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Jeffrey D. Laskin, Ph.D.


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

6 hours 51 min ago

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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]

Categories: Publications from UCDPER Members

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

Mon, 10/02/2017 - 14:00

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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]

Categories: Publications from UCDPER Members

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

Wed, 08/02/2017 - 02:00

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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]

Categories: Publications from UCDPER Members

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

Wed, 08/02/2017 - 02:00

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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]

Categories: Publications from UCDPER Members

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

Wed, 08/02/2017 - 02:00

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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]

Categories: Publications from UCDPER Members

Anti-TNFα Therapy in Inflammatory Lung Diseases bn.

Thu, 07/20/2017 - 02:00

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Anti-TNFα Therapy in Inflammatory Lung Diseases bn.

Pharmacol Ther. 2017 Jun 19;:

Authors: Malaviya R, Laskin JD, Laskin DL

Abstract
Increased levels of tumor necrosis factor (TNF) α have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFα plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNF-targeting biologics, therefore, present a potentially highly efficacious treatment option. This review summarizes current knowledge on the role of TNFα in pulmonary disease pathologies, with a focus on the therapeutic potential of TNFα-targeting agents in treating inflammatory lung diseases.

PMID: 28642115 [PubMed - as supplied by publisher]

Categories: Publications from UCDPER Members