X-Message-Number: 32569
Date: Sat, 24 Apr 2010 20:54:28 -0700 (PDT)
From:
Subject: acrolein as a driver of human aging Part 2
[Bisulfite is an interesting acrolein scavenger.]
Chem Biol Interact. 2010 Feb 12;183(3):416-24. Epub 2009 Dec 16.
Toxicity of smoke extracts towards A549 lung cells: role of acrolein and
suppression by carbonyl scavengers.
Burcham PC, Raso A, Thompson CA. Pharmacology and Anaesthesiology Unit, School
of Medicine and Pharmacology, The University of Western Australia, Nedlands, WA
6009, Australia.
Abstract
The noxious 3-carbon electrophile acrolein forms on combustion of diverse
organic matter including synthetic polymers such as polyethylene. While
known to play a key role in smoke inhalation injury (SII), the molecular
basis for the pulmonary toxicity of high dose acrolein-containing smoke is
unclear. As a result, drug interventions in SII are poorly directed against
pathogenetic smoke toxicants such as acrolein. The first aim of this study
was to confirm a role for acrolein in the acute toxicity of smoke extracts
towards A549 lung cells by monitoring adduction of known acrolein targets
and the expression of acrolein-inducible genes. A second aim was to evaluate
carbonyl scavengers for their abilities to protect cell targets and block
smoke extract toxicity. Extracts were prepared by bubbling smoke released by
smouldering polyethylene through a buffered saline-trap. Acrolein levels in
the extracts were estimated via HPLC after derivatisation with
2,4-dinitrophenylhydrazine. Extracts were highly toxic towards A549 cells,
eliciting greater ATP depletion than an equivalent concentration of acrolein
alone. The toxicity was accompanied by pronounced carbonylation of several
cytoskeletal targets, namely vimentin and keratins-7, -8 and -18. Western
blotting revealed that polyethylene combustion products also upregulated
several acrolein-responsive protein markers, including GADD45beta, NQO1,
HMOX, Hsp70, Nur77 and Egr1. Several carbonyl scavengers (bisulfite,
d-penicillamine, hydralazine and 1-hydrazinoisoquinoline) strongly
attenuated smoke extract toxicity, with bisulfite suppressing both the
adduction and cross-linking of intermediate filament targets. Bisulfite also
suppressed the cytotoxicity of smoke extracts when detected using real-time
monitoring of cellular impedance. These findings confirm a key role for
acrolein in smoke cytotoxicity and suggest drugs that block acrolein
toxicity deserve further investigation as possible interventions against
SII. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.
PMID: 20015449
[Flavonoids from diverse sources can also scavenge acrolein. Apple
derived phloretin was the most effective flavonoid.]
Chem Res Toxicol. 2009 Oct;22(10):1721-7.
Natural polyphenols as direct trapping agents of lipid peroxidation-derived
acrolein and 4-hydroxy-trans-2-nonenal.
Zhu Q, Zheng ZP, Cheng KW, Wu JJ, Zhang S, Tang YS, Sze KH, Chen J, Chen F, Wang
M. State Key Laboratory of Food Science and Technology, Jiangnan University,
Wuxi, PR China.
Abstract
Acrolein (ACR) and 4-hydroxy-trans-2-nonenal (HNE) are two cytotoxic
lipid-derived alpha,beta-unsaturated aldehydes which have been implicated as
causative agents in the development of carbonyl stress-associated
pathologies. In this study, 21 natural polyphenols were screened to identify
effective scavenging agents of ACR and/or HNE in simulated physiological
conditions. It was found that flavan-3-ols, theaflavins, cyanomaclurin, and
dihydrochalcones effectively trapped ACR and HNE by working as sacrificial
nucleophiles. The most effective one was phloretin, which quenched up to
99.6% ACR in 90 min and 90.1% HNE in 24 h. Subsequent LC-MS/MS analysis
showed that these effective polyphenols formed adducts with ACR and HNE. A
major adduct formed from phloretin and ACR was purified, and its structure
was characterized by LC-MS and NMR spectroscopy as diACR-conjugated
phloretin. The chemical nature of interactions between ACR and polyphenols
was proposed as the Michael addition reaction of phloretin to the C
horizontal lineC double bond of ACR, followed by the formation of hemiacetal
between the hydroxyl group in the A ring of phloretin and the C horizontal
lineO carbonyl group in ACR, thus yielding more stable products. Findings of
the present study highlighted certain classes of polyphenols as promising
sequestering agents of alpha,beta-unsaturated aldehydes to inhibit or
restrain carbonyl stress-associated diseases.
PMID: 19743801
[A phloretin precursor may be able to inhibit hair greying.]
Food Chem Toxicol. 2009 Oct;47(10):2436-40. Epub 2009 Jul 2.
Phloridzin-induced melanogenesis is mediated by the cAMP signaling pathway.
Jung E, Lee J, Huh S, Lee J, Kim YS, Kim G, Park D. Biospectrum Life Science
Institute, Gunpo City, 435-833 Gyunggi Do, Republic of Korea.
