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Wael Elrifai - One of the best experts on this subject based on the ideXlab platform.
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silencing of Glutathione Peroxidase 3 through dna hypermethylation is associated with lymph node metastasis in gastric carcinomas
PLOS ONE, 2012Co-Authors: Dunfa Peng, Wael Elrifai, Barbara G Schneider, Zheng ChenAbstract:Gastric cancer remains the second leading cause of cancer-related death in the world. H. pylori infection, a major risk factor for gastric cancer, generates high levels of reactive oxygen species (ROS). Glutathione Peroxidase 3 (GPX3), a plasma GPX member and a major scavenger of ROS, catalyzes the reduction of hydrogen peroxide and lipid peroxides by reduced Glutathione. To study the expression and gene regulation of GPX3, we examined GPX3 gene expression in 9 gastric cancer cell lines, 108 primary gastric cancer samples and 45 normal gastric mucosa adjacent to cancers using quantitative real-time RT-PCR. Downregulation or silencing of GPX3 was detected in 8 of 9 cancer cell lines, 83% (90/108) gastric cancers samples, as compared to non-tumor adjacent normal gastric samples (P<0.0001). Examination of GPX3 promoter demonstrated DNA hypermethylation (≥ 10% methylation level determined by Bisulfite Pyrosequencing) in 6 of 9 cancer cell lines and 60% of gastric cancer samples (P = 0.007). We also detected a significant loss of DNA copy number of GPX3 in gastric cancers (P<0.001). Treatment of SNU1 and MKN28 cells with 5-Aza-2' Deoxycytidine restored the GPX3 gene expression with a significant demethylation of GPX3 promoter. The downregulation of GPX3 expression and GPX3 promoter hypermethylation were significantly associated with gastric cancer lymph node metastasis (P = 0.018 and P = 0.029, respectively). We also observed downregulation, DNA copy number losses, and promoter hypermethylation of GPX3 in approximately one-third of tumor-adjacent normal gastric tissue samples, suggesting the presence of a field defect in areas near tumor samples. Reconstitution of GPX3 in AGS cells reduced the capacity of cell migration, as measured by scratch wound healing assay. Taken together, the dysfunction of GPX3 in gastric cancer is mediated by genetic and epigenetic alterations, suggesting impairment of mechanisms that regulate ROS and its possible involvement in gastric tumorigenesis and metastasis.
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abstract p3 04 05 hypermethylation and downregulation of Glutathione Peroxidase 3 in inflammatory breast carcinogenesis
Cancer Research, 2010Co-Authors: Salwa Sabet, Dunfa Peng, M M Mostafa, Mohamed Elshinawi, Mohamed A Nouh, Wael ElrifaiAbstract:Background: The breast tumor microenvironment is characterized by the release of endogenous reactive oxygen species (ROS), and has been suggested as being associated with disease aggressiveness. Normal cells have an antioxidant system that controls the balance between production and removal of oxygen radicals, thereby protecting against oxidative damage, such as the Glutathione Peroxidases (GPXs) enzymes. Epigenetics and DNA methylation play important roles in several inflammatory disorders. We therefore, analyzed the promoter of GPX3 and found a dense CpG island closest to the transcription start-site. The aim of the present study is to 1) investigate GPX3 expression in breast carcinoma and normal breast tissues, 2) identify whether GPX3 is epigenetically regulated in breast carcinoma tissues versus normal tissue, and 3) compare the levels of expression of GPX3 in Inflammatory Breast Cancer (IBC) versus non-IBC tissues. Material and Methods: We enrolled 40 breast cancer patients with tumor mass range from 1.8-9cm (with median size 4.77 ± 3.9). Patients were sub-grouped as IBC (n = 20) or non-IBC (n = 20), healthy breast tissues from the same patients were used as control. Using real-time PCR and immunohistochemistry, we assessed the level of expression of GPX3 at mRNA and protein levels in breast cancer tissues versus control. To identify whether the CpG island of the GPX3 gene was epigenetically regulated, we analyzed the methylation profile of GPX3 in breast carcinoma versus normal tissues using DNA bisulfate treatment and methylation-specific PCR (MSP). Results: GPX3-mRNA expression was down regulated in breast cancer samples compared to control tissues. There was a significant decrease (P = 0.01) in the mRNA expression level of IBC compared to non-IBC carcinoma tissues. MSP showed that the GPX3 gene was hypermethylated in breast carcinoma tissues compared to control. Moreover, confirmatory semiquantitative immunohistochemical scoring revealed weak or negative immunostain of carcinoma tissues compared to healthy breast tissues. Conclusion: These preliminary data suggest that epigenetic inactivation of GPX3 is a frequent finding in inflammatory breast cancer. Silencing of GPX3 in IBC versus non-IBC carcinoma cells suggested that GPX3 may be critical in the development and progression of IBC. To our knowledge, this is first study to test the role of GPX3 in breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-05.
