MicroRNA and gene signature of severe cutaneous drug hypersensitivity reactions reveal the role of miR-483- 5p/miR-28-5p in inflammation by targeting Granulysin gene

Elbakkoush, Abdallah Ahmed; Khaleel, Anas; Liu, Chien-Tsai

doi:10.4314/tjpr.v16i4.5

Cited by 4 publications

(5 citation statements)

References 25 publications

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“…18 Some studies suggest that miRNAs, such as miR-18a-5p, miR-124, miR-214 miR-483-5p and miR-28-5p, play an essential role in regulating gene expression and are associated with keratinocyte apoptosis in SJS/TEN. [19][20][21] A recent study found that overexpression of plasma exosomal miR-375-3p in SJS/TEN patients promoted keratinocyte apoptosis. 22 It is possible that the different outcomes of epidermal cell damage between SJS/TEN and DRESS might be related to differences in exosomal miRNA expression in both syndromes.…”

Section: Introductionmentioning

confidence: 99%

“…It was shown that overexpression of miR‐146a is important for allopurinol tolerance in HLA‐B*58:01 carriers, but how miR‐146a suppresses allopurinol hypersensitivity reaction is still unknown 18 . Some studies suggest that miRNAs, such as miR‐18a‐5p, miR‐124, miR‐214 miR‐483‐5p and miR‐28‐5p, play an essential role in regulating gene expression and are associated with keratinocyte apoptosis in SJS/TEN 19–21 . A recent study found that overexpression of plasma exosomal miR‐375‐3p in SJS/TEN patients promoted keratinocyte apoptosis 22 .…”

Section: Introductionmentioning

confidence: 99%

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Exosomal microRNAs from PBMCs stimulated with culprit drugs enhanced keratinocyte cell death in Stevens–Johnson syndrome/toxic epidermal necrolysis

Suthumchai

Buranapraditkun

Thantiworasit

et al. 2023

Acad Dermatol Venereol

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Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS) are both severe cutaneous adverse reactions. Keratinocyte death is much more prominent in SJS/ TEN compared to DRESS. Objective: This study aimed to investigate the role of exosomal miRNAs on keratinocyte death in SJS/TEN. Methods: Peripheral blood mononuclear cells (PBMCs) from SJS/TEN and DRESS patients were stimulated with the culprit drugs. The exosomes released in cell supernatants were co-incubated with HaCaT cells to study the cytotoxic effects on keratinocytes. Exosomal miRNA sequencing analysis was performed to compare the expression patterns between SJS/TEN and DRESS subjects. HaCaT cells were then transfected with miRNA mimics and inhibitors to explore the functions of miRNAs on keratinocyte cell death. Results: Cytotoxic effects of PBMC-derived exosomes on keratinocytes were demonstrated in SJS/TEN and could be neutralized with exosome inhibitors. Cytotoxic effects of PBMC-derived exosomes from SJS/TEN subjects were higher after incubating PBMCs with the culprit drugs than those incubating with irrelevant drugs and unstimulated controls. The sequencing data revealed differential expressions of 61 exosomal miRNAs between SJS/TEN and DRESS. Exosomal miR-4488 was upregulated while miR-486-5p, miR-96-5p and miR-132-3p were downregulated in SJS/TEN compared to DRESS as determined by quantitative real-time PCR. The increased percentage of apoptotic cells upon transfection of HaCat cells was 36.3% and 34.9% with miR-4488 mimic and miR-96-5p inhibitor, respectively. Conclusion: This study illustrated the regulatory functions of exosomal miRNAs in controlling keratinocyte death in SJS/TEN. Exosome inhibitors might have a therapeutic role in SJS/TEN.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exosomal microRNAs from PBMCs stimulated with culprit drugs enhanced keratinocyte cell death in Stevens–Johnson syndrome/toxic epidermal necrolysis

Suthumchai

Buranapraditkun

Thantiworasit

et al. 2023

Acad Dermatol Venereol

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“…For instance, histone modification and DNA methylation are risk factors for systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and other diseases [5][6][7][8][9]. Recent studies have shown that drug hypersensitivity was closely related to microRNAs (miRNAs) [10,11]. Another investigation described the overexpression of miRNA-18a-5p inhibited the expression of Bcell lymphoma/leukemia-2-like protein 10 (BCL2L10), which is an endogenous protein that inhibits apoptosis.…”

Section: Introductionmentioning

confidence: 99%

WGCNA-Based DNA Methylation Profiling Analysis on Allopurinol-Induced Severe Cutaneous Adverse Reactions: A DNA Methylation Signature for Predisposing Drug Hypersensitivity

