CN113069501A - Application of compound lightyellow sophora root injection in preparing medicine for treating chronic hepatic fibrosis - Google Patents
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Abstract
The invention provides an application of a compound radix sophorae flavescentis injection in preparing a medicine for treating chronic hepatic fibrosis, the compound radix sophorae flavescentis injection can also be applied in repairing liver injury, and liver tissues are recovered to be normal by inhibiting the deposition of collagen in the liver; in addition, the compound lightyellow sophora root injection can also inhibit the activation of hepatic stellate cells, and is prepared for treating chronic hepatic fibrosis by inhibiting the activation of the hepatic stellate cells; preparing a medicament for treating chronic liver fibrosis by down-regulating the expression of hepatic stellate cell activators; preparing a medicament for treating chronic hepatic fibrosis by selectively inhibiting hepatic stellate cell activation; preparing to treat chronic liver fibrosis by interfering the activation of TGF-beta/Smad signal axis in hepatic stellate cells; compared with the current clinical lack of approved medicines for treating hepatic fibrosis, the application of the invention shows that the compound lightyellow sophora root injection can be used as a promising candidate medicine for preventing or treating hepatic fibrosis and preventing hepatic fibrosis progression in clinical application.
Description
Technical Field
The invention belongs to the technical field of development of new functions of medicaments, and particularly relates to application of a compound sophora flavescens injection in preparation of a medicament for treating chronic hepatic fibrosis.
Background
Compound kuh-seng injection (CKI), a classic herbal Compound preparation, is approved by the National Medical Products Administration (NMPA) for clinical treatment of pain caused by cancer. However, the specific mechanism of the compound lightyellow sophora root injection for treating chronic hepatic fibrosis and relieving the progression of hepatic fibrosis to hepatocellular carcinoma is not clear.
Liver fibrosis is the pathological result of the liver caused by chronic or repetitive inflammation of the liver or liver injury, and can be generally defined as a continuous injury repair process occurring within the liver. The most prominent feature of hepatic fibrosis is an imbalance in the excessive deposition and degradation of extracellular matrix, resulting in the production and accumulation of large amounts of structural proteins, particularly type I collagen, in damaged areas of the liver. Cirrhosis is the terminal stage of development of liver fibrosis, resulting in about 116 million deaths worldwide each year. Hepatocellular carcinoma is the most common type of primary liver cancer, and nearly 80% to 90% of patients with hepatocellular carcinoma have a history of chronic liver disease and cirrhosis, which makes cirrhosis considered one of the most major risk factors for causing hepatocellular carcinoma. Hepatic Stellate Cells (HSCs) are an important class of cells in the development of chronic liver fibrosis. Normally, HSCs are in a quiescent state in normal liver tissues and function to store retinyl esters. However, when liver fibrosis occurs, HSCs in the resting state are activated and differentiate into myofibroblasts. While myofibroblasts formed by activated HSCs in the liver undergoing fibrosis are considered to be the major source of secreted extracellular matrix, which mainly includes collagen, alpha-smooth muscle actin (alpha-SMA), fibronectin and tissue-type matrix metalloproteinase inhibitor 1(TIMP 1). Transforming growth factor beta (TGF-beta) plays an important role in stimulating the activation of hepatic stellate cells and the transformation process of the hepatic stellate cells into myofibroblasts, and further promotes the occurrence and development of hepatic fibrosis.
Currently, the most effective methods of treating liver fibrosis are the removal of exogenous or endogenous stimuli leading to chronic fibrosis and liver transplantation surgery. Although more compounds or herbal compound shows better anti-hepatic fibrosis treatment effect in vivo and in vitro cell experiments of animals, no compound or herbal compound is completely commercialized and approved for the first-line treatment mode of clinical hepatic fibrosis patients. Meanwhile, in preclinical and clinical studies, TGF-beta signals are directly targeted by neutralizing TGF-beta in vivo or blocking TGF-beta receptors, and serious adverse reactions in organisms may occur due to the fact that TGF-beta has various functions depending on biological environments.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the application of the compound sophora flavescens injection in preparing the medicine for treating chronic hepatic fibrosis. At the same time, the role of TGF-beta in hepatic fibrosis is further understood, and the replaceability of a TGF-beta signal axis is effectively interfered.
The invention also aims to provide the application of the compound sophora flavescens injection in repairing liver injury.
The invention also aims to provide the application of the compound lightyellow sophora root injection in inhibiting the activation of hepatic stellate cells.
