CN115300510A - Application of lycorine hydrochloride in treating liver injury, hepatic fibrosis or primary liver cancer - Google Patents
Application of lycorine hydrochloride in treating liver injury, hepatic fibrosis or primary liver cancer Download PDFInfo
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- CN115300510A CN115300510A CN202210865851.7A CN202210865851A CN115300510A CN 115300510 A CN115300510 A CN 115300510A CN 202210865851 A CN202210865851 A CN 202210865851A CN 115300510 A CN115300510 A CN 115300510A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to the technical field of medicines, and provides application of lycorine hydrochloride in preparing a medicine for treating liver injury, hepatic fibrosis or primary liver cancer. Furthermore, the invention also provides a pharmaceutical composition for treating liver injury, hepatic fibrosis or primary liver cancer, which consists of lycorine hydrochloride and pharmaceutically acceptable auxiliary materials. In vitro experiments prove that the lycorine hydrochloride can inhibit the activation of hepatic stellate cells, relieve mouse hepatic fibrosis induced by ligation of carbon tetrachloride and bile duct, has certain prevention and treatment effects on primary liver cancer induced by diethylnitrosamine, and provides basis for treating, relieving or improving hepatic fibrosis and diseases or symptoms of the primary liver cancer by the lycorine hydrochloride.
Description
Technical Field
The invention belongs to the field of biological medicines, relates to a new medicine application of lycorine hydrochloride, and particularly relates to an application of lycorine hydrochloride in treating liver injury, hepatic fibrosis or primary liver cancer.
Background
Nearly 200 million people die of liver disease every year worldwide, of which 100 million die of cirrhosis complications and another part die of viral hepatitis and hepatocellular carcinoma. Hepatic Fibrosis (HF) is a pathological change caused by chronic liver injury and liver self-repair, and is a necessary stage for the development of chronic liver disease to cirrhosis and even liver cancer. There are many pathogenic factors of hepatic fibrosis, including Alcoholic Liver Disease (ALD) caused by long-term alcohol abuse, non-Alcoholic fatty liver disease (NAFLD) caused by long-term high-fat diet, viral Hepatitis B (HBV) and C (HCV), drug-induced metabolic poisoning, cholestatic liver disease, and autoimmune disease. Hepatic fibrosis is a dynamic reversible process and is an important period for reversing chronic liver diseases, so that intervention measures are actively taken in the hepatic fibrosis stage, and blocking hepatic fibrosis process has important significance for reducing the progress of chronic liver diseases to cirrhosis and even liver cancer.
The pathogenesis of liver cancer is a complex process of multiple factors and multiple steps, and epidemiological and experimental research data show that Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection, aflatoxin, drinking water pollution, alcohol, liver cirrhosis, nitrosamines, trace elements and the like are all related to the pathogenesis of liver cancer. Many factors of the liver fibrosis are in the middle of liver fibrosis, and uncontrolled liver fibrosis can finally cause liver cancer. At present, no medicine for effectively reversing hepatic fibrosis and preventing and treating liver cancer is on the market, and research on anti-hepatic fibrosis and liver cancer medicines is urgent.
The pathological features of hepatic fibrosis are mainly represented by excessive deposition of extracellular matrix in the liver, resulting in structural and functional alterations of the liver tissue. At present, the research considers that the activation of hepatic stellate cells is a core event in the process of hepatic fibrosis and is closely related to the occurrence and development of hepatic fibrosis. The hepatic stellate cells in a resting state are positioned in a Disse cavity of a hepatic sinusoid, are rich in vitamin A lipid droplets, and play an important role in maintaining the normal function and the steady state of the liver. After the liver is damaged, hepatic stellate cells are activated under the action of a soluble medium, differentiate into myofibroblasts with the functions of proliferation, fibrogenesis and collagen degradation, and express a large amount of extracellular matrix, so that the extracellular matrix is excessively deposited, and finally hepatic fibrosis is formed.
