Increased Expression of Ecto-NOX Disulfide-thiol Exchanger 1 (ENOX1) in Diabetic Mice Retina and its Involvement in Diabetic Retinopathy Development

Huang, Yu Chuen; Liu, Shih‐Ping; Chen, Shih Yin; Lin, Jinyao; Lin, Hui Ju; Lei, Yu; Wang, Yeh-Han; Huang, Wan Ting; Liao, Wen Ling; Tsai, Fuu Jen

doi:10.21873/invivo.11671

Cited by 3 publications

(5 citation statements)

References 32 publications

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“…Mice with a KO of Aoc3 which encodes VAP-1/SSAO are modestly obese, 139 , 140 consistent with our findings ( Table 3 ); interestingly, the human AOC3 gene is expressed in adipose tissue but not CNS and resides within a waist-hip ratio adjusted BMI cluster ( Table 4 ), suggesting a role for AOC3 in regulating visceral fat mass. Enox1 is a little-studied gene, 141 and the finding that Enox1 HET mice were obese in the IMPC HTS is consistent with the obesity observed in our Enox1 KO mice ( Table 3 ).…”

Section: Resultssupporting

confidence: 89%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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Purpose Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000 TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat. Materials and Methods KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC). Results Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 ( Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1 ) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only. Conclusion These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.

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Section: Resultssupporting

confidence: 89%

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Powell¹,

Revelli²,

Doree³

et al. 2021

DMSO

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“…To further confirm the in vivo findings of alphaB-crystallin in the RPE/choroid complex, we performed in vitro experiments using human RPE cells treated with high glucose, which is known to be an in vitro model for DR (20). Following 24 h treatment with 50 mM glucose AlphaB-crystallin mRNA levels were significantly decreased in RPE cells in comparison to mannitol-treated control cells (Figure 5A).…”

Section: Alphab-crystallin Was Downregulated Under High Glucose Stimulation In Human Rpe Cellsmentioning

confidence: 63%

Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related StimuliIn VivoandIn Vitro

Kase

LIU

et al. 2021

In Vivo

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Background/Aim: AlphaB-crystallin plays a pivotal role in many diseases. However, the involvement of alphaB-crystallin in retinal pigment epithelial (RPE) cells with diabetes stimuli remains unknown. The aim of this study is to examine the alterations of RPE cells and alphaB-crystallin expression in diabetic models in vivo and in vitro. Materials and Methods: Diabetic conditions in mice were induced by streptozotocin (STZ). The thickness of the RPE/choroid complex was measured by optical coherence tomography (OCT). Periodic acid-Schiff (PAS) staining was used to investigate the choriocapillaris in histological sections of murine eyeballs and oxidative stress was evaluated using immunofluorescence with anti-4-hydroxynonenal (HNE) antibody. AlphaB-crystallin expression was examined in the RPE/choroid complex using ELISA. Real-Time PCR was performed to evaluate the alphaB-crystallin expression in cultured human RPE cells with high glucose or following advanced glycation end-products (AGE) stimulation. Results: In diabetic mice, OCT-based RPE/choroidal layers were thickened 2 months after STZ stimulation, where PAS-positive dilated choriocapillaris was noted. Immunoreactivity of 4-HNE was strongly observed in the RPE layer, from which a significant number of RPE cells was lost. Meanwhile, alphaBcrystallin expression in 2-month STZ mice was significantly lower compared to controls. In accordance with these results, in vitro data showed that the alphaB-crystallin expression was also significantly lower in RPE cells with high glucose or following AGE stimulation compared to untreated cells. Conclusion: In both types of diabetic models the expression of alphaB-crystallin was found to be downregulated in RPE cells and was associated with increased levels of oxidative stress.

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“…Continuing analysis of Cluster 9/RSM gene expression, ENOX1 was highly expressed (Figure 4) and is important for reduction of oxygen to superoxide, an essential macrophage function (46) (47). CERS6 has been shown to contribute to mitochondrial dysfunction by promoting reactive oxygen species production in hepatocytes (48).…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis of Cluster 9/RSM gene expression revealed high expression of ENOX1 (Figure 4), involved with reduction of oxygen to superoxide (38). Likewise, CERS6 contributes to mitochondrial dysfunction by promoting reactive oxygen species production in hepatocytes (39).…”

Section: Discussionmentioning

confidence: 99%

“…However, LAMP3 is upregulated by THP-1 macrophages with in vitro LPS stimulation (36), and is constitutively expressed in primary macrophages in multiple species (37). Further analysis of Cluster 9/RSM gene expression revealed high expression of ENOX1 ( Figure 4 ), involved with reduction of oxygen to superoxide (38). Likewise, CERS6 contributes to mitochondrial dysfunction by promoting reactive oxygen species production in hepatocytes (39).…”

Section: Discussionmentioning

confidence: 99%

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Resident Synovial Macrophages in Synovial Fluid: Implications for Immunoregulation in Infectious and Inflammatory Arthritis

Cyndari,

Scorza,

Zacharias

et al. 2023

Preprint

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ObjectivesResident synovial macrophages (RSM) provide immune sequestration of the joint space and are likely involved in initiation and perpetuation of the joint-specific immune response. We sought to identify RSM in synovial fluid (SF) and demonstrate migratory ability, in additional to functional changes that may perpetuate a chronic inflammatory response within joint spaces.MethodsWe recruited human patients presenting with undifferentiated arthritis in multiple clinical settings. We used flow cytometry to identify mononuclear cells in peripheral blood and SF. We used a novel transwell migration assay with humanex-vivosynovium obtained intra-operatively to validate flow cytometry findings. We used single cell RNA-sequencing (scRNA-seq) to further identify macrophage/monocyte subsets. ELISA was used to evaluate the bone-resorption potential of SF.ResultsWe were able to identify a rare population of CD14dim, OPG+, ZO-1+cells consistent with RSM in SF via flow cytometry. These cells were relatively enriched in the SF during infectious processes, but absolutely decreased compared to healthy controls. Similar putative RSM were identified usingex vivomigration assays when MCP-1 and LPS were used as migratory stimulus. scRNA-seq revealed a population consistent with RSM transcriptionally related to CD56+cytotoxic dendritic cells and IDO+M2 macrophages.ConclusionWe identified a rare cell population consistent with RSM, indicating these cells are likely migratory and able to initiate or coordinate both acute (septic) or chronic (autoimmune or inflammatory) arthritis. RSM analysis via scRNA-seq indicated these cells are M2 skewed, capable of antigen presentation, and have consistent functions in both septic and inflammatory arthritis.

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Increased Expression of Ecto-NOX Disulfide-thiol Exchanger 1 (ENOX1) in Diabetic Mice Retina and its Involvement in Diabetic Retinopathy Development

Cited by 3 publications

References 32 publications

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes

Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related StimuliIn VivoandIn Vitro

Resident Synovial Macrophages in Synovial Fluid: Implications for Immunoregulation in Infectious and Inflammatory Arthritis

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