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Recent Publications of Rutgers University CounterACT Research Center of Excellence Members

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NCBI: db=pubmed; Term=Laskin JD OR Laskin DL OR Marion MK OR Gerecke DR OR Heindel ND OR Heck DE OR Sinko PJ
Updated: 22 min 58 sec ago

Hydroxyl Radicals in E-cigarette Vapor and E-vapor Oxidative Potentials under Different Vaping Patterns.

Sat, 04/13/2019 - 10:12

Hydroxyl Radicals in E-cigarette Vapor and E-vapor Oxidative Potentials under Different Vaping Patterns.

Chem Res Toxicol. 2019 Apr 12;:

Authors: Son Y, Mishin V, Laskin JD, Mainelis G, Wackowski OA, Delnevo C, Schwander S, Khlystov A, Samburova V, Meng Q

Abstract
Available studies, while limited in number, suggest that e-cigarette vaping induces oxidative stress, with one potential mechanism being the direct formation of reactive oxygen species (ROS) in e-vapor. In the present studies, we measured the formation of hydroxyl radical (•OH), the most destructive ROS, in e-vapor under a range of relevant vaping patterns (i.e., power settings, solvent concentrations, flavorings). Study results show that increased power output and puff volume correspond with the formation of significantly higher amounts of •OH in e-vapor due to elevated coil temperature and oxygen supply. Vegetable glycerin (VG) e-liquids generated higher •OH levels than propylene glycol (PG) e-liquids, as did flavored e-liquids relative to non-flavored e-liquids. E-vapor in combination with ascorbic acid, which is an abundant biological molecule in human epithelial lining fluid, can also induce •OH formation. The dose of radical per puff associated with e-cigarette vaping was 10-1000 times lower than the reported dose generated by cigarette smoking. However, the daily average •OH dose can be comparable to that from cigarette smoking depending on vaping patterns. Overall, e-cigarette users who use VG-based flavored e-cigarettes at higher power output settings may be at increased risk for •OH exposures and related health consequences such as asthma and chronic obstructive pulmonary disease.

PMID: 30977360 [PubMed - as supplied by publisher]

The sulfur mustard analog mechlorethamine (bis(2-chloroethyl)methylamine) modulates cell cycle progression via the DNA damage response in human lung epithelial A549 cells.

Wed, 04/10/2019 - 10:45

The sulfur mustard analog mechlorethamine (bis(2-chloroethyl)methylamine) modulates cell cycle progression via the DNA damage response in human lung epithelial A549 cells.

Chem Res Toxicol. 2019 Apr 09;:

Authors: Jan YH, Heck DE, Laskin DL, Laskin JD

Abstract
Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2) and sulfur mustard, are potent vesicants that modify and disrupt cellular macromolecules, including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 µM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (S1981), Chk2 (T68), H2AX (Ser139), and p53 (ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE-821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.

PMID: 30964658 [PubMed - as supplied by publisher]

Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase.

Tue, 04/02/2019 - 10:00
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Quinone and nitrofurantoin redox cycling by recombinant cytochrome b5 reductase.

Toxicol Appl Pharmacol. 2018 11 15;359:102-107

Authors: Szilagyi JT, Fussell KC, Wang Y, Jan YH, Mishin V, Richardson JR, Heck DE, Yang S, Aleksunes LM, Laskin DL, Laskin JD

Abstract
NADH cytochrome b5 reductase mediates electron transfer from NADH to cytochrome b5 utilizing flavin adenine dinucleotide as a redox cofactor. Reduced cytochrome b5 is an important cofactor in many metabolic reactions including cytochrome P450-mediated xenobiotic metabolism, steroid biosynthesis and fatty acid metabolism, hemoglobin reduction, and methionine and plasmalogen synthesis. Using recombinant human enzyme, we discovered that cytochrome b5 reductase mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity was oxygen-dependent and preferentially utilized NADH as a co-substrate; NADH was 5-10 times more active than NADPH in supporting redox cycling. Redox cycling activity was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione), nitrofurantoin and 2-hydroxyestradiol. Using menadione as the substrate, quinone redox cycling was found to inhibit reduction of cytochrome b5 by cytochrome b5 reductase, as measured by heme spectral changes in cytochrome b5. Under anaerobic conditions where redox cycling is inhibited, menadione had no effect on the reduction of cytochrome b5. Chemical redox cycling by cytochrome b5 reductase may be important in generating cytotoxic reactive oxygen species in target tissues. This activity, together with the inhibition of cytochrome b5 reduction by redox-active chemicals and consequent deficiencies in available cellular cytochrome b5, are likely to contribute to tissue injury following exposure to quinones and related redox active chemicals.

PMID: 30222979 [PubMed - indexed for MEDLINE]

Expression of cytokines and chemokines in mouse skin treated with sulfur mustard.

Fri, 03/15/2019 - 11:00
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Expression of cytokines and chemokines in mouse skin treated with sulfur mustard.

