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Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes.

ABSTRACT: Background and Objectives: Trifarotene is a topical retinoid selective for retinoic acid receptor gamma that was recently approved for treatment of acne vulgaris. We performed a gene expression analysis to identify the molecular and cellular impact of trifarotene treatment on acne papules. Methods: In this open-label prospective study, subjects with moderate inflammatory acne of the back were treated with trifarotene 0.005% or vehicle cream on dedicated areas for 27 days, and 4 biopsies were collected from each subject (1 from skin without a visible acne lesion and three at the site of an acne papule: one baseline, one after vehicle treatment, and one after trifarotene treatment). Large scale gene expression profiling of the biopsies was performed using Affymetrix technology, treatment-specific gene expression profiles were generated using statistical modeling, and pathway analysis was performed. Using single-cell RNAseq data, in silico deconvolution of transcriptomics data was performed to identify cellular signatures. Results: We discovered a unique set of 67 genes modulated by trifarotene that are primarily involved in cellular migration, inflammation, and extracellular matrix reorganization. Changes in cellular expression were similar in both trifarotene-treated and spontaneously-resolving lesions. However, only trifarotene treatment impacted SPP1⁺ macrophages, a subset of highly proliferative macrophages recently identified in fibrotic tissue. Conclusions: These results show that trifarotene has a novel action in acne treatment by affecting epidermal and immune components of acne pathogenesis.

SUBMITTER: Dreno B

PROVIDER: S-EPMC8569320 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes.

Dreno Brigitte B Chavda Rajeev R Julia Valerie V Khammari Amir A Blanchet-Réthoré Sandrine S Krishnaswamy Jayendra Kumar JK

Frontiers in medicine 20211022

<b>Background and Objectives:</b> Trifarotene is a topical retinoid selective for retinoic acid receptor gamma that was recently approved for treatment of acne vulgaris. We performed a gene expression analysis to identify the molecular and cellular impact of trifarotene treatment on acne papules. <b>Methods:</b> In this open-label prospective study, subjects with moderate inflammatory acne of the back were treated with trifarotene 0.005% or vehicle cream on dedicated areas for 27 days, and 4 bio ...[more]

PMID: 34746181

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Project description:Sarcopenia refers to the decline in muscle mass and function that occurs with advancing age. It is driven by alterations in multiple cellular processes. AMP-activated protein kinase (AMPK) is a cellular energy sensor that opposes many age-related changes, making it an attractive target for the treatment of sarcopenia. This study aimed to test the effect of chronic treatment of old mice with the AMPK-activating prodrug, AICAR, on treadmill running capacity and muscle mass, force production, gene expression, and intracellular markers relevant to sarcopenia. Old (23 months) mice were tested for treadmill running capacity, then randomly assigned to receive daily treatment with AICAR (OA; 300 to 500 mg/kg, delivered via subcutaneous injection) or an equivalent volume of saline vehicle (OS) for 31 days. Young (5 months) saline-treated mice (YS) served as controls. Treadmill posttesting was performed after 24 days, and the mice were euthanized after 31 days of treatment. Extensor digitorum longus (EDL) muscles were tested for force generation and RNA sequencing, RT-PCR, and western blotting were performed on quadricep muscles. Treadmill running capacity declined from pre- to posttesting by 24.5% in OS mice. This decline was not observed in YS or OA mice. Quadricep weight was ~8% higher, and tetanic force production by the EDL muscle increased by 26.4% in OA versus OS. These phenotypic improvements with AICAR treatment were accompanied by changes in gene expression in OA/YS versus OS muscles consistent with the "rejuvenation" of gene ontologies associated with connective tissue, neurodegenerative disease, Akt signaling, and mitochondrial function, among others. AICAR increased the mitochondrial markers cytochrome C by ~33%, and citrate synthase by ~22%. Serum insulin-like growth factor-1 levels increased, and Akt phosphorylation tended (p = 0.07) to increase with AICAR treatment. Although protein levels of the mTORC1 signaling pathway intermediate, rpS6, were higher in OA versus OS muscles, the phosphorylation of mTORC1 pathway intermediates was unaffected. On the other hand, gene expression of the muscle-specific ubiquitin ligases Mafbx and Murf1 were reduced with AICAR treatment. AICAR treatment mildly increased/preserved muscle mass and force production and prevented a decline in treadmill running performance in old mice. These effects were associated with altered skeletal muscle gene and protein expression, suggesting improved mitochondrial content and metabolic signaling (particularly through Akt) as contributing factors to the observed phenotypic effects. Our findings support further development of AMPK-activating drugs as a therapeutic strategy for improving age-related organismal dysfunction and sarcopenia.

Dataset Information

Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes.

Publications

Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes.

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