Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics

Abstract

Sulfur and nitrogen mustards, bis(2-chloroethyl)sulfide and tertiary bis(2-chloroethyl) amines, respectively, are vesicant warfare agents with alkylating activity. Moreover, oxidative/nitrosative stress, inflammatory response induction, metalloproteinases activation, DNA damage or calcium disruption are some of the toxicological mechanisms of sulfur and nitrogen mustard-induced injury that affects the cell integrity and function. In this review, we not only propose melatonin as a therapeutic option in order to counteract and modulate several pathways involved in physiopathological mechanisms activated after exposure to mustards, but also for the first time, we predict whether metabolites of melatonin, cyclic-3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and N1-acetyl-5-methoxykynuramine could be capable of exerting a scavenger action and neutralize the toxic damage induced by these blister agents. NLRP3 inflammasome is activated in response to a wide variety of infectious stimuli or cellular stressors, however, although the precise mechanisms leading to activation are not known, mustards are postulated as activators. In this regard, melatonin, through its anti-inflammatory action and NLRP3 inflammasome modulation could exert a protective effect in the pathophysiology and management of sulfur and nitrogen mustard-induced injury. The ability of melatonin to attenuate sulfur and nitrogen mustard-induced toxicity and its high safety profile make melatonin a suitable molecule to be a part of medical countermeasures against blister agents poisoning in the near future.

Escherichia coli RimI Encodes Serotonin N-Acetyltransferase Activity and Its Overexpression Leads to Enhanced Growth and Melatonin Biosynthesis

“…As reported in animals and plants, melatonin may have certain biological functions, such as antioxidation, in E . coli [ 4 , 41 , 73 , 74 ]. The EcRimI mutant strain showed no growth inhibition in nutrient-rich LB medium [ 37 ].…”

Therapeutic Benefits of Stem Cells and Exosomes for Sulfur-Mustard-Induced Tissue Damage

“…The accumulation of ROS also activates pro-inflammatory pathways and promotes apoptosis of skin cells. Moreover, SM-induced injury triggers the release of pro-inflammatory cytokines [ 33 , 34 , 35 ], such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), leading to an influx of inflammatory cells. The inflammatory response contributes to the formation of blisters and tissue damage.…”

Chitosan–sEPDM and Melatonin–Chitosan–sEPDM Composite Membranes for Melatonin Transport and Release

“…Starting with the circadian cycle [ 7 ], melatonin is involved in a series of biochemical processes related to: reducing oxidative stress [ 8 ], increasing aerobic performances [ 9 ], tissue repair [ 10 ], muscle adaptation and skeletal muscle capacity [ 11 ], sleep and neuroprotection [ 12 ], blood pressure [ 13 ], metabolic diseases [ 14 ], cancer [ 15 ], rheumatic diseases [ 16 ], trauma and accidents [ 17 ], stimulation of cartilage matrix development [ 18 ], cardiovascular diseases [ 19 ], arthritis [ 20 ], and depression [ 21 ]. In order to have an overview of all of melatonin’s connections with the body’s health level, one can imagine a spiral scheme of its effects on some diseases or conditions of the body ( Figure S1 , see supplementary material ).…”