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Vincent M Monnier - One of the best experts on this subject based on the ideXlab platform.
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reactive cysteine residues in the oxidative dimerization and cu2 induced aggregation of human γd crystallin implications for age related cataract
Biochimica et Biophysica Acta, 2018Co-Authors: Srinivasagan Ramkumar, Xingjun Fan, Benlian Wang, Sichun Yang, Vincent M MonnierAbstract:Cysteine (Cys) residues are major causes of crystallin disulfide formation and aggregation in Aging and cataractous human Lenses. We recently found that disulfide linkages are highly and partly conserved in β- and γ-crystallins, respectively, in human age-related nuclear cataract and glutathione depleted LEGSKO mouse Lenses, and could be mimicked by in vitro oxidation. Here we determined which Cys residues are involved in disulfide-mediated crosslinking of recombinant human γD-crystallin (hγD). In vitro diamide oxidation revealed dimer formation by SDS-PAGE and LC-MS analysis with Cys 111-111 and C111-C19 as intermolecular disulfides and Cys 111-109 as intramolecular sites. Mutation of Cys111 to alanine completely abolished dimerization. Addition of αB-crystallin was unable to protect Cys 111 from dimerization. However, Cu2+-induced hγD-crystallin aggregation was suppressed up to 50% and 80% by mutants C109A and C111A, respectively, as well as by total glutathionylation. In contrast to our recently published results using ICAT-labeling method, manual mining of the same database confirmed the specific involvement of Cys111 in disulfides with no free Cys111 detectable in γD-crystallin from old and cataractous human Lenses. Surface accessibility studies show that Cys111 in hγD is the most exposed Cys residue (29%), explaining thereby its high propensity toward oxidation and polymerization in the Aging Lens.
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vitamin c oxidation mediates protein Aging by oxoaldehyde stress in Lens and brain
Journal of the International Society of Antioxidants in Nutrition & Health, 2016Co-Authors: Vincent M Monnier, Xingjun Fan, David R SellAbstract:Oxoaldehyde stress recently emerged as a major mechanism of damage to cellular and extracellular structures in Aging and age-related diseases. The prevailing mechanism invoques methylglyoxal production as a consequence of glycolysis and impairment of arginine residues through the formation of the methyglyoxal hydroimidazolone MG-H1. We have here tested the hypothesis that in tissues rich in ascorbic acid, such as Lens and brain, vitamin C can contribute to this damage. MG-H1 quantitated by LC/MS was found several fold increased in Lens and brain from transgenic mice expressing the human vitamin C transporter 2 (hSVCT). Immunostaining of MG-H1 was intense in Aging and vitamin C incubated human Lens proteins and colocalized with neuronal plaques in brain from Alzheimer disease (AD) subjects. MG-H1 levels by LC/MS in AD hippocampus extract were two-four fold increased. Modeling studies and intraventricular injection of 13C-labeled ascorbic acid revealed that ascorbic acid backbone carbons 4-6 were incorporated into MG-H1 in vitro and in vivo, likely via a glyceraldehyde precursor. The results raise novel and important questions concerning the role of vitamin C in the Aging Lens and brain.
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anaerobic vs aerobic pathways of carbonyl and oxidant stress in human Lens and skin during Aging and in diabetes a comparative analysis
Free Radical Biology and Medicine, 2010Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:Abstract The effects of anaerobic (Lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones, carboxymethyllysine, and carboxyethyllysine are severalfold higher in Lens than in skin and markedly increase upon incubation of Lens crystallins with 5 mM ascorbic acid. In contrast, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones, metal-catalyzed oxidation (allysine), and H2O2-dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the Aging Lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P
Xingjun Fan - One of the best experts on this subject based on the ideXlab platform.
