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Susumu Ishida - One of the best experts on this subject based on the ideXlab platform.
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Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy.
Diabetologia, 2012Co-Authors: Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu IshidaAbstract:Aims/hypothesis The renin–angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in Retinal Inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy.
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Roles of AMP-activated protein kinase in diabetes-induced Retinal Inflammation
Investigative ophthalmology & visual science, 2011Co-Authors: Shunsuke Kubota, Yoko Ozawa, Seiji Miyake, Mariko Sasaki, Kousuke Noda, Susumu Ishida, Toshihide Kurihara, Kenya Yuki, Kazuo TsubotaAbstract:PURPOSE. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model. METHODS. C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-B p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT)1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the Retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. RESULTS. Induction of diabetes in mice led to Retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-B phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced Retinal leukocyte adhesion, together with Retinal expression of ICAM-1 and VEGF. CONCLUSIONS. The present findings reveal that diabetes-induced Retinal Inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-B activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:9142‐9148)
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(Pro)renin Receptor-Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation
Diabetes, 2009Co-Authors: Shingo Satofuka, Kazuo Tsubota, Yoko Ozawa, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Akiyoshi Fukamizu, Hiroshi Itoh, Yuichi Oike, Susumu IshidaAbstract:OBJECTIVE The term “receptor-associated prorenin system” (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced Retinal Inflammation. RESEARCH DESIGN AND METHODS Long-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the Retinal vasculature was evaluated with a concanavalin A lectin perfusion–labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal–regulated kinase (ERK) activation was analyzed by Western blotting. RESULTS Induction of diabetes led to significant increase in Retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced Retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R–deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R–deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R–deficient diabetic mice. CONCLUSIONS These results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced Retinal Inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy.
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Neuroprotective effect of an antioxidant, lutein, during Retinal Inflammation.
Investigative ophthalmology & visual science, 2008Co-Authors: Mariko Sasaki, Yoko Ozawa, Saori Kobayashi, Kousuke Noda, Susumu Ishida, Toshihide Kurihara, Yutaka Imamura, Kazuo TsubotaAbstract:PURPOSE. Lutein has been the focus of recent study as a possible therapeutic approach for Retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate, with the use of a mouse endotoxin-induced uveitis (EIU) model, the neuroprotective effects of lutein against Retinal neural damage caused by Inflammation. METHODS. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Each animal was given a subcutaneous injection of lutein or vehicle three times: concurrently with and 3 hours before and after the LPS injection. Analysis was carried out 24 hours after EIU induction. Levels of rhodopsin protein and STAT3 activation were analyzed by immunoblotting. Lengths of the outer segments of the photoreceptor cells were measured. Dark-adapted full-field electroretinograms were recorded. Oxidative stress in the retina was analyzed by dihydroethidium and fluorescent probe. Expression of glial fibrillary acidic protein (GFAP) was shown immunohistochemically. RESULTS. The ElU-induced decrease in rhodopsin expression followed by shortening of the outer segments and reduction in a-wave amplitude were prevented by lutein treatment. Levels of STAT3 activation, downstream of inflammatory cytokine signals, and reactive oxygen species (ROS), which are both upregulated during EIU, were reduced by lutein. Pathologic change of Miiller glial cells, represented by GFAP expression, was also prevented by lutein. CONCLUSIONS. The present data revealed that the antioxidant lutein was neuroprotective during EIU, suggesting a potential approach for suppressing Retinal neural damage during Inflammation.
