You are here

Recent Publications of Rutgers University CounterACT Research Center of Excellence Members

Subscribe to Recent Publications of Rutgers University CounterACT Research Center of Excellence Members feed Recent Publications of Rutgers University CounterACT Research Center of Excellence Members
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: 8 min 45 sec ago

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]

Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants.

Fri, 12/28/2018 - 11:57

Role of Macrophages in Acute Lung Injury and Chronic Fibrosis Induced by Pulmonary Toxicants.

Toxicol Sci. 2018 Dec 24;:

Authors: Laskin DL, Malaviya R, Laskin JD

Abstract
A diverse group of toxicants has been identified that cause injury to the lung including gases (e.g., ozone, chlorine), particulate matter (e.g., diesel exhaust, fly ash, smoke, dust, mustards), nanoparticles, silica, asbestos, chemotherapeutics (e.g., bleomycin), and radiation. The pathologic response to these toxicants depends on the dose and duration of exposure and their physical/chemical properties. A common response to pulmonary toxicant exposure is an accumulation of proinflammatory/cytotoxic M1 macrophages at sites of tissue injury, followed by the appearance of anti-inflammatory/wound repair M2 macrophages. It is thought that the outcome of the pathogenic responses to toxicants depends on the balance in the activity of these macrophage subpopulations. Overactivation of either M1 or M2 macrophages leads to injury and disease pathogenesis. Thus, the very same macrophage-derived mediators released in controlled amounts to destroy injurious materials and pathogens (e.g., reactive oxygen species [ROS], reactive nitrogen species [RNS], proteases, tumor necrosis factor [TNF]α) and initiate wound repair (e.g., transforming growth factor [TGF] β, connective tissue growth factor [CTGF], vascular endothelial growth factor [VEGF]), can exacerbate acute lung injury and/or induce chronic disease such as fibrosis, chronic obstructive pulmonary disease (COPD) and asthma, when released in excess. This review focuses on the role of macrophage subsets in acute lung injury and chronic fibrosis. Understanding how these pathologies develop following exposure to toxicants, and the contribution of resident and inflammatory macrophages to disease pathogenesis may lead to the development of novel approaches for treating lung diseases.

PMID: 30590802 [PubMed - as supplied by publisher]

Placental BCRP/ABCG2 transporter prevents fetal exposure to the estrogenic mycotoxin zearalenone.

Sun, 12/23/2018 - 21:32
Related Articles

Placental BCRP/ABCG2 transporter prevents fetal exposure to the estrogenic mycotoxin zearalenone.

Toxicol Sci. 2018 Dec 21;:

Authors: Szilagyi JT, Gorczyca L, Brinker A, Buckley B, Laskin JD, Aleksunes LM

Abstract
In the placenta, the BCRP/ABCG2 efflux transporter limits the maternal-to-fetal transfer of drugs and chemicals. Previous research has pointed to the estrogenic mycotoxin zearalenone as a potential substrate for BCRP. Here, we sought to assess the role of the BCRP transporter in the transplacental disposition of zearalenone during pregnancy. In vitro transwell transport assays employing BCRP/Bcrp-transfected MDCK cells and BeWo trophoblasts with reduced BCRP expression were used to characterize the impact of BCRP on the bidirectional transport of zearalenone. In both models, the presence of BCRP protein increased the basolateral-to-apical transport and reduced the apical-to-basolateral transport of zearalenone over a 2 h period. In vivo pharmacokinetic analyses were then performed using pregnant wild-type and Bcrp-/- mice after a single tail vein injection of zearalenone. Zearalenone and its metabolite α-zearalenol were detectable in serum, placentas, and fetuses from all animals, and β-zearalenol was detected in serum and fetuses, but not placentas. There were no significant differences in the maternal serum concentrations of any analytes between the two genotypes. In Bcrp-/- mice, the free fetal concentrations of zearalenone, α-zearalenol, and β-zearalenol were increased by 115%, 84%, and 150%, respectively, when compared to wild-type mice. Concentrations of free zearalenone and α-zearalenol were elevated 145% and 78% in Bcrp-/- placentas, respectively, when compared to wild-type placentas. Taken together, these data indicate that the placental BCRP transporter functions to reduce the fetal accumulation of zearalenone, which may impact susceptibility to developmental toxicities associated with in utero zearalenone exposure.

PMID: 30576553 [PubMed - as supplied by publisher]

Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.

Sun, 11/18/2018 - 11:27
Related Articles

Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats.

J Interdiscip Nanomed. 2018 Sep;3(3):146-159

Authors: Gu Z, Al-Zubaydi F, Adler D, Li S, Johnson S, Prasad P, Holloway J, Szekely Z, Love S, Gao D, Sinko PJ

Abstract
Ductal carcinoma in situ is the most commonly diagnosed early stage breast cancer. The efficacy of intraductally delivered poly(ethylene glycol)-doxorubicin (PEG-DOX) nanocarriers, composed of one or more DOX conjugated to various PEG polymers, was investigated in an orthotopic ductal carcinoma in situ-like rat model. In vitro cytotoxicity was evaluated against 13762 Mat B III cells using MTT assay. The orthotopic model was developed by inoculating cancer cells into mammary ducts of female Fischer 344 retired breeder rats. The ductal retention and in vivo antitumour efficacy of two of the six nanocarriers (5 kDa PEG-DOX and 40 kDa PEG-(DOX)4) were investigated based on in vitro results. Mammary retention of DOX and PEG-DOX nanocarriers was quantified using in vivo imaging. Histopathologic effects of DOX and PEG-DOX nanocarriers on mammary ductal structure were also investigated. Cytotoxicities of small linear PEG-DOX nanocarriers (5 and 10 kDa) were not different from DOX whereas larger PEG-DOX nanocarriers showed reduced potency. The order of mammary retention was 40 kDa PEG-(DOX)4 > 5 kDa PEG-DOX >> DOX, in normal and tumour-bearing rats. Intraductally administered PEG-DOX nanocarriers and DOX were effective in reducing tumour incidence and increasing survival rate, with no significant differences found among the three treatment groups. However, nanocarriers administered intravenously at the same doses were not effective, and intraductally administered free DOX caused severe local toxicity. Intraductal administration of PEG-DOX nanocarriers is effective and less toxic than that of free DOX, as well as IV DOX/PEG-DOX. Furthermore, PEG-DOX nanocarriers demonstrate the added benefit of prolonging DOX ductal retention, which would necessitate less frequent dosing.

PMID: 30443411 [PubMed]

Theme by Danetsoft and Danang Probo Sayekti inspired by Maksimer