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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: 42 min 52 sec ago

Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells.

Tue, 10/03/2017 - 10:59
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Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells.

Chem Res Toxicol. 2017 Jul 17;30(7):1406-1418

Authors: Yang S, Jan YH, Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
Reactive carbonyls such as diacetyl (2,3-butanedione) and 2,3-pentanedione in tobacco and many food and consumer products are known to cause severe respiratory diseases. Many of these chemicals are detoxified by carbonyl reductases in the lung, in particular, dicarbonyl/l-xylulose reductase (DCXR), a multifunctional enzyme important in glucose metabolism. DCXR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Using recombinant human enzyme, we discovered that DCXR 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 preferentially utilized NADH as a cosubstrate and was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione). Using 9,10-phenanthrenequinone as the substrate, quinone redox cycling was found to inhibit DCXR reduction of l-xylulose and diacetyl. Competitive inhibition of enzyme activity by the quinone was observed with respect to diacetyl (Ki = 190 μM) and l-xylulose (Ki = 940 μM). Abundant DCXR activity was identified in A549 lung epithelial cells when diacetyl was used as a substrate. Quinones inhibited reduction of this dicarbonyl, causing an accumulation of diacetyl in the cells and culture medium and a decrease in acetoin, the reduced product of diacetyl. The identification of DCXR as an enzyme activity mediating chemical redox cycling suggests that it may be important in generating cytotoxic reactive oxygen species in the lung. These activities, together with the inhibition of dicarbonyl/l-xylulose metabolism by redox-active chemicals, as well as consequent deficiencies in pentose metabolism, are likely to contribute to lung injury following exposure to dicarbonyls and quinones.

PMID: 28595002 [PubMed - indexed for MEDLINE]

Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

Fri, 08/25/2017 - 10:27

Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

PLoS Comput Biol. 2017 Aug;13(8):e1005570

Authors: Massa CB, Groves AM, Jaggernauth SU, Laskin DL, Gow AJ

Abstract
Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at airway opening, to a greater extent than overt acinar wall destruction. Model-predicted deficits in PEEP-dependent lung recruitment correlate with altered lung lining fluid composition independent of age or genotype.

PMID: 28837561 [PubMed - in process]

Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants.

Tue, 08/01/2017 - 20:47
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Macrophages and inflammatory mediators in pulmonary injury induced by mustard vesicants.

Ann N Y Acad Sci. 2016 Jun;1374(1):168-75

Authors: Malaviya R, Sunil VR, Venosa A, Vayas KN, Businaro R, Heck DE, Laskin JD, Laskin DL

Abstract
Sulfur mustard (SM) and nitrogen mustard (NM) are cytotoxic alkylating agents that cause severe and progressive injury to the respiratory tract, resulting in significant morbidity and mortality. Evidence suggests that macrophages and the inflammatory mediators they release play roles in both acute and long-term pulmonary injuries caused by mustards. In this article, we review the pathogenic effects of SM and NM on the respiratory tract and potential inflammatory mechanisms contributing to this activity.

PMID: 27351588 [PubMed - indexed for MEDLINE]

The molecules in the corneal basement membrane zone affected by mustard exposure suggest potential therapies.

Thu, 07/20/2017 - 10:34
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The molecules in the corneal basement membrane zone affected by mustard exposure suggest potential therapies.

Ann N Y Acad Sci. 2016 Aug;1378(1):158-165

Authors: Gordon MK, DeSantis-Rodrigues A, Hahn R, Zhou P, Chang Y, Svoboda KK, Gerecke DR

Abstract
Mustard exposures result in epithelial-stromal separations in the cornea and epidermal-dermal separations in the skin. Large blisters often manifest in skin, while the cornea develops microblisters, and, when enough form, the epithelium sloughs. If the exposure is severe, healing can be imperfect and can result in long-term adverse consequences. For the cornea, this could manifest as recurrent corneal erosions. Since the corneal epithelial-stromal separations are in the region identified by electron microscopy as the lamina lucida, the same region affected by the blistering disease junctional epidermolysis bullosa (JEB), we postulated that the molecules that are defective in JEB would be the same ones cleaved by mustard compounds. These molecules are α6β4 integrin and collagen XVII, which can be cleaved by matrix metalloproteinase-9 (MMP-9) and ADAM17, respectively. Therefore, our laboratory has tested MMP-9 and ADAM17 inhibitors as potential therapies to attenuate corneal mustard injury. Our results demonstrated that inhibiting MMP-9 and ADAM17 resulted in less epithelial-stromal separation in the corneas at 24 h postexposure, as compared with using only medium as a therapy.

PMID: 27737494 [PubMed - indexed for MEDLINE]

Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Thu, 07/20/2017 - 10:34
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Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury.

Ann N Y Acad Sci. 2016 Aug;1378(1):174-179

Authors: Lacey CJ, Wohlman I, Guillon C, Saxena J, Fianu-Velgus C, Aponte E, Young SC, Heck DE, Joseph LB, Laskin JD, Heindel ND

Abstract
The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years.

PMID: 27505078 [PubMed - indexed for MEDLINE]

Preparedness and response to chemical and biological threats: the role of exposure science.

Thu, 07/20/2017 - 10:34
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Preparedness and response to chemical and biological threats: the role of exposure science.

