Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

Jain, Anil K.; Tewari‐Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J.; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

doi:10.1016/j.taap.2015.03.009

Cited by 26 publications

(27 citation statements)

References 38 publications

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“…Phosphorylation of the histone H2A variant, H2A.X, which recruits DNA damage response proteins, is critical for the repair of DNA breaks (Mah et al, 2010; Scully and Xie, 2013). Consistent with previous findings (Inturi et al, 2014; Jain et al, 2015; Joseph et al, 2011), we found that NM caused a rapid increase in phospho H2A.X in the nuclei of basal and suprabasal cells of the interfollicular epidermis and the outer root sheath of hair follicles, presumably a response to DNA damage. Two-three days post-NM, phospho-H2A.X was also evident in infiltrating neutrophils and macrophages, which are known to undergo apoptosis.…”

Section: Discussionsupporting

confidence: 92%

Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug

Composto

Laskin

et al. 2016

Experimental and Molecular Pathology

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Nitrogen mustard (NM) is a bifunctional alkylating agent that is highly reactive in the skin causing extensive tissue damage and blistering. In the present studies, a modified cutaneous murine patch model was developed to characterize NM-induced injury and to evaluate the efficacy of an indomethacin pro-drug in mitigating toxicity. NM (20 µmol) or vehicle control was applied onto 6 mm glass microfiber filters affixed to the shaved dorsal skin of CD-1 mice for 6 min. This resulted in absorption of approximately 4 µmol of NM. NM caused localized skin damage within 1 d, progressing to an eschar within 2–3 d, followed by wound healing after 4–5 d. NM-induced injury was associated with increases in skin thickness, inflammatory cell infiltration, reduced numbers of sebocytes, basal keratinocyte double stranded DNA breaks, as measured by phospho-histone 2A.X expression, mast cell degranulation and increases in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Wound healing was characterized by epidermal hyperplasia and marked increases in basal cells expressing proliferating cell nuclear antigen. A novel indomethacin-anticholinergic prodrug (4338) designed to target cyclooxygenases and acetylcholinesterase (AChE), was found to markedly suppress NM toxicity, decreasing wound thickness and eschar formation. The prodrug also inhibited mast cell degranulation, suppressed keratinocyte expression of iNOS and COX-2, as well as markers of epidermal proliferation. These findings indicate that a novel bifunctional pro-drug is effective in limiting NM mediated dermal injury. Moreover, our newly developed cutaneous patch model is a sensitive and reproducible method to assess the mechanism of action of countermeasures.

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Section: Discussionsupporting

confidence: 92%

Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug

Composto

Laskin

et al. 2016

Experimental and Molecular Pathology

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“…Mustard gas exposure affects various organs including lungs, bone marrow and skin leading to early and late manifestations of morbidity 2,5,12,13 . If left untreated, mustard induced skin injury is characterized by erythema and edema that progresses to vesication of the skin resulting in epidermal separation, vacuolization and epidermal necrosis 14 .…”

Section: Discussionmentioning

confidence: 99%

“…Cutaneous exposure to SM triggers acute inflammatory lesions in the skin and in incidents of massive exposure, death 4 . Nitrogen mustard (NM), an analog of SM, has been used as a laboratory surrogate to develop animal models of cutaneous toxicity 5,6 . Although the DNA alkylating properties of NM have utility in a clinical setting for topical chemotherapy and treatment of cutaneous T cell lymphoma, such treatments have been associated with side effects that include cutaneous inflammation 7 .…”

