Protein‐Bound Acrolein

Calingasan, Noel Y.; Uchida, Koji; Gibson, Gary E.

doi:10.1046/j.1471-4159.1999.0720751.x

Cited by 361 publications

(64 citation statements)

References 26 publications

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“…Acrolein is a product of lipid peroxidation (15,16) and is a biomarker that has been used to implicate oxidative damage in several diseases (17)(18)(19)(20). Immunohistochemical staining of the retinas of rd1 mice with an antibody that specifically recognizes acrolein showed faint staining at P18 (Fig.…”

Section: Increased Staining For a Marker Of Oxidative Damage In Conesmentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

375

367

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Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; ␣-tocopherol (200 mg͞kg), ascorbic acid (250 mg͞kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg͞kg), and ␣-lipoic acid (100 mg͞kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit. oxidative damage ͉ photoreceptors ͉ retinal degenerations R etinitis pigmentosa (RP) refers to a group of diseases in which a mutation results in death of rod photoreceptors followed by gradual death of cones. The diseases referred to as RP show a similar phenotype consisting of pigmented spots scattered throughout the retina, narrowed retinal vessels, and retinal sheen suggesting atrophy. At one time, it was felt that inflammation was important in the pathogenesis, and hence the term ''retinitis'' was paired with a descriptor for the most prominent feature of the phenotype, the scattered pigment, resulting in the term retinitis pigmentosa. It is now known that this phenotype results whenever there is widespread rod photoreceptor cell death. Although toxins or infections can occasionally cause widespread rod death, it occurs most commonly when there is a mutation in a gene that is selectively expressed in rods and, either through gain or loss of function, the mutation promotes rod cell death. Mutations in 36 different genes have been found to cause RP, and mutations in many more cause widespread rod cell death in association with syndromes that have extraocular manifestations (www.sph.uth.tmc.edu͞RetNet͞ sum-dis.htm).How does diffuse death of rods throughout the retina result in the distinctive phenotype that ophthalmologists recognize as RP? Rods have an intimate relationship, both structurally and functionally, with retinal pigmen...

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Section: Increased Staining For a Marker Of Oxidative Damage In Conesmentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

375

367

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“…Acrolein-modified Protein-To investigate whether acrolein is produced in vivo, we previously raised mAb5F6 against acrolein-modified protein and demonstrated that acrolein was accumulated in the form covalently bound to proteins in vivo (10,16,17). In addition, based on the observations that the incubation of N ␣ -acetyllysine with acrolein predominantly generated FDP-lysine and that the antibody indeed recognized it, we regarded FDP-lysine as the epitope of the antibody (16).…”

Section: Identification Of Mp-lysine As the Major Epitope Of A Monoclmentioning

confidence: 99%

“…Immunohistochemical analysis of atheroscle-rotic lesions from a human aorta revealed that an acroleinderived epitope recognized by the antibody indeed constitutes the lesions in which intense positivity is associated primarily with macrophage-derived foam cells (16). In addition, Calingasan et al (17) have observed a strong immunoreactivity with mAb5F6 in the paired helical filament 1-labeled neurofibrillary tangles of Alzheimer's disease cases. Furthermore, utilizing an immunoassay system (18), the levels of protein-bound acrolein in human plasma have been recently determined, demonstrating that the extracellular concentrations of protein-bound acrolein in vivo could reach submillimolar ranges (19 -23).…”

mentioning

confidence: 97%

Nϵ-(3-Methylpyridinium)lysine, a Major Antigenic Adduct Generated in Acrolein-modified Protein