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roles of stat3 socs3 pathway in regulating the visual function and ubiquitin proteasome dependent degradation of rhodopsin during Retinal Inflammation
Journal of Biological Chemistry, 2008Co-Authors: Yoko Ozawa, Kazuo Tsubota, Susumu Ishida, Keiko Nakao, Toshihide Kurihara, Takuya Shimazaki, Shigeto Shimmura, Akihiko Yoshimura, Hideyuki OkanoAbstract:Inflammatory cytokines cause tissue dysfunction. We previously reported that Retinal Inflammation down-regulates rhodopsin expression and impairs visual function by an unknown mechanism. Here, we demonstrate that rhodopsin levels were preserved by suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of STAT3 activation. SOCS3 was expressed mainly in photoreceptor cells in the retina. In the SOCS3-deficient retinas, rhodopsin protein levels dropped sooner, and the reduction was more profound than in the wild type. Visual dysfunction, measured by electroretinogram, was prolonged in retina-specific SOCS3 conditional knock-out mice. Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency. Interleukin 6, one of the inflammatory cytokines found during Retinal Inflammation, activated STAT3 and decreased rhodopsin protein in adult Retinal explants. This was enhanced by inhibiting SOCS3 function in vitro, indicating that rhodopsin reduction was not a secondary effect in the mutant mice. Interestingly, in the inflamed SOCS3-deficient adult retina, rhodopsin decreased post-transcriptionally at least partly through ubiquitin-proteasome-dependent degradation accelerated by STAT3 activation and not transcriptionally as in the developing retina, on which we reported previously. A STAT3-dependent E3 ubiquitin ligase, Ubr1, was responsible for rhodopsin degradation and was up-regulated in the inflamed SOCS3-deficient retinas. These results indicate that in wild-type animals, a decrease in rhodopsin during Inflammation is minimized by endogenous SOCS3. However, when STAT3 activation exceeds some threshold beyond the compensatory activity of endogenous SOCS3, rhodopsin levels decrease. These findings suggest SOCS3 as a potential therapeutic target molecule for protecting photoreceptor cell function during Inflammation.
Yoko Ozawa - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective effect of activated 5'-adenosine monophosphate-activated protein kinase on cone system function during Retinal Inflammation
BMC neuroscience, 2016Co-Authors: Mamoru Kamoshita, Kaoru Fujinami, Eriko Toda, Kazuo Tsubota, Yoko OzawaAbstract:Background Retinal Inflammation can cause Retinal neural disorders. In particular, functional disorder in the cone photoreceptor system influences visual acuity. However, the underlying mechanism is not yet fully understood. In this study, we evaluated cone system function and the role of 5′-adenosine monophosphate-activated protein kinase (AMPK) during Retinal Inflammation.
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AMPK-NF-κB axis in the photoreceptor disorder during Retinal Inflammation.
PloS one, 2014Co-Authors: Mamoru Kamoshita, Yoko Ozawa, Seiji Miyake, Norihiro Nagai, Shigeto Shimmura, Shunsuke Kubota, Kenya Yuki, Chiduru Tsuda, Kazuo Umezawa, Kazuo TsubotaAbstract:Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of Retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the Retinal neural damage and visual function impairment caused by Inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced Inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During Inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during Inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during Inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during Retinal Inflammation.
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Roles of AMP-activated protein kinase in diabetes-induced Retinal Inflammation
Investigative ophthalmology & visual science, 2011Co-Authors: Shunsuke Kubota, Yoko Ozawa, Seiji Miyake, Mariko Sasaki, Kousuke Noda, Susumu Ishida, Toshihide Kurihara, Kenya Yuki, Kazuo TsubotaAbstract:PURPOSE. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model. METHODS. C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-B p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT)1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the Retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. RESULTS. Induction of diabetes in mice led to Retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-B phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced Retinal leukocyte adhesion, together with Retinal expression of ICAM-1 and VEGF. CONCLUSIONS. The present findings reveal that diabetes-induced Retinal Inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-B activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:9142‐9148)
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Vision preservation during Retinal Inflammation by anthocyanin-rich bilberry extract: cellular and molecular mechanism
Laboratory investigation; a journal of technical methods and pathology, 2011Co-Authors: Seiji Miyake, Kazuo Tsubota, Noriko Takahashi, Mariko Sasaki, Saori Kobayashi, Yoko OzawaAbstract:Anthocyanin-rich bilberry extract, a plant-derived antioxidant, has been utilized as a popular supplement for ocular health worldwide. However, it is unclear whether this extract has any biological effect on visual function, and the mechanism for such an effect is completely unknown. In this study, we generated a mouse model of endotoxin-induced uveitis (EIU) that shows Retinal Inflammation, as well as uveitis, by injecting lipopolysaccharide. We pretreated the mice with anthocyanin-rich bilberry extract and analyzed the effect on the retina. Anthocyanin-rich bilberry extract prevented the impairment of photoreceptor cell function, as measured by electroretinogram. At the cellular level, we found that the EIU-associated rhodopsin decreased and the shortening of outer segments in photoreceptor cells were suppressed in the bilberry-extract-treated animals. Moreover, the extract prevented both STAT3 activation, which induces Inflammation-related rhodopsin decrease, and the increase in interleukin-6 expression, which activates STAT3. In addition to its anti-inflammatory effect, the anthocyanin-rich bilberry extract ameliorated the intracellular elevation of reactive oxygen species and activated NF-κB, a redox-sensitive transcription factor, in the inflamed retina. Our findings indicate that anthocyanin-rich bilberry extract has a protective effect on visual function during Retinal Inflammation.