The mechanism of hepatic fibrosis development is very complex, and relates to various cytokines such as TGF-beta, PDGF, VEGF, IL-6 and the like and a plurality of signal paths such as TGF-beta/Smads signal path, MAPKs signal path, PI3K/Akt signal path, JAK/STAT3 signal path, NF-kappa B signal path, wnt/beta-Catenin signal path, notch signal path and the like. Among them, transforming growth factor-beta (TGF-. Beta.) is one of the strongest stimulators causing hepatic stellate cell activation. TGF- β transdifferentiates hepatic stellate cells into myofibroblasts by activating the Smads pathway to upregulate transcription of fibrogenic genes, synthesize excess extracellular matrix, interfere with matrix metalloproteinase synthesis, upregulate expression of matrix metalloproteinase inhibitors, thereby promoting extracellular matrix production and inhibiting degradation thereof. In addition, TGF-beta can also activate MAPKs signal pathways by means of three-stage enzymatic cascade reaction, and promote hepatic stellate cell activation. Deregulation of TGF- β signalling is also closely associated with tumorigenesis. In the later stage of cancer, TGF-beta has the effect of promoting tumor development, can increase the invasion and migration of tumors, and simultaneously, a TGF-beta signaling pathway can also interact with other signaling pathways to regulate cell functions in a synergistic or antagonistic mode. The activity rise of TGF-beta is closely related to the poor prognosis of the tumor, and the inhibition of TGF-beta signals can improve the prognosis of liver cancer treatment. Based on the important role of TGF-beta in hepatic fibrosis and liver cancer, the development of TGF-beta inhibitors has important significance in the treatment of hepatic fibrosis and liver cancer.
Lycorine is an isoquinoline alkaloid extracted from bulb of Lycoris radiata (L' her.) Herb of Lycoris of Amaryllidaceae, and is colorless prismatic crystal with antiinflammatory, antiaging, and antitumor activities. Lycorine Hydrochloride (LH) is Hydrochloride of Lycorine, and the structural formula is shown in the following formula I. The lycorine hydrochloride can effectively inhibit the generation of tumor angiogenesis dominated by ovarian cancer cells and a metastatic melanoma cell line C8161. In addition, the lycorine hydrochloride can inhibit the growth of melanoma cells A375, bile duct cancer cells RBE and esophageal cancer cells Eca-109, and can promote the apoptosis of various tumor cells such as human breast cancer cells MCF-7, liver cancer cells HCCLM3 and the like. Besides the anti-tumor effect, LH can also obviously inhibit the stress-induced cell premature senescence and promote the transcription of longevity genes SIRT1 and SIRT 6. At present, no report is available about the inhibition of TGF-beta to induce hepatic stellate cell activation and the resistance to hepatic fibrosis and liver cancer by lycorine hydrochloride.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a novel medical use of lycorine hydrochloride, and a pharmaceutical composition containing lycorine hydrochloride.
The first aspect of the invention provides the application of lycorine hydrochloride in preparing the medicine for treating liver injury, hepatic fibrosis or primary liver cancer.
Preferably, the medicament for treating liver injury or liver fibrosis is a medicament for reducing liver function index level, reducing hydroxyproline content in liver, reducing inflammatory cell infiltration in liver, inhibiting collagen deposition in liver, inhibiting activation of hepatic stellate cells or reducing expression of collagen and alpha-SMA in liver; the medicine for treating the primary liver cancer is a medicine for inhibiting the formation of tumor nodules in the liver.
In addition, the lycorine hydrochloride can also improve the transcription activity of Smads or inhibit the activation of TGF-beta/Smads signal channels in vivo, and has certain relieving effect on liver injury or hepatic fibrosis and primary liver cancer.
The invention firstly proves that lycorine hydrochloride can inhibit TGF (transforming growth factor) through in vitro pharmacodynamic experiments-beta-induced activation of hepatic stellate cells, improving CCl 4 BDL-induced liver injury and liver fibrosis of the mouse, inhibits activation of TGF-beta/Smads signal channels, and can inhibit primary liver cancer of the mouse induced by diethylnitrosamine.
The application of the lycorine hydrochloride in preparing the medicine for treating liver injury, hepatic fibrosis or primary liver cancer also has the technical characteristics that: the therapeutic drug takes the lycorine hydrochloride as the only active component or is a drug combination containing the lycorine hydrochloride. The content of lycorine hydrochloride is 0.1-99wt%.
In addition, the medicine or the medicine composition can be prepared into any dosage form with pharmaceutically common auxiliary materials, preferably injection and oral preparation.
The second aspect of the invention provides a pharmaceutical composition for treating liver injury, hepatic fibrosis or primary liver cancer, which consists of lycorine hydrochloride and pharmaceutically acceptable auxiliary materials.