Section: Introductionmentioning

confidence: 99%

Defining the timing of 25(OH)D rescue following nitrogen mustard exposure

Das

Binko

Traylor

et al. 2017

Cutaneous and Ocular Toxicology

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Objective Mass exposure to alkylating agents such as nitrogen mustard (NM), whether accidental or intentional as during warfare, are known to cause systemic toxicity and severe blistering from cutaneous exposure. Thus, establishing the timing and appropriate dose of any potential drug designed to reverse or impede these toxicities is critical for wound repair and survival. Our previous data demonstrates that a single intraperitoneal injection of low-dose 25-hydroxyvitamin D3 (25(OH)D) given as early as 1 h following NM exposure is sufficient to rescue mice from pancytopenia and death. However, the duration of time following exposure where intervention is still effective as a countermeasure is unknown. In this study, we sought to assess the maximal time permissible following NM exposure where 25(OH)D still affords protection against NM-induced cutaneous injury. Additionally, we determined if a higher dose of 25(OH)D would be more efficacious at time interval where low dose 25(OH)D is no longer effective. Methods Low (5 ng) and high (50 ng) doses of 25(OH)D were administered intraperitoneally to mice following exposure to topical NM to assess wound resolution and survival. Mice were imaged and weighed daily to measure wound healing and to monitor systemic toxicity. Results We demonstrated that 5 ng 25(OH)D administered as early as 1 h and as late as 24 h post-NM exposure is able to achieve 100% recovery in mice. In contrast, intervention at and beyond 48 h of NM exposure failed to achieve full recovery and resulted in ≥60% death between days 6 and 12, demonstrating the critical nature of timely intervention with 25(OH)D at each respective dose. In order to circumvent the observed failure at >48 h exposure, we provided two consecutive doses of 5 ng or 50 ng of 25(OH)D at 48 h and 72 h post-NM exposure. Repeat dosing with 25(OH)D at 48 h and beyond led to marked improvement of lesion size with 75% recovery from mortality. Conclusions The opportunity to use 25(OH)D as a medical countermeasure for NM-induced toxicity has a finite of window for intervention. However, modifications such as repeat dosing can be an effective strategy to extend the intervention potential of 25(OH)D.

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“…Silibinin (Figure 3G) is a natural product flavanone extract of the milk thistle plant[97]. It is commonly sold as a dietary supplement for treatment of hepatotoxicity but is also taken for a diverse range of ailments.…”

Section: 0 Potential Antioxidant Therapies: Mechanisms Efficacy Amentioning

confidence: 99%

“…Silibinin has been studied for its utility against oxidative stress, inflammation, and cancer, and has demonstrated potential medical utility in several models of toxicity. Its exact mechanism of action is poorly understood, but it has shown protection in models of vesicant toxicity including nitrogen mustard, CEES and SM[10,24,97–99]. Silibinin might also reduce the nitrosative stress observed following in-vitro SM exposures through its ability to inhibit iNOS[99].…”

Section: 0 Potential Antioxidant Therapies: Mechanisms Efficacy Amentioning

confidence: 99%

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

McElroy

Day

2016

Biochemical Pharmacology

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The continuing horrors of military conflicts and terrorism often involve the use of chemical warfare agents (CWAs) and toxic industrial chemicals (TICs). Many CWA and TIC exposures are difficult to treat due to the danger they pose to first responders and their rapid onset that can produce death shortly after exposure. While the specific mechanism(s) of toxicity of these agents are diverse, many are associated either directly or indirectly with increased oxidative stress in affected tissues. This has led to the exploration of various antioxidants as potential medical countermeasures for CWA/TIC exposures. Studies have been performed across a wide array of agents, model organisms, exposure systems, and antioxidants, looking at an almost equally diverse set of endpoints. Attempts at treating CWAs/TICs with antioxidants have met with mixed results, ranging from no effect to nearly complete protection. The aim of this commentary is to summarize the literature in each category for evidence of oxidative stress and antioxidant efficacy against CWAs and TICs. While there is great disparity in the data concerning methods, models, and remedies, the outlook on antioxidants as medical countermeasures for CWA/TIC management appears promising.

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Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

Cited by 26 publications

References 38 publications

Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug

Mitigation of nitrogen mustard mediated skin injury by a novel indomethacin bifunctional prodrug

Defining the timing of 25(OH)D rescue following nitrogen mustard exposure

Antioxidants as potential medical countermeasures for chemical warfare agents and toxic industrial chemicals

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