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Research square
2024
Abstract: The X-linked ... ...
| Abstract | The X-linked A |
|---|---|
| Language | English |
| Publishing date | 2024-03-11 |
| Publishing country | United States |
| Document type | Preprint |
| DOI | 10.21203/rs.3.rs-3931558/v1 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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2024 Volume 64, Issue 4, Page(s) 615–626
Abstract: Background: Donor genetic variation is associated with red blood cell (RBC) storage integrity and post-transfusion recovery. Our previous large-scale genome-wide association study demonstrated that the African G6PD deficient A- variant (rs1050828, ... ...
| Abstract | Background: Donor genetic variation is associated with red blood cell (RBC) storage integrity and post-transfusion recovery. Our previous large-scale genome-wide association study demonstrated that the African G6PD deficient A- variant (rs1050828, Val68Met) is associated with higher oxidative hemolysis after cold storage. Despite a high prevalence of X-linked G6PD mutation in African American population (>10%), blood donors are not routinely screened for G6PD status and its importance in transfusion medicine is relatively understudied. Study design and methods: To further evaluate the functional effects of the G6PD A- mutation, we created a novel mouse model carrying this genetic variant using CRISPR-Cas9. We hypothesize that this humanized G6PD A- variant is associated with reduced G6PD activity with a consequent effect on RBC hemolytic propensity and post-transfusion recovery. Results: G6PD A- RBCs had reduced G6PD protein with ~5% residual enzymatic activity. Significantly increased in vitro hemolysis induced by oxidative stressors was observed in fresh and stored G6PD A- RBCs, along with a lower GSH:GSSG ratio. However, no differences were observed in storage hemolysis, osmotic fragility, mechanical fragility, reticulocytes, and post-transfusion recovery. Interestingly, a 14% reduction of 24-h survival following irradiation was observed in G6PD A- RBCs compared to WT RBCs. Metabolomic assessment of stored G6PD A- RBCs revealed an impaired pentose phosphate pathway (PPP) with increased glycolytic flux, decreasing cellular antioxidant capacity. Discussion: This novel mouse model of the common G6PD A- variant has impaired antioxidant capacity like humans and low G6PD activity may reduce survival of transfused RBCs when irradiation is performed. |
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| MeSH term(s) | Humans ; Mice ; Animals ; Glucosephosphate Dehydrogenase/genetics ; Glucosephosphate Dehydrogenase/metabolism ; Hemolysis ; Glucosephosphate Dehydrogenase Deficiency/genetics ; Glucosephosphate Dehydrogenase Deficiency/epidemiology ; Antioxidants ; Genome-Wide Association Study ; Erythrocytes/metabolism ; Blood Donors |
| Chemical Substances | Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Antioxidants |
| Language | English |
| Publishing date | 2024-02-23 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 208417-x |
| ISSN | 1537-2995 ; 0041-1132 |
| ISSN (online) | 1537-2995 |
| ISSN | 0041-1132 |
| DOI | 10.1111/trf.17756 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
| Zs.A 284: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
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PloS one
2020 Volume 15, Issue 10, Page(s) e0240266
Abstract: Background: Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) ... ...
| Abstract | Background: Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population. Study design and methods: Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ. Results: Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ. Conclusions: Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency. |
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| MeSH term(s) | African Americans ; Animals ; COVID-19 ; Coronavirus Infections/drug therapy ; Disease Models, Animal ; Glucosephosphate Dehydrogenase Deficiency/pathology ; Humans ; Hydroxychloroquine/adverse effects ; Hydroxychloroquine/therapeutic use ; Male ; Mice ; Pandemics ; Pneumonia, Viral/drug therapy |
| Chemical Substances | Hydroxychloroquine (4QWG6N8QKH) |
| Keywords | covid19 |
| Language | English |
| Publishing date | 2020-10-02 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ISSN | 1932-6203 |
| ISSN (online) | 1932-6203 |
| DOI | 10.1371/journal.pone.0240266 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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Free radical biology & medicine
2012 Volume 52, Issue 5, Page(s) 889–897
Abstract: Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to ... ...
