Extension of Murine Lifespan by
Overexpression of Catalase Targeted to Mitochondria
SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE,
Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS.
Departments of Genome Sciences; Center for Molecular and Mitochondrial
Medicine and Genetics, Departments of Biological Chemistry and Ecology and
Evolutionary Biology, University of California, Irvine, Irvine CA 92697,
To determine the role of reactive oxygen species in mammalian longevity, we
generated transgenic mice that overexpress human catalase localized to the peroxisome (PCAT), nucleus (NCAT), or mitochondrion (MCAT). Median and
maximum lifespans were maximally
increased (average 5 months, and 5.5 months, respectively) in MCAT
animals. Cardiac pathology and cataract development were delayed,
oxidative damage was reduced, H2O2 production and H2O2-induced aconitase
inactivation were attenuated, and the development of mitochondrial deletions
was reduced.These results
support the free radical theory of aging and reinforce the importance
of mitochondria as a source of these radicals.
PMID: 15879174 [PubMed - as supplied by publisher]
physiological functions of polyphenols from apples.
Fundamental Research Laboratory, Asahi Breweries, Ltd., 1-21, Midori
1-chome, Moriya-shi, Ibaraki 302-0106, Japan. firstname.lastname@example.org
Apples contain many kinds of polyphenols, and the main components are
oligomeric procyanidins. Applephenon is apple polyphenol extract
produced commercially from unripe apples, and has been used as food additive
in order to prevent oxidation of components in foods and its application in
functional foods is expected. In a lipid metabolism regulation study,
administration of Applephenon has the potential to
exert strong anti-oxidative
activity and to
inhibit consumption of vitamin E and anti-oxidative enzymes.
Double blind clinical trials of Applephenon on pediatric patients with
atopic dermatitis, and tests using type I allergic model mice suggested that
Applephenon might regulate allergic reactions. We found the no observed
adverse effect level (NOAEL) of Applephenon is greater than 2000 mg/kg in a
90~day consecutive oral administration toxicity test in rats, and
Applephenon is safe and acceptable based on mutagenicity tests.
PMID: 15630302 [PubMed - in process]
Biochim Biophys Acta.
2002 Aug 15;1572(1):25-30.
Procyanidins protect Fao cells
against hydrogen peroxide-induced oxidative stress
Roig R, Cascon E, Arola L, Blade C, Salvado MJ.
Departament de Bioquimica i Biotecnologia, Unitat d'Enologia del Centre de
Referencia en Tecnologia dels Aliments de la Generalitat de Catalunya,
Universitat Rovira i Virgili, Imperial Tarraco, 1, E-43005 Tarragona, Spain.
In this paper, we evaluate the extent to which flavonoids in red wine (catechin,
quercetin and procyanidins) protect against hydrogen peroxide-induced
oxidative stress in Fao cells. When cells were exposed to H(2)O(2),
malondialdehyde (MDA) levels, oxidized glutathione (GSSG) levels and lactate
dehydrogenase (LDH) release increased, indicating membrane damage and
oxidative stress. All the flavonoids studied, and in particular epicatechin
and quercetin, protected the plasma membrane.
Only procyanidins lowered MDA
levels and LDH
leakage, maintained a higher reduced/oxidized glutathione ratio, and
increased catalase/superoxide dismutase and
glutathione peroxidase/superoxide dismutase ratios, and glutathione
and glutathione transferase
activities. These results show that the procyanidin mixture has a
greater antioxidant effect than the individual flavonoids studied,
probably due to its oligomer content and/or the additive/synergistic effect
of its compounds. This suggests that the mixture of flavonoids found in wine
has a greater effect than individual phenols, which may explain many of the
healthy effects attributed to wine.
PMID: 12204329 [PubMed - indexed for MEDLINE]
Eur J Nutr. 2005 Mar 25
Influence of quercetin and rutin on growth and
antioxidant defense system of a human hepatoma cell line (HepG2).
Alia M, Mateos R, Ramos S, Lecumberri E, Bravo L, Goya L.
Depto. de Metabolismo y Nutricion, Instituto del Frio (CSIC) C/Jose Antonio
Novais, 10. Ciudad Universitaria, 28040, Madrid, Espana, email@example.com.