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hypermethylation loss of expression of Glutathione Peroxidase 3 in barrett s tumorigenesis
Neoplasia, 2005Co-Authors: Ok Jae Lee, Regine Schneiderstock, Patricia A Mcchesney, Doerthe Kuester, Albert Roessner, Michael Vieth, Christopher A Moskaluk, Wael ElrifaiAbstract:Abstract Chronic gastroesophageal reflux disease is a known risk factor for Barrett's esophagus (BE), that induces oxidative mucosal damage. Glutathione Peroxidase-3 (GPx3) is a secretory protein with potent extracellular antioxidant activity. Herein, we have investigated the mRNA, protein expression of GPx3, explored promoter hypermethylation as an epigenetic mechanism for GPx3 gene inactivation during Barrett's carcinogenesis. Quantitative real-time reverse transcription polymerase chain reaction on 42 Barrett's adenocarcinomas (BAs) revealed consistently reduced levels of GPx3 mRNA in 91% of tumor samples. GPx3 promoter hypermethylation was detected in 62% of Barrett's metaplasia, 82% of dysplasia, 88% of BA samples. Hypermethylation of both alleles of GPx3 was most frequently seen in BA (P = .001). Immunohistochemical staining of GPx3 in matching tissue sections (normal, BE, Barrett's dysplasia, BA) revealed a weak-to-absent GPx3 staining in Barrett's dysplasia, adenocarcinoma samples where the promoter was hypermethylated. The degree of loss of immunohistochemistry correlated with the hypermethylation pattern (monoallelic versus biallelic). The observed high frequency of promoter hypermethylation, progressive loss of GPx3 expression in BA, its associated lesions, together with its known function as a potent antioxidant, suggest that epigenetic inactivation, regulation of Glutathione pathway may be critical in the development, progression of BE.
Seungwon Lee - One of the best experts on this subject based on the ideXlab platform.
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Glutathione Peroxidase 3 as a biomarker of recurrence after lung cancer surgery
Journal of Clinical Medicine, 2020Co-Authors: Bo Gun Kho, Hayoung Park, H Cho, Cheolkyu Park, Youngchul Kim, Jusik Yun, Sangyun Song, Yooduk Choi, Seungwon LeeAbstract:We aimed to examine the usefulness of serum Glutathione Peroxidase 3 (GPx3) as a biomarker of lung cancer recurrence after complete resection. We prospectively collected serial serum samples at the baseline, as well as 3, 6 and 12 months after surgery from complete resection cases in 2013. GPx3 levels were measured by enzyme-linked immunosorbent assay. Statistical tests including t-tests and Cox proportional hazard regression analyses were performed. Totally, 135 patients were enrolled, and 39 (28.9%) showed relapse during the median follow-up period (63.60 months; range, 0.167-81.867). The mean GPx3 change was significantly higher in the recurrence group at 6 months (0.32 ± 0.38 vs. 0.15 ± 0.29, p = 0.016) and 12 months (0.40 ± 0.37 vs. 0.13 ± 0.28, p = 0.001). The high GPx3 change group showed significantly higher 60-months recurrence rates than the low group (48.1% vs. 25.2% at 3 months, p = 0.005; 54.5% vs. 28.9% at 6 months, p = 0.018; 38.3% vs. 18.3% at 12 months, p = 0.035). High GPx3 change at 3 months were independent risk factors of recurrence (hazard ratio (HR) 3.318, 95% confidence interval (CI), 1.582-6.960, p = 0.002) and survival (HR 3.150, 95% CI, 1.301-7.628, p = 0.011). Therefore, serum GPx3 changes after surgery may be useful predictive biomarkers for recurrence in lung cancer. Larger-scale validation studies are warranted to confirm these findings.
