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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: 16 min 25 sec ago

A type IV collagenous inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), suppresses skin injury induced by sulfur mustard.

Tue, 06/02/2020 - 10:25

A type IV collagenous inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), suppresses skin injury induced by sulfur mustard.

Toxicol Appl Pharmacol. 2020 May 29;:115078

Authors: Chang YC, Hahn RA, Gordon MK, Laskin JD, Gerecke DR

Abstract
Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for its ability to protect the skin against injury induced by SM in the mouse ear vesicant model. SM induced inflammation, epidermal hyperplasia and microblistering at the dermal/epidermal junction of mouse ears 24-168 h post-exposure. This was associated with upregulation of MMP-9 mRNA and protein in the skin. Dual immunofluorescence labeling showed increases in MMP-9 in the epidermis and in the adjacent dermal matrix of the SM injured skin, as well as breakdown of type IV collagen in the basement membrane. Pretreatment of the skin with BiPS reduced signs of SM-induced cutaneous toxicity; expression of MMP-9 mRNA and protein was also downregulated in the skin by BiPS. Following BiPS pretreatment, type IV collagen appeared intact and was similar to control skin. These results demonstrate that inhibiting type IV collagenases in the skin improves basement membrane integrity after exposure to SM. BiPS may hold promise as a potential protective agent to mitigate SM induced skin injury.

PMID: 32479919 [PubMed - as supplied by publisher]

Skin remodeling and wound healing in the Gottingen minipig following exposure to sulfur mustard.

Sun, 05/24/2020 - 10:56

Skin remodeling and wound healing in the Gottingen minipig following exposure to sulfur mustard.

Exp Mol Pathol. 2020 May 20;:104470

Authors: Laskin JD, Wahler G, Croutch CR, Sinko PJ, Laskin DL, Heck DE, Joseph LB

Abstract
Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soaks. Animals were then euthanized, and full thickness skin biopsies prepared for histology and immunohistochemistry. Control skin contained a well differentiated epidermis with a prominent stratum corneum. A well-developed eschar covered the skin of SM treated animals, however, the epidermis beneath the eschar displayed significant wound healing with a hyperplastic epidermis. Stratum corneum shedding and a multilayered basal epithelium consisting of cuboidal and columnar cells were also evident in the neoepidermis. Nuclear expression of proliferating cell nuclear antigen (PCNA) was contiguous in cells along the basal epidermal layer of control and SM exposed skin; SM caused a significant increase in PCNA expression in basal and suprabasal cells. SM exposure was also associated with marked changes in expression of markers of wound healing including increases in keratin 10, keratin 17 and loricrin and decreases in E-cadherin. Trichrome staining of control skin showed a well-developed collagen network with no delineation between the papillary and reticular dermis. Conversely, a major delineation was observed in SM-exposed skin including a web-like papillary dermis composed of filamentous extracellular matrix, and compact collagen fibrils in the lower reticular dermis. Although the dermis below the wound site was disrupted, there was substantive epidermal regeneration following SM-induced injury. Further studies analyzing the wound healing process in minipig skin will be important to provide a model to evaluate potential vesicant countermeasures.

PMID: 32445752 [PubMed - as supplied by publisher]

Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard.

Tue, 05/19/2020 - 10:34
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Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard.

Anat Rec (Hoboken). 2020 May 18;:

Authors: Chang YC, Wang JD, Chang HY, Zhou P, Hahn RA, Gordon MK, Laskin JD, Gerecke DR

Abstract
Laminin-332 is a basement membrane protein composed of three genetically distinct polypeptide chains that actively promote both skin epidermal cell adhesion and migration. Proteolytic fragments of the laminin γ2 chain stimulate migration and scattering of keratinocytes and cancer cells. Sulfur mustard (SM) is a bifunctional alkylating agent that induces separation of basal keratinocytes from the dermal-epidermal junction and invokes a strong inflammatory response leading to delayed wound repair. In the present studies, the role of laminin γ2 in SM-induced skin injury and wound repair was investigated using the mouse ear vesicant model. We found that laminin γ2 chain mRNA was preferentially upregulated in mouse ear skin exposed to SM. In situ hybridization confirmed overexpression of laminin γ2 transcript. Western blot analysis showed increased protein expression of the full-length proform of laminin γ2 and smaller processed fragments of laminin γ2 in skin exposed to SM. Dual immunofluorescence labeling indicated that laminin γ2 fragments are prevalent in suprabasal keratinocytes behind the leading edge in areas of hyperplasia in injured skin. In addition, co-expression of laminin γ2 and the senescent marker, p16-INK4a was found to overlap with the hyperplastic migratory epithelial sheet. This observation is similar to hypermotile keratinocytes reported in invasive carcinoma cells. Overall, our studies indicate that laminin γ2 is preferentially expressed in skin post SM exposure and that protein expression appears to become progressively more fragmented. The laminin γ2 fragments may play a role in regulating SM-induced skin wound repair. Anat Rec, 2020. © 2020 American Association for Anatomy.