BACKGROUND : Dietary polyphenols like quercetin and rutin are considered
beneficial because of their potential protective role in the pathogenesis of
multiple diseases associated to oxidative stress such as cancer, coronary
heart disease and atherosclerosis. However, many of these effects may depend
on the concentration of the polyphenol utilized since high doses of some
phenolic compounds may be prooxidant and negatively affect cell growth and
viability. AIM OF THE STUDY : To test the potential chemoprotective effects
of quercetin and rutin, two flavonols with high antioxidant capacity, on
cell growth, viability and the response of the antioxidant defense system of
a human hepatoma cell line (HepG2). METHODS : Cell growth was measured by
diaminobenzoic acid and bromodeoxyuridine assays, cell toxicity by lactate
dehydrogenase leakage assay, reduced glutathione was quantified by a
fluorimetric assay, cellular malondialdehyde was analyzed by
high-performance liquid chromatography, reactive oxygen species were
quantified by the dichlorofluorescein assay, antioxidant enzyme activities
were determined by spectrophotometric analysis and their gene expression by
northern blot. RESULTS : Shortterm exposure (4 h) to these flavonols had no
antiproliferative nor cytotoxic effect. High doses of quercetin
(50-100 microM) increased
glutathione concentration and gene
expression of Cu/Zn superoxide dismutase and catalase
inhibiting the activity of the latter enzyme, whereas lower doses (0.1-1
microM) decreased gene expression of Cu/Zn superoxide dismutase and
increased that of glutathione peroxidase. All doses of quercetin and rutin
diminished reactive oxygen species and high doses (10-100 microM) decreased
malondialdehyde concentration. CONCLUSION : The results indicate that both
natural antioxidants induce favorable changes in the antioxidant defense
system of cultured HepG2 that prevent or delay conditions which favor
cellular oxidative stress.
PMID: 15782287 [PubMed - as supplied by publisher]
Reversal of haloperidol-induced orofacial dyskinesia by
quercetin, a bioflavonoid.
Naidu PS, Singh A, Kulkarni SK.
Pharmacology Division, University Institute of Pharmaceutical Sciences,
Panjab University, 160014 Chandigarh, India.
RATIONALE: Tardive dyskinesia is a serious neurological syndrome associate
with long-term administration of neuroleptics to humans and experimental
animals. It may be caused by loss of dopaminergic cells, due to free
radicals as a product of high synaptic dopamine levels. Quercetin is a
bioflavonoid with strong antioxidant properties. OBJECTIVES: To evaluate the
effect of chronic quercetin treatment on haloperidol-induced orofacial
dyskinesia. METHODS: Vacuous chewing movements (VCM) in rats, a widely
accepted animal model of tardive dyskinesia was employed in the present
study. VCM were induced in rats by daily administration of haloperidol (1.0
mg/kg) for a period of 21 days. Animals with established dyskinesia were
given quercetin for a period of 4 weeks and behavioral scoring was recorded
every week before administration of quercetin. Animals were killed after the
last behavioral recordings and biochemical estimations were carried out.
RESULTS: Chronic haloperidol (1.0 mg/kg for 21 days) treatment significantly
induced VCM and tongue protrusions in rats and quercetin (25-100 mg/kg for 4
weeks) significantly reversed haloperidol-induced VCM and tongue
protrusions. Biochemical analysis revealed that chronic haloperidol
treatment significantly induced lipid peroxidation, decreased glutathione (GSH),
superoxide dismutase (SOD), and catalase levels in the brains of rats.
Quercetin (25-100 mg/kg for 4 weeks)
significantly reduced lipid peroxidation and restored GSH,
SOD and catalase levels.
CONCLUSIONS: The results of the present study clearly indicate that
quercetin has a protective role against haloperidol-induced orofacial
dyskinesia. Consequently, the use of quercetin as a therapeutic agent for
the treatment of tardive dyskinesia should be considered.
PMID: 12669184 [PubMed - indexed for MEDLINE]
2003 Sep;77(9):506-10. Epub 2003 May 20.
The effect of quercetin on the
mRNA expression of different antioxidant enzymes in hepatoma cells.
The flavonol quercetin shows a wide range of effects in biological systems.
We investigated whether quercetin exerts its proposed antioxidant properties
via the antioxidant enzyme system. Quercetin in a concentration range from 5
to 100 microM decreased manganese superoxide dismutase, glutathione
peroxidase, and copper zinc superoxide dismutase mRNA expression levels each
by 30-40% in rat hepatoma H4IIE cells.
Catalase mRNA expression levels increased about
30% but only with the cytotoxic concentration
of 100 microM. Despite the down-regulation of antioxidant enzyme mRNA
expression quercetin treatment of cells induced only a mild oxidative
stress. Pretreatment of H4IIE cells with quercetin even protected against an
oxidative stress resulting from hydrogen peroxide exposure. In conclusion,
the antioxidant capacity of quercetin was shown not to be due to the
antioxidant enzyme system.
PMID: 12756520 [PubMed - indexed for MEDLINE]
Quercetin, a bioflavonoid, attenuates
haloperidol-induced orofacial dyskinesia.
Naidu PS, Singh A, Kulkarni SK.
Pharmacology Division, University Institute of Pharmaceutical Sciences,
Panjab University, -160014, Chandigarh, India.
Chronic treatment with neuroleptics leads to the development of abnormal
orofacial movements described as vacuous chewing movements (VCMs) in rats.
Vacuous chewing movements in rodents are widely accepted as one of the
animal models of tardive dyskinesia. Oxidative stress and the products of
lipid peroxidation are implicated in the pathophysiology of various
neurological disorders including tardive dyskinesia. In the present study
chronic haloperidol (1.0 mg kg(-1) for 21 days) treatment induced vacuous
chewing movements and tongue protrusions in rats. Co-administration of
quercetin, a bioflavonoid, dose dependently (25-100 mg kg(-1)) reduced
haloperidol-induced vacuous chewing movements and tongue protrusions.