The pharmaceutically acceptable adjuvants are excipient or carrier commonly used in pharmaceutical or food field, such as diluent, disintegrant, lubricant, etc.
Preferably, the lycorine hydrochloride is used in an amount of 10mg/kg in the medicament, and is administered orally or by injection.
Action and Effect of the invention
In vitro experiments prove that the lycorine hydrochloride can inhibit the activation of hepatic stellate cells induced by TGF-beta, improve mouse liver damage and hepatic fibrosis induced by CCl4 and BDL, inhibit the activation of TGF-beta/Smads signal pathways, and inhibit primary liver cancer of mice induced by diethylnitrosamine. Therefore, the invention provides a new basis for the lycorine hydrochloride hepatic fibrosis or primary liver cancer.
Drawings
FIG. 1 shows that lycorine hydrochloride inhibits TGF- β induced activation of hepatic stellate cells: a, B: real time PCR analysis of the influence of lycorine hydrochloride on the level of TGF-beta induced hepatic stellate cell activation marker collagen and alpha-SMAmRNA; c: and detecting the influence of the lycorine hydrochloride on the expression of a hepatic stellate cell activation marker collagen and alpha-SMA protein induced by TGF-beta by using Western blot.
FIG. 2 shows that lycorine hydrochloride improves CCl 4 Induced liver damage and fibrosis in mice: a, B: alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) to analyze liver function of mice; c: determining the collagen deposition condition in the liver of the mouse by the hydroxyproline content; d: HE staining is used for observing pathological damage conditions of mouse liver, sirius red and Masson staining is used for analyzing collagen deposition conditions in mouse liver, and alpha-SMA immunohistochemistry is used for analyzing hepatic stellate cell activation conditions in mouse liver; e: and detecting the expression conditions of collagen and alpha-SMA in the liver of the mouse by using Western blot.
Figure 3 shows that lycorine hydrochloride improves BDL-induced liver damage and fibrosis in mice: a, B, C, D, E: ALT, AST, alkaline phosphatase (AKP), total Bilirubin (TBIL) and bile acid (TBA) analysis of mouse liver function; f: determining the collagen deposition condition in the liver of the mouse by the hydroxyproline content; g: HE staining is used for observing pathological damage conditions of mouse liver, sirius red and Masson staining is used for analyzing collagen deposition conditions in mouse liver, and alpha-SMA immunohistochemistry is used for analyzing hepatic stellate cell activation conditions in mouse liver; h: and detecting the expression conditions of collagen and alpha-SMA in the liver of the mouse by using Western blot.
FIG. 4 shows that lycorine hydrochloride inhibits activation of the TGF- β/Smads signaling pathway: a: western blot analysis of the influence of lycorine hydrochloride on the activation of Smad2 stimulated by TGF-beta; b: analyzing the influence of lycorine hydrochloride on the transcription activity of the Smad2/3/4 complex by a luciferase reporter gene method; c, D: westernblot analyses the effect of lycorine hydrochloride on the activation of Smad2 in the liver of CCl4 and BDL model mice.
FIG. 5 shows that lycorine hydrochloride inhibits diethylnitrosamine-induced primary liver cancer in mice.
Detailed Description
The present invention will be described in detail below with reference to examples and the accompanying drawings. The following examples should not be construed as limiting the scope of the invention.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts of materials are by weight.
Example 1: lycorine hydrochloride inhibits TGF-beta induced hepatic stellate cell activation
Stimulating human hepatic stellate cell LX with TGF-beta (2 ng/mL) for 224 hours to induce hepatic stellate cell activation, and investigating the influence of lycorine hydrochloride on the expression levels of hepatic stellate cell activation markers alpha-SMA and Col1 alpha 1 by using Real time PCR and Westernblot. Real time PCR results showed that 0.5. Mu.M, 1. Mu.M lycorine hydrochloride significantly inhibited TGF-beta induced mRNA levels of α -SMA (P < 0.01) and Col1 α 1 (P < 0.05) (FIG. 1A, B); western blot results show that TGF-beta treatment can significantly increase protein expression of alpha-SMA and type-collagen, while lycorine hydrochloride at different concentrations can significantly inhibit protein expression of alpha-SMA and type-collagen (FIG. 1C).