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(Pro)renin Receptor-Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation
Diabetes, 2009Co-Authors: Shingo Satofuka, Kazuo Tsubota, Yoko Ozawa, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Akiyoshi Fukamizu, Hiroshi Itoh, Yuichi Oike, Susumu IshidaAbstract:OBJECTIVE The term “receptor-associated prorenin system” (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced Retinal Inflammation. RESEARCH DESIGN AND METHODS Long-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the Retinal vasculature was evaluated with a concanavalin A lectin perfusion–labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal–regulated kinase (ERK) activation was analyzed by Western blotting. RESULTS Induction of diabetes led to significant increase in Retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced Retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R–deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R–deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R–deficient diabetic mice. CONCLUSIONS These results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced Retinal Inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy.
Kazuo Tsubota - One of the best experts on this subject based on the ideXlab platform.
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Neuroprotective effect of activated 5'-adenosine monophosphate-activated protein kinase on cone system function during Retinal Inflammation
BMC neuroscience, 2016Co-Authors: Mamoru Kamoshita, Kaoru Fujinami, Eriko Toda, Kazuo Tsubota, Yoko OzawaAbstract:Background Retinal Inflammation can cause Retinal neural disorders. In particular, functional disorder in the cone photoreceptor system influences visual acuity. However, the underlying mechanism is not yet fully understood. In this study, we evaluated cone system function and the role of 5′-adenosine monophosphate-activated protein kinase (AMPK) during Retinal Inflammation.
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AMPK-NF-κB axis in the photoreceptor disorder during Retinal Inflammation.
PloS one, 2014Co-Authors: Mamoru Kamoshita, Yoko Ozawa, Seiji Miyake, Norihiro Nagai, Shigeto Shimmura, Shunsuke Kubota, Kenya Yuki, Chiduru Tsuda, Kazuo Umezawa, Kazuo TsubotaAbstract:Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of Retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the Retinal neural damage and visual function impairment caused by Inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced Inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During Inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during Inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during Inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during Retinal Inflammation.
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Roles of AMP-activated protein kinase in diabetes-induced Retinal Inflammation
Investigative ophthalmology & visual science, 2011Co-Authors: Shunsuke Kubota, Yoko Ozawa, Seiji Miyake, Mariko Sasaki, Kousuke Noda, Susumu Ishida, Toshihide Kurihara, Kenya Yuki, Kazuo TsubotaAbstract:PURPOSE. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model. METHODS. C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-B p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT)1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the Retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. RESULTS. Induction of diabetes in mice led to Retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-B phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced Retinal leukocyte adhesion, together with Retinal expression of ICAM-1 and VEGF. CONCLUSIONS. The present findings reveal that diabetes-induced Retinal Inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-B activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:9142‐9148)
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Vision preservation during Retinal Inflammation by anthocyanin-rich bilberry extract: cellular and molecular mechanism
Laboratory investigation; a journal of technical methods and pathology, 2011Co-Authors: Seiji Miyake, Kazuo Tsubota, Noriko Takahashi, Mariko Sasaki, Saori Kobayashi, Yoko OzawaAbstract:Anthocyanin-rich bilberry extract, a plant-derived antioxidant, has been utilized as a popular supplement for ocular health worldwide. However, it is unclear whether this extract has any biological effect on visual function, and the mechanism for such an effect is completely unknown. In this study, we generated a mouse model of endotoxin-induced uveitis (EIU) that shows Retinal Inflammation, as well as uveitis, by injecting lipopolysaccharide. We pretreated the mice with anthocyanin-rich bilberry extract and analyzed the effect on the retina. Anthocyanin-rich bilberry extract prevented the impairment of photoreceptor cell function, as measured by electroretinogram. At the cellular level, we found that the EIU-associated rhodopsin decreased and the shortening of outer segments in photoreceptor cells were suppressed in the bilberry-extract-treated animals. Moreover, the extract prevented both STAT3 activation, which induces Inflammation-related rhodopsin decrease, and the increase in interleukin-6 expression, which activates STAT3. In addition to its anti-inflammatory effect, the anthocyanin-rich bilberry extract ameliorated the intracellular elevation of reactive oxygen species and activated NF-κB, a redox-sensitive transcription factor, in the inflamed retina. Our findings indicate that anthocyanin-rich bilberry extract has a protective effect on visual function during Retinal Inflammation.