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Aging Lens epithelium is susceptible to ferroptosis
Free Radical Biology and Medicine, 2021Co-Authors: Zongbo Wei, Caili Hao, Jingru Huangfu, Ramkumar Srinivasagan, Xiang Zhang, Xingjun FanAbstract:Abstract Age-related cataracts (ARC) are the primary cause of blindness worldwide, and oxidative stress is considered the central pathogenesis of age-related cataractogenesis. Interestingly, ample evidence suggests that there is no remarkable apoptosis present in aged and cataractous human Lenses despite the profound disruption of redox homeostasis, raising an essential question regarding the existence of other cell death mechanisms. Here we sought to explore the Lens epithelial cell's (LEC) susceptibility to ferroptosis after documentation has concluded that aged and cataractous human Lenses manifest with increased reactive oxygen species (ROS) formation, elevated lipid peroxidation, and accumulative intracellular redox-active iron, constituting the three hallmarks of ferroptosis during Aging and cataractogenesis. Here we show that very low concentrations of system Xc- inhibitor Erastin (0.5 μM) and glutathione peroxidase 4 (GPX4) inhibitor RSL3 (0.1 μM) can drastically induce human LEC (FHL124) ferroptosis in vitro and mouse Lens epithelium ferroptosis ex vivo. Depletion of intracellular glutathione (GSH) in human LECs and mouse Lens epithelium significantly sensitizes ferroptosis, particularly under RSL3 challenge. Intriguingly, both human LECs and the mouse Lens epithelium demonstrate an age-related sensitization of ferroptosis. Transcriptome analysis indicates that clusters of genes are up-or down-regulated in aged LECs, impacting cellular redox and iron homeostases, such as downregulation of both cystine/glutamate antiporter subunits SLC7A11 and SLC3A2 and iron exporter ferroportin (SLC40A1). Here, for the first time, we are suggesting that LECs are highly susceptible to ferroptosis. Moreover, aged and cataractous human Lenses may possess more pro-ferroptotic criteria than any other organ in the human body.
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reactive cysteine residues in the oxidative dimerization and cu2 induced aggregation of human γd crystallin implications for age related cataract
Biochimica et Biophysica Acta, 2018Co-Authors: Srinivasagan Ramkumar, Xingjun Fan, Benlian Wang, Sichun Yang, Vincent M MonnierAbstract:Cysteine (Cys) residues are major causes of crystallin disulfide formation and aggregation in Aging and cataractous human Lenses. We recently found that disulfide linkages are highly and partly conserved in β- and γ-crystallins, respectively, in human age-related nuclear cataract and glutathione depleted LEGSKO mouse Lenses, and could be mimicked by in vitro oxidation. Here we determined which Cys residues are involved in disulfide-mediated crosslinking of recombinant human γD-crystallin (hγD). In vitro diamide oxidation revealed dimer formation by SDS-PAGE and LC-MS analysis with Cys 111-111 and C111-C19 as intermolecular disulfides and Cys 111-109 as intramolecular sites. Mutation of Cys111 to alanine completely abolished dimerization. Addition of αB-crystallin was unable to protect Cys 111 from dimerization. However, Cu2+-induced hγD-crystallin aggregation was suppressed up to 50% and 80% by mutants C109A and C111A, respectively, as well as by total glutathionylation. In contrast to our recently published results using ICAT-labeling method, manual mining of the same database confirmed the specific involvement of Cys111 in disulfides with no free Cys111 detectable in γD-crystallin from old and cataractous human Lenses. Surface accessibility studies show that Cys111 in hγD is the most exposed Cys residue (29%), explaining thereby its high propensity toward oxidation and polymerization in the Aging Lens.
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vitamin c oxidation mediates protein Aging by oxoaldehyde stress in Lens and brain
Journal of the International Society of Antioxidants in Nutrition & Health, 2016Co-Authors: Vincent M Monnier, Xingjun Fan, David R SellAbstract:Oxoaldehyde stress recently emerged as a major mechanism of damage to cellular and extracellular structures in Aging and age-related diseases. The prevailing mechanism invoques methylglyoxal production as a consequence of glycolysis and impairment of arginine residues through the formation of the methyglyoxal hydroimidazolone MG-H1. We have here tested the hypothesis that in tissues rich in ascorbic acid, such as Lens and brain, vitamin C can contribute to this damage. MG-H1 quantitated by LC/MS was found several fold increased in Lens and brain from transgenic mice expressing the human vitamin C transporter 2 (hSVCT). Immunostaining of MG-H1 was intense in Aging and vitamin C incubated human Lens proteins and colocalized with neuronal plaques in brain from Alzheimer disease (AD) subjects. MG-H1 levels by LC/MS in AD hippocampus extract were two-four fold increased. Modeling studies and intraventricular injection of 13C-labeled ascorbic acid revealed that ascorbic acid backbone carbons 4-6 were incorporated into MG-H1 in vitro and in vivo, likely via a glyceraldehyde precursor. The results raise novel and important questions concerning the role of vitamin C in the Aging Lens and brain.
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anaerobic vs aerobic pathways of carbonyl and oxidant stress in human Lens and skin during Aging and in diabetes a comparative analysis
Free Radical Biology and Medicine, 2010Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:Abstract The effects of anaerobic (Lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones, carboxymethyllysine, and carboxyethyllysine are severalfold higher in Lens than in skin and markedly increase upon incubation of Lens crystallins with 5 mM ascorbic acid. In contrast, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones, metal-catalyzed oxidation (allysine), and H2O2-dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the Aging Lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P
Chuan S Ooi - One of the best experts on this subject based on the ideXlab platform.
