CN-121971441-A - Application of (+) -SPARTEINE in preparing medicine for preventing, relieving or treating liver fibrosis

Abstract

The invention belongs to the technical field of biological medicines, and relates to application of (+) -SPARTEINE (SPA) or pharmaceutically acceptable salt thereof in preparation of medicines for preventing, relieving or treating hepatic fibrosis. The invention proves that (+) -SPARTEINE can activate Natural Killer (NK) cells in the environment of chronic inflammatory fibrosis, strengthen the adhesion and cytotoxicity of the natural killer cells to activated Hepatic Stellate Cells (HSCs), thereby remarkably improving serum biochemical indexes (AST, ALT and total bilirubin) of hepatic fibrosis mice and reducing hepatic tissue collagen deposition. The invention provides a new strategy and molecular target for treating hepatic fibrosis.

Inventors

• LI MINGQIAN
• CHEN YUXIN
• ZHU XINPING
• Cao jili

Assignees

• 浙江省中医药研究院

Dates

Publication Date

20260505

Application Date

20260227

Claims (10)

1. 1. Use of (+) -SPARTEINE or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention, alleviation or treatment of liver fibrosis.
2. 2. The use according to claim 1, wherein the (+) -SPARTEINE effects prevention, alleviation or treatment of liver fibrosis by inducing apoptosis of activated hepatic stellate cells by enhancing the cytotoxic effect of natural killer cells on activated hepatic stellate cells.
3. 3. The use according to claim 2, wherein (+) -SPARTEINE is capable of promoting the adhesion of NK cells to activated hepatic stellate cells and up-regulating the expression of NK cell surface integrin ITGA 1.
4. 4. The use according to claim 1, wherein (+) -SPARTEINE is capable of reversing or partially antagonising the inhibition of NK cell activity, adhesion capacity and killing function by TGF- β in a TGF- β enriched chronic inflammatory fibrosis microenvironment.
5. 5. The use according to claim 1, wherein the (+) -SPARTEINE is acting as the E3 ubiquitin ligase UBR7 target and the (+) -SPARTEINE acts by specifically binding to UBR7 protein.
6. 6. The use as claimed in claim 5 wherein (+) -SPARTEINE forms a hydrogen bond with the GLN-178 amino acid residue of UBR7 protein to stabilize the binding conformation.
7. 7. The use according to claim 5, wherein (+) -SPARTEINE inhibits UBR7 interaction with the CARD domain of NOD-1, reducing K63 polyubiquitination modification of NOD-1.
8. 8. The use according to claim 7, wherein (+) -SPARTEINE reduces NOD-1 ubiquitination levels, activating NK cells by activating an NLR-mediated NF- κb signaling pathway.
9. 9. The use according to claim 1, wherein (+) -SPARTEINE is capable of up-regulating the expression level of the activation receptor NKG2D, NKp46, NKp44 or cytotoxic effector TRAIL, GNLY, IFN- γ in NK cells.
10. 10. The use as claimed in claim 1 wherein (+) -SPARTEINE is capable of reducing serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and total bilirubin levels.

Description

Application of (+) -SPARTEINE in preparing medicine for preventing, relieving or treating liver fibrosis Technical Field The invention belongs to the field of biological medicine, in particular to medical application of natural products, and particularly relates to application of tetracyclic quinolizinidine alkaloid (+) -SPARTEINE (SPA) or pharmaceutically acceptable salts thereof in preparation of medicines for activating Natural Killer (NK) cells and treating liver fibrosis and related liver diseases. Background Liver fibrosis is a pathological process by which various chronic liver diseases progress to cirrhosis and hepatocellular carcinoma (HCC). The central link is the activation of Hepatic Stellate Cells (HSCs) manifested by lipid droplet loss, enhanced proliferation migration and massive secretion of extracellular matrix (e.g. type I and type III collagens). If effective to clear activated HSCs or inhibit their activity, it will block or even reverse liver fibrosis progression. Natural Killer (NK) cells are key cells for immune surveillance of the liver, capable of directly inducing apoptosis of activated HSCs by releasing perforin, granzyme, TRAIL, and the like. However, in the fibrotic microenvironment formed by chronic liver injury, there are high concentrations of transforming growth factor- β (TGF- β) and other inhibitory factors, resulting in impaired NK cell surface-activated receptor down-regulation and killing, and thus "immune escape" occurs, leading to continued progression of fibrosis. The existing anti-fibrosis treatment strategies have the bottleneck that the target point is single, the side effect is large, or the curative effect is difficult to be exerted in an immunosuppression microenvironment. Although research has focused on the role of the NOD-like receptor (NLR) pathway in immune activation, there has been no report before on how to modulate ubiquitination modification of key proteins of the NLR pathway (such as NOD-1) by specific small molecule drugs, thereby reversing the "depleted" state of NK cells in the fibrotic environment. SPARTEINE is a naturally occurring tetracyclic quinolizinidine alkaloid, mainly extracted from leguminous plants. SPARTEINE and derivatives thereof have wide application in the field of chemical synthesis and biological medicine. SPARTEINE is a very valuable bidentate chiral ligand in the field of organic synthesis, and is widely applied to asymmetric deprotonation, oxidation kinetic resolution, henry reaction and various transition metal catalysis processes, thus being an important tool for constructing chiral molecules with high optical purity. The medical application of SPARTEINE in the prior art mainly relates to the application for resisting tumors. For example, CN103772388a states that the fumarate salt of sparteine has good water solubility and stability, and has been developed as a drug for treating cancer. The salt form is more pharmaceutically advantageous than the free base. CN109055313a describes that the SPARTEINE derivative can significantly enhance the proliferation of CIK cells and the killing activity against K562 tumor cells. Disclosure of Invention The invention aims to solve the problem that medicines capable of effectively activating NK cell activity and specifically clearing and activating hepatic stellate cells in a fibrosis microenvironment are lacking in the prior art. The invention provides application of (+) -SPARTEINE or pharmaceutically acceptable salt thereof in preparing medicines for preventing, relieving or treating hepatic fibrosis. The invention provides application of (+) -SPARTEINE in preparation of NK cell activator, especially in reversing TGF-beta induced NK cell immunosuppression. (+) -SPARTEINE relieves liver fibrosis by inducing apoptosis of activated hepatic stellate cells by enhancing the cytotoxic effect of Natural Killer (NK) cells on activated Hepatic Stellate Cells (HSCs). In vitro experiments show that (+) -SPARTEINE has increased concentration dependence on cytotoxicity of activated hepatic stellate cells, and the apoptosis rate of NK cells treated with (+) -SPARTEINE on activated hepatic stellate cells is improved. (+) -SPARTEINE can promote adhesion of NK cells and activated hepatic stellate cells, and up regulate expression of NK cell surface integrin ITGA 1. (+) -SPARTEINE is capable of reversing or partially antagonizing the inhibition of TGF-beta on NK cell activity, adhesion capacity and killing function in TGF-beta enriched chronic inflammatory fibrosis microenvironment. Under the environment of chronic inflammation fibrosis, factors such as TGF-beta and the like can obviously inhibit the activity of NK cells, and (+) -SPARTEINE can partially reverse the inhibition of the TGF-beta on NK cell adhesion and killing functions. The acting target of (+) -SPARTEINE is E3 ubiquitin ligase UBR7, and (+) -SPARTEINE acts by specifically binding to UBR7 protein. Target analysis shows that (+) -SPARTEINE is