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Mangala Lahkar - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
Ashok Jangra - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the role of breast cancer resistance protein bcrp abcg2 and multidrug resistance associated protein 4 mrp4 abcc4 in the urinary excretion of sulfate and glucuronide metabolites of Edaravone mci 186 3 methyl 1 phenyl 2 pyrazolin 5 one
Drug Metabolism and Disposition, 2007Co-Authors: Naomi Mizuno, Tsuyoshi Takahashi, Hiroyuki Kusuhara, Takuro Niwa, John D Schuetz, Yuichi SugiyamaAbstract:Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. Edaravone is mainly excreted into the urine after conjugation to glucuronide or sulfate. Previous studies have demonstrated that Edaravone sulfate is a good substrate of human organic anion transporter (OAT) 1 (SLC22A6) and human OAT3 (SLC22A8). In this study, we examined the involvement of breast cancer resistance protein [BCRP (ABCG2)] and [multidrug resistance-associated protein 4 MRP4 (ABCC4)] in the luminal efflux in the kidney. Increased ATP-dependent uptake of Edaravone sulfate but not Edaravone glucuronide was observed in BCRP-expressing membrane vesicles compared with control vesicles (Km = 16.5 microM). In contrast, Edaravone glucuronide, but not Edaravone sulfate, exhibited greater ATP-dependent uptake in MRP4-expressing membrane vesicles than that in control vesicles (Km = 9.85 microM). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of Edaravone glucuronide by MRP4. The functional importance of BCRP and MRP4 in the urinary excretion of Edaravone sulfate and Edaravone glucuronide, respectively, was investigated using Bcrp and Mrp4 knockout mice. The renal clearance with respect to the kidney concentration of Edaravone sulfate was reduced significantly but not abolished in Bcrp knockout mice compared with wild-type mice (3.62 versus 4.85 ml/min/kg b.wt.). The renal clearance of Edaravone glucuronide was lower in Mrp4 knockout mice than wild-type mice (2.01 versus 5.06 ml/min/kg BW). Our results suggest that Bcrp and Mrp4 are partly involved in the luminal efflux of Edaravone sulfate and Edaravone glucuronide, respectively.
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human organic anion transporters 1 hoat1 slc22a6 and 3 hoat3 slc22a8 transport Edaravone mci 186 3 methyl 1 phenyl 2 pyrazolin 5 one and its sulfate conjugate
Drug Metabolism and Disposition, 2007Co-Authors: Naomi Mizuno, Tsuyoshi Takahashi, Yumiko Iwase, Hiroyuki Kusuhara, Takuro Niwa, Yuichi SugiyamaAbstract:3-Methyl-1-phenyl-2-pyrazolin-5-one (MCI-186; Edaravone), a novel free radical scavenger, is used for the treatment of acute cerebral infarction. After marketing, a few cases of acute renal failure were reported in patients following treatment with this drug. Because Edaravone is mainly excreted into the urine following conjugation to glucuronide or sulfate, the renal excretion mechanisms of Edaravone should help provide important information when considering the clinical cases. We examined the transport of Edaravone and its sulfate and glucuronide conjugates via human organic anion transporter 1 (hOAT1) and 3 (hOAT3), expressed on the basolateral membranes of proximal tubules. The hOAT1- and hOAT3-transfected human embryonic kidney (HEK)-293 cells exhibited a markedly higher uptake of Edaravone sulfate and a slightly higher uptake of Edaravone than vector-transfected cells. The Km values of Edaravone sulfate uptake by hOAT1 and hOAT3 were 11 and 15 μM, respectively. Estimation of the relative contribution of hOAT1 and hOAT3 using reference compounds suggested that hOAT1 and hOAT3 might contribute to the renal uptake of Edaravone sulfate to the same extent. However, Edaravone and its sulfate showed no cytotoxicity toward both hOAT1-HEK and control cells, suggesting that higher uptake in hOAT1-HEK did not associate with cytotoxicity of these compounds. In conclusion, our results suggest that both hOAT1 and hOAT3 are responsible for the basolateral uptake of Edaravone sulfate in the kidney.
Kiyoshi Kikuchi - One of the best experts on this subject based on the ideXlab platform.
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Edaravone, a Synthetic Free Radical Scavenger, Enhances Alteplase-Mediated Thrombolysis.
