title: Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.
abstract: Chemical warfare agent sulfur mustard (HD) inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES)-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM) treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p<0.05) reversal in CEES-induced decrease in cell viability, apoptotic and necrotic cell death, DNA damage, and an increase in oxidative stress. Silibinin (1 mg) applied topically to mouse skin 30 min post-CEES exposure (2 mg), was effective in reversing CEES-induced increases in skin bi-fold (62%) and epidermal thickness (85%), apoptotic cell death (70%), myeloperoxidase activity (complete reversal), induction of iNOS, COX-2, and MMP-9 protein levels (>90%), and activation of transcription factors NF-κB and AP-1 (complete reversal). Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid)-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Neera
authors.initials: N
authors.lastname: Tewari-Singh
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jain
authors.forename: Swetha
authors.initials: S
authors.lastname: Inturi
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002619:Chemical Warfare Agents / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000931:Antidotes; D002619:Chemical Warfare Agents; D012838:Silymarin; D000077385:Silybin; C031278:2-chloroethyl ethyl sulfide; D000080242:8-Hydroxy-2'-Deoxyguanosine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal; D009151:Mustard Gas