Glutathione (GSH) protects against oxidative damage in many tissues, including retinal pigment epithelium (RPE). Oxidative stress-mediated senescence and death of RPE and subsequent death of ...photoreceptors have been observed in age-related macular degeneration (AMD). Although the consequences of GSH depletion have been described previously, questions remain regarding the molecular mechanisms. We herein examined the downstream effects of GSH depletion on stress-induced premature senescence (SIPS) and cell death in human RPE cells. Briefly, cultured ARPE-19 cells were depleted of GSH using: (1) incubation in cystine (Cys
)-free culture medium; (2) treatment with buthionine sulphoximine (BSO, 1000 µM) to block de novo GSH synthesis for 24-48 h; or (3) treatment with erastin (10 µM for 12-24 h) to inhibit Cys
/glutamate antiporter (system x
). These treatments decreased cell viability and increased both soluble and lipid reactive oxygen species (ROS) generation but did not affect mitochondrial ROS or mitochondrial mass. Western blot analysis revealed decreased expression of ferroptotic modulator glutathione peroxidase 4 (GPX4). Increased autophagy was apparent, as reflected by increased LC3 expression, autophagic vacuoles, and autophagic flux. In addition, GSH depletion induced SIPS, as evidenced by increased percentage of the senescence-associated β-galactosidase-positive cells, increased senescence-associated heterochromatin foci (SAHF), as well as cell cycle arrest at the G1 phase. GSH depletion-dependent cell death was prevented by selective ferroptosis inhibitors (8 μM Fer-1 and 600 nM Lip-1), iron chelator DFO (80 μM), as well as autophagic inhibitors Baf-A1 (75 nM) and 3-MA (10 mM). Inhibiting autophagy with Baf-A1 (75 nM) or 3-MA (10 mM) promoted SIPS. In contrast, inducing autophagy with rapamycin (100 nM) attenuated SIPS. Our findings suggest that GSH depletion induces ferroptosis, autophagy, and SIPS. In addition, we found that autophagy is activated in the process of ferroptosis and reduces SIPS, suggesting an essential role of autophagy in ferroptosis and SIPS.
The worldwide epidemic of diabetic retinopathy Zheng, Yingfeng; He, Mingguang; Congdon, Nathan
Indian Journal of Ophthalmology/Indian journal of ophthalmology,
09/2012, Volume:
60, Issue:
5
Journal Article
Peer reviewed
Open access
Diabetic retinopathy (DR), a major microvascular complication of diabetes, has a significant impact on the world's health systems. Globally, the number of people with DR will grow from 126.6 million ...in 2010 to 191.0 million by 2030, and we estimate that the number with vision-threatening diabetic retinopathy (VTDR) will increase from 37.3 million to 56.3 million, if prompt action is not taken. Despite growing evidence documenting the effectiveness of routine DR screening and early treatment, DR frequently leads to poor visual functioning and represents the leading cause of blindness in working-age populations. DR has been neglected in health-care research and planning in many low-income countries, where access to trained eye-care professionals and tertiary eye-care services may be inadequate. Demand for, as well as, supply of services may be a problem. Rates of compliance with diabetes medications and annual eye examinations may be low, the reasons for which are multifactorial. Innovative and comprehensive approaches are needed to reduce the risk of vision loss by prompt diagnosis and early treatment of VTDR.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal ...components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)- and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α and chemokine (C-C motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro-inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims
Soil nematode community is an important component of the soil food web, which has been widely recognized as a key bio-indicator for assessing the influence of nature restoration on ecological ...functions. However, the dynamics of the abundance, structure of soil nematode community remain unclear under nature restoration.
Methods
The soil nematode community of natural secondary forests was investigated using a chronosequence approach in subtropical forests in China. Six succession stages of nature restoration were sampled to represent forest stand age groups with 4-5, 8-12, 18-22, 25-30, 35-40 and over 100 years. To enhance our understanding of the factors influencing soil nematode communities, we also examined the relationships between plant community, soil microbial community, and soil properties by structural equation modeling.
Results
Soil nematode abundance gradually increased with forest stand ages, which reached a peak value (574 individuals 100 g
−1
dry soil) in the oldest stands. Soil available nitrogen and phosphorus were key factors influencing soil nematode abundance and diversity during secondary forest succession. The plant parasite index decreased with forest stand ages, which indicated that ecosystem function and health would be improved as nature restoration. The structure of soil nematode community was more sensitive to microbial community compared to plant community. The bottom-up effects of microbial communities on soil nematode communities were important drivers of nematode communities in subtropical forests.
Conclusions
This study demonstrates the active responses of soil nematode community to nature restoration and highlights the importance of the above-ground and below-ground interactions to the soil food web.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic ...transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.
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•Single-cell RNA-seq reveals EC heterogeneity in choroidal neovascularization•ECs display metabolic transcriptome heterogeneity in the cell cycle and quiescence•Data integration with a genome-scale metabolic model identifies angiogenic targets•SQLE and ALDH18A1 are validated as metabolic angiogenic candidates
Rohlenova et al. employ single-cell RNA sequencing to characterize angiogenic endothelial cells (ECs) in murine choroidal neovascularization and compare the phenotypes to ECs in tumor angiogenesis. Using integrated analysis, genome-scale metabolic modeling, and in vivo methods, they identify and validate SQLE and ALDH18A1 as metabolic angiogenic candidates.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To examine the relationship of retinal vascular tortuosity to age, blood pressure, and other cardiovascular risk factors.