| Abstract | Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to demonstrate the decisive part of the mitochondrial pathway in UVC-induced apoptosis in mouse embryo fibroblasts (MEFs). UVC-induced apoptosis proceeded independent of the activation of death receptor components. In contrast, soon after UV radiation, MAPK activation and generation of reactive oxygen species (ROS) increased, followed by a decline in mitochondrial membrane potential (MMP) and cytochrome c release, as well as activation of caspase-9 and -3 and the upregulation of p47-phox. Deficiency of apaf-1, a critical member of the apoptosome, dramatically abolished all the UV-induced signal deterioration and cell death. In parallel, UVC-induced apoptosis was largely attenuated by either DN-caspase-9 or Bcl-X(L) overexpression. Pretreatment of cells with N-acetylcysteine or catalase but not Tempol decreased UVC-induced MAPK activation and apoptosis. Inhibition of JNK and caspase attenuated p47-phox upregulation. Altogether, we have for the first time demonstrated the critical role of Apaf-1 in the regulation of MAPK, ROS, and MMP in UVC-radiated MEFs and propose that the amplification feedback loop among mitochondrial signal molecules culminates in the demise of the cell. |
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| MeSH term(s) | Animals ; Apoptosis/radiation effects ; Apoptotic Protease-Activating Factor 1/deficiency ; Caspase 8/metabolism ; Cell Cycle Proteins/metabolism ; Cell Division/radiation effects ; Cell Nucleus Shape/radiation effects ; Cells, Cultured ; Enzyme Activation ; Fas-Associated Death Domain Protein/genetics ; Fas-Associated Death Domain Protein/metabolism ; Fibroblasts/physiology ; Fibroblasts/radiation effects ; MAP Kinase Signaling System ; Membrane Potential, Mitochondrial ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Ultraviolet Rays |
| Chemical Substances | Apaf1 protein, mouse ; Apoptotic Protease-Activating Factor 1 ; Cell Cycle Proteins ; Fadd protein, mouse ; Fas-Associated Death Domain Protein ; Reactive Oxygen Species ; Casp8 protein, mouse (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) |
| Language | English |
| Publishing date | 2012-03-01 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 807032-5 |
| ISSN | 1873-4596 ; 0891-5849 |
| ISSN (online) | 1873-4596 |
| ISSN | 0891-5849 |
| DOI | 10.1016/j.freeradbiomed.2011.11.028 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
| Zs.A 2109: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
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Free Radical Biology and Medicine. 2012 Mar. 1, v. 52, no. 5
2012
Abstract: Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to ... ...
| Abstract | Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to demonstrate the decisive part of the mitochondrial pathway in UVC-induced apoptosis in mouse embryo fibroblasts (MEFs). UVC-induced apoptosis proceeded independent of the activation of death receptor components. In contrast, soon after UV radiation, MAPK activation and generation of reactive oxygen species (ROS) increased, followed by a decline in mitochondrial membrane potential (MMP) and cytochrome c release, as well as activation of caspase-9 and -3 and the upregulation of p47-phox. Deficiency of apaf-1, a critical member of the apoptosome, dramatically abolished all the UV-induced signal deterioration and cell death. In parallel, UVC-induced apoptosis was largely attenuated by either DN-caspase-9 or Bcl-XL overexpression. Pretreatment of cells with N-acetylcysteine or catalase but not Tempol decreased UVC-induced MAPK activation and apoptosis. Inhibition of JNK and caspase attenuated p47-phox upregulation. Altogether, we have for the first time demonstrated the critical role of Apaf-1 in the regulation of MAPK, ROS, and MMP in UVC-radiated MEFs and propose that the amplification feedback loop among mitochondrial signal molecules culminates in the demise of the cell. |
|---|---|
| Keywords | acetylcysteine ; apoptosis ; caspase-9 ; catalase ; cytochrome c ; death ; fibroblasts ; membrane potential ; mice ; mitochondrial membrane ; mitogen-activated protein kinase ; reactive oxygen species ; signal transduction ; ultraviolet radiation |
| Language | English |
| Dates of publication | 2012-0301 |
| Size | p. 889-897. |
| Publishing place | Elsevier Inc. |
| Document type | Article |
| ZDB-ID | 807032-5 |
| ISSN | 1873-4596 ; 0891-5849 |
| ISSN (online) | 1873-4596 |
| ISSN | 0891-5849 |
| DOI | 10.1016/j.freeradbiomed.2011.11.028 |
| Database | NAL-Catalogue (AGRICOLA) |
| Zs.A 2109: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
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Differentiation; research in biological diversity
2007 Volume 75, Issue 8, Page(s) 682–693
Abstract: Embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts maintain their pluripotency through a complex interplay of different signaling pathways and transcription factors including Leukemia Inhibitory Factor (LIF), homeo-domain protein ...
