Biomedical Engineering Reference
In-Depth Information
2009). ROS can modulate signaling pathways involving protein kinases
and transcription factors such as nuclear factor transcription factor
kappa B (NF-
B), p53, mitogen-activated protein kinases (MAPK), and
protein kinase C (Halliwell and Gutteridge, 2007). ROS-initiated
transcription factor activation can alter cellular gene expression leading
to the downstream cellular response (Brown and Griendling, 2009). A
specific example of xenobiotic-initiated ROS-mediated signal trans-
duction altering embryonic development is phenytoin, an antiepileptic
drug given during pregnancy to mitigate seizure occurrence. Our lab has
shown the involvement of the NF-
k
B signaling pathway in phenytoin-
initiated embryopathies in culture (Kennedy et al., 2004). Using anti-
sense oligonucleotides, inhibition of the downstream NF-
k
k
B signaling
cascade blocked embryopathies, suggesting the involvement of ROS-
initiated NF-
k
B signaling in phenytoin-initiated embryopathies. The
NF-
k
B family of transcription factors regulates the expression of many
genes involved in development, as well as immunity and the inflam-
matory response (Baeuerle and Baltimore, 1996). Another example is
thalidomide, a drug used for its sedative-hypnotic effects in pregnant
women, and is still in clinical use for the treatment of leprosy and
multiple myeloma because of its strong immunomodulatory, anti-
inflammatory, and antiangiogenic properties. When taken during the
third to eighth week of pregnancy, thalidomide can initiate birth defects
predominantly involving the limbs (phocomelia is the most well known)
but can also affect the ears, eyes, heart, kidneys, and other internal organs
(Knobloch and Ruther, 2008). The mechanisms by which thalidomide
initiates birth defects are not clear; however, several mechanisms have
been suggested, including oxidative stress and alterations in signal
transduction pathways. Thalidomide has been demonstrated to suppress
numerous survival signaling pathways including the canonical Wnt/
-
catenin pathway (Knobloch et al., 2007) and Akt signaling, while
upregulating phosphatase and tensin homolog (PTEN) and stimulating
caspase-dependent cell death (Knobloch et al., 2008).
b
7.4.1.3 Macromolecular Damage Elevated ROS concentrations
increase the likelihood that they will react with molecular oxygen to
form superoxide via a one-electron reduction, hydrogen peroxide via a
