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hearing loss and cochlear degeneration, and this was found to be related to
LF accumulation in spiral ganglion neurons (340). Moreover, in a study per-
formed in C. elegans , intestinal LF levels were reduced in curcumin-treated
adult day-4 and -8 nematodes, compared with untreated controls (341). Grape
seed proanthocyanidin extract was shown to reduce LF accumulation in female
Wistar rats 6 and 15 months of age (342).
Similar to LF, other protein aggregates are also able to inhibit the protea-
some, as the tau aggregates are shown to affect proteasome and cause dysfunc-
tion in the proteasomal activity in the brain of patients with AD (343). In
human studies, there are several pathological events related to lipofuscinoses
(344, 345). These are known as lysosomal storage diseases, which includes
Batten disease (346, 347). An age-related accumulation of LF in
-cells of
humans, rhesus monkeys, and mice has been reported (348, 349). Aggregates
were found to be present in
-cells from the earliest age (1 year) and increased
significantly with age up to 84 years in man (350). Nrf2 −/− mice developed an
age-dependent degenerative pathology in the RPE with the accumulation of
LF in mice after 12 months (351). Interestingly, a regional difference in the LF
accumulation has been determined in the female hamster brain stem, suggest-
ing a possible neuroprotective role of estrogen, since the degree of accumula-
tion is related inversely to the density of estrogen receptors (352).
Besides other factors, the aging process depends on environmental factors.
Most of the environmental-related factors such as tobacco smoking, diet,
alcohol, ionizing radiations, biocides, pesticides, viral infections, and xenobiot-
ics shift cells into a state of oxidative stress and initiate the protein oxidation
process in the organisms (353). One of the examples for environmentally
induced stress is the dietary exposure to ions, so mouse renal medullary cells,
normally exposed to high NaCl, express senescence markers earlier than cells
in the renal cortex, which has the same level of NaCl as peripheral blood (354).
Environmentally released nitric oxide and nitrogen dioxide react readily
with thiols. This appears important both in smog-induced inactivation of thiol-
dependent enzymes and in cigarette smoke toxicology. Fresh, undiluted gas-
phase cigarette smoke is remarkable in containing more than 1000 reactive
oxy-radicals per puff. Undiluted cigarette smoke also contains several hundred
parts per million (ppm) of NOx; in contrast, polluted air generally contains
less than 1 ppm NOx. It has been shown that some of the effects of cigarette
smoke result from its very high NOx content (355). For example, the oxidative
inactivation of the human antiprotease,
appears to be caused by species produced from the reactions of NO 2 with
isoprene and other constituents of cigarette smoke. These reactions produce
oxy-radicals and oxidants such as peroxynitrates that can oxidize a critical
methionine in
-I-proteinase inhibitor (
1PI, inactivating the protein (356).
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