Porcupine inhibitors LGK-974 and ETC-159 inhibit Wnt/β-catenin signaling and result in inhibition of the fibrosis.

IF 2.6 3区医学 Q3 TOXICOLOGY Toxicology in Vitro Pub Date : 2024-12-06 DOI:10.1016/j.tiv.2024.105986

Ayşe Koçak, Semih Gülle, Merih Birlik

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引用次数: 0

Abstract

Objectives: We evaluated potential therapeutic efficacy of LGK-974 and ETC-159 in fibrotic scleroderma cells.

Methods: Primary scleroderma dermal fibroblast cells of mouse origin (SSc fibroblasts) and primary fibrotic lung fibroblast cells of human origin (CCL-191) were used in this study. PORCN inhibitors LGK-974 (S7143, 1 μM; Selleckchem, USA) and ETC-159 (S7143, 10 μM; Selleckchem, USA) were used . The possible therapeutic effects of LGK-974 and ETC-159 on scleroderma cells and fibrosis cells were examined. Cell viability experiments were performed for each substance, and the expression levels of WNT and fibrosis marker genes were determined by qPCR. Western blotting was also used to determine collagen, fibronectin and α-SMA protein markers.

Results: This study showed that LGK-974 and ETC-159 probable protein-cysteine N-palmitoyltransferase porcupine (PORCN) inhibitors exert potent antifibrotic effects and reduce fibrosis by modulating the TGF-β signaling pathway in scleroderma cells. Using LGK-974 and ETC-159 PORCN inhibitors, either alone or in combination, can affect collagen deposition and fibrosis in patients with SSc.

Conclusions: LGK-974 and ETC-159 may be a possible long-term therapeutic target for scleroderma.

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.