US-12616688-B2 - Cell glycocalyx protection effect of anisodamine

US12616688B2US 12616688 B2US12616688 B2US 12616688B2US-12616688-B2

Abstract

A use of anisodamine or a pharmaceutically acceptable salt thereof in the preparation of a cellular glycocalyx protectant and a use of the anisodamine or the pharmaceutically acceptable salt thereof as a cellular glycocalyx protectant in the restoration and protection of cellular glycocalyx and a cell adhesion junction are provided. The use of the anisodamine or the pharmaceutically acceptable salt thereof in the preparation of cellular glycocalyx protectant also has an effect of protecting the structure and function of an endothelial cell.

Inventors

Zhaohua Liu
YE ZENG

Assignees

CHENGDU FIRST PHARMACEDTICAL CO., LTD

Dates

Publication Date: 20260505
Application Date: 20210901
Priority Date: 20200903

Claims (12)

1 . A method of restoring and protecting a cellular glycocalyx of a subject in need, comprising administering an effective amount of a cellular glycocalyx protectant, wherein the cellular glycocalyx protectant comprises an anisodamine or a pharmaceutically acceptable salt thereof; and the restoring and protecting the cellular glycocalyx refers to inhibiting a loss of glycocalyx heparan sulfate and/or increasing a coverage rate of the glycocalyx heparan sulfate, and inhibiting a loss of cadherin and/or increasing a coverage rate of the cadherin.
2 . The method according to claim 1 , wherein the pharmaceutically acceptable salt is one or more selected from the group consisting of a hydrobromide, a hydrochloride, and a sulfate of the anisodamine; and the anisodamine is (Z)-racanisodamine and/or raceanisodamine.
3 . The method according to claim 1 , wherein the cellular glycocalyx is that of an endothelial cell, and the endothelial cell is a human brain microvascular endothelial cell.
4 . The method according to claim 1 , wherein the anisodamine or the pharmaceutically acceptable salt thereof is further able to protect a structure and a function of an endothelial cell; and the protecting the structure and the function of the endothelial cell refers to reducing an increase in a permeability of the endothelial cell and/or reducing a production of nitric oxide (NO) of the endothelial cell.
5 . The method according to claim 1 , wherein the anisodamine or the pharmaceutically acceptable salt thereof has a plurality of effects comprising restoring and protecting cellular glycocalyx, restoring and protecting a cell adhesion junction, reducing an increase in a permeability of an endothelial cell, or reducing a production of NO of an endothelial cell; and the cellular glycocalyx protectant is able to simultaneously restore and protect endothelial glycocalyx and the cell adhesion junction and reduce the increase in the permeability and the production of the NO of the endothelial cell.
6 . The method according to claim 1 , wherein the anisodamine or the pharmaceutically acceptable salt thereof is further able to promote a proliferation of an endothelial cell.
7 . The method according to claim 1 , wherein protecting cellular glycocalyx, protecting a structure and a function of an endothelial cell, and/or promoting a proliferation of the endothelial cell is achieved under an action of a lipopolysaccharide.
8 . A method for restoring and protecting a cell adhesion junction, reducing an increase in a permeability of an endothelial cell, or reducing a production of NO of the endothelial cell in a body of a subject in need, comprising: administering the anisodamine or the pharmaceutically acceptable salt thereof according to claim 1 to the subject.
9 . The method according to claim 2 , wherein the cellular glycocalyx is that of an endothelial cell, and the endothelial cell is a human brain microvascular endothelial cell.
10 . The method according to claim 2 , wherein the anisodamine or the pharmaceutically acceptable salt thereof is able to protect a structure and a function of an endothelial cell; and the protecting the structure and the function of the endothelial cell refers to reducing an increase in a permeability of the endothelial cell and/or reducing a production of NO of the endothelial cell.
11 . The method according to claim 1 , wherein the cellular glycocalyx protectant comprises anisodamine hydrobromide.
12 . The method according to claim 11 , wherein a concentration of the anisodamine that directly acts on a cell is 5 μg/mL to 25 μg/mL.