Abstract
Melanogenesis is a physiological process that results in the synthesis of
melanin pigments, which play a crucial protective role in protection against
skin photocarcinogenesis. Phloridzin is a phloretin 2'-glucoside that is
found in many parts of the apple tree that reportedly increases tyrosinase
activity and melanin contents through inhibition of protein kinase C (PKC)
activity in B16 melanoma cells. In this study, we attempted to accurately
determine the effects and mechanisms of action of phloridzin on
melanogenesis. Specifically, we observed that phloridzin-induced a
dose-dependent increase in tyrosinase activity and melanin contents, and
that these changes were accompanied by an increase in the levels of
tyrosinase and the tyrosinase-related proteins, TRP-1 and TRP-2.
Furthermore, the cAMP-dependent protein kinase A (PKA) inhibitor H89
impaired the response of the tyrosinase activity and melanin synthesis to
phloridzin. Additionally, phloridzin stimulated cAMP production and
phosphorylation of the cAMP-response element binding protein (CREB). Taken
together, the results of this study indicate that phloridzin increases
tyrosinase gene expression through the cAMP signaling pathway, thereby
leading to the stimulation of melanogenesis.
PMID: 19576939
[N-acetylcysteine blocked the generation of acrolein, and dramatically
reduced age associated lesions in Long-Evans Cinnamon rats.]
Toxicol Pathol. 2005;33(5):584-92.
Effects of N-acetylcysteine, quercetin, and phytic acid on spontaneous hepatic
and renal lesions in LEC rats.
Kitamura Y, Nishikawa A, Nakamura H, Furukawa F, Imazawa T, Umemura T, Uchida K,
Hirose M. Division of Pathology, National Institute of Health Sciences, 1-18-1
Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.
Abstract
The effects of anti-oxidants were examined in Long-Evans Cinnamon (LEC)
rats, which develop acute hepatic injury, and subsequent hepatic and renal
tumors due to accumulation of excess Cu. The rats, at the age of 15 weeks,
were supplied a diet containing either 1% of N-acetylcysteine (NAC),
quercetin (QC), or phytic acid (PA), or basal diet alone. At weeks 2 and 6
posttreatment, animals were sacrificed for collection of blood and tissue
samples. In the NAC-treated group, the development of hepatic and renal
lesions was dramatically reduced. In addition, accumulation of Cu and Fe in
the liver was suppressed. Acrolein-modified protein, a new marker for lipid
peroxidation, was not detected in the liver or kidney of NAC treated rats,
even though deposition was evident in control. Neither QC nor PA affected
the development of spontaneous hepatic lesions. These results indicate that
oxidative stress was reduced by NAC in the liver and kidney, and suggest
that Cu and Fe may be involved in the generation of oxidative stress in the
liver. In addition, it was suggested that the different effects of the
anti-oxidants on lesion development in LEC rats might be related to
different mechanisms of action with regard to oxidative stress.
PMID: 16178122
[Cysteamine is more effective than N-acetylcysteine is protecting cells
against acrolein, and is also more effective in extending the lifespan of
the short lived cancer prone NZB x NZW F1 mice.]
Brain Res. 2007 Jul 16;1158:158-63. Epub 2007 May 10.
Cellular thiol pools are responsible for sequestration of cytotoxic reactive
aldehydes: central role of free cysteine and cysteamine.
Wood PL, Khan MA, Moskal JR. The Falk Center for Molecular Therapeutics,
Department of Biomedical Engineering, McCormick School of Engineering and
Applied Sciences, Northwestern University, 1801 Maple Ave., Suite 4306,
Evanston, IL 60201, USA.
Abstract
Cellular thiol pools have been shown to be important in the regulation of
the redox status of cells, providing a large antioxidant pool consisting of
free thiols, thiols bound in the disulfide form and thiols bound to
proteins. However, experimental studies with the thiol cysteamine and its
disulfide cystamine have demonstrated dramatic cytoprotection in
experimental models where antioxidants provide only minor protection. These
data suggest that an alternate action of thiols is important in their
cytoprotective actions. A common feature of the in vitro and in vivo models,
where these thiol agents demonstrate cytoprotection, is the generation of
cytotoxic aldehydes. We therefore studied the actions of cystamine,
cysteamine and several reference thiol agents as cytoprotectants against
cell death induced by increased "aldehyde load". We found that all the thiol
agents examined provided dramatic protection against aldehyde-induced cell
death in SN56 cholinergic neurons, under conditions in which acrolein
induced 100% cell death. With regard to mechanism of action, the reference
thiols cysteine, N-acetylcysteine, 2-mercaptoethanesulfonic acid,
mercapto-propionyglycine, and cysteamine can directly sequester aldehydes.
In addition, these thiols were all found to augment intracellular cysteine
levels via disulfide interchange reactions. Cysteamine and cystamine also
augmented basal intracellular cysteamine levels. Our data, for the first
time, demonstrate the importance of intracellular thiols in sequestering
toxic reactive aldehyde products of lipid peroxidation and polyamine
metabolism. In addition it appears that pharmacological manipulation of
intracellular thiol pools might offer a new approach in the design of
neuroprotective drug candidates.
