Research models of sulfur mustard- and nitrogen mustard-induced ocular injuries and potential therapeutics

Mishra, Neha; Agarwal, Rajesh

doi:10.1016/j.exer.2022.109209

Cited by 10 publications

(4 citation statements)

References 108 publications

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“…This is the first study that reports the development of an NM-exposure ex vivo human corneal culture model with optimized injury time points, to our knowledge. The pathophysiological injury biomarkers validated in the ex vivo human corneas parallel those observed in previous studies of vesicant-induced corneal injuries (Goswami et al, 2019;Mishra et al, 2022).…”

Section: Discussionsupporting

confidence: 80%

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Nitrogen Mustard-Induced Ex Vivo Human Cornea Injury Model and Therapeutic Intervention by Dexamethasone

Mishra

Kant

Kandhari

et al. 2023

J Pharmacol Exp Ther

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Sulfur mustard (SM), a vesicating agent first used during World War I, remains a potent threat as a chemical weapon to cause intentional/accidental chemical emergencies. Eyes are extremely susceptible to SM toxicity. Nitrogen mustard (NM), a bifunctional alkylating agent and potent analog of SM, is used in laboratories to study mustard vesicant-induced ocular toxicity.Previously, we showed that SM-/NM-induced injuries (in vivo and ex vivo rabbit corneas) are reversed upon dexamethasone (DEX) treatment, an FDA approved, steroidal anti-inflammatory drug. Here, we optimized NM injuries in ex vivo human corneas and assessed DEX efficacy. For injury optimization, one cornea (randomly selected from paired eyes) was exposed to NM: 100 nmoles for 2 h or 4 h, and 200 nmoles for 2 h, and the other cornea served as a control. Injuries were assessed 24 h post NM-exposure. NM 100 nmoles exposure for 2 h was found to cause optimal corneal injury (epithelial thinning [~69%]; epithelial-stromal separation [6-fold increase]). In protein arrays studies, 24 proteins displayed ≥40% change in their expression in NM exposed corneas compared to controls. DEX administration initiated 2 h post NM exposure and every 8 h thereafter until 24 h post-exposure reversed NM-induced corneal epithelial-stromal separation [2-fold decrease]). Of the 24 proteins dysregulated upon NM exposure, 6 proteins (DLL1, FGFbasic, CD54, CCL7, endostatin, ERBB4) associated with angiogenesis, immune/inflammatory responses, and cell differentiation/proliferation, showed significant reversal upon DEX treatment (Student's t-test; p≤0.05). Complementing our animal model studies, DEX was shown to mitigate vesicant-induced toxicities in ex vivo human corneas.

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Section: Discussionsupporting

confidence: 80%

“…Since SM is tightly regulated as a category 1 chemical, its prototype nitrogen mustard (NM) is used in laboratory settings. NM is also a potent vesicant and a bifunctional alkylating agent, with similar toxicity and vesicating properties as SM (Calvet et al, 1999;Mishra et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Nitrogen Mustard-Induced Ex Vivo Human Cornea Injury Model and Therapeutic Intervention by Dexamethasone

Mishra

Kant

Kandhari

et al. 2023

J Pharmacol Exp Ther

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“…Curcumin and resveratrol have also been observed to synergistically inhibit IL-8 expression by human cells in vitro exposed to the chemical weapon sulfur mustard (Cowan et al unpublished observations). An area of special interest but limited experimentation and information is the ability of phytochemicals to augment the therapeutic potential of pharmaceutical drugs by enhancing their potency, which allows a reduction in drug dose, thus lessening toxicity [ 9 , 10 , 17 , 18 , 19 ]. An example of this effect is provided by the use of Ginkgo biloba extracts to lower the effective dosage of the immunosuppressive drug, FK506, required for cardioprotection in vivo [ 18 , 20 ].…”

Section: Introduction and Main Topic Reviewmentioning

confidence: 99%

Evolving Strategies for Use of Phytochemicals in Prevention and Long-Term Management of Cardiovascular Diseases (CVD)