Ann N Y Acad Sci. 2016 Aug;1378(1):108-117

Authors: Lioy PJ, Laskin JD, Georgopoulos PG

Abstract
There are multiple components to emergency preparedness and the response to chemical and biological threat agents. The 5Rs framework (rescue, reentry, recovery, restoration, and rehabitation) outlines opportunities to apply exposure science in emergency events. Exposure science provides guidance and refined tools for characterizing, assessing, and reducing risks from catastrophic events, such as the release of hazardous airborne chemicals or biological agents. Important challenges to be met include deployment of assets, including medications, before and after an emergency response situation. Assessment of past studies demonstrates the value of integrating exposure science methods into risk analysis and the management of catastrophic events.

PMID: 27479653 [PubMed - indexed for MEDLINE]

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Thu, 07/20/2017 - 10:34
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Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.

Ann N Y Acad Sci. 2016 Aug;1378(1):80-86

Authors: Jan YH, Richardson JR, Baker AA, Mishin V, Heck DE, Laskin DL, Laskin JD

Abstract
Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.

PMID: 27441453 [PubMed - indexed for MEDLINE]

Multidisciplinary approaches to stimulate wound healing.

Thu, 07/20/2017 - 10:34
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Multidisciplinary approaches to stimulate wound healing.

Ann N Y Acad Sci. 2016 Aug;1378(1):137-142

Authors: Businaro R, Corsi M, Di Raimo T, Marasco S, Laskin DL, Salvati B, Capoano R, Ricci S, Siciliano C, Frati G, De Falco E

Abstract
New civil wars and waves of terrorism are causing crucial social changes, with consequences in all fields, including health care. In particular, skin injuries are evolving as an epidemic issue. From a physiological standpoint, although wound repair takes place more rapidly in the skin than in other tissues, it is still a complex organ to reconstruct. Genetic and clinical variables, such as diabetes, smoking, and inflammatory/immunological pathologies, are also important risk factors limiting the regenerative potential of many therapeutic applications. Therefore, optimization of current clinical strategies is critical. Here, we summarize the current state of the field by focusing on stem cell therapy applications in wound healing, with an emphasis on current clinical approaches being developed. These involve protocols for the ex vivo expansion of adipose tissue-derived mesenchymal stem cells by means of a patented Good Manufacturing Practice-compliant platelet lysate. Combinations of multiple strategies, including genetic modifications and stem cells, biomimetic scaffolds, and novel vehicles, such as nanoparticles, are also discussed as future approaches.

PMID: 27434638 [PubMed - indexed for MEDLINE]

Tetramethylenedisulfotetramine: pest control gone awry.

Thu, 07/20/2017 - 10:34
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Tetramethylenedisulfotetramine: pest control gone awry.

Ann N Y Acad Sci. 2016 Aug;1378(1):68-79

Authors: Shakarjian MP, Laukova M, Velíšková J, Stanton PK, Heck DE, Velíšek L

Abstract
Incidences of pesticide poisonings are a significant cause of morbidity and mortality worldwide. The seizure-inducing rodenticide tetramethylenedisulfotetramine is one of the most toxic of these agents. Although banned, it has been responsible for thousands of accidental, intentional, and mass poisonings in mainland China and elsewhere. An optimal regimen for treatment of poisoning has not been established. Its facile synthesis from easily obtained starting materials, extreme potency, and lack of odor, color, or taste make it a potential chemical threat agent. This review describes the toxicologic properties of this agent, more recent advances in our understanding of its properties, and recommendations for future research.

PMID: 27384716 [PubMed - indexed for MEDLINE]

Tissue injury and repair following cutaneous exposure of mice to sulfur mustard.

Thu, 07/20/2017 - 10:34
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Tissue injury and repair following cutaneous exposure of mice to sulfur mustard.

Ann N Y Acad Sci. 2016 Aug;1378(1):118-123

Authors: Joseph LB, Composto GM, Heck DE

Abstract
In mouse skin, sulfur mustard (SM) is a potent vesicant, damaging both the epidermis and the dermis. The extent of wounding is dependent on the dose of SM and the duration of exposure. Initial responses include erythema, pruritus, edema, and xerosis; this is followed by an accumulation of inflammatory leukocytes in the tissue, activation of mast cells, and the release of mediators, including proinflammatory cytokines and bioactive lipids. These proinflammatory mediators contribute to damaging the epidermis, hair follicles, and sebaceous glands and to disruption of the epidermal basement membrane. This can lead to separation of the epidermis from the dermis, resulting in a blister, which ruptures, leading to the formation of an eschar. The eschar stimulates the formation of a neoepidermis and wound repair and may result in persistent epidermal hyperplasia. Epidermal damage and repair is associated with upregulation of enzymes generating proinflammatory and pro-growth/pro-wound healing mediators, including cyclooxygenase-2, which generates prostanoids, inducible nitric oxide synthase, which generates nitric oxide, fibroblast growth factor receptor 2, and galectin-3. Characterization of the mediators regulating structural changes in the skin during SM-induced tissue damage and wound healing will aid in the development of therapeutic modalities to mitigate toxicity and stimulate tissue repair processes.

PMID: 27371823 [PubMed - indexed for MEDLINE]

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.

Wed, 07/05/2017 - 10:06

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis.

Toxicol Appl Pharmacol. 2017 Jun 30;:

Authors: Schumacher JD, Kong B, Pan Y, Zhan L, Sun R, Aa J, Rizzolo D, Richardson JR, Chen A, Goedken M, Aleksunes LM, Laskin DL, Guo GL

Abstract
Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15(-/-) and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.

PMID: 28673684 [PubMed - as supplied by publisher]

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