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mir 921 directly downregulates gpx3 in a549 lung cancer cells
Gene, 2019Co-Authors: Jangyeol Choi, Ju Han Kim, In Jung Jung, Seungwon LeeAbstract:Glutathione Peroxidase 3 (GPx3), a major antioxidant enzyme in plasma, catalyzes the reduction of H2O2, lipid peroxides and organic hydroperoxides by reducing Glutathione (GSH). Hypermethylation of the GPx3 promoter and suppression of GPx3 expression are associated with inflammation, tumorigenesis, and response to chemotherapy in various types of cancer. We previously reported the possibility of GPx3 as a serological marker for lung cancer. In this study, we assessed the role of the microRNA (miRNA) hsa-miR-921 (miR-921) in the regulation of GPx3 expression in A549 lung cancer cells. The expression patterns of the miRNAs of A549, H1650, and H1975 cells were compared and analyzed. Of 25 miRNAs from the A549 cell line, the expression of 10 decreased and the expression of 15 increased in comparison to the miRNAs from the other cell lines. Of the miRNAs with reduced expression, the most reduced miRNA was miR-921 and the expected binding site of which is in the 3'-untranslated region (UTR) of GPx3. We found that miR-921 inhibited the expression of GPx3 and bound directly to the 3'-UTR of GPx3.
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epigenetic and glucocorticoid receptor mediated regulation of Glutathione Peroxidase 3 in lung cancer cells
Molecules and Cells, 2016Co-Authors: Nakkyun Jung, Yooduk Choi, Chun Young Park, Jaeil Park, Seungwon LeeAbstract:Glutathione Peroxidase 3 (GPx3), an antioxidant enzyme, acts as a modulator of redox signaling, has immunomodulatory function, and catalyzes the detoxification of reactive oxygen species (ROS). GPx3 has been identified as a tumor suppressor in many cancers. Although hyper-methylation of the GPx3 promoter has been shown to down-regulate its expression, other mechanisms by which GPx3 expression is regulated have not been reported. The aim of this study was to further elucidate the mechanisms of GPx3 regulation. GPx3 gene analysis predicted the presence of ten glucocorticoid response elements (GREs) on the GPx3 gene. This result prompted us to investigate whether GPx3 expression is regulated by the glucocorticoid receptor (GR), which is implicated in tumor response to chemotherapy. The corticosteroid dexamethasone (Dex) was used to examine the possible relationship between GR and GPx3 expression. Dex significantly induced GPx3 expression in H1299, H1650, and H1975 cell lines, which exhibit low levels of GPx3 expression under normal conditions. The results of EMSA and ChIP-PCR suggest that GR binds directly to GRE 6 and 7, both of which are located near the GPx3 promoter. Assessment of GPx3 transcription efficiency using a luciferase reporter system showed that blocking formation of the GR-GRE complexes reduced luciferase activity by 7-8-fold. Suppression of GR expression by siRNA transfection also induced down-regulation of GPx3. These data indicate that GPx3 expression can be regulated independently via epigenetic or GR-mediated mechanisms in lung cancer cells, and suggest that GPx3 could potentiate glucocorticoid (GC)-mediated anti-inflammatory signaling in lung cancer cells.
