Biomedical Engineering Reference
In-Depth Information
normal cell metabolism and are important for cell signalling but can also be toxic to
cells by causing damage to nearly all macromolecules [
15
] . Cells possess enzymatic
and non-enzymatic antioxidants involved in ROS elimination [
20
] . However, when
production of ROS is increased upon certain stimuli, the balance of ROS formation
and degradation may be disturbed. Such a state is called oxidative stress.
ROS can be formed in the cell as by-products of electron transfer by a chain of
cytochromes in mitochondrial respiration; cytochromes of the P450 family, involved
in detoxification of various compounds, also produce ROS. Cellular oxidases, such
as NADPH oxidase, myeloperoxidase, glucose oxidase, cyclooxygenase and xan-
thine oxidase, are another potent ROS source [
95
]. Oxidative stress can result in
damage to most biological molecules. Lipid peroxidation is one of the best known
markers of oxidative stress [
76
]. It comprises a set of chain reactions in which lipid
peroxyl radicals are formed from unsaturated fatty acids and induce similar reac-
tions in other fatty acid molecules. Peroxyl radicals can be rearranged via a cyclisa-
tion reaction to endoperoxides, which decompose to aldehydes, such as
malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) [
13,
91
] . Other lipids,
such as cholesterol, can also undergo oxidation reactions [
63
]. ROS can also oxidise
proteins. The changes in amino acid residue side chains caused by ROS can induce
conformational changes in protein structure that eventually can lead to loss of activ-
ity and protein misfolding [
91
]. Cells possess the mechanism to cope with unfolded
and misfolded proteins called the unfolded protein response (UPR) [
75
] . UPR
inhibits general translation, but induces gene expression and protein translation of
chaperones, such as heat shock proteins (HSP) [
64
]. Although there are reports
connecting oxidative stress to UPR [
54
] the link between those two processes has
been poorly studied.
Cells possess mechanisms to defend themselves against ROS. Natural com-
pounds present in the cell, such as vitamin E, vitamin C, carotenoids, polyphe-
nols, bioflavonoids, selenium, copper, zinc and manganese, can function as
non-enzymatic antioxidants [
20
]. On the other hand, antioxidant enzymes catal-
yse highly specific reactions which detoxify ROS and organic peroxides (Fig.
4.1
).
These include antioxidant enzymes, such as superoxide dismutase (SOD), cata-
lase and glutathione peroxidise (GPX), which determine the response of cells to
oxidative stress [
6
]. Two isoforms of SOD, cytosolic and nuclear (in endothelial
cells) Cu/Zn-SOD (SOD1) and mitochondrial Mn-SOD (SOD2), catalyse the dis-
mutation of superoxide radicals into H
2
O
2
and O
2
by successive oxidation and
reduction of the transition metal ion in the active site (
4.9
) [
30
] . Interestingly,
·
O
2
−
can interact with nitric oxide (NO), forming another highly reactive compound
peroxinitrite (ONOO
−
) [
91
] . H
2
O
2
can be degraded by both catalase and GPX.
Catalase is a heme-containing enzyme that catalyses hydrolysis of H
2
O
2
(
4.10
),
which is localised in peroxisomes and protects cells from H
2
O
2
formed during
b-oxidation of long-chain fatty acids [
13
]. GPX, which is mostly a cytosolic
enzyme, can catalytically reduce H
2
O
2
(
4.11
) as well as lipid peroxides (
4.12
)
[
92
]. GPX requires glutathione (g-glutamyl-cysteinyl-glycine, GSH) for these
reactions. GSH, in turn, can react with H
2
O
2
directly or through a GPX-catalysed
reaction. As a result, two GSH molecules are oxidised to form GSSH, which is
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