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锰（III）四（4 - 苯甲酸）卟啉（MnTBAP）和巴瑞替尼治疗对哈钦森 - 吉尔福德早衰症成纤维细胞的影响。

Impact of MnTBAP and Baricitinib Treatment on Hutchinson-Gilford Progeria Fibroblasts.

作者信息

Vehns Elena, Arnold Rouven, Djabali Karima

机构信息

Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering, Technical University of Munich (TUM), 85748 Garching, Germany.

出版信息

Pharmaceuticals (Basel). 2022 Jul 29;15(8):945. doi: 10.3390/ph15080945.

DOI:10.3390/ph15080945
PMID:36015093
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9415676/
Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease. It is caused by a mutation in the gene, which results in a 50-amino-acid truncation of prelamin A. The resultant truncated prelamin A (progerin) lacks the cleavage site for the zinc-metallopeptidase ZMPSTE24. Progerin is permanently farnesylated, carboxymethylated, and strongly anchored to the nuclear envelope. This leads to abnormalities, such as altered nuclear shape, mitochondrial dysfunction, and inflammation. HGPS patients display symptoms of physiological aging, including atherosclerosis, alopecia, lipodystrophy, and arthritis. Currently, no cure for HGPS exists. Here we focus on a drug combination consisting of the superoxide dismutase mimetic MnTBAP and JAK1/2 inhibitor baricitinib (Bar) to restore phenotypic alterations in HGPS fibroblasts. Treating HGPS fibroblasts with the MnTBAP/Bar combination improved mitochondrial functions and sustained Bar's positive effects on reducing progerin and pro-inflammatory factor levels. Collectively, MnTBAP/Bar combination treatment ameliorates the aberrant phenotype of HGPS fibroblasts and is a potential treatment strategy for patients with HGPS.

摘要

哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的早衰疾病。它由基因中的突变引起，导致前层粘连蛋白A截短50个氨基酸。由此产生的截短型前层粘连蛋白A（早老素）缺乏锌金属肽酶ZMPSTE24的切割位点。早老素被永久法尼基化、羧甲基化，并牢固地锚定在核膜上。这导致了诸如核形状改变、线粒体功能障碍和炎症等异常情况。HGPS患者表现出生理衰老的症状，包括动脉粥样硬化、脱发、脂肪营养不良和关节炎。目前，尚无治愈HGPS的方法。在此，我们聚焦于由超氧化物歧化酶模拟物MnTBAP和JAK1/2抑制剂巴瑞替尼（Bar）组成的药物组合，以恢复HGPS成纤维细胞的表型改变。用MnTBAP/Bar组合处理HGPS成纤维细胞可改善线粒体功能，并维持Bar对降低早老素和促炎因子水平的积极作用。总体而言，MnTBAP/Bar联合治疗改善了HGPS成纤维细胞的异常表型，是HGPS患者的一种潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/d8408a7c6260/pharmaceuticals-15-00945-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/75e379d74183/pharmaceuticals-15-00945-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/d8408a7c6260/pharmaceuticals-15-00945-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/627f606f7b16/pharmaceuticals-15-00945-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/b11e758ba80c/pharmaceuticals-15-00945-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/f437d3cfd311/pharmaceuticals-15-00945-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/6c084f538501/pharmaceuticals-15-00945-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/75e379d74183/pharmaceuticals-15-00945-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b25/9415676/d8408a7c6260/pharmaceuticals-15-00945-g006.jpg

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