Comparative analysis of perturbed molecular pathways identified in in vitro and in vivo toxicology studies.

Toxicol In Vitro. 2012 Apr 9;

Authors: Wiesinger M, Mayer B, Jennings P, Lukas A

Abstract
The development of in vitro toxicological testing strategies are hampered by the difficulty in extrapolation to the intact organism. Academic toxicological literature contains a wealth of mechanistically rich information, especially arising from omic studies, which could potentially be utilized to uncover commonalities between in vitro and in vivo observations on the cellular level. Using a literature mining strategy, we identified 1221 unique human genes as being associated to nephrotoxicity, hepatotoxicity, or CNS toxicity, either linked to in vitro, in vivo, or both experimental conditions. Among this large set of relevant molecular features four genes were found in common to all tissues and experimental conditions analyzed, namely heme oxygenase-1, nitric oxide synthetase 2, NF?B1 and p53. Pathway enrichment revealed 17 relevant pathways for kidney, 26 for liver, and 30 for CNS bridging in vitro and in vivo toxicity effects. Such joint markers and pathways may serve as indicators for extrapolating from in vitro results to in vivo.

PMID: 22515967 [PubMed - as supplied by publisher]

Glucose reintroduction triggers the activation of Nrf2 during experimental ischemia reperfusion.

Mol Cell Biochem. 2012 Mar 30;

Authors: Crean D, Felice L, Taylor CT, Rabb H, Jennings P, Leonard MO

Abstract
Reperfusion results in a rapid reintroduction of oxygen, glucose, and other restricted components to an ischemic tissue. It brings with it not only the necessary components for cell survival but also a burst of oxidative stress and cellular damage. In this study, our primary aims were to investigate glucose as a determining factor for the activation of the transcription factor NF-E2-related factor 2 (Nrf2) upon reperfusion and the expression of downstream anti-oxidant NADPH-dependent reductases. Exposure of renal epithelial HK-2 cells to oxygen and glucose reintroduction after depletion resulted in an increase in nuclear translocation of Nrf2 protein in a manner dependent upon glucose. This activation and the induction of the Nrf2-dependent gene NAD(P)H dehydrogenase, quinone 1 (NQO1) was observed to be maximum at a concentration of 5 mM glucose. Microarray analysis of mRNA from siRNA targeted cells under these conditions revealed the Nrf2-dependent expression of NADPH-dependent reductase enzymes NQO1, Aldo-keto reductase family 1, members C1-3 and dehydrogenase/reductase (SDR family) member 2 (DHRS2), all genes demonstrated to protect against oxidative stress-mediated cellular injury. In addition, NQO1 and DHRS2 mRNA levels were specifically upregulated on glucose reintroduction and were also increased in an in vivo ischemia reperfusion injury model of murine renal pedicle clamping. In conclusion, we demonstrate that glucose reintroduction after depletion activates Nrf2 and Nrf2 regulated NADPH-dependent reductase expression. We suggest these findings represent a previously unreported mechanism for the activation of Nrf2 as a cytoprotective pathway in IRI.

PMID: 22460831 [PubMed - as supplied by publisher]