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serum Glutathione Peroxidase 3 as a biomarker of postoperative relapse in patients with lung cancer
Journal of Thoracic Oncology, 2016Co-Authors: H Cho, Youngchul Kim, Sangyun Song, Yooduk Choi, Taeok Kim, Chulkyu Park, Junghwan Lim, Jusik Yoon, Byungchul Ahn, Seungwon LeeAbstract:Background: Glutathione Peroxidase 3 (GPx3) which is an extracellular secretory protein is down regulated in patients with early stage lung cancer. We examined the usefulness of serum GPx3 as a biomarker for monitoring of relapse after surgery. Methods: We prospectively collected serial serum samples at baseline, 3 months (3m), 6 months (6m), and 12 months (12m) after operation from the patients who underwent surgery during the year 2013. GPx3 levels were measured three times per sample using the enzyme-linked immunosorbent assay, and the mean values were analyzed by t-test and paired t-test. Results: A total of 170 (100 adenocarcinoma, 41 squamous cell carcinoma, 29 others) patients were analyzed in this study. Mean age was 64.1 years old (range, 39-80) and 27 (15.9%) out of 165 lung cancer patients were confirmed relapse during the median follow-up period of 597.5 days (range, 5-938). The mean GPx3 value at postoperative 6m was significantly elevated in relapsed group than control group (7.90 ± 2.44 mg/mL vs. 6.99 ± 1.79 mg/mL, p1⁄40.047). The mean GPx3 differences were significantly higher in relapsed group than control group at 3m (-0.38 ± 0.39 mg/mL vs. -0.21 ± 0.36 mg/mL, p1⁄40.044), 6m (-0.37 ± 0.42 mg/mL vs. -0.19 ± 0.30 mg/mL, p1⁄40.024), and 12m (-0.38 ± 0.42 mg/mL vs. -0.19 ± 0.28 mg/mL, p1⁄40.012). The mean time to relapse was significantly shorter in high level of GPx3 group at postoperative 3m (694.83 ± 31.86 days vs. 839.05 ± 24.31 days, p1⁄40.007). The mean time to relapse was significantly shorter in high GPx3 difference group between baseline and postoperative 3m (729.76 ± 34.89 days vs. 838.18 ± 24.03 days, p1⁄40.002). Conclusion: Serum mean GPx3 value at postoperative 6m and the mean GPx3 difference were significantly elevated in relapsed lung cancer. The mean time to relapse was significantly shorter in high level of GPx3 group at postoperative 3m. More large scaled validation studies are warranted.
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free paper presentation f 74 serum Glutathione Peroxidase 3 as a biomarker of postoperative relapse in patients with lung cancer
대한결핵및호흡기학회 추계학술발표초록집, 2015Co-Authors: H Cho, Youngchul Kim, Sangyun Song, Yooduk Choi, Chulkyu Park, Jusik Yoon, Byung Hwan Gimhae Ahn, Seungwon LeeAbstract:Background: Glutathione Peroxidase 3 (GPx3) which is an extracellular secretory protein is down regulated in patients with early stage lung cancer. We examined the usefulness of serum GPx3 as a biomarker for monitoring of relapse after surgery. Methods: We prospectively collected serial serum samples at baseline, 3 months (3m), 6 months (6m), and 12 months (12m) after operation from the patients who underwent surgery during the year 2013. GPx3 levels were measured three times per sample using the enzyme-linked immunosorbent assay, and the mean values were analyzed by t-test and paired t-test. Results: A total of 170 (100 adenocarcinoma, 41 squamous cell carcinoma, 29 others) patients were analyzed in this study. Mean age was 64.1 years old (range, 39-80) and 27 (15.9%) out of 165 lung cancer patients were confirmed relapse during the median follow-up period of 597.5 days. The mean GPx3 value at postoperative 6m was significantly elevated in relapsed group (7.90 vs. 6.99 μg/mL, p=0.047). The mean changes of GPx3 were significantly higher in relapsed group than control group at 3m (-0.38 vs. -0.21 μg/mL, p=0.044), 6m (-0.37 vs. -0.19 μg/mL, p=0.024), and 12m (-0.38 vs. -0.19 μg/mL, p=0.012). The mean time to relapse was significantly shorter in high level of GPx3 group at postoperative 3m (694.83 vs. 839.05 days, p=0.007). Conclusion: Serum mean GPx3 value at postoperative 6m and the mean changes of GPx3 were significantly elevated in relapsed lung cancer. The mean time to relapse was also significantly shorter in the group of high GPx3 at postoperative 3m.