In order to achieve one of the purposes, the solution of the invention is as follows:
application of compound radix Sophorae Flavescentis injection (CKI) in preparing medicine for treating chronic hepatic fibrosis is provided.
To achieve the second purpose, the solution of the invention is:
application of compound radix Sophorae Flavescentis injection in repairing liver injury is provided.
Further, by inhibiting the deposition of collagen in the liver, the liver tissue is restored to normal.
To achieve the third purpose, the solution of the invention is:
application of compound radix Sophorae Flavescentis injection in inhibiting hepatic stellate cell activation is provided.
Furthermore, the preparation for treating chronic hepatic fibrosis is prepared by inhibiting the activation of hepatic stellate cells.
Further, the preparation for treating chronic hepatic fibrosis is prepared by down-regulating the expression of hepatic stellate cell activators.
Further, the preparation for treating chronic hepatic fibrosis is prepared by selectively inhibiting the activation of hepatic stellate cells.
Furthermore, the medicine is prepared to treat chronic hepatic fibrosis by interfering the activation of TGF-beta/Smad signal axis in hepatic stellate cells.
Due to the adoption of the scheme, the invention has the beneficial effects that:
compared with the current clinical lack of approved drugs for treating hepatic fibrosis, the invention shows that CKI can be used as a promising candidate drug for preventing or treating hepatic fibrosis and preventing hepatic fibrosis progression in clinical application.
Drawings
FIG. 1 shows the CCl of a mouse with fibrosis after the compound lightyellow sophora root injection of the invention is used for treatment4Schematic of induced liver function.
Fig. 2 is a schematic diagram of the liver function of a fibrosis mouse induced by MCD after treatment by the compound sophora flavescens injection.
FIG. 3 shows the CCl of the mouse with fibrosis after the compound lightyellow sophora root injection of the present invention is used for treatment4Schematic representation of the changes induced in liver tissue morphology.
Fig. 4 is a schematic diagram of the change of liver tissue morphology induced by MCD of the fibrosis mouse after the treatment of the compound sophora flavescens injection.
FIG. 5 shows the CCl of the mouse with fibrosis after the compound radix sophorae flavescentis injection of the invention is used for treatment4Schematic representation of changes in relevant fibrosis markers in the induced liver.
Fig. 6 is a schematic diagram showing the changes of related fibrosis markers in the liver induced by MCD of a fibrosis mouse after treatment by the compound sophora flavescens injection.
FIG. 7 shows the CCl of the mouse with fibrosis after the compound radix sophorae flavescentis injection of the invention is used for treatment4Schematic representation of induced hepatic stellate cell activation in liver.
Fig. 8 is a schematic diagram of the activation of hepatic stellate cells in liver induced by MCD of the fibrotic mouse after the treatment of the compound lightyellow sophora root injection of the present invention.
FIG. 9 shows the CCl of the mouse with fibrosis after the compound radix sophorae flavescentis injection of the invention is used for treatment4Schematic representation of the activation of TGF-. beta./Smad signaling axis in induced liver.
FIG. 10 is a schematic diagram showing the activation of TGF-beta/Smad signaling axis in the liver induced by MCD in a fibrotic mouse after the treatment with the compound lightyellow sophora root injection of the present invention.
FIG. 11 is a schematic diagram showing the effect of the compound radix Sophorae Flavescentis injection of the present invention on the occurrence of fibrosis of human hepatic stellate cell line LX-2.
FIG. 12 is a schematic diagram showing the effect of the compound radix Sophorae Flavescentis injection of the present invention on the activation of human hepatic stellate cell line LX-2.
FIG. 13 is a schematic view of the activation of TGF-beta/Smad signal axis of human hepatic stellate cell line by the compound radix Sophorae Flavescentis injection of the present invention.
Detailed Description
The invention provides an application of a compound lightyellow sophora root injection in preparing a medicine for treating chronic hepatic fibrosis.
The present invention is further illustrated by the following examples.
Example (b):
chronic liver fibrosis animal model
(1) By tetrachlorochlorination for the construction ofCarbon (CCl)4) Induced chronic liver fibrosis model, C57BL/6 mice were injected with saline or 5 wt% CCl intraperitoneally4The solution (4mL/kg, diluted with olive oil) was injected 3 times per week for 3 or 6 weeks of molding. Mice at 5 wt% CCl4After 3 weeks of molding, the molded bodies were randomly divided into 3 groups including a control group and CCl4Group sum CCl4+ CKI group. CKI fibrotic mice were treated daily by intraperitoneal injections at a dose of 7.5mL/kg for a period of 3 or 6 weeks.
