Retinal ganglion cell（RGC） degeneration is irreversible in glaucoma and tyrosine kinase receptor B（Trk B）-associated signaling pathways have been implicated in the process.In this study,we attempted to examine whe...Retinal ganglion cell（RGC） degeneration is irreversible in glaucoma and tyrosine kinase receptor B（Trk B）-associated signaling pathways have been implicated in the process.In this study,we attempted to examine whether imipramine,a tricyclic antidepressant,may protect hydrogen peroxide（H_2O_2）-induced RGC degeneration through the activation of the Trk B pathway in RGC-5 cell lines.RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H_2O_2.Western blot assay showed that in H_2O_2-damaged RGC-5 cells,imipramine activated Trk B pathways through extracellular signal-regulated protein kinase/Trk B phosphorylation.TUNEL staining assay also demonstrated that imipramine ameliorated H_2O_2-induced apoptosis in RGC-5 cells.Finally,Trk B-Ig G intervention was able to reverse the protective effect of imipramine on H_2O_2-induced RGC-5 apoptosis.Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the Trk B signaling pathway.展开更多
Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation,the hexosamine pathway,the polyol pathway and diacylglycerol...Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation,the hexosamine pathway,the polyol pathway and diacylglycerol-protein kinase C.Oxidative stress may lead to the production of hydroxyl free radicals,which can attack macromolecules,such as lipids,nucleic acids or amino acids.Phenylalanine(Phe) can be enzymatically converted to the physiological para-tyrosine(p-Tyr);however,a hydroxyl free radical attack on Phe may yield meta-and ortho-tyrosine(m-and o-Tyr,respectively) in addition to p-Tyr.Hence,m-and o-Tyr may be regarded as markers of hydroxyl free radical-induced damage.Their accumulation has been described;e.g.,this accumulation has been found in the urine of patients with diabetes mellitus(DM) and/or chronic kidney disease,in cataract lenses,in vessel walls,in irradiated food and in amniotic fluid,and it may serve as an indicator of oxidative stress.The use of resveratrol to treat patients with type 2 DM led to a decrease in the urinary excretion of o-Tyr and concomitantly led to an improvement in insulin signaling and insulin sensitivity.Literature data also suggest that m-and o-Tyr may interfere with intracellular signaling.Our group has shown that erythropoietin(EPO) has insulin-like metabolic effects on fat cells in addition to its ability to promote the proliferation of erythroid precursor cells.We have shown that the supplementation of cell culture medium with m-and o-Tyr inhibits erythroblast cell proliferation,which could be ameliorated by p-Tyr.Additionally,in vivo,the o-Tyr/p-Tyr ratio is higher in patients with renal replacement therapy and a greater need for EPO.However,the o-Tyr/p-Tyr ratio was an independent determinant of EPO-resistance indices in our human study.The o-Tyr content of blood vessel walls inversely correlates with insulin-and acetylcholineinduced vasodilation,which could be further impaired by artificial oxidative stress and improved by the use of antioxidants.In rats that receive o-Tyr supplements,decreased vasorelaxation is detected in response to insulin.Additionally,o-Tyr supplementation led to the incorporation of the unnatural amino acid into cellular proteins and caused a decrease in the insulin-induced phosphorylation of endothelial nitric oxide synthase.Our data suggest that m-and o-Tyr may not only be markers of oxidative stress;instead,they may also be incorporated into cellular proteins,leading to resistance to insulin,EPO and acetylcholine.展开更多