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(Pro)renin Receptor-Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation
Diabetes, 2009Co-Authors: Shingo Satofuka, Kazuo Tsubota, Yoko Ozawa, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Akiyoshi Fukamizu, Hiroshi Itoh, Yuichi Oike, Susumu IshidaAbstract:OBJECTIVE The term “receptor-associated prorenin system” (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced Retinal Inflammation. RESEARCH DESIGN AND METHODS Long-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)-deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the Retinal vasculature was evaluated with a concanavalin A lectin perfusion–labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal–regulated kinase (ERK) activation was analyzed by Western blotting. RESULTS Induction of diabetes led to significant increase in Retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced Retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R–deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R–deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R–deficient diabetic mice. CONCLUSIONS These results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced Retinal Inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy.
Azza B. El-remessy - One of the best experts on this subject based on the ideXlab platform.
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High fat diet dysregulates microRNA-17-5p and triggers Retinal Inflammation: Role of endoplasmic-reticulum-stress.
World journal of diabetes, 2017Co-Authors: Maha Coucha, Islam N. Mohamed, Sally L Elshaer, Osinakachuk Mbata, Megan L. Bartasis, Azza B. El-remessyAbstract:High fat diet dysregulates microRNA-17-5p and triggers Retinal Inflammation: Role of endoplasmic-reticulum-stress
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MicroRNA-146b-3p Regulates Retinal Inflammation by Suppressing Adenosine Deaminase-2 in Diabetes
BioMed research international, 2015Co-Authors: Sadanand Fulzele, Azza B. El-remessy, Suraporn Matragoon, Ahmed Elsherbini, Saif Ahmad, Rajnikumar Sangani, Reshmitha Radhakrishnan, Gregory I. LiouAbstract:Hyperglycemia- (HG-) Amadori-glycated albumin- (AGA-) induced activation of microglia and monocytes and their adherence to Retinal vascular endothelial cells contribute to Retinal Inflammation leading to diabetic retinopathy (DR). There is a great need for early detection of DR before demonstrable tissue damages become irreversible. Extracellular adenosine, required for endogenous anti-Inflammation, is regulated by the interplay of equilibrative nucleoside transporter with adenosine deaminase (ADA) and adenosine kinase. ADA, including ADA1 and ADA2, exists in all organisms. However, because ADA2 gene has not been identified in mouse genome, how diabetes alters adenosine-dependent anti-Inflammation remains unclear. Studies of pig Retinal microglia and human macrophages revealed a causal role of ADA2 in Inflammation. Database search suggested miR-146b-3p recognition sites in the 3′-UTR of ADA2 mRNA. Coexpression of miR-146b-3p, but not miR-146-5p or nontargeting miRNA, with 3′-UTR of the ADA2 gene was necessary to suppress a linked reporter gene. In the vitreous of diabetic patients, decreased miR-146b-3p is associated with increased ADA2 activity. Ectopic expression of miR-146b-3p suppressed ADA2 expression, activity, and TNF-α release in the AGA-treated human macrophages. These results suggest a regulatory role of miR-146b-3p in diabetes related Retinal Inflammation by suppressing ADA2.
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Modulation of p75NTR prevents diabetes- and proNGF-induced Retinal Inflammation and blood–retina barrier breakdown in mice and rats
Diabetologia, 2013Co-Authors: Barbara A. Mysona, Mohammed M.h. Al-gayyar, Suraporn Matragoon, Mohammed Abdelsaid, Mona F. El-azab, H. Uri Saragovi, Azza B. El-remessyAbstract:Aims/hypothesis Diabetic retinopathy is characterised by early blood–retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75NTR), suggesting a possible pathological role of the proNGF–p75NTR axis in the diabetic retina. To date, the role of this axis in diabetes-induced Retinal Inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75NTR would prevent diabetes- and proNGF-induced Retinal Inflammation and BRB breakdown.
