahepatic cholestasis, can effectively improve serum liver function indexes, liver tissue oxidative stress indexes and liver tissue pathological states of cholestasis hepatitis rats, and can be used for downwards regulating expression of liver tissue CYP7A1, NF-kappa B, I kappa B alpha and TNF-alpha proteins by upwards regulating expression of liver tissue FXR, NTCP, BSEP, MRP and TGR5 proteins, so that the swertia davidiana extract has an obvious protective effect on the ANIT induced cholestasis hepatitis rats.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a swertia pseudolaricis extract for improving cholestatic liver injury and application thereof.
Background
Cholestatic hepatitis, also called cholestatic liver disease, is a liver disease caused by liver cell or capillary bile duct dysfunction caused by pathogenic factors such as drug-induced injury, autoimmune disease, alcoholism and the like, reduces bile acid excretion, even causes diseases such as cirrhosis, liver failure, liver cancer and the like, the incidence rate of cholestatic hepatitis is rising year by year in the national range, and the clinical value of 1.5 times serum alkaline phosphatase (Alkaline phosphatase, ALP) is used as an index for critical judgment. Intrahepatic cholestasis is a common syndrome of liver diseases, and is mostly related to bile secretion disorder and accumulation of bile acid in liver cells, and the specific cause is not clear. Intrahepatic cholestasis is a high-frequency liver disease in newborns with a morbidity of between 1:2500 and 1:5000.
The bile acid is taken up by the liver cells, transported in the liver cells and excreted through the capillary bile duct, and abnormal any step in the liver cells can lead to unsmooth bile excretion and cholestasis. Currently, the main treatment modes of cholestatic hepatitis include drug treatment and liver transplantation, ursodeoxycholic acid (Ursodeoxycholic acid, UDCA) is approved by FDA as the first choice drug for CLI treatment, but the curative effect is poor; obeticholic acid (OCA) is a farnesol X receptor (Farnesyl X receptor, FXR) agonist, can regulate bile flow rate and cholate reabsorption to improve CLI symptoms, and is used as an alternative medicament for PBC patients who do not respond to UDCA, but OCA can increase side effects such as itching, abdominal pain, and the like. The Western medicine is mainly used for treating cholestatic liver diseases, has no specific therapeutic medicine aiming at etiology and related complications, and has serious physical and psychological burden on patients due to symptoms such as systemic pruritus and the like, high medical cost and long disease process. Currently, liver transplantation is the only effective method for treating cholestasis end-stage liver disease, but the problems of bile duct blockage, massive hemorrhage, immune rejection, canceration and the like after liver transplantation still remain to be overcome. Therefore, finding new targets and clinically effective drugs with little side effects is of great importance for treating cholestatic hepatitis.
Disclosure of Invention
The invention aims to provide a swertia davidi extract for improving cholestatic liver injury and application thereof, so as to solve the problems of large side effect and poor treatment effect in the treatment of cholestatic hepatitis in the prior art.
In order to achieve the above purpose, the invention adopts the following technical scheme: a swertia davidi extract for improving cholestatic liver injury is prepared from fresh swertia davidi through extracting with organic solvent, centrifuging, concentrating, and redissolving.
On the other hand, the technical scheme provides an application of the swertia davidiana extract for improving cholestatic liver injury in preparing medicines for treating cholestatic hepatitis.
Preferably, as an improvement, a preparation method of swertia davidiana extract for improving cholestatic liver injury comprises the following steps:
step one, selecting raw materials: taking fresh swertia pseudochinensis as a raw material;
step two, drying: placing the cleaned whole grass of swertia pseudochinensis in an oven for drying;
step three, extracting: reflux-extracting the dried swertia davidiana with ethanol as a solvent;
step four, concentrating by a centrifugal machine: centrifuging the extractive solution to remove impurities, concentrating the supernatant under reduced pressure, and adding ultrapure water for redissolution.
Preferably, as a modification, in the second step, the drying temperature is 50 ℃.
Preferably, in the third improvement step, the swertia pseudolariciresiana is sheared into segments of 3-5 cm before the solvent extraction is performed.
Preferably, in the third step, the extraction solvent is 50-70% ethanol, and the mass ratio of the extraction solvent to the swertia pseudochinensis is (8-12): 1.
Preferably, in the third step, the number of times of extraction is 3, each time of extraction is 2 hours, and the extraction liquid is filtered and combined after the extraction is finished.
Preferably, in the fourth step, the centrifugation speed is 3000rpm/min and the centrifugation time is 15-20min.
Preferably, as a modification, in the fourth step, the concentration temperature is 45-55 ℃.
