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

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.

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

10.1101/19009035 ◽

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.

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Role of Novel UV Filters in Human Lens Protein Damage Link to Age Related Nuclear Cataract

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2010.10.608 ◽

2010 ◽

Vol 49 ◽

pp. S209

Author(s):

Nicholas Gad ◽

Jasminka Mizdrak ◽

David Pattison ◽

Michael Davies ◽

Roger Truscott ◽

...

Keyword(s):

Protein Damage ◽

Human Lens ◽

Lens Protein ◽

Nuclear Cataract ◽

Uv Filters ◽

Age Related

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

Ophthalmic Research ◽

10.1159/000507962 ◽

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

Purpose: 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. Methods: 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). Results: HLECs were subjected to 3 different treatment models, including prolonged exposure to low-dose H2O2, 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. Conclusion: 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.

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The ageing lens and cataract: a model of normal and pathological ageing

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2010.0300 ◽

2011 ◽

Vol 366 (1568) ◽

pp. 1278-1292 ◽

Cited By ~ 204

Author(s):

R. Michael ◽

A. J. Bron

Keyword(s):

Visual Loss ◽

Global Scale ◽

Human Lens ◽

Light Scatter ◽

Nuclear Cataract ◽

Post Translational Modification ◽

Visual Axis ◽

Age Related ◽

Fourth Decade ◽

Stress Damage

Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103730118 ◽

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.

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Role of the Undergraduate Student Research Assistant in the New Millennium

Cell Biology Education ◽

10.1187/cbe.04-02-0032 ◽

2004 ◽

Vol 3 (4) ◽

pp. 235-240 ◽

Cited By ~ 5

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.

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Critical role of medical education among dentists and dental students on HIV/AIDS: a systematic review

HIV & AIDS Review ◽

10.5114/hivar.2020.93236 ◽

2020 ◽

Vol 19 (1) ◽

pp. 1-7

Author(s):

Irna Sufiawati ◽

Eliza Munthe

Keyword(s):

Systematic Review ◽

Medical Education ◽

Critical Role ◽

Dental Students ◽

Hiv Aids

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/4856431 ◽

2016 ◽

Vol 2016 ◽

pp. 1-17 ◽

Cited By ~ 5

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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