Furuhata

Ishii

Kumazawa

et al. 2003

Journal of Biological Chemistry

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106

115

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Acrolein, a representative carcinogenic aldehyde, that could be ubiquitously generated in biological systems under oxidative stress shows facile reactivity with a nucleophile such as a protein. In this study, to gain a better understanding of the molecular basis of acrolein modification of protein, we characterized the acrolein modification of a model peptide (the oxidized B chain of insulin) by electrospray ionization-liquid chromatography/mass spectrometry method and established a novel acrolein-lysine condensation reaction. In addition, we found that this condensation adduct represented the major antigenic adduct generated in acrolein-modified protein. To identify the modification site and structures of adducts generated in the acrolein-modified insulin B chain, both the acrolein-pretreated and untreated peptides were digested with V8 protease and the resulting peptides were subjected to electrospray ionization-liquid chromatography/mass spectrometry. This technique identified nine peptides, which contained the acrolein adducts at Lys-29 and the N terminus, and revealed that the reaction of the insulin B chain with acrolein gave multiple adducts, including an unknown adduct containing two molecules of acrolein per lysine. To identify this adduct, we incubated N ␣ -acetyllysine with acrolein and isolated a product having the same molecular mass as the unknown acrolein-lysine adduct. On the basis of the chemical and spectroscopic evidence, the adduct was determined to be a novel pyridinium-type lysine adduct, N ⑀ -(3-methylpyridinium)lysine (MP-lysine). The formation of MP-lysine was confirmed by amino acid analysis of proteins treated with acrolein. More notably, this condensation adduct appeared to be an intrinsic epitope of a monoclonal antibody 5F6 that had been raised against acrolein-modified protein.Several lines of evidence indicate that the oxidative modification of protein and the subsequent accumulation of the modified proteins have been found in cells during aging and oxidative stress and in various pathological states including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis (1-4). The important agents that give rise to the modification of a protein may be represented by reactive aldehydic intermediates such as ketoaldehydes, 2-alkenals and 4-hydroxy-2-alkenals (3, 5, 6). These reactive aldehydes are considered important mediators of cell damage because of their ability to covalently modify biomolecules, which can disrupt important cellular functions and can cause mutations (5). Furthermore, the adduction of aldehydes to apolipoprotein B in low density lipoproteins has been strongly implicated in the mechanism by which low density lipoproteins is converted to an atherogenic form that is taken up by macrophages, leading to the formation of foam cells (7,8).Acrolein, an unpleasant and troublesome byproduct of overheated organic matter, occurs as a ubiquitous pollutant in the environment, e.g. the incomplete combustion of plastic materials, cigarette smoking, and over...

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“…Brains of patients afflicted with Alzheimer's disease show abnormal expression of numerous oxidative stress indicators (1)(2)(3)(4)(5) as well as extensive evidence of oxidative damage to proteins (6) and nucleic acids (7,8). A prominent feature of the Alzheimer's disease brain is the widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) 1 in the form of amyloid fibrils within senile plaques and in cerebral and meningeal blood vessels (9,10).…”

mentioning

confidence: 99%

Potent Neuroprotective Properties against the Alzheimer β-Amyloid by an Endogenous Melatonin-related Indole Structure, Indole-3-propionic Acid

Chyan

Pöeggeler

Omar

et al. 1999

Journal of Biological Chemistry

348

254

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Widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that A␤ is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to A␤. In the process of screening indole compounds for neuroprotection against A␤, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to A␤, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.Brains of patients afflicted with Alzheimer's disease show abnormal expression of numerous oxidative stress indicators (1-5) as well as extensive evidence of oxidative damage to proteins (6) and nucleic acids (7,8). A prominent feature of the Alzheimer's disease brain is the widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) 1 in the form of amyloid fibrils within senile plaques and in cerebral and meningeal blood vessels (9, 10). A large body of data suggests that A␤ causes neuronal degeneration and death by mechanisms that involve reactive oxygen species reviewed in Ref. 15).Since the severity of the dementia in Alzheimer's disease has been correlated best with the extent of synaptic loss and the degree of neuronal death (16, 17), enhancing neuronal survival has been a primary objective of many therapeutic strategies. We have recently reported that melatonin prevents oxidative stress and death of neurons exposed to the amyloid peptide (18,19). In the process of screening indole compounds as neuroprotective agents, new properties were uncovered for an endogenous species, indole-3-propionic acid (IPA). IPA has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known (20,21). IPA has, like melatonin, a heterocyclic aromatic ring structure with high resonance stability, which led us to suspect similar neuroprotective and antioxidant properties. Here, we report that IPA prevented oxidative stress and death of primary neurons and neuroblastoma cells exposed to A␤. In addition, IPA also showed a strong level of neuroprotection in two other paradigms of oxidative stress. We found...

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Protein‐Bound Acrolein

Cited by 361 publications

References 26 publications

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Nϵ-(3-Methylpyridinium)lysine, a Major Antigenic Adduct Generated in Acrolein-modified Protein

Potent Neuroprotective Properties against the Alzheimer β-Amyloid by an Endogenous Melatonin-related Indole Structure, Indole-3-propionic Acid

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