(2) To construct a model of nonalcoholic steatohepatitis induced by MCD diet, C57BL/6 mice were maintained on either the normal diet or MCD diet for a period of 4 weeks. Mice were randomized into 3 groups including control, MCD and MCD + CKI 2 weeks after MCD diet molding. CKI fibrotic mice were treated daily by intraperitoneal injections at a dose of 7.5mL/kg for a period of 2 weeks.
Cell model
Firstly, recovering human hepatic stellate cell line LX-2 cells by using a DMEM high-sugar culture medium containing 10% fetal bovine serum, wherein the culture temperature is 37 ℃, and the culture gas contains 5% by volume of CO2. When LX-2 cells reached around 80% growth density (approximately 3-4 days after recovery), they were digested with 0.25% pancreatic enzyme, according to 1: 3 proportion was passaged to DMEM high-sugar medium containing 2% fetal bovine serum for culture. For in vitro LX-2 cell activation experiments, LX-2 cells were treated with medium containing 5ng/mL of TGF-. beta.1 for a period of 12 h. At the same time, LX-2 cells were treated with CKI added at 0.5mg/mL, 1mg/mL, or 1.5 mg/mL.
In order to explore the intervention effect and action mechanism of CKI in the development process of chronic hepatic fibrosis, carbon tetrachloride (CCl) is constructed in a C57BL/6 mouse4) Induced chronic liver fibrosis model (figure 1) and Methionine and Choline Deficiency (MCD) diet-induced non-alcoholic steatohepatitis model (figure 2). The mice are treated by administration through intraperitoneal injection, and the administration period is 2-3 weeks respectively. At the treatment end point, serum and liver tissues from each group of mice were collected for evaluation of the effect of CKI on mouse liver function and the degree of liver fibrosis. First, AST, ALT and T-BI in the serum of each group of mice were examinedContent of L (FIGS. 1 and 2). The detection result shows that CCl4The levels of AST, ALT and T-BIL in the serum of mice were significantly increased after treatment (FIG. 1) or after MCD diet induction (FIG. 2), indicating CCl compared to the placebo group4Treatment or MCD diet can cause significant liver damage. However, following CKI intervention in mice, detection by CCl was performed4And levels of AST, ALT, T-BIL in the serum of mice in the MCD diet-induced mouse fibrosis model, CKI was found to be able to significantly restore liver function in mice (fig. 1 and 2). In addition, further histochemical techniques including hematoxylin-eosin staining (H) were used&E) Sirius red staining (Sirius red), Masson staining (Masson) and type I collagen (COL1A) immunohistochemical staining, the extent of liver damage and fibrosis in mice was assessed systematically (fig. 3 and 4). H&The result of E shows that CCl4Treatment resulted in necrosis of the central region of hepatic lobules in the mouse liver with increased infiltration of inflammatory cells around the hepatic lobules (fig. 3), and significant swelling, ballooning and necrosis of hepatic cells in the mouse liver following MCD diet induction (fig. 4). In addition, sirius red staining, masson staining and type I collagen immunohistochemical staining results showed CCl4And MCD diet treatment both apparently caused collagen deposition in the liver (fig. 3 and 4). However, CKI treatment effectively inhibited CCl4And deposition of collagen within the mouse liver caused by MCD diet and tended to normalize the histological morphology of the mouse liver (fig. 3 and 4). The mRNA and protein expression levels of markers associated with the occurrence of profibrosis in mouse livers, including transforming growth factor beta 1 (TGF-. beta.1), type I collagen (COL1A), Fibronectin (Fibronectin) and matrix metalloproteinase 1(TIMP1) were further examined using qRT-PCR and Western Blot experiments. The experimental results show that CCl4And MCD diet treatment resulted in expression of the relevant profibrotic markers in mouse liver, but CKI was able to significantly inhibit its expression (fig. 5 and 6). Therefore, CKI can effectively relieve the occurrence and the development of hepatic fibrosis.
Subsequently, the activation of hepatic stellate cells in the livers of the mice of the different treatment groups was examined using qRT-PCR and Western Blot experiments. The results show that CCl4Or MCD diet modeling could significantly cause the up-regulation of the expression level of hepatic stellate cell activation markers α -SM Α and Desmin (Desmin) in mouse liver, but CKI treatment could effectively inhibit its expression (fig. 7 and 8). Therefore, CKI exerts a therapeutic effect against hepatic fibrosis by inhibiting the activation of hepatic stellate cells.
