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Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach.

ABSTRACT: BACKGROUND:Topical Betamethasone (BM) and Pimecrolimus (PC) are widely used drugs in the treatment of atopic dermatitis (AD). Though the biomolecules and biological pathways affected by the drugs are known, the causal inter-relationships among these pathways in the context of skin is not available. We aim to derive this insight by using transcriptomic data of AD skin samples treated with BM and PC using systems biology approach. METHODS:Transcriptomic datasets of 10 AD patients treated with Betamethasone and Pimecrolimus were obtained from GEO datasets. We used a novel computational platform, eSkIN ( www.persistent.com/eskin ), to perform pathway enrichment analysis for the given datasets. eSkIN consists of 35 skin specific pathways, thus allowing skin-centric analysis of transcriptomic data. Fisher's exact test was used to compute the significance of the pathway enrichment. The enriched pathways were further analyzed to gain mechanistic insights into the action of these drugs. RESULTS:Our analysis highlighted the molecular details of the mechanism of action of the drugs and corroborated the known facts about these drugs i.e. BM is more effective in triggering anti-inflammatory response but also causes more adverse effect on skin barrier than PC. In particular, eSkIN helped enunciate the biological pathways activated by these drugs to trigger anti-inflammatory response and its effect on skin barrier. BM suppresses pathways like TNF and TLRs, thus inhibiting NF-?B while PC targets inflammatory genes like IL13 and IL6 via known calcineurin-NFAT pathway. Furthermore, we show that the reduced skin barrier function by BM is due to the suppression of activators like AP1 transcription factors, CEBPs. CONCLUSION:We thus demonstrate the detailed mechanistic insight into drug action of AD using a novel computational approach.

SUBMITTER: Subramanian I

PROVIDER: S-EPMC5803917 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach.

Subramanian Indhupriya I Singh Vivek K VK Jere Abhay A

BMC dermatology 20180207 1

<h4>Background</h4>Topical Betamethasone (BM) and Pimecrolimus (PC) are widely used drugs in the treatment of atopic dermatitis (AD). Though the biomolecules and biological pathways affected by the drugs are known, the causal inter-relationships among these pathways in the context of skin is not available. We aim to derive this insight by using transcriptomic data of AD skin samples treated with BM and PC using systems biology approach.<h4>Methods</h4>Transcriptomic datasets of 10 AD patients tr ...[more]

PMID: 29415693

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Project description:Atopic dermatitis (AD) is a complex, relapsing inflammatory skin disease with a considerable social and economic burden globally. AD is primarily characterized by its chronic pattern and it can have important modifications in the quality of life of the patients and caretakers. One of the fastest-growing topics in translational medicine today is the exploration of new or repurposed functional biomaterials into drug delivery therapeutic applications. This area has gained a considerable amount of research which produced many innovative drug delivery systems for inflammatory skin diseases like AD. Chitosan, a polysaccharide, has attracted attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine, and has been considered a promising candidate for AD treatment due to its antimicrobial, antioxidative, and inflammatory response modulation properties. The current pharmacological treatment for AD involves prescribing topical corticosteroid and calcineurin inhibitors. However, the adverse reactions associated with the long-term usage of these drugs such as itching, burning, or stinging sensation are also well documented. Innovative formulation strategies, including the use of micro- and nanoparticulate systems, biopolymer hydrogel composites, nanofibers, and textile fabrication are being extensively researched with an aim to produce a safe and effective delivery system for AD treatment with minimal side effects. This review outlines the recent development of various chitosan-based drug delivery systems for the treatment of AD published in the past 10 years (2012–2022). These chitosan-based delivery systems include hydrogels, films, micro-, and nanoparticulate systems as well as chitosan textile. The global patent trends on chitosan-based formulations for the AD are also discussed. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s13346-023-01307-w.

Project description:Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Dataset Information

Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach.

Publications

Elucidating mechanistic insights into drug action for atopic dermatitis: a systems biology approach.

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