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Drug for treating systemic lupus erythematosus

A lupus erythematosus, systemic technique, applied in the field of medicine

Pending Publication Date: 2020-08-11
PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The role of ferroptosis in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus, has not been studied

Method used

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  • Drug for treating systemic lupus erythematosus
  • Drug for treating systemic lupus erythematosus
  • Drug for treating systemic lupus erythematosus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Peripheral blood samples were obtained from 98 treatment-naïve SLE patients according to the criteria established by the American College of Rheumatology. Post-treatment blood samples from these 98 SLE patients were collected through follow-up. Neutrophil counts were measured and analyzed on the day of blood collection. Patients were excluded if they had received antibiotic treatment within the three months prior to enrollment. Patients with chronic or acute infections or serious underlying diseases such as acute coronary syndrome, chronic renal failure and cancer were also excluded. Healthy controls were age- and sex-matched individuals without autoimmune, inflammatory, or infectious diseases.

[0038] It was found that the number of neutrophils in the peripheral blood of new-onset and untreated SLE patients was lower than that of healthy controls (HCs) ( figure 1 ), the number of neutrophils increased after their clinical treatment was effective.

Embodiment 2

[0039] Example 2 The decrease in neutropenia in patients with newly diagnosed lupus is caused by ferroptosis

[0040] Peripheral blood from healthy controls and SLE patients was collected using K2E (EDTA) tubes (BD Vacutainer). In order to separate neutrophils, the peripheral blood is firstly diluted with phosphate buffered saline solution in equal proportions for later use, and an appropriate amount of Ficoll-Hypaqu separation solution is poured into a 15 ml centrifuge tube, and then the diluted peripheral blood is spread on the upper layer of the separation solution, paying attention Without destroying the separating liquid interface, then perform centrifugation. The speed is 500G, the speed of increase is the largest, and the speed of decrease is the smallest. Centrifuge for 20 minutes at room temperature. After the centrifugation is completed, use a pipette to absorb the white precipitate on the upper layer of the red blood cells, which is the neutrophils. In the next st...

Embodiment 3

[0045] Example 3 Inducing ferroptosis can cause lupus

[0046] C57 / B6-GPX4 fl / fl (027964, Jackson) and C57 / B6-LysMcre (004781, Jackson) mice were purchased from Jackson lab. The loxP site of the GPX4 allele is located between exons 2-4 of the GPX4 gene. The LysMcre knock-in allele has a nuclear-localized Cre recombinase inserted into the first encoded ATG of the lysozyme 2 gene (Lyz2), which both abolishes the function of the endogenous Lyz2 gene and regenerates NLS-Cre expression Placed under the control of the endogenous Lyz2 promoter / enhancer element. GPX4 fl / fl After the mice were crossed with LysMcre mice, the progeny mice were backcrossed with LysMcre mice, and genotype identification was performed to obtain GPX4 fl / wt LysMcre+ mice (homozygous for the LysMcre allele). GPX4 fl / fl and GPX4fl / wt LysMcre+ mice were used for experiments. According to current research, GPX4 is the most critical molecule for clearing intracellular Lipid-ROS and blocking ferroptosis. T...

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Abstract

The invention discloses application of an ferroptosis inhibitor as an active ingredient in preparation of a drug for treating systemic lupus erythematosus. Researches find that neutrophils of an SLE patient spontaneously generate ferroptosis, and the neutrophils return to normal after effective systemic treatment. The ferroptosis inhibitor liproxstatin-1 (LPX-1) can be used for delaying the deathrate of neutrophils and inhibiting ferroptosis. The Crispr / cas9 technology demonstrates that increased ferroptosis can enable C57 / B6 mice to spontaneously develop lupus phenotype. In an MRL / lpr mice model, the LPX-1 treatment can slow down the progress of lupus diseases, and the spleen, lymph node size, nephritis and proteinuria levels, deposition of renal immune complexes, and levels of inflammatory factors in the treated mice are similar to those in the cyclophosphamide-treated group, indicating that the treatment effect of LPX-1 is similar to that of cyclophosphamide. Due to different action mechanisms, the LPX-1 does not have cytotoxicity similar to cyclophosphamide, so that the LPX-1 can be a better lupus treatment drug.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a medicine for treating systemic lupus erythematosus. Background technique [0002] Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and the involvement of multiple organs. Both innate and adaptive immune abnormalities related to genetic and environmental factors have been shown to play crucial roles in the pathogenesis of SLE. However, SLE is highly heterogeneous, current treatments are far from satisfactory, and effective targeted therapies are urgently needed. Over the past decade, studies have shown that, in addition to cells of the adaptive immune system, neutrophils (the most abundant type of innate immune cell) are involved in the onset and progression of SLE and contribute to organ damage. [0003] In 1894, British physician Payne reported for the first time that quinine was used to treat discoid lupus erythema...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/122A61K31/355A61K31/45A61K31/137A61K33/04A61P37/02
CPCA61K31/122A61K31/137A61K31/355A61K31/45A61K33/04A61K45/00A61P37/02
Inventor 张烜李鹏冲姜明红
Owner PEKING UNION MEDICAL COLLEGE HOSPITAL CHINESE ACAD OF MEDICAL SCI
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