scholarly journals Cataract in the human lens: a systematic review of proteomic studies

2019 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Lens Crystallins ◽  
Ability To Act ◽  
Age Related

AbstractBackground/AimThe aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens.MethodsWe searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses.ResultsDeamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7.ConclusionD-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in man, while the role of oxidant stress in age-related cataract formation is dominant.SynopsisThe oxidative stress and the post-translational modification of deamidation in lens crystallins seem to play a significant role in the formation of age-related cataract in human.

Pathogenesis of Age-related Cataract: a systematic review of proteomic studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Christina Karakosta ◽  
Argyrios Tzamalis ◽  
Michalis Aivaliotis ◽  
Ioannis Tsinopoulos
Keyword(s):  
Systematic Review ◽  
Oxidant Stress ◽  
Critical Role ◽  
Human Lens ◽  
Nuclear Cataract ◽  
Cataract Formation ◽  
Post Translational Modification ◽  
Ability To Act ◽  
Age Related

Background/Objective:: The aim of this systematic review is to identify all the available data on human lens proteomics with a critical role to age-related cataract formation in order to elucidate the physiopathology of the aging lens. Materials and Methods:: We searched on Medline and Cochrane databases. The search generated 328 manuscripts. We included nine original proteomic studies that investigated human cataractous lenses. Results:: Deamidation was the major age-related post-translational modification. There was a significant increase in the amount of αA-crystallin D-isoAsp58 present at all ages, while an increase in the extent of Trp oxidation was apparent in cataract lenses when compared to aged normal lenses. During aging, enzymes with oxidized cysteine at critical sites included GAPDH, glutathione synthase, aldehyde dehydrogenase, sorbitol dehydrogenase, and PARK7. Conclusion:: D-isoAsp in αA crystallin could be associated with the development of age-related cataract in human, by contributing to the denaturation of a crystallin, and decreasing its ability to act as a chaperone. Oxidation of Trp may be associated with nuclear cataract formation in human, while the role of oxidant stress in age-related cataract formation is dominant.

Up-Regulation of GATA4 Regulates Human Lens Epithelial Cell Function in Age-Related Cataract

2020 ◽  
Vol 63 (6) ◽  
pp. 564-571
Author(s):  
Xiaodong Xie ◽  
Xiaofei Song ◽  
Xin Liu ◽  
Xiaogang Luo ◽  
Maidina Nabijiang ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Cell Function ◽  
Critical Role ◽  
Lens Epithelial Cell ◽  
Human Lens ◽  
Dependent Manner ◽  
Age Related

<b><i>Purpose:</i></b> GATA4 has emerged as a novel regulator that plays a critical role in mediating senescence. However, the role of GATA4 in age-related cataract (ARC), the leading cause of visual impairment, requires further elucidation. <b><i>Methods:</i></b> GATA4 expression was measured by quantitative RT-PCR and capillary Western immunoassay (WES). The MTT assay, EdU assay, and rhodamine-123/Hoechst and calcein-AM/propidium iodide double staining were used to investigate the role of GATA4 in the viability, proliferation, and apoptosis of cultured human lens epithelial cells (HLECs). <b><i>Results:</i></b> HLECs were subjected to 3 different treatment models, including prolonged exposure to low-dose H<sub>2</sub>O<sub>2</sub>, UVB irradiation, and mild heating, to simulate senescence and apoptosis. GATA4 expression was significantly increased in these models in a time- and dose-dependent manner. Overexpression of GATA4 reduced cell viability, accelerated apoptosis development, and reduced the proliferation of HLECs. Furthermore, the expression of GATA4 from ARC was up-regulated at both mRNA and at protein level compared with clear lenses. <b><i>Conclusion:</i></b> GATA4 is up-regulated in all 3 models of HLECs in vitro and the cells from ARC lenses in vivo. Up-regulation of GATA4 mediates HLEC dysfunction. GATA4-mediated effects in HLECs would provide a novel insight into the pathogenesis of ARC.

scholarly journals Hotspots of age-related protein degradation: the importance of neighboring residues for the formation of non-disulfide crosslinks derived from cysteine

2017 ◽  
Vol 474 (14) ◽  
pp. 2475-2487 ◽  
Author(s):  
Michael G. Friedrich ◽  
Zhen Wang ◽  
Aaron J. Oakley ◽  
Kevin L. Schey ◽  
Roger J.W. Truscott
Keyword(s):  
Protein Degradation ◽  
Disulfide Bonds ◽  
Nucleophilic Attack ◽  
Human Lens ◽  
Related Protein ◽  
Lens Crystallins ◽  
Age Related ◽  
Cross Links ◽  
Dha Production

