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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
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Phototoxicity of 7-oxycoumarins with keratinocytes in culture.

Wed, 09/23/2020 - 10:59
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Phototoxicity of 7-oxycoumarins with keratinocytes in culture.

Bioorg Chem. 2019 08;89:103014

Authors: Guillon C, Jan YH, Heck DE, Mariano TM, Rapp RD, Jetter M, Kardos K, Whittemore M, Akyea E, Jabin I, Laskin JD, Heindel ND

Abstract
Seventy-one 7-oxycoumarins, 66 synthesized and 5 commercially sourced, were tested for their ability to inhibit growth in murine PAM212 keratinocytes. Forty-nine compounds from the library demonstrated light-induced lethality. None was toxic in the absence of UVA light. Structure-activity correlations indicate that the ability of the compounds to inhibit cell growth was dependent not only on their physiochemical characteristics, but also on their ability to absorb UVA light. Relative lipophilicity was an important factor as was electron density in the pyrone ring. Coumarins with electron withdrawing moieties - cyano and fluoro at C3 - were considerably less active while those with bromines or iodine at that location displayed enhanced activity. Coumarins that were found to inhibit keratinocyte growth were also tested for photo-induced DNA plasmid nicking. A concentration-dependent alteration in migration on neutral gels caused by nicking was observed.

PMID: 31170642 [PubMed - indexed for MEDLINE]

The Amplex Red/horseradish peroxidase assay requires superoxide dismutase to measure hydrogen peroxide in the presence of NAD(P)H.

Sat, 09/12/2020 - 10:48

The Amplex Red/horseradish peroxidase assay requires superoxide dismutase to measure hydrogen peroxide in the presence of NAD(P)H.

Free Radic Res. 2020 Sep 10;:1-32

Authors: Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
A sensitive fluorescence assay based on Amplex Red (AR) oxidation by horseradish peroxidase (AR/HRP) is described which continuously monitor rates of H2O2 production by microsomal enzymes in the presence of relatively high concentrations of NADPH. NADPH and NADH are known to interact with HRP and generate significant quantities of superoxide anion, a radical that spontaneously dismutates to form H2O2 which interferes with the AR/HRP assay. Microsomal enzymes generate H2O2 as a consequence of electron transfer from NADPH to cytochrome P450 hemoproteins with subsequent oxygen activation. We found that superoxide anion formation via the interaction of NADPH with HRP was inhibited by superoxide dismutase (SOD) without affecting H2O2 generation by microsomal enzymes. Using SOD in enzyme assays, we consistently detected rates of H2O2 production using microgram quantities of microsomal proteins (2.62 ± 0.20 picomol/min/µg protein for liver microsomes from naïve female rats, 12.27 ± 1.29 for liver microsomes from dexamethasone induced male rats, and 2.17 ± 0.25 picomol/min/µg protein for human liver microsomes). This method can also be applied to quantify rates of H2O2 production by oxidases where superoxide anion generation by NADH or NADPH and HRP can interfere with enzyme assays.

PMID: 32912004 [PubMed - as supplied by publisher]

Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard.

Sat, 08/22/2020 - 10:42
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Lung injury, oxidative stress and fibrosis in mice following exposure to nitrogen mustard.

Toxicol Appl Pharmacol. 2020 01 15;387:114798

Authors: Sunil VR, Vayas KN, Abramova EV, Rancourt R, Cervelli JA, Malaviya R, Goedken M, Venosa A, Gow AJ, Laskin JD, Laskin DL

Abstract
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Herein, we developed a murine model of NM-induced pulmonary toxicity with the goal of assessing inflammatory mechanisms of injury. C57BL/6J mice were euthanized 1-28 d following intratracheal exposure to NM (0.08 mg/kg) or PBS control. NM caused progressive alveolar epithelial thickening, perivascular inflammation, bronchiolar epithelial hyperplasia, interstitial fibroplasia and fibrosis, peaking 14 d post exposure. Enlarged foamy macrophages were also observed in the lung 14 d post NM, along with increased numbers of microparticles in bronchoalveolar lavage fluid (BAL). Following NM exposure, rapid and prolonged increases in BAL cells, protein, total phospholipids and surfactant protein (SP)-D were also detected. Flow cytometric analysis showed that CD11b+Ly6G-F4/80+Ly6Chi proinflammatory macrophages accumulated in the lung after NM, peaking at 3 d. This was associated with macrophage expression of HMGB1 and TNFα in histologic sections. CD11b+Ly6G-F4/80+Ly6Clo anti-inflammatory/pro-fibrotic macrophages also increased in the lung after NM peaking at 14 d, a time coordinate with increases in TGFβ expression and fibrosis. NM exposure also resulted in alterations in pulmonary mechanics including increases in tissue elastance and decreases in compliance and static compliance, most prominently at 14 d. These findings demonstrate that NM induces structural and inflammatory changes in the lung that correlate with aberrations in pulmonary function. This mouse model will be useful for mechanistic studies of mustard lung injury and for assessing potential countermeasures.

PMID: 31678244 [PubMed - indexed for MEDLINE]

Regulation of Macrophage Foam Cell Formation During Nitrogen Mustard (NM)-Induced Pulmonary Fibrosis by Lung Lipids.

Sat, 08/22/2020 - 10:42
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Regulation of Macrophage Foam Cell Formation During Nitrogen Mustard (NM)-Induced Pulmonary Fibrosis by Lung Lipids.

