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      Silibinin Attenuates Sulfur Mustard Analog-Induced Skin Injury by Targeting Multiple Pathways Connecting Oxidative Stress and Inflammation

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          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.

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          Medical aspects of sulphur mustard poisoning.

          Sulphur mustard is one of the major chemical warfare agents developed and used during World War I. Large stockpiles are still present in several countries. It is relatively easy to produce and might be used as a terroristic weapon. Sulphur mustard is a vesicant agent and causes cutaneous blisters, respiratory tract damage, eye lesions and bone marrow depression. The clinical picture of poisoning is well known from the thousands of victims during World War I and the Iran-Iraq war. In the latter conflict, sulphur mustard was heavily used and until now about 30,000 victims still suffer from late effects of the agent like chronic obstructive lung disease, lung fibrosis, recurrent corneal ulcer disease, chronic conjunctivitis, abnormal pigmentation of the skin, and several forms of cancer. Despite enormous research efforts during the last 90 years, no specific sulphur mustard antidote has been found. The prospering knowledge and developments of modern medicine created nowadays new chances to minimize sulphur mustard-induced organ damage and late effects.
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            Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential against cancer.

            Cancer is a major health problem around the world. Research efforts in the last few decades have been successful in providing better and effective treatments against both early stage and localized cancer, but clinical options against advanced metastatic stage/s of cancer remain limited. The high morbidity and mortality in most of the cancers are attributed to their metastatic spread to distant organs. Due to its extreme clinical relevance, metastasis has been extensively studied and is now understood as a highly complex biological event that involves multiple steps including acquisition of invasiveness by cancer cells, intravasation into circulatory system, survival in the circulation, arrest in microvasculature, extravasation, and growth at distant organs. The increasing understanding of molecular underpinnings of these events has provided excellent opportunity to target metastasis especially through nontoxic and biologically effective nutraceuticals. Silibinin, a popular dietary supplement isolated from milk thistle seed extracts, is one such natural agent that has shown biological efficacy through pleiotropic mechanisms against a variety of cancers and is currently in clinical trials. Recent preclinical studies have also shown strong efficacy of silibinin to target cancer cell's migratory and invasive characteristics as well as their ability to metastasize to distant organs. Detailed mechanistic analyses revealed that silibinin targets signaling molecules involved in the regulation of epithelial-to-mesenchymal transition, proteases activation, adhesion, motility, invasiveness as well as the supportive tumor-microenvironment components, thereby inhibiting metastasis. Overall, the long history of human use, remarkable nontoxicity, and preclinical efficacy strongly favor the clinical use of silibinin against advanced metastatic cancers.
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              Silymarin and silibinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silibinin with flavanolignan mixture silymarin.

              Here, we assessed and compared the anticancer efficacy and associated mechanisms of silymarin and silibinin in human prostate cancer (PCA) PC3 cells; silymarin is comprised of silibinin and its other stereoisomers, including isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silymarin and silibinin (50-100 microg/ml) inhibited cell proliferation, induced cell death, and caused G1 and G2-M cell cycle arrest in a dose/time-dependent manner. Molecular studies showed that G1 arrest was associated with a decrease in cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)4, CDK6 and CDK2 protein levels, and CDK2 and CDK4 kinase activity, together with an increase in CDK inhibitors (CDKIs) Kip1/p27 and Cip1/p21. Further, both agents caused cytoplasmic sequestration of cyclin D1 and CDK2, contributing to G1 arrest. The G2-M arrest by silibinin and silymarin was associated with decreased levels of cyclin B1, cyclin A, pCdc2 (Tyr15), Cdc2, and an inhibition of Cdc2 kinase activity. Both agents also decreased the levels of Cdc25B and cell division cycle 25C (Cdc25C) phosphatases with an increased phosphorylation of Cdc25C at Ser216 and its translocation from nucleus to the cytoplasm, which was accompanied by an increased binding with 14-3-3beta. Both agents also increased checkpoint kinase (Chk)2 phosphorylation at Thr68 and Ser19 sites, which is known to phosphorylate Cdc25C at Ser216 site. Chk2-specific small interfering RNA largely attenuated the silymarin and silibinin-induced G2-M arrest. An increase in the phosphorylation of histone 2AX and ataxia telangiectasia mutated was also observed. These findings indicate that silymarin and silibinin modulate G1 phase cyclins-CDKs-CDKIs for G1 arrest, and the Chk2-Cdc25C-Cdc2/cyclin B1 pathway for G2-M arrest, together with an altered subcellular localization of critical cell cycle regulators. Overall, we observed comparable effects for both silymarin and silibinin at equal concentrations by weight, suggesting that silibinin could be a major cell cycle-inhibitory component in silymarin. However, other silibinin stereoisomers present in silymarin also contribute to its efficacy, and could be of interest for future investigation.

                Author and article information

                [1 ]Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, United States of America
                [2 ]Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America
                National Institutes of Health, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NTS CA CWW RA. Performed the experiments: NTS AKJ SI CA. Analyzed the data: NTS AKJ SI CA RA. Contributed reagents/materials/analysis tools: RA CWW. Wrote the paper: NTS CWW RA.

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                27 September 2012
                : 7
                : 9

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 12
                This work was supported by the CounterACT Program, Office of the Director, National Institutes of Health (OD) and the National Institute of Environmental Health Sciences (NIEHS), Grant Number [U54 ES-015678]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Model Organisms
                Animal Models
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                Apoptotic Signaling Cascade
                Cell Death
                Cellular Stress Responses
                Toxic Agents
                Drugs and Devices
                Drug Research and Development



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