PMID: 32421930 [PubMed - as supplied by publisher]

Breast intraductal nanoformulations for treating ductal carcinoma in situ I: Exploring metal-ion complexation to slow ciclopirox release, enhance mammary persistence and efficacy.

Sat, 04/18/2020 - 10:10

Breast intraductal nanoformulations for treating ductal carcinoma in situ I: Exploring metal-ion complexation to slow ciclopirox release, enhance mammary persistence and efficacy.

J Control Release. 2020 Apr 14;:

Authors: Al-Zubaydi F, Gao D, Kakkar D, Li S, Adler D, Holloway J, Szekely Z, Gu Z, Chan N, Kumar S, Love S, Sinko PJ

Abstract
INTRODUCTION: Ductal Carcinoma In Situ (DCIS) represents a significant fraction (~20-25%) of all newly diagnosed breast cancer cases and, if left untreated, a significant fraction of patients will progress to invasive disease. Surgery is the only treatment option. Ciclopirox (CPX), an FDA-approved antifungal drug, has exhibited promising antitumor activity by down-regulating the expression of vital antiapoptotic cellular proteins and inhibiting the genetic expression of several oncogenic pathways. In this study, the feasibility of using nanoscale delivery systems to control release and prolong mammary tissue persistence of a lipophilic metal complex of CPX and Zinc (CPXZn) after intraductal administration was investigated.
METHODS: CPX and CPX-Zn nanosuspensions (NSs) were prepared using an evaporative nanoprecipitation-ultra-sonication method. Flash nanoprecipitation was used to prepare PLGA nanoparticles (NPs) loaded with CPXZn. Our established orthotopic DCIS rat model was used to evaluate efficacy. Briefly, two days after 13,762 Mat B III cell intraductal inoculation, rats were divided into treatment groups and a single intraductal injection of CPX NS, CPX-Zn NS or CPX-Zn NPs was administered. In the first study arm, the efficacy of CPX NS (1, 3, 5 mg/duct) was evaluated. In the second arm, the in vivo efficacy of CPX NS, CPX-Zn NS and CPX-Zn loaded NPs was evaluated and compared at equivalent CPX doses. The mammary persistence of CPX from CPX NS, CPX-Zn NS, and CPX-Zn PLGA NPs was also assessed.
RESULTS: CPX-Zn complex was successfully synthesized and characterized by several spectral analyses. CPX release was slowed from the CPX-Zn NS and further slowed by incorporating CPX-Zn into PLGA NPs as compared to the CPX NS with release half times following the order: CPX NS < CPX-Zn NS < < CPX-Zn NP. Intraductal CPX NS administration was dose and time dependent in suppressing tumor initiation suggesting. In the second arm, mammary tissue persistence of CPX followed the rank order CPX NS < CPX-Zn NS < < CPX-Zn NP at 6 h and 48 h post-administration. Prolonged mammary CPX exposure was highly correlated to improved efficacy. Prolonged CPX tissue persistence, attributed to slower release from the zinc complex and the PLGA NPs, resulted in a 5-fold dose reduction compared to the CPX NS.
CONCLUSIONS: The current results demonstrate that slowing drug release in the mammary duct after intraductal administration overcomes the rapid ductal clearance of CPX, prolongs mammary tissue persistence, improves efficacy against DCIS lesions in vivo, and requires 5-fold less CPX to achieve equivalent efficacy. The studies also provide a strategic path forward for developing a locally administered drug delivery system for treating DCIS, for which no primary chemotherapy option is available.

PMID: 32302762 [PubMed - as supplied by publisher]

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

Tue, 04/14/2020 - 10:47
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Hydroxyl Radicals in E-Cigarette Vapor and E-Vapor Oxidative Potentials under Different Vaping Patterns.

Chem Res Toxicol. 2019 06 17;32(6):1087-1095

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 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 because of 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 nonflavored 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 - indexed for MEDLINE]

Sulfur Mustard Analog Mechlorethamine (Bis(2-chloroethyl)methylamine) Modulates Cell Cycle Progression via the DNA Damage Response in Human Lung Epithelial A549 Cells.

Tue, 04/14/2020 - 10:47
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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 06 17;32(6):1123-1133

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 mutated- and Rad3-related (ATR) as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between the 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 (Ser1981), Chk2 (Thr68), 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 VE821, 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 - indexed for MEDLINE]

NETs: a new biomarker of traffic-related air pollution exposure: are they ready to catch fish?

Sun, 04/05/2020 - 10:50
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NETs: a new biomarker of traffic-related air pollution exposure: are they ready to catch fish?

