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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