Example 2: improvement of CCl by lycorine hydrochloride 4 Induced liver damage and fibrosis in mice
CCl 4 Preparing a hepatic fibrosis mouse model: male C57BL/6J (8 week old) mice, i.p. injection 10% 4 Solution (solvent is sterile olive oil), 5mL/kg, 2 times a week for 8 weeks. The blank group was injected intraperitoneally with an equal amount of sterile olive oil solution. The model group mice were randomized into solvent groups (CCl) at week 5 4 Model group), lycorine hydrochloride low dose group (10 mg/kg), lycorine hydrochloride high dose group (20 mg/kg), the stomach is irrigated according to 10mL/kg, the blank group and the solvent group are irrigated with 0.5 percent CMC-Na solution with the same amount, 1 time per day and 4 weeks continuously, after the last administration, the patient freely eats for 24 hours, and samples are collected.
The serum biochemical index detection result shows that the lycorine hydrochloride can obviously reduce CCl 4 Levels of the model mice liver function indices ALT and AST, alleviated liver injury (fig. 2a, b). The hydroxyproline detection result shows that the lycorine hydrochloride can obviously reduce CCl 4 Hydroxyproline content in the liver of model mice (fig. 2C). HE dyeing results show that lycorine hydrochloride can obviously reduce CCl 4 Inflammatory cell infiltration in the liver of the model mouse restores the normal tissue structure of the liver; masson dyeing and sirius red dyeing results show that lycorine hydrochloride can obviously inhibit CCl 4 Collagen deposition in the liver of the model mouse; the results of alpha-SMA immunohistochemistry show that hydrochloric acid stoneAllicin can remarkably reduce CCl 4 Protein expression of α -SMA in the liver of model mice inhibited the activation of hepatic stellate cells (fig. 2D). Western-blot results show that the lycorine hydrochloride can obviously reduce CCl 4 Expression of collagen and α -SMA in the liver of model mice (fig. 2E). In conclusion, the research result shows that the lycorine hydrochloride can improve CCl 4 Resulting in liver damage and fibrosis.
Example 3: lycorine hydrochloride for improving BDL-induced liver injury and liver fibrosis of mice
Preparing a BDL hepatic fibrosis mouse model: male C57BL/6J (8 week old) mice were anesthetized by intraperitoneal injection with 0.75% sodium pentobarbital solution at a dose of 10 mL/kg; wiping and disinfecting the abdomen with a 75% alcohol cotton ball; opening along the midline of the abdomen, exposing the lower margin of the liver to the site of the duodenum; carefully separating the common bile duct, penetrating the common bile duct through the lower part of the common bile duct by using a suture line, knotting, and doubly ligating the common bile duct at the liver-proximal end; the wound was sutured with 4-0 sutured suture and the operative part was sterilized with iodophor disinfectant. Sham group (Sham group) mice were abdominally dissected and total bile duct detached, with only thread and no ligation, and the remaining procedures were identical to BDL group. After the animals revive, the animals are put into a feeding box to eat freely. After 72h of operation, the mice in the BDL group are randomly divided into a solvent group (BDL model group), a lycorine hydrochloride low-dose group (10 mg/kg) and a lycorine hydrochloride high-dose group (20 mg/kg), after the grouping is completed, each group is gavaged according to 10mL/kg, a blank group and the solvent group are gavaged with 0.5 percent CMC-Na solution with the same amount, 1 time per day, the administration is continuously carried out for 11 days, after the last administration, the mice in the BDL group freely eat for 24h, and samples are collected.
The serum biochemical index detection result shows that the lycorine hydrochloride can obviously reduce the levels of liver function indexes ALT, AST and AKP of a BDL model mouse and the levels of TBIL and TBA for representing bilirubin metabolism and cholestasis (fig. 3A-E). The hydroxyproline detection result shows that lycorine hydrochloride can obviously reduce the content of hydroxyproline in the liver of the BDL model mouse (figure 3F). HE staining results show that the lycorine hydrochloride can remarkably reduce inflammatory cell infiltration in the liver of the BDL model mouse and restore the normal tissue structure of the liver; masson dyeing and sirius red dyeing results show that lycorine hydrochloride can obviously inhibit collagen deposition in the liver of a BDL model mouse; the results of immunohistochemistry for alpha-SMA show that lycorine hydrochloride can significantly reduce protein expression of alpha-SMA in the liver of the BDL model mouse and inhibit activation of hepatic stellate cells (fig. 3G). The Western-blot result shows that the lycorine hydrochloride can obviously reduce the expression of the collagen and the alpha-SMA in the liver of the BDL model mouse (figure 3H). In conclusion, the research results show that the lycorine hydrochloride can improve the liver injury and the liver fibrosis caused by BDL.
