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The widespread use of topical antibiotics enriches for resistance in Staphylococcus aureus isolated from Atopic Dermatitis patients

ABSTRACT: The widespread use of topical antibiotics enriches for resistance in Staphylococcus aureus isolated from Atopic Dermatitis patients

PROVIDER: PRJEB25052 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2309520_1.fastq.gz	Fastqsanger.gz
	ERR2309520_2.fastq.gz	Fastqsanger.gz
	ERR2309530_1.fastq.gz	Fastqsanger.gz
	ERR2309530_2.fastq.gz	Fastqsanger.gz
	ERR2309540_1.fastq.gz	Fastqsanger.gz

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A Phase 1b Randomized Single-Center Trial of Topical Cerdulatinib (DMVT-502) in Patients with Mild-to-Moderate Atopic Dermatitis

Project description:This phase 1b, single-center, double-blind study evaluated safety, efficacy, and effect on molecular profiles of a topical Janus kinase/spleen tyrosine kinase (JAK/Syk) inhibitor, cerdulatinib gel 0.37%, in ten adults with mild-to-moderate atopic dermatitis (AD).

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Effect of topical emollient on the development of atopic dermatitis and atopic march in a mice model

Project description:To investigate the effect of emollient on atopic march in a murine model of chronic atopic dermatitis (AD). Mice were divided into 3 groups and treated with topical calcipotriol and ovalbumin alone or with a linoleic acid-ceramide-containing emollient. After 28 days, clinical, histological, and transcriptomic analyses were performed in skin lesions, lung and serum. Calcipotriol combined with ovalbumin induced a typical AD model with concomitant increased expression of Th2 and basophil-related genes in the lung. Compared to AD group, emollient group: 1) Skin: clinical severity and inflammatory cell infiltration were significantly reduced and transcriptomic analysis revealed significant downregulation of AD-related genes (286 of 1450 differentially expressed genes (DEGs)) including those related to innate inflammation (S100a8/a9, Il1b, Defb3/6, Mmp12), chemokines (Cxcl1/3, Ccl3/4) and barrier (Krt2/6b/80, Serpinb12, Lce3e, Sprr2). DEGs down-regulated by emollient were enriched in mitochondrial OXPHOS-related pathways, while up-regulated DEGs were mainly enriched in axon guidance, tight junctions, as shown by KEGG analyses. 2) Serum: total IgE and TSLP levels were significantly decreased, and IL-4 levels showed a decreasing tendency. 3) Lung: 187 of 275 upregulated DEGs were significantly downregulated in lung tissue including genes involved in cytokine and cytokine receptor interaction (Cxcl2/Cxcr2, Ccl2/3, Csf3r, etc.) and basophil activation (Mcpt8, Cd200r3, Ms4a2). Thus, topical emollient not only reduces skin inflammation and maintain skin barrier homeostasis by inhibiting the mitochondrial respiratory chain, but also limits systemic inflammation by decreasing TSLP and IgE levels. Moreover, it reduces respiratory chemokine production and basophil infiltration and activation, providing a molecular basis for blocking the atopic march.

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mRNA expression of Atopic Dermatitis keratinocytes

Project description:mRNA array analysis of total RNA from primary kertinocytes from three healthy controls, three atopic dermatitis patients and three psoriasis patients was carried out

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Effect of topical emollient on the development of atopic dermatitis and atopic march in a mice model

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Project description:Atopic dermatitis (AD) is a chronic inflammatory skin disease driven by cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) and associated with skin barrier disruption and pruritis. Interleukin-2-inducible T cell kinase (ITK) is a tyrosine kinase expressed by T cells which functions to amplify T cell receptor (TCR)-dependent signals, and ITK deletion or kinase inhibition reduces TCR-induced IL-4 and IL-13 production. Nerve growth factor (NGF) is a neurotrophic factor which signals via the receptor tropomyosin-related kinase A (TRKA) and can promote pruritis in the skin. The expression of both NGF and TRKA are enhanced in atopic dermatitis skin lesions, and levels of NGF in AD skin lesions correlated with itch severity. Here we describe a compound, PF-07245303, which potently inhibits ITK and TRK kinases (TRKA, B, and C). This compound demonstrated inhibition of TCR-induced, ITK-dependent phosphorylation of PLCγ1 and potently inhibits TCR stimulated IL-2 production from purified human T cells. Moreover, this ITK/TRK kinase inhibitor suppressed production of inflammatory cytokines from Th1, Th2, Th17, and CD8 T cells. In biochemical and cell-based assays PF-07245303 inhibited receptor kinases TRKA, TRKB, and TRKC and suppressed NGF-induced human basophil activation. Using a human skin explant model of atopic dermatitis, PF-07245303 demonstrated pharmacological activity by inhibiting phosphorylation of TRKA and suppressed expression of cytokines from TCR-activated resident dermal T cells. These results suggest that dual inhibition of ITK and TRKs with PF-07245303 suppress(es) dermal T cell activation and NGF-dependent responses which contribute to atopic dermatitis.

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