Description

CROSS REFERENCE TO THE RELATED APPLICATIONS This application is the national phase entry of International Application No. PCT/CN2021/115900, filed on Sep. 1, 2021, which is based upon and claims priority to Chinese Patent Application 202010914458.3, filed on Sep. 3, 2020, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD The present disclosure relates to the field of pharmaceuticals, health foods, or foods, and in particular, the present disclosure relates to the restorative and protective effects of anisodamine for endothelial glycocalyx (EG), cadherin, and permeability. BACKGROUND Vascular diseases are closely related to endothelial dysfunction. Serum lipopolysaccharides (LPSs) are closely related to atherosclerosis (AS). High-density lipoproteins (HDLs) can bind to LPS. The sharp drop in an HDL level during AS, stroke, and sepsis may lead to a decrease in LPS clearance. LPS can inhibit the formation of endothelial adhesion junctions by down-regulating the vascular endothelial cadherin (VE-cadherin) in pulmonary endothelial cells, destroying the pulmonary vascular integrity, and aggravating the inflammatory damage. LPS can destroy the endothelium and promote thrombosis. In addition, LPS inhibits the expression of endothelial nitric oxide synthase (eNOS) but induces the expression of inducible nitric oxide synthase (iNOS), thereby increasing the production of endothelial nitric oxide (NO). LPS can reduce a diastolic response of a blood vessel to acetylcholine (ACh) by increasing oxidative stress, thereby causing hepatic endothelial dysfunction. Therefore, the prevention of endothelial cell damage is deemed a promising new therapeutic strategy. Glycocalyx covers a surface of vascular endothelial cells (VECs) and has a variety of functions. The chemical composition, mechanical properties, and various physiological functions of EG have been widely described. Glycocalyx plays an important role in maintaining the normal functions of a vascular system and is an adhesion barrier for mechanical receptors and sensors, molecular sieves, and circulating cells such as leukocytes and tumor cells. In mouse embryonic stem cell (mESC)-derived endothelial cells, the degradation of glycocalyx heparan sulfate (HS) will inhibit the shear stress-induced expression of cadherin and eNOS. It has also been observed by atomic force microscopy (AFM) that HS plays an important role in the regulation of NO production. The protection of glycocalyx in a microvessel can also maintain the permeability of the microvessel. Currently, drugs related to glycocalyx that can be used to fight against vascular diseases include serum albumin (sphingosine-1 phosphate (S1P)), sulodexide, pentosan polysulfate, wheat germ agglutinin (WGA), rhamnan sulfate (RS), hawthorn extract WSS 1442, or the like. However, there are currently no drugs that can directly act on glycocalyx. Anisodamine is an active ingredient extracted from the root of Anisodus tanguticus (Maxim.) Pascher of the family Solanaceae in China. Since 1965, anisodamine has been used for the clinical treatment of septic shock, microcirculation disorders, organophosphorus poisoning, smooth muscle spasm, and the like. SUMMARY The present disclosure discloses a new use of anisodamine for protecting glycocalyx and cadherin of an endothelial cell and inhibiting the LPS-induced endothelial permeability and NO production. The present disclosure provides a use of anisodamine or a pharmaceutically acceptable salt thereof in the preparation of a cellular glycocalyx protectant. Preferably, in the use, the cellular glycocalyx protectant is provided to restore and protect cellular glycocalyx. Preferably, in the use, the restoring and protecting cellular glycocalyx refers to inhibiting a loss of glycocalyx HS and/or increasing a coverage rate of the glycocalyx HS. Preferably, in the use, the cellular glycocalyx protectant is further provided to restore and protect a cell adhesion junction; and preferably, the restoring and protecting a cell adhesion junction refers to inhibiting a loss of cadherin and/or increasing a coverage rate of cadherin. Preferably, in the use, the pharmaceutically acceptable salt is one or more selected from the group consisting of a hydrobromide, a hydrochloride, and a sulfate of anisodamine; and preferably, the anisodamine is (Z)-racanisodamine and/or raceanisodamine. Preferably, in the use, a cell refers to an endothelial cell, and preferably, the endothelial cell is a VEC; and preferably, the endothelial cell is derived from a human, and more preferably, the endothelial cell is a human brain microvascular endothelial cell (HBMVEC). In addition, in the use, the anisodamine or the pharmaceutically acceptable salt thereof is further able to protect a structure and function of an endothelial cell; and preferably, the protecting a structure and function of an endothelial cell refers to reducing an increase in permeability of the endothelial cell and/o