Population-based, cross-sectional study.
A total of 3280 participants aged 40 ...to 80 years from the Singapore Malay Eye Study (78.7% response rate).
Retinal arteriolar and venular (vascular) tortuosity were quantitatively measured from fundus images using a computer-assisted program. Retinal vascular tortuosity was defined as the integral of the curvature square along the path of the vessel, normalized by the total path length. Data on blood pressure and major cardiovascular disease (CVD) risk factors were collected from all participants.
Retinal arteriolar and venular tortuosity.
A total of 2915 participants contributed data to this study. The mean (standard deviation) and median were 2.99 (1.40) and 2.73 for retinal arteriolar tortuosity (×10(4)), and 4.64 (2.39) and 4.19 for retinal venular tortuosity (×10(4)), respectively. Retinal venules were significantly more tortuous than retinal arterioles (P<0.001). In multivariable-adjusted linear regression models, less arteriolar tortuosity was independently associated with older age, higher blood pressure, higher body mass index (BMI), and narrower retinal arteriolar caliber (all P<0.05); greater venular tortuosity was independently associated with younger age, higher blood pressure, lower high-density lipoprotein (HDL) cholesterol level, and wider retinal venular caliber (all P<0.05).
Retinal arteriolar tortuosity was associated with older age and higher levels of blood pressure and BMI, whereas venular tortuosity was also associated with lower HDL level. The quantitative assessment of retinal vascular tortuosity from retinal images may provide further information regarding effects of cardiovascular risk factors on the retinal vasculature.
Genomic sequencing reads compressors are essential for balancing high-throughput sequencing short reads generation speed, large-scale genomic data sharing, and infrastructure storage expenditure. ...However, most existing short reads compressors rarely utilize big-memory systems and duplicative information between diverse sequencing files to achieve a higher compression ratio for conserving reads data storage space. We employ compression ratio as the optimization objective and propose a large-scale genomic sequencing short reads data compression optimizer, named PMFFRC, through novelty memory modeling and redundant reads clustering technologies. By cascading PMFFRC, in 982 GB fastq format sequencing data, with 274 GB and 3.3 billion short reads, the state-of-the-art and reference-free compressors HARC, SPRING, Mstcom, and FastqCLS achieve 77.89%, 77.56%, 73.51%, and 29.36% average maximum compression ratio gains, respectively. PMFFRC saves 39.41%, 41.62%, 40.99%, and 20.19% of storage space sizes compared with the four unoptimized compressors. PMFFRC rational usage big-memory of compression server, effectively saving the sequencing reads data storage space sizes, which relieves the basic storage facilities costs and community sharing transmitting overhead. Our work furnishes a novel solution for improving sequencing reads compression and saving storage space. The proposed PMFFRC algorithm is packaged in a same-name Linux toolkit, available un-limited at https://github.com/fahaihi/PMFFRC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully ...elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell-cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo ...with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtypespecific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
To describe the prevalence and risk factors for age-related macular degeneration (AMD) in a multiethnic Asian cohort of Chinese, Malay, and Indian persons.
Population-based cross-sectional study.
A ...total of 10 033 persons (3280 Malay, 3400 Indian, and 3353 Chinese; response rate, 75%) 40 years of age or older residing in Singapore.
We performed comprehensive systemic and ocular examinations, retinal photography, and laboratory investigations for all participants. We graded early and late AMD signs from retinal photographs using the modified Wisconsin AMD grading scale. We calculated the age-standardized prevalence of AMD using the 2010 Singapore adult population and analyzed risk factors for AMD using logistic regression models.
Early and late AMD.
Of the 9799 participants with gradable photographs, 588 had early AMD and 60 had late AMD. The age-standardized prevalence was 5.1% (95% confidence interval CI, 4.6-5.5) for early AMD and 0.5% (95% CI, 0.4-0.6) for late AMD. The prevalence of early AMD was similar between Chinese (5.7%) and Indian (4.5%; P = 0.27) persons and lower in Malays (3.5%; P = 0.002 compared with Chinese; P = 0.09 compared with Indians); in contrast, the prevalence for late AMD was similar across ethnic groups (Chinese, 0.6%; Indian, 0.3%; and Malay, 0.3%; P = 0.20). Risk factors for early AMD were older age (odds ratio OR, 1.40 per 5-year increase in age; 95% CI, 1.33-1.47), male gender (OR, 1.81; 95% CI, 1.43-2.29), hypertension (OR, 1.28; 95% CI, 1.02-1.61), and hyperopic refraction (OR, 1.17 per 1-diopter increase in spherical equivalent; 95% CI, 1.11-1.24). Risk factors for late AMD include older age (OR, 1.87 per 5-year increase in age; 95% CI, 1.54-2.19), smoking more than 5 packs per week (OR, 3.63; 95% CI, 1.34-9.80), and presence of chronic kidney disease (OR, 2.17; 95% CI, 1.22-3.88).
Early AMD is more common in Chinese and Indians than in Malays, but there were no racial variations in the prevalence of late AMD.
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