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Profiling Immune Expression to Consider Repurposing Therapeutics for the Ichthyoses.

ABSTRACT: Despite extensive discovery about the mutations underlying genetic skin disorders, there have been few therapeutic advances. Better understanding of the molecular changes that may lead to the phenotypic manifestations of genetic disorders may lead to the discovery of new pharmacologic interventions. The ichthyoses are characterized by scaling, inflammation, and an impaired epidermal barrier. Recent studies have uncovered T helper type 17 skewing in ichthyotic skin, resembling psoriasis, and high frequencies of IL-17- and IL-22-expressing T cells in blood, correlating with severity and transepidermal water loss. Repurposing systemic T helper type 17/IL-23-inhibitory therapies for psoriasis may prove useful for patients with ichthyosis.

SUBMITTER: Paller AS

PROVIDER: S-EPMC7259373 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Profiling Immune Expression to Consider Repurposing Therapeutics for the Ichthyoses.

Paller Amy S AS

The Journal of investigative dermatology 20190119 3

Despite extensive discovery about the mutations underlying genetic skin disorders, there have been few therapeutic advances. Better understanding of the molecular changes that may lead to the phenotypic manifestations of genetic disorders may lead to the discovery of new pharmacologic interventions. The ichthyoses are characterized by scaling, inflammation, and an impaired epidermal barrier. Recent studies have uncovered T helper type 17 skewing in ichthyotic skin, resembling psoriasis, and high ...[more]

PMID: 30670307

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Project description:The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.

Dataset Information

Profiling Immune Expression to Consider Repurposing Therapeutics for the Ichthyoses.

Publications

Profiling Immune Expression to Consider Repurposing Therapeutics for the Ichthyoses.

Similar Datasets

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