Preferably, in the fourth step, the re-dissolved swertia davidiana extract is subjected to D101 macroporous resin, gradient elution is sequentially performed by water, 20% ethanol, 40% ethanol, 60% ethanol, 80% ethanol and 100% ethanol, 6 column volumes are eluted in each gradient, finally the water elution part and the 100% ethanol elution part are discarded, the rest parts are mixed, then the mixture is concentrated under reduced pressure by a rotary evaporator, and ultrapure water is added for dissolution and volume fixing is performed to 400mL.
The principle and the advantages of the scheme are as follows: proved by an intrahepatic cholestasis rat model, the swertia davidiana extract has an obvious effect of improving intrahepatic cholestasis, can effectively improve serum liver function indexes, liver tissue oxidative stress indexes and liver tissue pathological states of cholestasis hepatitis rats, and can be used for downwards regulating expression of liver tissue CYP7A1, NF-kappa B, I kappa B alpha and TNF-alpha proteins by upwards regulating expression of liver tissue FXR, NTCP, BSEP, MRP and TGR5 proteins, so that the swertia davidiana extract has an obvious protective effect on the ANIT induced cholestasis hepatitis rats. The results show that the swertia davidi can regulate the expression of bile acid synthase CYP7A1, bile acid uptake transporter NTCP, efflux transporter MRP2 and BSEP by activating FXR nuclear receptor and TGR5 nuclear receptor, thereby reducing the synthesis of bile acid, reducing the uptake of bile acid by liver cells, increasing the efflux of bile acid, and improving intrahepatic cholestatic hepatitis; meanwhile, swertia davidiana can inhibit the expression of NF-kappa B, I kappa B alpha and TNF-alpha proteins by regulating an NF-kappa B inflammatory pathway, reduce the expression of downstream inflammatory cytokines, and improve ANIT-induced cholestatic hepatitis. During the research and development period, the research on the drug effect and pharmacological mechanism of swertia davidiana for improving cholestasis is one of the difficulties of the technical scheme, wherein the ANIT modeling dosage is particularly critical, and long-time fumbling and research are required.
Drawings
FIG. 1 is a flow chart of HE staining in an embodiment of the invention.
FIG. 2 is a flow chart of the Western blot experiment steps of liver tissue.
Fig. 3 is the liver index effect of swertia davidiana on intrahepatic cholestasis rats (x±s, n=8).
FIG. 4 shows the change of serum biochemical index of swertia pseudochinensis in the liver on cholestasis rats.
Fig. 5 is the effect of swertia davidiana on the content of SOD, GSH and MDA in liver tissue homogenates of intrahepatic cholestasis rats (x±s, n=8).
Fig. 6 is the effect of swertia davidiana on liver pathology in intrahepatic cholestasis rats (HE, 200×).
FIG. 7 shows the effect of swertia davidi on FXR, CYP7a1, NTCP, BSEP, MRP2, TGR5, NF- κ B p65, IκB- α, TNF- α protein expression in rat liver tissue.
Detailed Description
The following is a detailed description of embodiments, but embodiments of the invention are not limited thereto. The technical means used in the following embodiments are conventional means well known to those skilled in the art unless otherwise specified; the experimental methods used are all conventional methods; the materials, reagents, and the like used are all commercially available.
Example 1
Swertia pseudochinensis extract for improving cholestatic liver injury: the preparation method comprises the steps of taking fresh swertia pseudochinensis as a raw material, extracting with an organic solvent, centrifuging, concentrating and redissolving.
A preparation method of swertia pseudochinensis extract for improving cholestatic liver injury comprises the following steps:
step one, washing impurities such as sediment and the like from fresh swertia pseudochinensis;
step two, putting the cleaned swertia pseudochinensis in an oven, and drying at 50 ℃ to constant weight;
step three, taking out whole grass of swertia davidiana which is baked to constant weight, cutting the whole grass into sections of 3-5 cm, weighing 200g of swertia davidiana medicinal material, adding 10 times of 50% ethanol, reflux-extracting for 3 times, each time for 2 hours (calculated from the micro boiling of the solution), filtering the extracting solution with 8 layers of gauze, and combining the extracting solutions obtained for 3 times;
centrifuging the combined extracting solution for 15-20min by using a low-speed centrifuge (3000 rpm/min), concentrating the supernatant under reduced pressure by using a rotary evaporator at 50 ℃, and then adding ultrapure water for dissolution;
step five, subjecting the dissolved swertia davidi extract to D101 macroporous resin, sequentially performing gradient elution with water, 20% ethanol, 40% ethanol, 60% ethanol, 80% ethanol and 100% ethanol, performing gradient elution with 6 column volumes each, discarding the water elution part and the 100% ethanol elution part, mixing the rest parts, concentrating under reduced pressure by a rotary evaporator, adding ultrapure water for dissolution, and fixing the volume to 400mL (the concentration is 0.5g/mL calculated by crude drug).