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Potential roles of adenosine deaminase-2 in diabetic retinopathy
Biochemical and biophysical research communications, 2013Co-Authors: Nehal M. Elsherbiny, Azza B. El-remessy, Mohammed M.h. Al-gayyar, Sadanand Fulzele, Ahmed Elsherbini, Saif Ahmad, Mohammad Naime, Shuaib Mohammad, Laila A. Eissa, Mamdouh M. El-shishtawyAbstract:The early activation of microglia that induces Retinal Inflammation in DR may serve as a target for therapeutic intervention of DR. Our demonstration that Retinal Inflammation is attenuated via adenosine receptor A2AAR supports the hypothesis that a mechanism to maintain extracellular concentrations of adenosine important in normal physiology is impaired in DR. Extracellular concentrations of adenosine are regulated by the interplay of equiliberative nucleoside transporter (ENT)s with enzymes of adenosine metabolism including adenosine deaminase-1 (ADA1), adenosine kinase (AK) and CD73. In the vertebrates but not rodents, a macrophage-associated ADA2 is identified. The role of ADA2 is, therefore, understudied as the sequencing probes or antibodies to mouse ADA2 are not available. We identified increased ADA2 expression and activity in human and porcine retinas with diabetes, and in Amadori glycated albumin (AGA)- or hyperglycemia-treated porcine and human microglia. In rodent as well as porcine cells, modulation of TNF-α release is mediated by A2AAR. Quantitative analysis of normal and diabetic porcine retinas reveals that while the expression levels of ADA2, A2AAR, ENT1, TNF-α and MMP9 are increased, the levels of AK are reduced during Inflammation as an endogenous protective mechanism. To determine the role of ADA2, we found that AGA induces ADA2 expression, ADA2 activity and TNF-α release, and that TNF-α release is blocked by ADA2-neutralizing antibody or ADA2 siRNA, but not by scrambled siRNA. These results suggest that Retinal Inflammation in DR is mediated by ADA2, and that the anti-inflammatory activity of A2AAR signaling is impaired in diabetes due to increased ADA2 activity.
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Thioredoxin interacting protein is a novel mediator of Retinal Inflammation and neurotoxicity
British journal of pharmacology, 2011Co-Authors: Mohammed M.h. Al-gayyar, Suraporn Matragoon, Mohammed Abdelsaid, Bindu Pillai, Azza B. El-remessyAbstract:BACKGROUND AND PURPOSE Up-regulation of thioredoxin interacting protein (TXNIP), an endogenous inhibitor of thioredoxin (Trx), compromises cellular antioxidant and anti-apoptotic defences and stimulates pro-inflammatory cytokines expression, implying a role for TXNIP in apoptosis. Here we have examined the causal role of TXNIP expression in mediating Retinal neurotoxicity and assessed the neuroprotective actions of verapamil, a calcium channel blocker and an inhibitor of TXNIP expression. EXPERIMENTAL APPROACH Retinal neurotoxicity was induced by intravitreal injection of NMDA in Sprague–Dawley rats, which received verapamil (10 mg·kg−1, p.o.) or vehicle. Neurotoxicity was examined by terminal dUTP nick-end labelling assay and ganglion cell count. Expression of TXNIP, apoptosis signal-regulating kinase 1 (ASK-1), NF-κB, p38 MAPK, JNK, cleaved poly-ADP-ribose polymerase (PARP), caspase-3, nitrotyrosine and 4-hydroxy-nonenal were examined by Western and slot-blot analysis. Release of TNF-α and IL-1β was examined by elisa. KEY RESULTS NMDA injection enhanced TXNIP expression, decreased Trx activity, causing increased oxidative stress, glial activation and release of TNF-α and IL-1β. Enhanced TXNIP expression disrupted Trx/ASK-1 inhibitory complex leading to release of ASK-1 and activation of the pro-apoptotic p38 MAPK/JNK pathway, as indicated by cleaved PARP and caspase-3 expression. Treatment with verapamil blocked these effects. CONCLUSION AND IMPLICATIONS Elevated TXNIP expression contributed to Retinal neurotoxicity by three different mechanisms, inducing release of inflammatory mediators such as TNF-α and IL-1β, altering antioxidant status and disrupting the Trx-ASK-1 inhibitory complex leading to activation of the p38 MAPK/JNK apoptotic pathway. Targeting TXNIP expression is a potential therapeutic target for Retinal neurodegenerative disease.
Hideyuki Okano - One of the best experts on this subject based on the ideXlab platform.