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change with age of the refractive index gradient of the human ocular Lens
Investigative Ophthalmology & Visual Science, 1995Co-Authors: R P Hemenger, L F Garner, Chuan S OoiAbstract:PURPOSE To study age-related changes in the refractive index distribution of the human ocular Lens. METHODS Biometric data collected on 48 eyes in subjects ranging in age from 19 to 31 years and 48 eyes in subjects ranging in age from 49 to 61 years allowed estimation of a single parameter related to the refractive index distribution of the crystalline Lens. The authors selected a gradient index model of the Lens characterized by a fixed index at the Lens center, a somewhat lower fixed index at the surface, and a continuum of index values between center and surface depending on a single parameter, beta. This parameter was evaluated for each of the two age groups. RESULTS The distributions of the gradient index parameter beta for the two age groups were found to be statistically well separated. On average, the older group was found to have an index gradient that was flatter near the Lens center and steeper near the surface, implying a lower refractive power of about 2 D for representative Lens surface curvatures. CONCLUSIONS It has been observed that surface curvatures and thicknesses of the ocular Lens increase with age, whereas other ocular dimensions apparently do not change, implying a trend toward myopia. This trend has not been observed. The authors' results are consistent with and strongly in support of the hypothesis that subtle index changes in the Aging Lens compensate to a large extent for changes in surface curvatures.
Ramanakoppa H Nagaraj - One of the best experts on this subject based on the ideXlab platform.
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Glyoxalase I activity and immunoreactivity in the Aging human Lens
Biogerontology, 2009Co-Authors: Maneesh Mailankot, Smitha Padmanabha, Nagarekha Pasupuleti, Denice L. Major, Scott Howell, Ramanakoppa H NagarajAbstract:Glyoxalase I (GLOI) is the first enzyme of the glyoxalase system that catalyzes the metabolism of reactive dicarbonyls, such as methylglyoxal (MGO). During Aging and cataract development, human Lens proteins are chemically modified by MGO, which is likely due to inadequate metabolism of MGO by the glyoxalase system. In this study, we have determined the effect of Aging on GLOI activity and the immunoreactivity and morphological distribution of GLOI in the human Lens. A monoclonal antibody was developed against human GLOI. GLOI immunoreactivity was strongest in the anterior epithelial cells and weaker in rest of the Lens. Cultured human Lens epithelial cells showed immunostaining throughout the cytoplasm. In the human Lens, GLOI activity and immunoreactivity both decreased with age. We believe that this would lead to promotion of MGO-modification in Aging Lens proteins.
Peter D Davies - One of the best experts on this subject based on the ideXlab platform.
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the Aging human Lens structure growth and physiological behaviour
British Journal of Ophthalmology, 1997Co-Authors: G Duncan, I M Wormstone, Peter D DaviesAbstract:The Aging human Lens has been the subject of intense research over the past 20 years, for a number of quite disparate reasons. The fact that the incidence of cataract rises exponentially with age after 50 years1 provides the driving influence for much of the effort, but the unique accessibility, homogeneity, and basic simplicity of structure of the organ itself makes it a fruitful system for fundamental studies of tissue growth, development, and differentiation.2-4 Images of the whole human Lens in vivo have been available for detailed analysis since the introduction of the quantitative slit lamp (or Scheimpflug) camera (Fig 1). This has been invaluable in providing an understanding of the changes in shape and optical properties both of the ‘normal’ and cataractous Aging Lens.5-7 The Lens is also accessible as an in vitro system of study through the provision of donor eyes for corneal transplant and general research. Since the Lens has no direct blood supply, it survives well both in the globe itself and in organ culture media.8-10 Whole cataractous Lenses were also once routinely available before the advent of extracapsular cataract extraction (ECCE) with intraocular Lens implantation and in the past there have been combined slit lamp and in vitro studies which have correlated changes in light scatter and absorbance with specific alterations in ion and protein levels (Fig 1 and Marcantonio et al 11 and Hockwin et al 12). Figure 1 Images of normal human Lenses (A, B, and C), posterior polar cataract (D, E, F), and pure nuclear cataract (G, H, I). Note that slit lamp camera images (A, D, G) all have a scattering reflect artefact (small white rectangle). The normal subject (A) was 40 years of age and the accompanying in vitro grid photographs (B) and polarising images (C) were …