Example 2 pharmacodynamic evaluation of swertia pseudochinensis extract to improve intrahepatic cholestasis in rats
1. Laboratory animals and groups
32 SPF-class male Wistar rats (weight at 180-220 g), 1 week of adaptive feeding were weighed and randomly divided into 4 groups of 8:
(1) Blank Control group (Control);
(2) Model control group (ANIT/Model);
(3) Positive drug group (ursodeoxycholic acid, UDCA);
(4) Swertia pseudochinensis extract group (SDF, 0.525 g.kg) -1 )。
2. Preparation and administration of cholestatic hepatitis model
Day 1-6: the ursodeoxycholic acid group and the swertia pseudochinensis group are respectively administered by preventive gastric lavage; the blank and model groups were gastrected with 0.5% CMC-Na solution.
Day 7: the ursodeoxycholic acid group and the swertia pseudochinensis group are respectively administered by preventive gastric lavage; the blank and model groups were gastrected with 0.5% CMC-Na solution. Ursodeoxycholic acid group, swertia pseudochinensis group and model group stomach infusion ANIT 60 mg/kg -1 Modeling, ANIT single acute modeling requires that rats are fasted for 12 hours before and after administration; the blank control group was given an equal volume of olive oil blank solution.
Day 8: each group was dosed as received.
Day 9: 40 mg/kg -1 Pentobarbital sodium anesthetizes rats, and the abdominal aorta is used for taking blood and liver tissues for later use. No water was forbidden for 12 hours before sample collection. The specific operations are shown in Table 1.
Table 1 experimental animal grouping and dosing regimen
Note that: -:0.5% cmc-Na; and (2) the following steps: olive oil; delta: an ANIT modeling agent; o: UDCA; and ∈: swertia-swertia drug administration group
3. Liver index determination
All rats were weighed after the end of the experiment, animals were sacrificed, livers were obtained by dissection and weighed, and liver index was calculated. The results are shown in FIG. 3, wherein FIG. 3 (left) shows the body weight of each group of rats, FIG. 3 (middle) shows the liver mass of each group of rats, and FIG. 3 (right) shows the liver index of each group of rats. In fig. 3, P <0.01, compared to the blank control group; # P <0.01, compared to model group. As can be seen from the data in fig. 3: the model group had significantly increased liver index (P < 0.01) compared to the placebo group, and the SDF group had significantly improved liver index increase (P < 0.01) due to cholestasis compared to the model group.
4. Serum and tissue sample collection
No water was forbidden for 12 hours before the test. Anesthetized rat, blood is taken from abdominal aorta, and after standing for 1h, 3000 r.min -1 Centrifuging for 15min, collecting supernatant, centrifuging for 15min under 12000r/min, collecting supernatant, sub-packaging, and storing in a refrigerator at-80deg.C in dark place. The rat was dissected and the liver (normal saline perfusion) was removed, the filter paper was blotted to remove water, weighed and cut into four parts, one part was fixed with 4% paraformaldehyde, and the remaining samples were stored in a-80 ℃ refrigerator for use.
5. Pharmacodynamic index detection
TBIL (μmol.L) was detected by a fully automated biochemical analyzer and according to the kit instructions -1 )、DBIL(μmol·L -1 )、TBA(μmol·L -1 ) Content and ALP (U.L) -1 )、ALT(U·L -1 )、AST(U·L -1 ) Activity. As shown in FIG. 4, it is clear from the data of FIG. 4 that the enzyme activity of ALP, ALT, AST and the content of DBIL, TBIL, TBA in the serum of the model group are extremely high as compared with those of the blank group (P<0.001 And) indicate that the model was successful. The enzyme activity of ALP, ALT, AST and the content of DBIL, TBIL, TBA in serum of SDF group were significantly reduced compared to model group (P<0.01)。
6. Determination of SOD, GSH and MDA in liver tissue homogenates
The method is strictly adhered to the operation instructions of the kit, and the absorbance of the liver tissue SOD, MDA, GSH is detected by an enzyme-labeled instrument and calculated to obtain the content of the liver tissue SOD, MDA, GSH. As shown in fig. 5, it is clear from the data of fig. 5 that the SOD activity and GSH content were significantly reduced (P < 0.01) and the MDA content was significantly increased (P < 0.01) in the model group compared to the blank group. Compared with the model group, the SOD activity and GSH content of the SDF group rats are obviously increased (P < 0.01), and the MDA content is obviously reduced (P < 0.01).
7. Liver histopathological observations
The liver tissue HE staining flow chart is shown in fig. 1, the experimental result is shown in fig. 6, the blank control group can be seen to have complete liver cells, the cell nucleus can be seen clearly, and the cell morphology is not abnormal. Compared with the blank control group, the model group can see inflammatory cell infiltration, hepatocyte degeneration and focal necrosis. Compared with the model group, the SDF group can improve liver histopathological damage caused by ANIT, and the number of hepatic cell necrosis is obviously reduced.