PMID: 17555724
[Control survival; 33 weeks; N-acetylcysteine: 38 weeks; Cysteamine: 48 weeks]
Lupus. 2001;10(4):258-65.
Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of
systemic lupus erythematosus (SLE).
Suwannaroj S, Lagoo A, Keisler D, McMurray RW. Division of Rheumatology,
Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen,
Thailand.
Abstract
Inflammation produces reactive oxygen intermediates (ROI) that cause
vascular damage and activate T lymphocytes. Conversely, antioxidants not
only protect tissue from oxidative damage but also suppress immune
reactivity. The objective of this study was to examine immunomodulatory
effects of the non-enzymatic antioxidants, N-acetylcysteine (NAC) and
cysteamine (CYST), on autoimmune disease, glomerulonephritis, and mortality
in the female B/W mouse model of human systemic lupus erythematosus (SLE).
The development of murine lupus was assessed during the lifespan of female
B/W mice given NAC or CYST. Morbidity and mortality were assessed daily. At
6 week intervals mice were examined for weight change, albuminuria, serum
BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum prolactin,
estrogen and progesterone were measured at 18 weeks of age. In a parallel
study, NAC- and CYST-treated and control B/W mice were examined at 24 weeks
of age for interval renal histopathology, lymphocyte adhesion molecule
expression, and antibody titers and in vitro cytokine production in response
to immunization with DNP-KLH. CYST significantly suppressed development of
albuminuria and azotemia at 36 and 42 weeks of age compared to control and
NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at
24 weeks. In contrast CYST significantly increased anti-DNA antibody levels
at 18 weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys
of CYST-treated mice also had accelerated inflammatory histologic changes
despite their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.)
survival of control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in
NAC-treated mice (P < 0.05 vs control), and 48 +/- 2 weeks in the
CYST-treated group (P < 0.01 vs control mice). The antioxidants, NAC and
CYST, significantly improved mortality in the female B/W mouse model of SLE.
NAC suppressed autoantibody formation and modestly prolonged survival.
CYST, despite its augmentation of anti-DNA levels and renal inflammatory
changes, inhibited the development of renal insufficiency and markedly
improved survival. These findings suggest that ROIs play a role in the
pathogenesis of lupus nephritis and that antioxidants reduce the damage
causing renal insufficiency. Antioxidants may be a beneficial adjunctive
therapy in the treatment of human SLE.
PMID: 11341102
[The cysteamine precursor pantethine increases fly lifespan.]
Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6988-93. Epub 2010 Mar 29.
Pantethine rescues a Drosophila model for pantothenate kinase-associated
neurodegeneration.
Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B, van der Want JJ,
Hayflick S, Reijngoud DJ, Kayser O, Sibon OC.
Department of Cell Biology, Radiation and Stress Cell Biology, University
Medical Center Groningen, University of Groningen, 9713 AV Groningen, The
Netherlands.
Abstract
Pantothenate kinase-associated neurodegeneration (PKAN), a progressive
neurodegenerative disorder, is associated with impairment of pantothenate kinase
function. Pantothenate kinase is the first enzyme required for de novo
synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN
is not understood, and there is no cure to halt or reverse the symptoms of this
devastating disease. Recently, we and others presented a PKAN Drosophila model,
and we demonstrated that impaired function of pantothenate kinase induces a
neurodegenerative phenotype and a reduced lifespan. We have explored this
Drosophila model further and have demonstrated that impairment of pantothenate
kinase is associated with decreased levels of CoA, mitochondrial dysfunction,
and increased protein oxidation. Furthermore, we searched for compounds that can
rescue pertinent phenotypes of the Drosophila PKAN model and identified
pantethine. Pantethine feeding restores CoA levels, improves mitochondrial
function, rescues brain degeneration, enhances locomotor abilities, and
increases lifespan. We show evidence for the presence of a de novo CoA
biosynthesis pathway in which pantethine is used as a precursor compound.
Importantly, this pathway is effective in the presence of disrupted pantothenate
kinase function. Our data suggest that pantethine may serve as a starting point
to develop a possible treatment for PKAN.
PMID: 20351285 [PubMed - in process]
[Pantethine 900 mg/day is effective for lowering lipids in humans.]
Clin Ter. 1989 Mar 31;128(6):411-22.
[Pantethine, diabetes mellitus and atherosclerosis. Clinical study of 1045
patients]
[Article in Italian]
Donati C, Bertieri RS, Barbi G.
Abstract
After a review of the clinical studies on the treatment of diabetic patients
with pantethine, the authors discuss the results obtained in a
postmarketing surveillance (PMS) study on 1045 hyperlipidemic patients
receiving pantethine (900 mg/day on average). Of these patients, 57 were
insulin-dependent (Type I) and 241 were non insulin-dependent (Type II)
diabetics. Beyond the epidemiological considerations made possible by a PMS
study, the authors show that pantethine brought about a statistically
significant and comparable improvement of lipid metabolism in the three
groups of patients, with very good tolerability. Pantethine should therefore
be considered for the treatment of lipid abnormalities also in patients at
risk such as those with diabetes mellitus.
PMID: 2524328
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