Oxidative medicine and cellular longevity, 2017Co-Authors: Kiyoshi Kikuchi, Kentaro Setoyama, Ko-ichi Kawahara, Tomoka Nagasato, Takuto Terashi, Koki Ueda, Kazuki Nakanishi, Shotaro Otsuka, Naoki Miura, Hisayo SameshimaAbstract:The combination of alteplase, a recombinant tissue plasminogen activator, and Edaravone, an antioxidant, reportedly enhances recanalization after acute ischemic stroke. We examined the influence of Edaravone on the thrombolytic efficacy of alteplase by measuring thrombolysis using a newly developed microchip-based flow-chamber assay. Rat models of embolic cerebral ischemia were treated with either alteplase or alteplase-Edaravone combination therapy. The combination therapy significantly reduced the infarct volume and improved neurological deficits. Human blood samples from healthy volunteers were exposed to Edaravone, alteplase, or a combination of alteplase and Edaravone or hydrogen peroxide. Whole blood was perfused over a collagen- and thromboplastin-coated microchip; capillary occlusion was monitored with a video microscope and flow-pressure sensor. The area under the curve (extent of thrombogenesis or thrombolysis) at 30 minutes was 69.9% lower in the Edaravone-alteplase- than alteplase-treated group. The thrombolytic effect of alteplase was significantly attenuated in the presence of hydrogen peroxide, suggesting that oxidative stress might hinder thrombolysis. D-dimers were measured to evaluate these effects in human platelet-poor plasma samples. Although hydrogen peroxide significantly decreased the elevation of D-dimers by alteplase, Edaravone significantly inhibited the decrease. Edaravone enhances alteplase-mediated thrombolysis, likely by preventing oxidative stress, which inhibits fibrinolysis by alteplase in thrombi.
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The free radical scavenger Edaravone rescues rats from cerebral infarction by attenuating the release of high-mobility group box-1 in neuronal cells
2016Co-Authors: Kiyoshi Kikuchi, Ko-ichi Kawahara, Naoki Miura, Salunya Tancharoen, Fumiyo Matsuda, Yoko Morimoto, Takashi Ito, Kamal Krishna Biswas, Kazunori Takenouchi, Yoko OyamaAbstract:Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we exam-ined the effects of Edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cy-toplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg Edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 10.4 and 43.8 0.5 % reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, Edaravone also decreased plasma HMGB1 levels. In vitro, Edaravone dose
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the efficacy of Edaravone radicut a free radical scavenger for cardiovascular disease
International Journal of Molecular Sciences, 2013Co-Authors: Kiyoshi Kikuchi, Salunya Tancharoen, Nobuyuki Takeshige, Munetake Yoshitomi, Motohiro Morioka, Yoshinaka Murai, Eiichiro TanakaAbstract:Edaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, Edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of Edaravone for treatment of cardiovascular disease, and covers clinical and experimental studies conducted between 1984 and 2013. We propose that Edaravone, which scavenges free radicals, may offer a novel option for treatment of cardiovascular diseases. However, additional clinical studies are necessary to verify the efficacy of Edaravone.
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the free radical scavenger Edaravone rescues rats from cerebral infarction by attenuating the release of high mobility group box 1 in neuronal cells
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Kiyoshi Kikuchi, Ko-ichi Kawahara, Naoki Miura, Salunya Tancharoen, Fumiyo Matsuda, Yoko Morimoto, Takashi Ito, Kamal Krishna Biswas, Kazunori Takenouchi, Yoko OyamaAbstract:Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of Edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg Edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 +/- 10.4 and 43.8 +/- 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, Edaravone also decreased plasma HMGB1 levels. In vitro, Edaravone dose-dependently (1-10 microM) suppressed OGD- and H(2)O(2)-induced HMGB1 release in PC12 cells. Furthermore, Edaravone (3-30 microM) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for Edaravone that abrogates the release of HMGB1.
Chandra Shaker Sriram - One of the best experts on this subject based on the ideXlab platform.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
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sodium phenylbutyrate and Edaravone abrogate chronic restraint stress induced behavioral deficits implication of oxido nitrosative endoplasmic reticulum stress cascade and neuroinflammation
Cellular and Molecular Neurobiology, 2017Co-Authors: Ashok Jangra, Chandra Shaker Sriram, Shubham Dwivedi, Satendra Singh Gurjar, Md Iftikar Hussain, Parashjyoti Borah, Mangala LahkarAbstract:Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and Edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or Edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and Edaravone treatment. In addition, SPB and Edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and Edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and Edaravone treatment in CRS mice. Our study provides evidence that SPB and Edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.