8. Effect of Swertia in Rabdosia on FXR, CYP7a1, NTCP, BSEP, MRP, TGR5, NF- κ B p65, IκB- α, TNF- α protein expression in rat liver tissue
The experiment researches the influence of swertia pseudochinensis extract on the expression level of liver tissue bile acid nuclear receptor (FXR and TGR 5) proteins; effects on liver tissue bile acid synthase (CYP 7 A1) protein expression levels; the effect on the expression level of liver tissue bile acid transporter (uptake transporter: NTCP; efflux transporter: BSEP and MRP 2) protein and on the expression level of liver tissue inflammatory pathway-related protein (κB inhibitor kinase: NF-. Kappa.B, kappa B inhibitor kinase: IκBα, tumor necrosis factor: TNF-. Alpha.).
The Western blot experimental process of liver tissues is shown in figure 2, and the result is shown in figure 7, which shows that swertia davidiana can down regulate the expression of CYP7A1, NF-kappa B, I kappa B alpha and TNF-alpha proteins of liver tissues by up-regulating the expression of FXR, NTCP, BSEP, MRP and TGR5 proteins of liver tissues, and has obvious protection effect on rats with ANIT cholestatic hepatitis. The results show that the swertia davidi can regulate the expression of bile acid synthase CYP7A1, bile acid uptake transporter NTCP, efflux transporter MRP2 and BSEP by activating FXR nuclear receptor and TGR5 nuclear receptor, thereby reducing the synthesis of bile acid, reducing the uptake of bile acid by liver cells, increasing the efflux of bile acid, and improving intrahepatic cholestatic hepatitis; meanwhile, swertia davidiana can inhibit the expression of NF-kappa B, I kappa B alpha and TNF-alpha proteins by regulating an NF-kappa B inflammatory pathway, reduce the expression of downstream inflammatory cytokines, and improve ANIT-induced cholestatic hepatitis.
The foregoing is merely exemplary of the present invention, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present invention, and these should also be regarded as the protection scope of the present invention, which does not affect the effect of the implementation of the present invention and the practical applicability of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (10)
1. An extract of swertia pseudochinensis Franch for improving cholestatic liver injury, which is characterized in that: the preparation method comprises the steps of taking fresh swertia pseudochinensis as a raw material, extracting with an organic solvent, centrifuging, concentrating and redissolving.
2. The method for preparing a swertia davidi extract for improving cholestatic liver injury according to claim 1, comprising the steps of:
step one, selecting raw materials: taking fresh swertia pseudochinensis as a raw material;
step two, drying: placing the cleaned whole grass of swertia pseudochinensis in an oven for drying;
step three, extracting: reflux-extracting the dried swertia davidiana with ethanol as a solvent;
step four, concentrating by a centrifugal machine: centrifuging the extractive solution to remove impurities, concentrating the supernatant under reduced pressure, and adding ultrapure water for redissolution.
3. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 2, which is characterized in that: in the second step, the drying temperature is 50 ℃.
4. A method for preparing a swertia pseudochinensis extract for improving cholestatic liver injury according to claim 3, wherein: in the third step, the swertia pseudochinensis is sheared into segments of 3-5 cm before solvent extraction.
5. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 4, wherein the method comprises the following steps: in the third step, the extraction solvent is 50-70% ethanol, and the mass ratio of the extraction solvent to swertia pseudochinensis is (8-12): 1.
6. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 5, wherein the method comprises the following steps: in the third step, the extraction times are 3 times, the extraction time is 2 hours each time, and the extraction liquid is filtered and combined after the extraction is finished.
7. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 6, wherein the method comprises the following steps: in the fourth step, the centrifugation speed is 3000rpm/min, and the centrifugation time is 15-20min.
8. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 7, wherein the method comprises the following steps: in the fourth step, the concentration temperature is 45-55 ℃.
9. The method for preparing the swertia davidi extract for improving cholestatic liver injury according to claim 8, wherein the method comprises the following steps: in the fourth step, the re-dissolved swertia davidiana extract is subjected to D101 macroporous resin, water, 20% ethanol, 40% ethanol, 60% ethanol, 80% ethanol and 100% ethanol are sequentially subjected to gradient elution, 6 column volumes are eluted in each gradient, finally the water elution part and the 100% ethanol elution part are discarded, the rest parts are mixed, and then the mixture is concentrated under reduced pressure by a rotary evaporator, and ultrapure water is added for dissolution and volume fixing to 400mL.
10. Use of a swertia pseudolariciresiana extract for improving cholestatic liver injury according to claim 1 in the manufacture of a medicament for treating cholestatic hepatitis.
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| CN117018058A (en) * | 2023-07-06 | 2023-11-10 | 成都市畜禽遗传资源保护中心 | New use of swertia southwest or its extract and screening method of active marker for treating acute liver failure |
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