Dunfa Peng - One of the best experts on this subject based on the ideXlab platform.
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promoter hypermethylation and suppression of Glutathione Peroxidase 3 are associated with inflammatory breast carcinogenesis
Oxidative Medicine and Cellular Longevity, 2014Co-Authors: Mona Mostafa Mohamed, Salwa Sabet, Dunfa PengAbstract:Reactive oxygen species (ROS) play a crucial role in breast cancer initiation, promotion, and progression. Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth. Studies showed that inhibition of Glutathione Peroxidase-3 (GPX3) was associated with cancer progression. Although the role of GPX3 has been studied in different cancer types, its role in breast cancer and its epigenetic regulation have not yet been investigated. The aim of the present study was to investigate GPX3 expression and epigenetic regulation in carcinoma tissues of breast cancer patients' in comparison to normal breast tissues. Furthermore, we compared GPX3 level of expression and methylation status in aggressive phenotype inflammatory breast cancer (IBC) versus non-IBC invasive ductal carcinoma (IDC). We found that GPX3 mRNA and protein expression levels were downregulated in the carcinoma tissues of IBC compared to non-IBC. However, we did not detect significant correlation between GPX3 and patients' clinical-pathological prosperities. Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues. In addition, IBC carcinoma tissues showed a significant increase in the promoter hypermethylation of GPX3 gene compared to non-IBC. Our results propose that downregulation of GPX3 in IBC may play a role in the disease progression.
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silencing of Glutathione Peroxidase 3 through dna hypermethylation is associated with lymph node metastasis in gastric carcinomas
PLOS ONE, 2012Co-Authors: Dunfa Peng, Wael Elrifai, Barbara G Schneider, Zheng ChenAbstract:Gastric cancer remains the second leading cause of cancer-related death in the world. H. pylori infection, a major risk factor for gastric cancer, generates high levels of reactive oxygen species (ROS). Glutathione Peroxidase 3 (GPX3), a plasma GPX member and a major scavenger of ROS, catalyzes the reduction of hydrogen peroxide and lipid peroxides by reduced Glutathione. To study the expression and gene regulation of GPX3, we examined GPX3 gene expression in 9 gastric cancer cell lines, 108 primary gastric cancer samples and 45 normal gastric mucosa adjacent to cancers using quantitative real-time RT-PCR. Downregulation or silencing of GPX3 was detected in 8 of 9 cancer cell lines, 83% (90/108) gastric cancers samples, as compared to non-tumor adjacent normal gastric samples (P<0.0001). Examination of GPX3 promoter demonstrated DNA hypermethylation (≥ 10% methylation level determined by Bisulfite Pyrosequencing) in 6 of 9 cancer cell lines and 60% of gastric cancer samples (P = 0.007). We also detected a significant loss of DNA copy number of GPX3 in gastric cancers (P<0.001). Treatment of SNU1 and MKN28 cells with 5-Aza-2' Deoxycytidine restored the GPX3 gene expression with a significant demethylation of GPX3 promoter. The downregulation of GPX3 expression and GPX3 promoter hypermethylation were significantly associated with gastric cancer lymph node metastasis (P = 0.018 and P = 0.029, respectively). We also observed downregulation, DNA copy number losses, and promoter hypermethylation of GPX3 in approximately one-third of tumor-adjacent normal gastric tissue samples, suggesting the presence of a field defect in areas near tumor samples. Reconstitution of GPX3 in AGS cells reduced the capacity of cell migration, as measured by scratch wound healing assay. Taken together, the dysfunction of GPX3 in gastric cancer is mediated by genetic and epigenetic alterations, suggesting impairment of mechanisms that regulate ROS and its possible involvement in gastric tumorigenesis and metastasis.
