Ferroptosis inhibitors for improving GPR40 agonist TAK-875 hepatotoxicity

Abstract

The invention discloses a ferroptosis inhibitor for improving liver toxicity of a GPR40 agonist TAK-875. The ferroptosis inhibitor comprises an iron complexing agent, an antioxidant, a lipoxygenase (LOX) inhibitor, an ACSL4 inhibitor, nitrogen oxide and selenium supplement, the iron complexing agent comprises deferoxamine, deferiprone, Deferasirox, curcumin and hepcidin, so that unstable iron in cells can be reduced, and a Fenton reaction can be inhibited; the antioxidant is prepared from Ferrostain-1, Liproxstain-1, Trolox and XJB-5-131, and the antioxidant is prepared from the following raw materials: sodium alginate, sodium alginate and sodium alginate; the lipoxygenase (LOX) inhibitor comprises Zileuton, AA861, PD146176 and baicalin, the ACSL4 inhibitor comprises Troglitazole, Rosiglitazole and Pioglitazole, the nitrogen oxides comprise TEMPO and PHOXNO, the Fenton reaction can be blocked, and the generation of hydroxyl free radicals can be inhibited; the selenium supplement comprises selenium, methyl selenocysteine and selenocystamine, the abundance of GPX4 is supplemented, and the lipid peroxide removing capacity is enhanced. Compared with the prior art, the invention has the advantage that the iron inhibitor is effectively proved to treat hepatotoxicity.

Description

Technical Field

[0001] The present invention relates to the technical field of ferroptosis inhibitors, and in particular to a ferroptosis inhibitor for improving the liver toxicity of a GPR40 agonist TAK-875. Background Art

[0002] GPR40 is a G protein-coupled receptor that can be activated by medium- and long-chain fatty acids. It plays a significant role in promoting insulin release, regulating glucose homeostasis, and preventing and treating type 2 diabetes. TAK-875 is a GPR40 / FFAR1 allosteric agonist that increases insulin secretion in a glucose-dependent manner and promotes GLP1 secretion from intestinal L cells. However, it withdrew from the Phase III clinical trial due to a 3-7-fold increase in ALT / AST and liver toxicity. The mechanism of TAK-875 hepatotoxicity is unclear. Our study found that ferroptosis inhibitors can rescue liver ferroptosis. Summary of the invention

[0003] The technical problem to be solved by the present invention is to overcome the above technical defects.

[0004] In order to solve the above problems, the technical solution of the present invention is: a ferroptosis inhibitor for improving the liver toxicity of GPR40 agonist TAK-875, comprising an iron complex, an antioxidant, a lipoxygenase (LOX) inhibitor, an ACSL4 inhibitor, nitrogen oxides and selenium supplementation;

[0005] The iron complex includes deferoxamine, deferiprone, Deferasirox, curcumin and hepcidin, thereby reducing unstable iron in cells and inhibiting the Fenton reaction;

[0006] The antioxidants include Ferrostain-1, Liproxstain-1, Trolox and XJB-5-131. Ferrostain-1 removes ROS and reduces unstable iron in cells, Liproxstain-1 removes ROS, activates Nrf2 pathway, and restores GPX4 level, Trolox inhibits lipid peroxidation, and XJB-5-131 targets mitochondria to remove ROS;

[0007] The lipoxygenase (LOX) inhibitors include Zileuton, AA861, PD146176 and Huanglingsu, wherein Zileuton and AA861 can inhibit 5-LOX, PD146176 can inhibit 15-LOX, and Huanglingsu can inhibit 12 / 15-LOX;

[0008] The ACSL4 inhibitors include Troglitazone, Rosiglitazone and Pioglitazone, which can inhibit the function of ACSL4, block the activation and phospholipidation process of PUFA, and reduce the generation of lipid peroxidation raw materials;

[0009] The nitrogen oxides include TEMPO and PHOXNO, which can block the Fenton reaction and inhibit the generation of hydroxyl radicals;

[0010] The selenium supplement includes selenium, methylselenocysteine ​​and selenocystamine, which supplements the abundance of GPX4 and enhances the lipid peroxide clearance ability.

[0011] Furthermore: the ferroptosis inhibitor adopts one or more combinations of the above materials.

[0012] The advantages of the present invention compared with the prior art are:

[0013] The present invention utilizes iron complexes, antioxidants, lipoxygenase (LOX) inhibitors, ACSL4 inhibitors, nitrogen oxides and selenium supplements to effectively inhibit hepatotoxicity, and uses ferroptosis inhibitors in the treatment of radiation-induced lung injury diseases, providing a new approach for the treatment of radiation-induced lung injury diseases, and at the same time, this is of great significance for the development of new drugs for the prevention and treatment of radiation-induced lung injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 It is the quantitative result of the key ferroptosis protein of the ferroptosis inhibitor used in the present invention to improve the hepatotoxicity of GPR40 agonist TAK-875. DETAILED DESCRIPTION

[0015] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings, wherein the same components are represented by the same reference numerals.