Cheng

Sun

Xiong

et al. 2022

JPM

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Background: The role of aberrant DNA methylation in allopurinol-induced severe cutaneous adverse reactions (SCARs) is incompletely understood. To fill the gap, we analyze the DNA methylation profiling in allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients and identify the DNA methylation signature for predisposing allopurinol hypersensitivity. Methods: Genome-scale methylation analysis was conducted using the Illumina® HumanMethylation450 BeadChip. Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to analyze the data. Results: A total of 21,497 annotated promoter regions were analyzed. Ten modules were identified between allopurinol hypersensitivity and tolerance, with turquoise and yellow modules being the most significant correlation. ATG13, EPM2AIP1, and SRSF11 were the top three hub genes in the turquoise module. MIR412, MIR369, and MIR409 were the top three hub genes in the yellow module. Gene Ontology (GO) analysis revealed that the turquoise module was related to the metabolic process in intracellular organelles and the binding of various compounds, proteins, or nucleotides. The yellow module, however, was related to stimulus sensory perception in cytoskeletal elements and the activity of the receptor or transducer. Conclusion: DNA methylation plays a vital role in allopurinol-induced severe cutaneous adverse reactions (SCARs). DNA methylation profiling of SJS/TEN is significantly related to autophagy and microRNAs (miRNAs).

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“…Hemorrhoids are anal pad tissue and vascular proliferative disease with symptoms of bleeding, pain, prolapse, and perianal itching. The worldwide prevalence of hemorrhoids is as high as 39 % [1,2]. The initial treatment for hemorrhoids includes dietary control, proper hygiene, and sue of stool softeners for easy defecation.…”

Section: Introductionmentioning

confidence: 99%

“…MicroRNAs (miRNAs) are non-coding small RNA molecules with total lengths of 19 -23 bases [2]. The miRNAs regulate the expressions of multiple target genes in organisms, thereby affecting various physiological processes, including the proliferation, differentiation, and apoptosis of cells [3].…”

Section: Introductionmentioning

confidence: 99%

Fulvestrant, an estrogen receptor inhibitor, relieves postoperative hemorrhoid edema via up-regulation of miR- 424-5p

Meng¹,

Chen²,

Liu³

et al. 2022

Trop. J. Pharm Res

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Purpose: To investigate estrogen receptor (ER) expression in postoperative hemorrhoid edema tissues, and the likely mechanism involved in fulvestrant-mediated reduction of postoperative hemorrhoid edema.Methods: One hundred and eighty-five patients admitted to Jinshan Hospital of Fudan University, Shanghai who accepted hemorrhoidectomy were enrolled in this study. Primary cells were extracted from the anal margin tissues of patients for the determination of changes in ERα and vascular endothelial growth factor (VEGF). In vitro cellular experiments were performed in primary vascular endothelial cells to verify whether ER promoted postoperative perianal edema via the miR-424-5p estrogen receptor α gene (ESR1) axis. The cells were exposed to Fulvestrant, estradiol, and miR-424-5p mimic. Changes in expressions of ERα and VEGF were determined.Results: Fourteen patients (7.57 %), comprising 2 males (2.60 %) and 12 females (11.1 %), developedpostoperative anal margin edema. There was a significant difference in the incidence of postoperative anal edema between males and females (p < 0.05). Both immunohistochemistry and immunoblotting revealed markedly higher ERα levels in postoperative anal edema tissues than in preoperative tissues (p < 0.05). Moreover, ERα level was regulated by estradiol, and miR-424-5p targeted the estrogen receptor α gene (ESR1).Conclusion: Estradiol inhibits miR-424-5p through ERα in perianal tissues after hemorrhoid surgery. It increases VEGF and promotes perianal edema. However, fulvestrant inhibits ERα, thereby reducing VEGF expression and mitigating postoperative hemorrhoid edema, and therefore, has potential application for the management of postoperative hemorrhoid edema.

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MicroRNA and gene signature of severe cutaneous drug hypersensitivity reactions reveal the role of miR-483- 5p/miR-28-5p in inflammation by targeting Granulysin gene

Abstract: Purpose: To build a microRNA and gene signature of severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN

Cited by 4 publications

References 25 publications

Exosomal microRNAs from PBMCs stimulated with culprit drugs enhanced keratinocyte cell death in Stevens–Johnson syndrome/toxic epidermal necrolysis

Exosomal microRNAs from PBMCs stimulated with culprit drugs enhanced keratinocyte cell death in Stevens–Johnson syndrome/toxic epidermal necrolysis

WGCNA-Based DNA Methylation Profiling Analysis on Allopurinol-Induced Severe Cutaneous Adverse Reactions: A DNA Methylation Signature for Predisposing Drug Hypersensitivity

Fulvestrant, an estrogen receptor inhibitor, relieves postoperative hemorrhoid edema via up-regulation of miR- 424-5p

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