Toxicol Sci. 2019 12 01;172(2):344-358

Authors: Venosa A, Smith LC, Murray A, Banota T, Gow AJ, Laskin JD, Laskin DL

Abstract
Nitrogen mustard (NM) is a vesicant known to target the lung, causing acute injury which progresses to fibrosis. Evidence suggests that activated macrophages contribute to the pathologic response to NM. In these studies, we analyzed the role of lung lipids generated following NM exposure on macrophage activation and phenotype. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in a time-related increase in enlarged vacuolated macrophages in the lung. At 28 days postexposure, macrophages stained positively for Oil Red O, a marker of neutral lipids. This was correlated with an accumulation of oxidized phospholipids in lung macrophages and epithelial cells and increases in bronchoalveolar lavage fluid (BAL) phospholipids and cholesterol. RNA-sequencing and immunohistochemical analysis revealed that lipid handling pathways under the control of the transcription factors liver-X receptor (LXR), farnesoid-X receptor (FXR), peroxisome proliferator-activated receptor (PPAR)-ɣ, and sterol regulatory element-binding protein (SREBP) were significantly altered following NM exposure. Whereas at 1-3 days post NM, FXR and the downstream oxidized low-density lipoprotein receptor, Cd36, were increased, Lxr and the lipid efflux transporters, Abca1 and Abcg1, were reduced. Treatment of naïve lung macrophages with phospholipid and cholesterol enriched large aggregate fractions of BAL prepared 3 days after NM exposure resulted in upregulation of Nos2 and Ptgs2, markers of proinflammatory activation, whereas large aggregate fractions prepared 28 days post NM upregulated expression of the anti-inflammatory markers, Il10, Cd163, and Cx3cr1, and induced the formation of lipid-laden foamy macrophages. These data suggest that NM-induced alterations in lipid handling and metabolism drive macrophage foam cell formation, potentially contributing to the development of pulmonary fibrosis.

PMID: 31428777 [PubMed - indexed for MEDLINE]

Chemical warfare agent research in precision-cut tissue slices-a useful alternative approach.

Wed, 08/19/2020 - 10:27

Chemical warfare agent research in precision-cut tissue slices-a useful alternative approach.

Ann N Y Acad Sci. 2020 Aug 17;:

Authors: Herbert J, Laskin DL, Gow AJ, Laskin JD

Abstract
The use of chemical warfare agents (CWAs) in military conflicts and against civilians is a recurrent problem. Despite ongoing CWA research using in vitro or in vivo models, progress to elucidate mechanisms of toxicity and to develop effective therapies, decontamination procedures, and general countermeasures is still limited. Novel scientific approaches to address these questions are needed to expand perspectives on existing knowledge and gain new insights. To achieve this, the use of ex vivo techniques like precision-cut tissue slices (PCTSs) can be a valuable approach. Existing studies employing this economical and relatively easy to implement method show model suitability and comparability with the use of in vitro and in vivo models. In this article, we review research on CWAs in PCTSs to illustrate the advantages of the approach and to promote future applications.

PMID: 32808309 [PubMed - as supplied by publisher]

Transcriptional profiling of lung macrophages during pulmonary injury induced by nitrogen mustard.

Sun, 08/09/2020 - 10:46
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Transcriptional profiling of lung macrophages during pulmonary injury induced by nitrogen mustard.

Ann N Y Acad Sci. 2020 Aug 06;:

Authors: Smith LC, Venosa A, Gow AJ, Laskin JD, Laskin DL

Abstract
Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1β. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity.

PMID: 32767459 [PubMed - as supplied by publisher]

Derivatives of 1,2,4-triazole imines acting as dual iNOS and tumor cell growth inhibitors.

Tue, 08/04/2020 - 10:27

Derivatives of 1,2,4-triazole imines acting as dual iNOS and tumor cell growth inhibitors.

Bioorg Chem. 2020 Jul 22;103:104128

Authors: Guillon C, Vetrano AM, Saxena J, Hunter A, Verderone G, Finetti TM, Wisnoski J, DeMatteo PW, Rapp RD, Heindel ND, Joseph LB, Heck DE, Laskin JD

Abstract
A set of 4-(R2-imino)-3-mercapto-5-(R1)-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and growth inhibition cytotoxicity. Noticeably, the compounds designed to be nitrofurantoin mimics were the most potent anti-neoplastic agents.

PMID: 32745761 [PubMed - as supplied by publisher]

Disease-modifying treatment of chemical threat agent-induced acute lung injury.

Thu, 07/30/2020 - 10:07

Disease-modifying treatment of chemical threat agent-induced acute lung injury.

Ann N Y Acad Sci. 2020 Jul 29;:

Authors: Radbel J, Laskin DL, Laskin JD, Kipen HM

Abstract
Acute respiratory distress syndrome (ARDS) is a highly morbid lung pathology induced by exposure to chemical warfare agents, including vesicants, phosgene, chlorine, and ricin. In this review, we describe the pathology associated with the development of ARDS in humans and experimental models of acute lung injury following animal exposure to these high-priority threat agents. Potential future approaches to disease-modifying treatment used in preclinical animal studies, including antioxidants, anti-inflammatories, biologics, and mesenchymal stem cells, are also described. As respiratory pathologies, including ARDS, are the major cause of morbidity and mortality following exposure to chemical threat agents, understanding mechanisms of disease pathogenesis is key to the development of efficacious therapeutics beyond the primary intervention principle, which remains mechanical ventilation.

PMID: 32726497 [PubMed - as supplied by publisher]

Nutraceuticals as potential therapeutics for vesicant-induced pulmonary fibrosis.

Thu, 07/30/2020 - 10:07
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Nutraceuticals as potential therapeutics for vesicant-induced pulmonary fibrosis.

Ann N Y Acad Sci. 2020 Jul 29;:

Authors: Businaro R, Maggi E, Armeli F, Murray A, Laskin DL

Abstract
Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.

PMID: 32725637 [PubMed - as supplied by publisher]

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