Eur Respir J. 2020 Apr;55(4):

Authors: Kipen HM, Laskin DL

PMID: 32245775 [PubMed - as supplied by publisher]

A Novel Bivalent Mannosylated Targeting Ligand Displayed on Nanoparticles Selectively Targets Anti-Inflammatory M2 Macrophages.

Thu, 03/19/2020 - 10:02
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A Novel Bivalent Mannosylated Targeting Ligand Displayed on Nanoparticles Selectively Targets Anti-Inflammatory M2 Macrophages.

Pharmaceutics. 2020 Mar 08;12(3):

Authors: Chen P, Zhang X, Venosa A, Lee IH, Myers D, Holloway JA, Prud'homme RK, Gao D, Szekely Z, Laskin JD, Laskin DL, Sinko PJ

Abstract
Persistent activation of macrophages (MP)s into a proinflammatory M1 or anti-inflammatory M2 phenotype plays a role in several pathological conditions, including autoimmune diseases, fibrosis, infections, atherosclerosis and tumor development. The mannose receptor (MR, CD206), expressed at low levels on resting MPs and absent on M1 MPs, is highly expressed on M2 MPs, making it a potential target and drug delivery portal. Recently, we developed a novel, highly selective MR targeting ligand (MRTL), consisting of two mannose molecules separated by a monodisperse 12 unit poly(ethylene glycol) linker, to enhance the cellular uptake of polymeric nanocarriers. The feasibility of using the MRTL ligand for selectively targeting M2 MPs for intracellular delivery of nanoparticles (NPs) was investigated. Rat peritoneal MPs were differentiated into an M1 or M2 phenotype using IFN-γ and IL-4/IL-13, respectively. Expression of the M1 marker, inducible nitric oxide synthase (iNOS), and the M2 markers arginase (Arg)-1 and MR (at both the mRNA and protein levels) confirmed MP phenotypic activation. Resting, M1 and M2 MPs were treated with fluorescein isothiocyanate (FITC)-labeled MRTL or NPs displaying FITC-labeled MRTL at two surface densities (1 and 10%) and examined by confocal microscopy. Intracellular fluorescence was also quantified. Uptake of the MRTL was 2.4- and 11.8-fold higher in M2 MPs when compared to resting or M1 MPs, respectively, consistent with marker expression levels. Mannan, a competitive inhibitor of the MR, abrogated MRTL uptake. MRTL also co-localized with a fluid-phase endocytosis marker, further suggesting that uptake was mediated by MR-mediated endocytosis. Intracellular NP fluorescence was confirmed by flow cytometry and by confocal microscopy. MRTL-NPs accumulated intracellularly with no significant cell surface binding, suggesting efficient translocation. NPs displaying a low surface density (1%) of the MRTL exhibited significantly higher (2.3-fold) uptake into M2 MPs, relative to resting and M1 MPs. The 10% MRTL-NPs displayed greater uptake by M2 MPs when compared to resting and M1 MPs, but less uptake than 1% MRTL-NPs into M2 MPs. Control FITC-labeled plain NPs did not exhibit selective MP uptake. These studies demonstrate that M2 MPs are selectively targeted by NPs displaying a novel bivalent ligand that utilizes the MR as a target/portal for cell entry. This study also establishes the feasibility of the approach allowing for further investigation in vivo.

PMID: 32182675 [PubMed]

DNA damage signaling in the cellular responses to mustard vesicants.

Tue, 03/17/2020 - 10:55
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DNA damage signaling in the cellular responses to mustard vesicants.

Toxicol Lett. 2020 Mar 12;:

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

Abstract
Mustard vesicants, including sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents synthesized for chemical warfare. Because they contain highly reactive electrophilic chloroethyl side chains, they readily react with cellular macromolecules like DNA forming monofunctional and bifunctional adducts. By targeting DNA, mustards can compromise genomic integrity, disrupt the cell cycle, and cause mutations and cytotoxicity. To protect against genotoxicity following exposure to mustards, cells initiate a DNA damage response (DDR). This involves activation of signaling cascades including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase, catalytic unit). Signaling induced by the DDR leads to the recruitment and activation of repair related proteins such as H2AX and p53 to sites of DNA lesions. Excessive DNA modifications by mustards can overwhelm DNA repair leading to single and double strand DNA breaks, cytotoxicity and tissue damage, sometimes leading to cancer. Herein we summarize DDR signaling pathways induced by SM, HN2 and the half mustard, 2-chloroethyl ethyl sulfide (CEES). At the present time, little is known about how mustard-induced DNA damage leads to the activation of DDR signaling. A better understanding of mechanisms by which mustard vesicants induce the DDR may lead to the development of countermeasures effective in mitigating tissue injury.

PMID: 32173488 [PubMed - as supplied by publisher]

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