Toxicol Appl Pharmacol. 2018 09 15;355:52-59

Authors: Chang YC, Soriano M, Hahn RA, Casillas RP, Gordon MK, Laskin JD, Gerecke DR

Abstract
Sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemokines in the ear skin. We found that SM caused an accumulation of macrophages and neutrophils in the tissue within one day which persisted for at least 7 days. This was associated with a 2-15 fold increase in expression of the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α at time points up to 7 days post-SM exposure. Marked increases (20-1000 fold) in expression of chemokines associated with recruitment and activation of macrophages were also noted in the tissue including growth-regulated oncogene α (GROα/CXCL1), monocyte chemoattractant protein 1 (MCP-1/CCL2), granulocyte-colony stimulating factor (GCSF/CSF3), macrophage inflammatory protein 1α (MIP1α/CCL3), and IFN-γ-inducible protein 10 (IP10/CXCL10). The pattern of cytokines/chemokine expression was coordinate with expression of macrophage elastase/MMP12 and neutrophil collagenase/MMP8 suggesting that macrophages and neutrophils were, at least in part, a source of cytokines and chemokines. These data support the idea that inflammatory cell-derived mediators contribute to the pathogenesis of SM induced skin damage. Modulating the infiltration of inflammatory cells and reducing the expression of inflammatory mediators in the skin may be an important strategy for mitigating SM-induced cutaneous injury.

PMID: 29935281 [PubMed - indexed for MEDLINE]

Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers.

Sat, 03/09/2019 - 11:18
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Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers.

Int J Environ Res Public Health. 2019 Mar 06;16(5):

Authors: Sunil VR, Radbel J, Hussain S, Vayas KN, Cervelli J, Deen M, Kipen H, Udasin I, Laumbach R, Sunderram J, Laskin JD, Laskin DL

Abstract
Sarcoid-like granulomatous diseases (SGD) have been previously identified in cohorts of World Trade Center (WTC) dust-exposed individuals. In the present studies, we analyzed lung and/or lymph node biopsies from patients referred to our clinic with suspected WTC dust-induced lung disease to evaluate potential pathophysiologic mechanisms. Histologic sections of lung and/or lymph node samples were analyzed for markers of injury, oxidative stress, inflammation, fibrosis, and epigenetic modifications. Out of seven patients examined, we diagnosed four with SGD and two with pulmonary fibrosis; one was diagnosed later with SGD at another medical facility. Patients with SGD were predominantly white, obese men, who were less than 50 years old and never smoked. Cytochrome b5, cytokeratin 17, heme oxygenase-1, lipocalin-2, inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, ADP-ribosylation factor-like GTPase 11, mannose receptor-1, galectin-3, transforming growth factor β, histone-3 and methylated histone-3 were identified in lung and lymph nodes at varying levels in all samples examined. Three of the biopsy samples with granulomas displayed peri-granulomatous fibrosis. These findings are important and suggest the potential of WTC dust-induced fibrotic sarcoid. It is likely that patient demographics and/or genetic factors influence the response to WTC dust injury and that these contribute to different pathological outcomes.

PMID: 30845693 [PubMed - in process]

Synthetically modified methoxsalen for enhanced cytotoxicity in light and dark reactions.

Tue, 01/15/2019 - 14:03

Synthetically modified methoxsalen for enhanced cytotoxicity in light and dark reactions.

Bioorg Med Chem Lett. 2018 Dec 22;:

Authors: Guillon CD, Jan YH, Foster N, Ressner J, Heck DE, Laskin JD, Heindel ND

Abstract
Linear furocoumarins, also known as psoralens, are clinically useful photo-activated pharmaceuticals employed to address hyperproliferative skin diseases. Seven diverse cytotoxic pharmacophores have been synthetically attached to 8-methoxypsoralen via a 5-amino functionality. The resulting unique set of compounds was evaluated for dark and light toxicity against PAM212 keratinocytes in culture.

PMID: 30638875 [PubMed - as supplied by publisher]

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis.

Sun, 01/06/2019 - 11:26

Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis.

Pharmacol Res. 2019 Jan 02;:

Authors: Szilagyi JT, Composto-Wahler GM, Joseph LB, Wang B, Rosen T, Laskin JD, Aleksunes LM

Abstract
The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ˜30%. Similarly, treatment of BeWo trophoblasts with AEA (0-10 µM, 3-24 h) coordinately down-regulated mRNAs for hCGß, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated trophoblasts also demonstrated reduced BCRP transport of the mycoestrogen zearalenone and the diabetes drug glyburide, labeled with BODIPY. The AEA-mediated reduction of BCRP mRNA was abrogated when placental cells were co-treated with AM630, a CB2 receptor inhibitor, or 8-Br-cAMP, a cAMP analog. AEA reduced intracellular cAMP levels in trophoblasts by 75% at 1 hr, and completely inhibited forskolin-induced phosphorylation of the cAMP response element binding protein (CREB). AEA also decreased p-CREB binding to the BCRP promoter. Taken together, our data indicate that AEA down-regulates placental transporter expression and activity via CB2-cAMP signaling. This novel mechanism may explain the repression of placental BCRP expression observed during diseases of pregnancy.

PMID: 30610963 [PubMed - as supplied by publisher]

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