Biochemical analysis revealed that chronic haloperidol treatment induces
lipid peroxidation and decreases the glutathione (GSH) levels in the
forebrains of rats. The antioxidant defense enzymes, superoxide dismutase
(SOD) and catalase were also decreased due to chronic haloperidol treatment.
Co-administration of quercetin (25-100 mg kg(-1)) significantly reduced the
lipid peroxidation and restored the decreased glutathione levels in
these animals. Further quercetin
(50-100 mg kg(-1)) also reversed the haloperidol-induced decrease in
forebrain SOD and catalase
levels in rats. The major findings
of the present study suggested that oxidative stress plays a significant
role in neuroleptic-induced orofacial dyskinesia and quercetin
co-administration reverses these behavioral and biochemical changes.
Quercetin, a naturally occurring bioflavonoid could prove to be a useful
agent in neuroleptic-induced orofacial dyskinesia.
PMID: 12763102 [PubMed - indexed for MEDLINE]
polyphenol extracts prevent damage to human gastric epithelial cells
in vitro and to rat gastric mucosa in vivo
G Graziani1, G
D’Argenio2, C Tuccillo3, C Loguercio3, A
Ritieni1, F Morisco1, C Del Vecchio Blanco3,
V Fogliano1 and M Romano3
1 Dipartimento di Scienza degli Alimenti, Università di Napoli "Federico
II" Parco Gussone, Ed 84-80055 Portici (NA), Italy 2 Gastroenterologia, Università Federico II, Napoli, Italy 3 Centro Interuniversitario di Ricerche su Alimenti, Nutrizione
ed Apparato Digerente (CIRANAD) and Dipartimento Medico Chirurgico di
Internistica Clinica e Sperimentale, Cattedra di Gastroenterologia y Seconda
Università di Napoli, Napoli, Italy
Dr M Romano
Dipartimento di Internistica Clinica e Sperimentale-Gastroenterologia, II
Policlinico, Edificio 3, II piano, Via Pansini 5, 80131 Napoli, Italy;
Background: Fresh fruit and vegetables exert
multiple biologicaleffects on the gastrointestinal mucosa.
Aim: To assess whether
apple extracts counteract
oxidative orindomethacin induced damage to gastric epithelial
cells in vitroand to rat gastric mucosa in vivo.
Methods:Apple extracts were obtained
from freeze dried appleflesh of the "Annurca" variety. Cell
damage was induced by incubatingMKN 28 cells with
xanthine-xanthine oxidase or indomethacinand quantitated by MTT.
In vivo gastric damage was induced byindomethacin 35 mg/kg.
Intracellular antioxidant activity wasdetermined using the
Malondialdehyde intracellular concentration, an indexof lipid
peroxidation, was determined by high pressure liquid
chromatography with fluorometric detection.
Results: (1) Apple extracts decreased
xanthine-xanthine oxidaseor indomethacin induced injury to
gastric epithelial cells by50%; (2) catechin or chlorogenic acid
(the main phenolic componentsof apple extracts) were equally
effective as apple extractsin preventing oxidative injury to
gastric cells; and (3) appleextracts (i)
caused a fourfold increase in intracellular
activity, (ii) prevented its
decrease induced by xanthine-xanthineoxidase, (iii) counteracted
xanthine-xanthine oxidase inducedlipid peroxidation, and (iv)
decreased indomethacin injury tothe rat gastric mucosa by 40%.
Conclusions: Apple extracts prevent exogenous
damage to humangastric epithelial cells in vitro and to the rat
gastric mucosain vivo. This effect seems to be associated with
the antioxidantactivity of apple phenolic compounds. A diet rich
in apple antioxidantsmight exert a beneficial effect in the
prevention of gastricdiseases related to generation of reactive
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915-22
Oxidants, antioxidants, and the degenerative diseases
Ames BN, Shigenaga MK, Hagen TM.
Division of Biochemistry and Molecular Biology, University of California,
Metabolism, like other aspects of life, involves tradeoffs. Oxidant
by-products of normal metabolism cause extensive damage to DNA, protein, and
lipid. We argue that this damage
(the same as that produced by radiation) is a major contributor to aging and
to degenerative diseases of aging such as cancer, cardiovascular
disease, immune-system decline,
brain dysfunction, and cataracts. Antioxidant defenses against this
damage include ascorbate, tocopherol, and carotenoids. Dietary fruits and
vegetables are the principal source of ascorbate and carotenoids and are one
source of tocopherol. Low dietary intake of fruits and vegetables doubles
the risk of most types of cancer as compared to high intake and also
markedly increases the risk of heart disease and cataracts. Since only 9% of
Americans eat the recommended five servings of fruits and vegetables per
day, the opportunity for improving health by improving diet is great.