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roles of stat3 socs3 pathway in regulating the visual function and ubiquitin proteasome dependent degradation of rhodopsin during Retinal Inflammation
Journal of Biological Chemistry, 2008Co-Authors: Yoko Ozawa, Kazuo Tsubota, Susumu Ishida, Keiko Nakao, Toshihide Kurihara, Takuya Shimazaki, Shigeto Shimmura, Akihiko Yoshimura, Hideyuki OkanoAbstract:Inflammatory cytokines cause tissue dysfunction. We previously reported that Retinal Inflammation down-regulates rhodopsin expression and impairs visual function by an unknown mechanism. Here, we demonstrate that rhodopsin levels were preserved by suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of STAT3 activation. SOCS3 was expressed mainly in photoreceptor cells in the retina. In the SOCS3-deficient retinas, rhodopsin protein levels dropped sooner, and the reduction was more profound than in the wild type. Visual dysfunction, measured by electroretinogram, was prolonged in retina-specific SOCS3 conditional knock-out mice. Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency. Interleukin 6, one of the inflammatory cytokines found during Retinal Inflammation, activated STAT3 and decreased rhodopsin protein in adult Retinal explants. This was enhanced by inhibiting SOCS3 function in vitro, indicating that rhodopsin reduction was not a secondary effect in the mutant mice. Interestingly, in the inflamed SOCS3-deficient adult retina, rhodopsin decreased post-transcriptionally at least partly through ubiquitin-proteasome-dependent degradation accelerated by STAT3 activation and not transcriptionally as in the developing retina, on which we reported previously. A STAT3-dependent E3 ubiquitin ligase, Ubr1, was responsible for rhodopsin degradation and was up-regulated in the inflamed SOCS3-deficient retinas. These results indicate that in wild-type animals, a decrease in rhodopsin during Inflammation is minimized by endogenous SOCS3. However, when STAT3 activation exceeds some threshold beyond the compensatory activity of endogenous SOCS3, rhodopsin levels decrease. These findings suggest SOCS3 as a potential therapeutic target molecule for protecting photoreceptor cell function during Inflammation.
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Roles of STAT3/SOCS3 pathway in regulating the visual function and ubiquitin-proteasome-dependent degradation of rhodopsin during Retinal Inflammation.
The Journal of biological chemistry, 2008Co-Authors: Yoko Ozawa, Kazuo Tsubota, Susumu Ishida, Keiko Nakao, Toshihide Kurihara, Takuya Shimazaki, Shigeto Shimmura, Akihiko Yoshimura, Hideyuki OkanoAbstract:Inflammatory cytokines cause tissue dysfunction. We previously reported that Retinal Inflammation down-regulates rhodopsin expression and impairs visual function by an unknown mechanism. Here, we demonstrate that rhodopsin levels were preserved by suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of STAT3 activation. SOCS3 was expressed mainly in photoreceptor cells in the retina. In the SOCS3-deficient retinas, rhodopsin protein levels dropped sooner, and the reduction was more profound than in the wild type. Visual dysfunction, measured by electroretinogram, was prolonged in retina-specific SOCS3 conditional knock-out mice. Visual dysfunction and decreased rhodopsin levels both correlated with increased STAT3 activation enhanced by SOCS3 deficiency. Interleukin 6, one of the inflammatory cytokines found during Retinal Inflammation, activated STAT3 and decreased rhodopsin protein in adult Retinal explants. This was enhanced by inhibiting SOCS3 function in vitro, indicating that rhodopsin reduction was not a secondary effect in the mutant mice. Interestingly, in the inflamed SOCS3-deficient adult retina, rhodopsin decreased post-transcriptionally at least partly through ubiquitin-proteasome-dependent degradation accelerated by STAT3 activation and not transcriptionally as in the developing retina, on which we reported previously. A STAT3-dependent E3 ubiquitin ligase, Ubr1, was responsible for rhodopsin degradation and was up-regulated in the inflamed SOCS3-deficient retinas. These results indicate that in wild-type animals, a decrease in rhodopsin during Inflammation is minimized by endogenous SOCS3. However, when STAT3 activation exceeds some threshold beyond the compensatory activity of endogenous SOCS3, rhodopsin levels decrease. These findings suggest SOCS3 as a potential therapeutic target molecule for protecting photoreceptor cell function during Inflammation.