[0016] It should be noted that the words "front", "rear", "left", "right", "up" and "down" used in the following description refer to directions in the drawings, and the words "inside" and "outside" refer to directions toward or away from the geometric center of a specific component, respectively.

[0017] In order to make the contents of the present invention more clearly understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention.

[0018] like Figure 1 As shown, ferroptosis inhibitors used to improve the hepatotoxicity of the GPR40 agonist TAK-875 include iron complexes, antioxidants, lipoxygenase (LOX) inhibitors, ACSL4 inhibitors, nitric oxides, and selenium supplementation;

[0019] The iron complex includes deferoxamine, deferiprone, Deferasirox, curcumin and hepcidin, thereby reducing unstable iron in cells and inhibiting the Fenton reaction;

[0020] The antioxidants include Ferrostain-1, Liproxstain-1, Trolox and XJB-5-131. Ferrostain-1 removes ROS and reduces unstable iron in cells, Liproxstain-1 removes ROS, activates Nrf2 pathway, and restores GPX4 level, Trolox inhibits lipid peroxidation, and XJB-5-131 targets mitochondria to remove ROS;

[0021] The lipoxygenase (LOX) inhibitors include Zileuton, AA861, PD146176 and Huanglingsu, wherein Zileuton and AA861 can inhibit 5-LOX, PD146176 can inhibit 15-LOX, and Huanglingsu can inhibit 12 / 15-LOX;

[0022] The ACSL4 inhibitors include Troglitazone, Rosiglitazone and Pioglitazone, which can inhibit the function of ACSL4, block the activation and phospholipidation process of PUFA, and reduce the generation of lipid peroxidation raw materials;

[0023] The nitrogen oxides include TEMPO and PHOXNO, which can block the Fenton reaction and inhibit the generation of hydroxyl radicals;

[0024] The selenium supplement includes selenium, methylselenocysteine ​​and selenocystamine, which supplements the abundance of GPX4 and enhances the lipid peroxide clearance ability.

[0025] In a specific implementation, the ferroptosis inhibitor adopts one or more combinations of the above materials.

[0026] The present invention and its embodiments are described above, and such description is not restrictive. The drawings show only one embodiment of the present invention, and the actual structure is not limited thereto. In short, if ordinary technicians in the field are inspired by it, without departing from the purpose of the invention, they can design a structure and embodiment similar to the technical solution without creativity, which should belong to the protection scope of the present invention.

Claims

1. A ferroptosis inhibitor for improving the hepatotoxicity of GPR40 agonist TAK-875, characterized in that: These include iron complexes, antioxidants, lipoxygenase (LOX) inhibitors, ACSL4 inhibitors, nitric oxide, and selenium supplementation; The iron complex includes deferoxamine, deferiprone, Deferasirox, curcumin and hepcidin, thereby reducing unstable iron in cells and inhibiting the Fenton reaction; The antioxidants include Ferrostain-1, Liproxstain-1, Trolox and XJB-5-131. Ferrostain-1 removes ROS and reduces unstable iron in cells, Liproxstain-1 removes ROS, activates Nrf2 pathway, and restores GPX4 level, Trolox inhibits lipid peroxidation, and XJB-5-131 targets mitochondria to remove ROS; The lipoxygenase (LOX) inhibitors include Zileuton, AA861, PD146176 and Huanglingsu, wherein Zileuton and AA861 can inhibit 5-LOX, PD146176 can inhibit 15-LOX, and Huanglingsu can inhibit 12 / 15-LOX; The ACSL4 inhibitors include Troglitazone, Rosiglitazone and Pioglitazone, which can inhibit the function of ACSL4, block the activation and phospholipidation process of PUFA, and reduce the generation of lipid peroxidation raw materials; The nitrogen oxides include TEMPO and PHOXNO, which can block the Fenton reaction and inhibit the generation of hydroxyl radicals; The selenium supplement includes selenium, methylselenocysteine ​​and selenocystamine, which supplements the abundance of GPX4 and enhances the lipid peroxide clearance ability.

2. The ferroptosis inhibitor for improving the hepatotoxicity of the GPR40 agonist TAK-875 according to claim 1, characterized in that: The ferroptosis inhibitor is a combination of one or more of the above materials.

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