| Abstract | Embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts maintain their pluripotency through a complex interplay of different signaling pathways and transcription factors including Leukemia Inhibitory Factor (LIF), homeo-domain protein Nanog and POU-domain-containing transcription factor Oct3/4. LIF can maintain the self-renewal of mouse ESCs by activating the Jak/Stat3 pathway; however, it is dispensable for human ESCs. Nanog, a homeo-domain transcription factor alone is sufficient for sustaining the self-renewal of ESCs. Overexpression of Nanog by heterologous promoters can maintain self-renewal of human and mouse ESCs in the absence of LIF/Stat3 pathway. The mechanisms that control the expression of Nanog, however, remain poorly understood. In this report we demonstrate that retinol, the alcohol form of Vitamin A, can suppress the differentiation of ESCs by up-regulating the expression of Nanog. Retinol is mainly associated with differentiation through its active metabolite retinoic acid during early development of the embryo. The activation of Nanog by retinol is not mediated via retinoic acid signaling and appears to be independent of previously described LIF/Stat3, bone morphogenic proteins, Wnt/beta-catenin, and Oct3/4-Sox2 pathways. These studies therefore, reveal a previously unknown function of retinol and offer a model system to define alternate regulatory pathways that control the self-renewal of ESCs as well as to identify upstream "master" regulatory factors that are responsible for maintaining the integrity of stem cells. |
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| MeSH term(s) | Animals ; Cell Differentiation/physiology ; Cell Line ; DNA-Binding Proteins/biosynthesis ; DNA-Binding Proteins/genetics ; Down-Regulation/physiology ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Gene Expression Regulation, Developmental/physiology ; Growth Inhibitors/physiology ; Homeodomain Proteins/biosynthesis ; Homeodomain Proteins/genetics ; Humans ; Mice ; Mice, Inbred C57BL ; Nanog Homeobox Protein ; Vitamin A/physiology |
| Chemical Substances | DNA-Binding Proteins ; Growth Inhibitors ; Homeodomain Proteins ; Nanog Homeobox Protein ; Nanog protein, mouse ; Vitamin A (11103-57-4) |
| Language | English |
| Publishing date | 2007-10 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 184540-8 |
| ISSN | 1432-0436 ; 0301-4681 |
| ISSN (online) | 1432-0436 |
| ISSN | 0301-4681 |
| DOI | 10.1111/j.1432-0436.2007.00169.x |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
| Zs.A 1170: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.
Free Radical Biology and Medicine
Volume v. 52,, Issue no. 5
Abstract: Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to ... ...
| Abstract | Apoptosis requires tightly regulated cell death pathways. The signaling pathways that trigger a cell to undergo apoptosis after UV radiation are cell type specific and are currently being defined. Here, we have used pharmacological and genetic tools to demonstrate the decisive part of the mitochondrial pathway in UVC-induced apoptosis in mouse embryo fibroblasts (MEFs). UVC-induced apoptosis proceeded independent of the activation of death receptor components. In contrast, soon after UV radiation, MAPK activation and generation of reactive oxygen species (ROS) increased, followed by a decline in mitochondrial membrane potential (MMP) and cytochrome c release, as well as activation of caspase-9 and -3 and the upregulation of p47-phox. Deficiency of apaf-1, a critical member of the apoptosome, dramatically abolished all the UV-induced signal deterioration and cell death. In parallel, UVC-induced apoptosis was largely attenuated by either DN-caspase-9 or Bcl-XL overexpression. Pretreatment of cells with N-acetylcysteine or catalase but not Tempol decreased UVC-induced MAPK activation and apoptosis. Inhibition of JNK and caspase attenuated p47-phox upregulation. Altogether, we have for the first time demonstrated the critical role of Apaf-1 in the regulation of MAPK, ROS, and MMP in UVC-radiated MEFs and propose that the amplification feedback loop among mitochondrial signal molecules culminates in the demise of the cell. |
|---|---|
| Keywords | apoptosis ; death ; reactive oxygen species ; caspase-9 ; membrane potential ; catalase ; mitogen-activated protein kinase ; signal transduction ; ultraviolet radiation ; mice ; acetylcysteine ; fibroblasts ; mitochondrial membrane ; cytochrome c |
| Language | English |
| Document type | Article |
| ISSN | 0891-5849 |
| Database | AGRIS - International Information System for the Agricultural Sciences and Technology |
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.
Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.