Further utilizes Western Blot experiment to detect the protein expression condition related to TGF-beta/Smad signal axis in mouse liver. The results show CCl4The treatment or MCD diet modeling can obviously improve the expression of TGF beta R1, p-Samd2 and p-Smad3 in the liver and inhibit the expression of Smad 7. However, the expression levels of TGF beta R1, p-Samd2 and p-Smad3 in mouse liver decreased after CKI treatment, and the expression level of Smad7 was significantly increased (FIGS. 9 and 10). CKI can effectively inhibit activation of the TGF-beta/Smad signaling axis in the course of chronic fibrosis.
In order to further verify whether CKI can inhibit the differentiation and transformation process of hepatic stellate cells, a primary human hepatic stellate cell line LX-2 cell model is utilized in vitro experiments. First, in a model in which TGF-. beta.1 induced LX-2 cell activation, the effect of different doses of CKI (0.5mg/mL, 1mg/mL, and 1.5mg/mL) treatment for 12h on LX-2 cell activation and fibrosis was evaluated (FIG. 11). Both the qRT-PCR and Western Blot results show that TGF- β 1 induces expression of hepatic fibrosis-promoting related genes TGF- β 1, COL1A, fibrinectin and TIMP1 in LX-2, but CKI intervention treatment was effective in inhibiting expression of related genes in a dose-dependent manner (fig. 11).
Meanwhile, CKI significantly inhibited the induction of LX-2 cell activation by TGF- β 1 by down-regulating the expression levels of hepatic stellate cell activation markers α SMA and Desmin (fig. 12). However, CKI treatment did not affect expression of TGF-. beta.1, COL1A, Fibronection, TIMP1 (in FIG. 11), and. alpha.SMA and Desmin (in FIG. 12) in quiescent liver stellate cells. Therefore, CKI can selectively inhibit hepatic stellate cell activation and fibrosis induced by TGF- β 1.
Subsequently, the effect of CKI on the TGF- β/Smad signaling axis during LX-2 cell activation was further evaluated. The Western Blot result showed that the expression levels of P-Smad2, P-Smad3 and TGF β R1 were increased in LX-2 cells activated by TGF-. beta.1 induction, but the expression of Smad7 protein was down-regulated (FIG. 13). However, CKI treatment significantly down-regulated the protein expression levels of P-Smad2, P-Smad3, and TGF β R1 in activated LX-2 cells, increasing the protein expression level of Smad7 (FIG. 13).
Taken together, CKI has been shown in preclinical and clinical studies to mitigate the development of chronic liver fibrosis by remodeling TGF- β/Smad signaling pathways in hepatic stellate cells. Therefore, CKI is an effective candidate for the treatment of liver fibrosis.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (8)
1. Application of compound radix Sophorae Flavescentis injection in preparing medicine for treating chronic hepatic fibrosis is provided.
2. Application of compound radix Sophorae Flavescentis injection in repairing liver injury is provided.
3. Use according to claim 2, characterized in that: the liver tissue is recovered to be normal by inhibiting the deposition of collagen in the liver.
4. Application of compound radix Sophorae Flavescentis injection in inhibiting hepatic stellate cell activation is provided.
5. Use according to claim 4, characterized in that: can be used for treating chronic hepatic fibrosis by inhibiting hepatic stellate cell activation.
6. Use according to claim 5, characterized in that: the preparation for treating chronic hepatic fibrosis is prepared by down regulating the expression of hepatic stellate cell activators.
7. Use according to claim 4, characterized in that: the preparation for treating chronic hepatic fibrosis is prepared by selectively inhibiting the activation of hepatic stellate cells.
8. Use according to claim 4, characterized in that: the medicine is used for treating chronic hepatic fibrosis by interfering the activation of TGF-beta/Smad signal axis in hepatic stellate cells.
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Non-Patent Citations (3)
| Title |
|---|
| 夏炜，等: "复方苦参注射液治疗慢性乙型病毒性肝炎肝纤维化疗效观察", 《中西医结合研究》 * |
| 曾维政，等: "氧化苦参碱对肝纤维化大鼠Smad基因表达的影响", 《世界华人消化杂志》 * |
| 梁高林: "复方苦参注射液治疗慢性乙型肝炎肝纤维化32例", 《广西医学》 * |
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