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abstract p3 04 05 hypermethylation and downregulation of Glutathione Peroxidase 3 in inflammatory breast carcinogenesis
Cancer Research, 2010Co-Authors: Salwa Sabet, Dunfa Peng, M M Mostafa, Mohamed Elshinawi, Mohamed A Nouh, Wael ElrifaiAbstract:Background: The breast tumor microenvironment is characterized by the release of endogenous reactive oxygen species (ROS), and has been suggested as being associated with disease aggressiveness. Normal cells have an antioxidant system that controls the balance between production and removal of oxygen radicals, thereby protecting against oxidative damage, such as the Glutathione Peroxidases (GPXs) enzymes. Epigenetics and DNA methylation play important roles in several inflammatory disorders. We therefore, analyzed the promoter of GPX3 and found a dense CpG island closest to the transcription start-site. The aim of the present study is to 1) investigate GPX3 expression in breast carcinoma and normal breast tissues, 2) identify whether GPX3 is epigenetically regulated in breast carcinoma tissues versus normal tissue, and 3) compare the levels of expression of GPX3 in Inflammatory Breast Cancer (IBC) versus non-IBC tissues. Material and Methods: We enrolled 40 breast cancer patients with tumor mass range from 1.8-9cm (with median size 4.77 ± 3.9). Patients were sub-grouped as IBC (n = 20) or non-IBC (n = 20), healthy breast tissues from the same patients were used as control. Using real-time PCR and immunohistochemistry, we assessed the level of expression of GPX3 at mRNA and protein levels in breast cancer tissues versus control. To identify whether the CpG island of the GPX3 gene was epigenetically regulated, we analyzed the methylation profile of GPX3 in breast carcinoma versus normal tissues using DNA bisulfate treatment and methylation-specific PCR (MSP). Results: GPX3-mRNA expression was down regulated in breast cancer samples compared to control tissues. There was a significant decrease (P = 0.01) in the mRNA expression level of IBC compared to non-IBC carcinoma tissues. MSP showed that the GPX3 gene was hypermethylated in breast carcinoma tissues compared to control. Moreover, confirmatory semiquantitative immunohistochemical scoring revealed weak or negative immunostain of carcinoma tissues compared to healthy breast tissues. Conclusion: These preliminary data suggest that epigenetic inactivation of GPX3 is a frequent finding in inflammatory breast cancer. Silencing of GPX3 in IBC versus non-IBC carcinoma cells suggested that GPX3 may be critical in the development and progression of IBC. To our knowledge, this is first study to test the role of GPX3 in breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-04-05.
Paul Pang - One of the best experts on this subject based on the ideXlab platform.
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pre clinical model of severe Glutathione Peroxidase 3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function
Nephrology Dialysis Transplantation, 2018Co-Authors: Paul Pang, Molly Abbott, Malyun Abdi, Quynhanh Fucci, Nikita Chauhan, Murti Mistri, Brandon M Proctor, Matthew S Chin, Bin Wang, Tzongshi LuAbstract:Background Chronic kidney disease (CKD) patients have deficient levels of Glutathione Peroxidase-3 (GPx3). We hypothesized that GPx3 deficiency may lead to cardiovascular disease in the presence of chronic kidney disease due to an accumulation of reactive oxygen species and decreased microvascular perfusion of the myocardium. Methods. To isolate the exclusive effect of GPx3 deficiency in kidney disease–induced cardiac disease, we studied the GPx3 knockout mouse strain (GPx3−/−) in the setting of surgery-induced CKD. Results. Ribonucleic acid (RNA) microarray screening of non-stimulated GPx3−/− heart tissue show increased expression of genes associated with cardiomyopathy including myh7, plac9, serpine1 and cd74 compared with wild-type (WT) controls. GPx3−/− mice underwent surgically induced renal mass reduction to generate a model of CKD. GPx3−/− + CKD mice underwent echocardiography 4 weeks after injury. Fractional shortening (FS) was decreased to 32.9 ± 5.8% in GPx3−/− + CKD compared to 62.0% ± 10.3 in WT + CKD (P < 0.001). Platelet aggregates were increased in the myocardium of GPx3−/− + CKD. Asymmetric dimethylarginine (ADMA) levels were increased in both GPx3−/− + CKD and WT+ CKD. ADMA stimulated spontaneous platelet aggregation more quickly in washed platelets from GPx3−/−. In vitro platelet aggregation was enhanced in samples from GPx3−/− + CKD. Platelet aggregation in GPx3−/− + CKD samples was mitigated after in vivo administration of ebselen, a Glutathione Peroxidase mimetic. FS improved in GPx3−/− + CKD mice after ebselen treatment.