Example 4: lycorine hydrochloride inhibits TGF-beta/Smads signal path activation
Western blot results show that under the stimulation of TGF-beta, the phosphorylation level of Smad2 in LX2 cells is remarkably increased, and 1 mu M of lycorine hydrochloride can remarkably inhibit the phosphorylation of Smad 2. Next, we used the luciferase reporter gene method to examine the effect of lycorine hydrochloride on Smads (Smad 2/3/4) transcriptional activity, and the results showed that Smads transcriptional activity was significantly increased under TGF- β stimulation, and that lycorine hydrochloride dose-dependently inhibited Smads transcriptional activity (FIG. 4A, B).
Next, we examined the effect of lycorine hydrochloride on the TGF- β/Smads signaling pathway in liver of mice as a liver fibrosis model. The results show that Smad2 in the liver of mice in both CCl4 and BDL model groups is significantly activated, and the level of p-Smad2 is significantly reduced after the lycorine hydrochloride treatment, indicating that the lycorine hydrochloride can inhibit the activation of TGF-beta/Smads signaling pathway in vivo (FIG. 4C, D).
Example 5: lycorine hydrochloride for inhibiting primary liver cancer of mice induced by diethylnitrosamine
The C57 male mice were divided into a blank group, a model group and a lycorine hydrochloride (10 mg/kg) treatment group, 10 mice per group. The primary liver cancer model is characterized in that a 2-week old mouse is injected with 25mg/kg of DEN solution (solvent is physiological saline) in the abdominal cavity, 35mg/kg of DEN solution is injected in the abdominal cavity after 2 weeks, the injection is performed once every week for 25 weeks, and in order to accelerate tumor formation, the mouse is given high-fat diet. The treatment group was administered by gavage starting at week 10, once every two days for 15 weeks. And (3) killing the mice after the molding is finished, observing the liver tumor forming condition of the mice, and evaluating the liver cancer resistance effect of the lycorine hydrochloride. The results show that the number of tumor nodules in the liver of the mice in the model group is remarkably increased, and the lycorine hydrochloride can remarkably inhibit the formation of the tumor nodules in the liver of the DEN model mice compared with the model group, which indicates that the lycorine hydrochloride can inhibit primary liver cancer of the mice induced by diethylnitrosamine (figure 5).
The foregoing shows and describes the general principles, principal features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. Use of lycorine hydrochloride in preparing medicine for treating liver injury, hepatic fibrosis or primary liver cancer is provided.
2. Use according to claim 1, characterized in that:
wherein, the medicament for treating liver injury or hepatic fibrosis is a medicament for improving liver function index level, reducing hydroxyproline content in liver, reducing inflammatory cell infiltration in liver, inhibiting collagen deposition in liver or inhibiting hepatic stellate cell activation;
the medicine for treating the primary liver cancer is a medicine for inhibiting the formation of tumor nodules in the liver.
3. Use according to claim 2, characterized in that:
wherein the drug is a drug that inhibits Smads transcriptional activity or inhibits TGF-. Beta./Smads signaling pathway activation in vivo.
4. Use according to any one of claims 1 to 3, characterized in that:
wherein the medicament is lycorine hydrochloride as the only active ingredient or a pharmaceutical composition containing lycorine hydrochloride.
5. Use according to claim 4, characterized in that:
wherein, the content of lycorine hydrochloride in the medicine is 0.1-99wt%.
6. Use according to claim 1, characterized in that:
wherein, the medicine is injection or oral preparation.
7. A pharmaceutical composition for treating liver injury, hepatic fibrosis or primary liver cancer is characterized by comprising lycorine hydrochloride and pharmaceutically acceptable auxiliary materials.
8. The pharmaceutical composition of claim 7, wherein:
wherein the pharmaceutically acceptable auxiliary materials comprise excipient or carrier.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117018195A (en) * | 2023-08-04 | 2023-11-10 | 中国人民解放军海军军医大学 | Application of small molecular compound or combination in preparation of medicine for starting liver in-situ regeneration |
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|---|---|---|---|---|
| CN117018195A (en) * | 2023-08-04 | 2023-11-10 | 中国人民解放军海军军医大学 | Application of small molecular compound or combination in preparation of medicine for starting liver in-situ regeneration |
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