NAD+ in sulfur mustard toxicity

Ruszkiewicz, Joanna A.; Bürkle, Alexander; Mangerich, Aswin

doi:10.1016/j.toxlet.2020.01.024

Cited by 12 publications

(9 citation statements)

References 166 publications

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“…Additionally, NAD + depletion might impair redox homeostasis, leading to oxidative-nitrosative stress (ONS) and mitochondrial dysfunction [16]; affect intracellular calcium signaling [17]; or activate inflammatory responses [18]. Thus, preventing the decline of cellular NAD + levels appears to be a feasible strategy in addressing toxicity induced by mustard agent exposure [19].…”

Section: Of 22mentioning

confidence: 99%

“…Intracellular NAD + levels can also be regulated by the activity of nicotinamide N-methyltransferase that methylates nicotinamide, preventing its use in the NAD + salvage pathway [23]. To date, only NA and NAM have been investigated regarding mustard agent exposure, providing partial but not sufficient protection against cytotoxicity or histopathological damage, as we reviewed elsewhere [19]. Since NAD + is not cell-permeable and therefore cannot be used as a supplement on its own, in the present study, we examined the effects of NR supplementation, which shows better bioavailability and tolerance in comparison to NA or NAM, as demonstrated in recent studies [24,25].…”

Section: Of 22mentioning

confidence: 99%

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NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

Ruszkiewicz,

Papatheodorou,

Jäck

et al. 2023

Cells

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Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD+ supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD+ depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD+ booster nicotinamide riboside (NR) and NAD+ synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD+ levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD+ via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD+ levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD+ levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD+ is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD+ booster.

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Section: Of 22mentioning

confidence: 99%

Section: Of 22mentioning

confidence: 99%

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

Ruszkiewicz,

Papatheodorou,

Jäck

et al. 2023

Cells

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“…PARP-1 overactivation depletes the NAD+ reservoir 95. This depletion interrupts catabolic processes such as glycolysis, resulting in ATP exhaustion 92 94 96. The intense ATP evacuation leads to inhibition of PARP cleavage by caspase-3, and this overactivation results in cellular necrosis PARP resulting in cellular necrosis 97…”

Section: Introductionmentioning

confidence: 99%

Chemical exposure and alveolar macrophages responses: ‘the role of pulmonary defense mechanism in inhalation injuries’

et al. 2023

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Epidemiological and clinical studies have indicated an association between particulate matter (PM) exposure and acute and chronic pulmonary inflammation, which may be registered as increased mortality and morbidity. Despite the increasing evidence, the pathophysiology mechanism of these PMs is still not fully characterised. Pulmonary alveolar macrophages (PAMs), as a predominant cell in the lung, play a critically important role in these pathological mechanisms. Toxin exposure triggers events associated with macrophage activation, including oxidative stress, acute damage, tissue disruption, remodelling and fibrosis. Targeting macrophage may potentially be employed to treat these types of lung inflammation without affecting the natural immune response to bacterial infections. Biological toxins, their sources of exposure, physical and other properties, and their effects on the individuals are summarised in this article. Inhaled particulates from air pollution and toxic gases containing chemicals can interact with alveolar epithelial cells and immune cells in the airways. PAMs can sense ambient pollutants and be stimulated, triggering cellular signalling pathways. These cells are highly adaptable and can change their function and phenotype in response to inhaled agents. PAMs also have the ability to polarise and undergo plasticity in response to tissue damage, while maintaining resistance to exposure to inhaled agents.

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“…Previous studies had shown that mustard exposure resulted in a partial depletion of NAD + levels in various experimental conditions [21][22][23][24][25][26]. This NAD + reduction has been attributed to the overactivation of NAD + -consuming enzymes, such as diphtheria-toxin-like ADP ribosyl transferases (ARTDs, aka PARPs) in the response to DNA damage [27,28]. ARTDs utilise NAD + to synthesise poly(ADP-ribose) (PAR), which serves as a signalling and scaffold molecule to recruit repair proteins to the site of the DNA damage [20,29].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, PAR degradation does not restore NAD + levels; instead, NAD + needs to be resynthesized, e.g., from nicotinamide (NAM) which is a by-product of ARTDs' catalytic activity [29]. The mustard-induced ARTDs overactivation and subsequent reduction of the cellular NAD + pool can affect the activity level of multiple NAD + -dependent pathways, including sirtuins (SIRTs) activity, energy metabolism, or redox homeostasis, leading to pathological conditions and cell death, as reviewed elsewhere [20,28]. As NAD + synthesis and metabolism are highly conserved [31,32], these pathways can be conveniently studied in the nematode.…”

Section: Introductionmentioning

confidence: 99%

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

Ruszkiewicz,

Endig,

Güver

et al. 2023

Cells

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Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms’ developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons–HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.

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NAD+ in sulfur mustard toxicity

Cited by 12 publications

References 166 publications

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

Chemical exposure and alveolar macrophages responses: ‘the role of pulmonary defense mechanism in inhalation injuries’

Life-Cycle-Dependent Toxicities of Mono- and Bifunctional Alkylating Agents in the 3R-Compliant Model Organism C. elegans

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