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pre clinical model of severe Glutathione Peroxidase 3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function
Nephrology Dialysis Transplantation, 2018Co-Authors: Paul Pang, Molly Abbott, Malyun Abdi, Quynhanh Fucci, Nikita Chauhan, Murti Mistri, Brandon M Proctor, Matthew S Chin, Bin Wang, Wenqing YinAbstract:Background Chronic kidney disease (CKD) patients have deficient levels of Glutathione Peroxidase-3 (GPx3). We hypothesized that GPx3 deficiency may lead to cardiovascular disease in the presence of chronic kidney disease due to an accumulation of reactive oxygen species and decreased microvascular perfusion of the myocardium. Methods. To isolate the exclusive effect of GPx3 deficiency in kidney disease-induced cardiac disease, we studied the GPx3 knockout mouse strain (GPx3-/-) in the setting of surgery-induced CKD. Results. Ribonucleic acid (RNA) microarray screening of non-stimulated GPx3-/- heart tissue show increased expression of genes associated with cardiomyopathy including myh7, plac9, serpine1 and cd74 compared with wild-type (WT) controls. GPx3-/- mice underwent surgically induced renal mass reduction to generate a model of CKD. GPx3-/- + CKD mice underwent echocardiography 4 weeks after injury. Fractional shortening (FS) was decreased to 32.9 ± 5.8% in GPx3-/- + CKD compared to 62.0% ± 10.3 in WT + CKD (P < 0.001). Platelet aggregates were increased in the myocardium of GPx3-/- + CKD. Asymmetric dimethylarginine (ADMA) levels were increased in both GPx3-/- + CKD and WT+ CKD. ADMA stimulated spontaneous platelet aggregation more quickly in washed platelets from GPx3-/-. In vitro platelet aggregation was enhanced in samples from GPx3-/- + CKD. Platelet aggregation in GPx3-/- + CKD samples was mitigated after in vivo administration of ebselen, a Glutathione Peroxidase mimetic. FS improved in GPx3-/- + CKD mice after ebselen treatment. Conclusion These results suggest GPx3 deficiency is a substantive contributing factor to the development of kidney disease-induced cardiac disease.
Karima Zitouni - One of the best experts on this subject based on the ideXlab platform.