Over time, the long-lived proteins that are present throughout the human body deteriorate. Typically, they become racemized, truncated, and covalently cross-linked. One reaction responsible for age-related protein cross-linking in the lens was elucidated recently and shown to involve spontaneous formation of dehydroalanine (DHA) intermediates from phosphoserine. Cys residues are another potential source of DHA, and evidence for this was found in many lens crystallins. In the human lens, some sites were more prone to forming non-disulfide covalent cross-links than others. Foremost among them was Cys5 in βA4 crystallin. The reason for this enhanced reactivity was investigated using peptides. Oxidation of Cys to cystine was a prerequisite for DHA formation, and DHA production was accelerated markedly by the presence of a Lys, one residue separated from Cys5. Modeling and direct investigation of the N-terminal sequence of βA4 crystallin, as well as a variety of homologous peptides, showed that the epsilon amino group of Lys can promote DHA production by nucleophilic attack on the alpha proton of cystine. Once a DHA residue was generated, it could form intermolecular cross-links with Lys and Cys. In the lens, the most abundant cross-link involved Cys5 of βA4 crystallin attached via a thioether bond to glutathione. These findings illustrate the potential of Cys and disulfide bonds to act as precursors for irreversible covalent cross-links and the role of nearby amino acids in creating ‘hotpsots’ for the spontaneous processes responsible for protein degradation in aged tissues.

Age-Related Changes in Human Lens Crystallins Identified by HPLC and Mass Spectrometry

1998 ◽  
Vol 67 (1) ◽  
pp. 21-30 ◽  
Author(s):  
ZHIXIANG MA ◽  
STACY R.A. HANSON ◽  
KIRSTEN J. LAMPI ◽  
LARRY L. DAVID ◽  
DAVID L. SMITH ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Human Lens ◽  
Lens Crystallins ◽  
Age Related ◽  
Age Related Changes

scholarly journals Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

2021 ◽  
Vol 118 (23) ◽  
pp. e2103730118
Author(s):  
Yuka Nakajima ◽  
Kenji Chamoto ◽  
Takuma Oura ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Effector Memory ◽  
T Cell Subset ◽  
Aged Mice ◽  
Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

scholarly journals Role of the Undergraduate Student Research Assistant in the New Millennium

2004 ◽  
Vol 3 (4) ◽  
pp. 235-240 ◽  
Author(s):  
Thais Dutra Nascimento Silva ◽  
Lúcia Cristina da Cunha Aguiar ◽  
Jaqueline Leta ◽  
Dilvani Oliveira Santos ◽  
Fernanda Serpa Cardoso ◽  
...  
Keyword(s):  
Undergraduate Students ◽  
Undergraduate Student ◽  
Critical Role ◽  
Academic Research ◽  
Scientific Data ◽  
Research Assistant ◽  
Age Related ◽  
Research Careers ◽  
New Research

In this study, we analyze the contribution of the undergraduate student who participates in the process of generating scientific data and developing a research project using Brazilian research as an example. Historically, undergraduate students have performed the critical role of research assistants in developing countries. This aspect has been underappreciated as a means of generating scientific data in Brazilian research facilities. Brazilian educational institutions are facing major age-related generational changes among the science faculty within the next 5–10 yr. A lack of adequate support for graduate students leads to a concern that undergraduates will not be interested in choosing research assistant programs and, subsequently, academic research careers. To remedy this situation it is important to focus on ways to encourage new research careers and enhance university–industry collaborations.

scholarly journals Thioredoxin Binding Protein-2 Regulates Autophagy of Human Lens Epithelial Cells under Oxidative Stress via Inhibition of Akt Phosphorylation

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Jiaojie Zhou ◽  
Ke Yao ◽  
Yidong Zhang ◽  
Guangdi Chen ◽  
Kairan Lai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Binding Protein ◽  
Negative Regulator ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Human Lens Epithelial Cells ◽  
Age Related

Oxidative stress plays an essential role in the development of age-related cataract. Thioredoxin binding protein-2 (TBP-2) is a negative regulator of thioredoxin (Trx), which deteriorates cellular antioxidant system. Our study focused on the autophagy-regulating effect of TBP-2 under oxidative stress in human lens epithelial cells (LECs). Human lens epithelial cells were used for cell culture and treatment. Lentiviral-based transfection system was used for overexpression of TBP-2. Cytotoxicity assay, western blot analysis, GFP/mCherry-fused LC3 plasmid, immunofluorescence, and transmission electronic microscopy were performed. The results showed that autophagic response of LECs with increased LC3-II, p62, and GFP/mCherry-LC3 puncta (P<0.01) was induced by oxidative stress. Overexpression of TBP-2 further strengthens this response and worsens the cell viability (P<0.01). Knockdown of TBP-2 attenuates the autophagic response and cell viability loss induced by oxidative stress. TBP-2 mainly regulates autophagy in the initiation stage, which is mTOR-independent and probably caused by the dephosphorylation of Akt under oxidative stress. These findings suggest a novel role of TBP-2 in human LECs under oxidative stress. Oxidative stress can cause cell injury and autophagy in LECs, and TBP-2 regulates this response. Hence, this study provides evidence regarding the role of TBP-2 in lens and the possible mechanism of cataract development.

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