Haines,

Cowan,

Tosaki

2024

IJMS

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This report describes major pathomechanisms of disease in which the dysregulation of host inflammatory processes is a major factor, with cardiovascular disease (CVD) as a primary model, and reviews strategies for countermeasures based on synergistic interaction between various agents, including drugs and generally regarded as safe (GRAS) natural medical material (NMM), such as Ginkgo biloba, spice phytochemicals, and fruit seed flavonoids. The 15 well-defined CVD classes are explored with particular emphasis on the extent to which oxidative stressors and associated ischemia-reperfusion tissue injury contribute to major symptoms. The four major categories of pharmaceutical agents used for the prevention of and therapy for CVD: statins, beta blockers (β-blockers), blood thinners (anticoagulants), and aspirin, are presented along with their adverse effects. Analyses of major cellular and molecular features of drug- and NMM-mediated cardioprotective processes are provided in the context of their development for human clinical application. Future directions of the evolving research described here will be particularly focused on the characterization and manipulation of calcium- and calcineurin-mediated cascades of signaling from cell surface receptors on cardiovascular and immune cells to the nucleus, with the emergence of both protective and pathological epigenetic features that may be modulated by synergistically-acting combinations of drugs and phytochemicals in which phytochemicals interact with cells to promote signaling that reduces the effective dosage and thus (often) toxicity of drugs.

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“…Although the toxic effects of SM have been largely documented, its precise mechanism of action remains quite elusive. The routes of exposure to SM are primarily the eyes, skin, and the respiratory system via the inhalation of toxic fumes [5]. The eyes are the most sensitive organs after SM airborne exposure, but ocular injuries have only been sporadically studied at least from a mechanistic point of view [6].…”

Section: Introductionmentioning

confidence: 99%

Metabolomics Analysis of Rabbit Plasma after Ocular Exposure to Vapors of Sulfur Mustard

Bouhlel,

Caffin,

Gros-Désormeaux

et al. 2024

Metabolites

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Sulfur mustard (SM) is a highly potent alkylating vesicant agent and remains a relevant threat to both civilians and military personnel. The eyes are the most sensitive organ after airborne SM exposure, causing ocular injuries with no antidote or specific therapeutics available. In order to identify relevant biomarkers and to obtain a deeper understanding of the underlying biochemical events, we performed an untargeted metabolomics analysis using liquid chromatography coupled to high-resolution mass spectrometry of plasma samples from New Zealand white rabbits ocularly exposed to vapors of SM. Metabolic profiles (332 unique metabolites) from SM-exposed (n = 16) and unexposed rabbits (n = 8) were compared at different time intervals from 1 to 28 days. The observed time-dependent changes in metabolic profiles highlighted the profound dysregulation of the sulfur amino acids, the phenylalanine, the tyrosine and tryptophan pathway, and the polyamine and purine biosynthesis, which could reflect antioxidant and anti-inflammatory activities. Taurine and 3,4-dihydroxy-phenylalanine (Dopa) seem to be specifically related to SM exposure and correspond well with the different phases of ocular damage, while the dysregulation of adenosine, polyamines, and acylcarnitines might be related to ocular neovascularization. Additionally, neither cysteine, N-acetylcysteine, or guanine SM adducts were detected in the plasma of exposed rabbits at any time point. Overall, our study provides an unprecedented view of the plasma metabolic changes post-SM ocular exposure, which may open up the development of potential new treatment strategies.

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Research models of sulfur mustard- and nitrogen mustard-induced ocular injuries and potential therapeutics

Cited by 10 publications

References 108 publications

Nitrogen Mustard-Induced Ex Vivo Human Cornea Injury Model and Therapeutic Intervention by Dexamethasone

Nitrogen Mustard-Induced Ex Vivo Human Cornea Injury Model and Therapeutic Intervention by Dexamethasone

Evolving Strategies for Use of Phytochemicals in Prevention and Long-Term Management of Cardiovascular Diseases (CVD)

Metabolomics Analysis of Rabbit Plasma after Ocular Exposure to Vapors of Sulfur Mustard

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