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derepression of glomerular filtration renal blood flow and antioxidant defence in patients with type 2 diabetes at high risk of cardiorenal disease
Free Radical Biology and Medicine, 2020Co-Authors: Karima Zitouni, Mia Steyn, Frank J Kelly, Paul Cook, Irina Chis Ster, Eliza Lyka, Kenneth A EarleAbstract:Abstract Background The role of antioxidant status on microvascular blood flow and glomerular filtration (eGFR) in patients with type 2 diabetes and hypertension whose risk of progressive renal disease varies by ethnicity is unknown. Methods Adult, non-Caucasian (n = 101) and Caucasian (n = 69) patients with type 2 diabetes, hypertension and/or microalbuminuria and an eGFR > 45 mL/min/1.73 m2 were randomised to receive 400 IU vitamin E and/or 20 μg selenium daily or matching placebo. eGFR (CKD-EPI) was measured at baseline, 3,6 and 12 months and renal blood flow by contrast-enhanced ultrasonography in a sub-group (n = 9) at baseline and 3 months by assessing the area under the time intensity curve (TIC). Circulating Glutathione Peroxidase 3 (GPx-3) activity was measured as a biomarker of oxidative defence status. Results The time to change in eGFR was shortest with combined vitamin E and selenium than usual care (5.6 [4.0–7.0] vs 8.9 [6.8–10.9 months]; p = 0.006). Area under the TIC was reduced compared to baseline (38.52 [22.41–90.49] vs 123 [86.98–367.03]dB.s; P ≤ 0.05 and 347 [175.88–654.92] vs 928.03 [448.45–1683]dB.s; P ≤ 0.05, respectively] at 3 months suggesting an increase in rate of perfusion. The proportional change in eGFR at 12 months was greater in the group whose GPx-3 activity was above, compared with those below the cohort median (360 U/L) in the non-Caucasian and the Caucasian groups (19.1(12.5–25.7] % vs 6.5[-3.5 to 16.5] % and 12.8 [0.7 to 24] % vs 0.2 [-6.1 to 6.5] %). Conclusion In these patients with type 2 diabetes and early CKD, antioxidant treatment derepresses renal blood flow and a rise in eGFR correlated directly with GPx-3 activity. Significance Diabetes mellitus is the world's leading cause of end-stage renal disease which has a predilection for black and minor ethnic groups compared with Caucasians. The differences in risk despite the benefits of conventional care may be related to oxidative stress. We found that glomerular filtration and renal blood flow is suppressed when renal function is preserved in high-risk patients with type 2 diabetes. Conventional care supplemented with selenium - the co-factor for Glutathione Peroxidase-3 (GPx-3) - improves renal perfusion and increase glomerular filtration according to host antioxidant defence determined by GPx-3 activity. Circulating GPx-3 activity warrants further investigation as a novel biomarker of reversible haemodynamic changes in early diabetic kidney disease to better enable targeting of renoprotective strategies.
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predictive change in renal function and Glutathione Peroxidase 3 activity in type 2 diabetes
Social Science Research Network, 2019Co-Authors: Karima Zitouni, Mia Steyn, Frank J Kelly, Paul Cook, Irina Chis Ster, Kenneth Anthony EarleAbstract:Background: Hyperglycaemia causes oxidative stress which accelerates the loss of renal function. In experimental studies, antioxidant enzymes such as Glutathione Peroxidase (GPx-3) mitigate this effect and clinical studies suggest that antioxidant therapy stimulates an increase glomerular filtration (eGFR) in advanced disease. It is unknown whether these changes occur with preserved renal function or varies between groups with differences in renal disease susceptibility. Methods: Patients with type 2 diabetes of Caucasian and non-Caucasian heritage with an eGFR >45mls/min/1.73m2 with microalbuminuria and/or hypertension were randomized in four groups to receive selenium and vitamin E together, individually or as double-placebo with usual care. A series of mixed models were fit to assess treatment efficacy and modulation by GPx-3 activity status on eGFR over 12 months. Findings: Estimated glomerular filtration increased in all treatment groups with the time to peak rise (TPR) being shortest with both antioxidants given together (5.6 [4-7] months) compared to double-placebo (8.9 [6.8-10.9] months; p=0.006) and was longer for non-Caucasian compared with the Caucasian group regardless of the intervention. Patients with low GPx-3 activity ( 360 U/L) receiving usual care after adjusting for age, ethnicity and albuminuria (p=0.003). Interpretation: The activity of GPx-3 is a biomarker of the rise in eGFR that occurs with antioxidants and usual care. These biochemical and physiological markers could be useful in tailoring nephroprotective treatments for patients with type 2 diabetes at risk of renal dysfunction. Trial Registration Number: ISRCTN 97358113 Funding Statement: This research is supported by a grant from Dialysis Clinic Inc (C-3305) and the National Institutes of Health Research (UKCRN ID: 8432). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The protocol was approved by the UK National Health Service (NHS) National Research and Ethics Committee and written informed consent was obtained from all trial participants prior to enrollment.