目的:探讨鸢尾素调节Janus蛋白酪氨酸激酶2(Janus protein tyrosine kinase 2,JAK2)/信号转导和转录激活子3(Signal transduction and activator of transcription 3,STAT3)信号通路对牙周炎大鼠牙周组织损伤的影响。方法:通过结扎和接...目的:探讨鸢尾素调节Janus蛋白酪氨酸激酶2(Janus protein tyrosine kinase 2,JAK2)/信号转导和转录激活子3(Signal transduction and activator of transcription 3,STAT3)信号通路对牙周炎大鼠牙周组织损伤的影响。方法:通过结扎和接种牙龈卟啉单胞菌液建立牙周炎大鼠模型,将大鼠随机分为模型组、鸢尾素低(鸢尾素-L,50 mg/kg)、中(鸢尾素-M,100 mg/kg)、高剂量(鸢尾素-H,200 mg/kg)组、鸢尾素-H+激活剂(200 mg/kg鸢尾素+2 mg/kg香豆霉素)组,每组10只,并以注射等体积生理盐水的正常大鼠对照组。干预结束后,对大鼠牙龈出血指数、牙齿松动度评分;牙槽骨吸收、肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α)、白细胞介素(Interleukin,IL)-6、IL-1β以及丙二醛(Malondialdehyde,MDA)、超氧化物歧化酶(Superoxide dismutase,SOD)水平分别以Micro-CT试剂盒检测;HE检测牙周组织病理学变化;Western blot检测JAK2、STAT3、p-JAK2、p-STAT3蛋白表达。结果:与对照组相比,模型组大鼠牙周组织被破坏,炎性浸润严重,牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著增加,SOD水平显著降低(P<0.05);与模型组相比,不同剂量的鸢尾素组大鼠病理损伤得到改善,牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著降低,SOD水平显著增加,具有剂量依赖性(P<0.05);与鸢尾素-H组相比,鸢尾素-H组+激活剂组大鼠病理损伤加重,大鼠牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著增加,SOD水平显著降低(P<0.05)。结论:鸢尾素抑制牙周炎大鼠氧化应激、炎性反应,减轻大鼠牙周组织损伤,减少牙槽骨吸收,可能与抑制JAK2/STAT3信号通路有关。展开更多
目的探讨左旋多巴对帕金森病(PD)大鼠模型结肠平滑肌收缩性和神经递质的影响。方法 6-羟多巴胺损毁制备偏侧PD大鼠模型。动物分为对照组、PD组、左旋多巴组、PD+左旋多巴组4组;左旋多巴组和PD+左旋多巴组给予左旋多巴灌胃治疗35 d,对照...目的探讨左旋多巴对帕金森病(PD)大鼠模型结肠平滑肌收缩性和神经递质的影响。方法 6-羟多巴胺损毁制备偏侧PD大鼠模型。动物分为对照组、PD组、左旋多巴组、PD+左旋多巴组4组;左旋多巴组和PD+左旋多巴组给予左旋多巴灌胃治疗35 d,对照组和PD组给予生理盐水灌胃治疗35 d;采用生物信号采集分析系统记录各组结肠平滑肌收缩频率和幅度;免疫组织化学SP法观察结肠肌间神经丛神经元型一氧化氮合酶(nN O S)、酪氨酸羟化酶(TH)和乙酰胆碱转移酶(C hAT)的变化;R T-PC R检测nN O S、TH、C hAT m R-N A在结肠的表达。结果①与对照组比较,PD组和PD+左旋多巴组收缩频率和幅度明显下降(P<0.05);与PD组比较,PD+左旋多巴组收缩频率和幅度增加(P<0.05)。②与对照组比较,PD组和PD+左旋多巴组nN O S免疫阳性产物积分光密度(IO D)和nN O S m R N A表达明显升高(P<0.05),TH免疫阳性产物IO D和TH m R N A表达明显降低(P<0.05);与PD组比较,PD+左旋多巴组nN O S免疫阳性产物IO D和m R N A表达降低(P<0.05),TH免疫阳性产物IO D和m R N A表达升高(P<0.05);各组C hAT免疫阳性产物IO D和C hAT m R N A表达无明显差异。结论 PD大鼠结肠收缩性下降,其机制可能与nN O S的增多和多巴胺的减少有关。左旋多巴可改善PD大鼠结肠收缩功能,可能与nN O S的减少和多巴胺的增多有关。展开更多
Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in...Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in the pathogenesis of Parkinson＇s disease. A Parkinson＇s disease model was produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into C57BL/6 mice. Real-time reverse transcription-PCR, western blot analysis and colorimetric assay showed that the levels of thioredoxin reductase 1 mRNA and protein were decreased, along with a significant reduction in thioredoxin reductase activity, in the midbrain of Parkinson＇s disease mice compared with normal mice. Immunohistochemical staining revealed that the number of thioredoxin reductase 1-positive neurons in the substantia nigra pars compacta of Parkinson＇s disease mice was significantly decreased compared with normal mice. These experimental findings suggest that the expression of thioredoxin reductase 1 in the substantia nigra pars compacta of Parkinson＇s disease mice is significantly decreased, and that the enzyme may be associated with disease onset.展开更多
文摘Retinal ganglion cell（RGC） degeneration is irreversible in glaucoma and tyrosine kinase receptor B（Trk B）-associated signaling pathways have been implicated in the process.In this study,we attempted to examine whether imipramine,a tricyclic antidepressant,may protect hydrogen peroxide（H_2O_2）-induced RGC degeneration through the activation of the Trk B pathway in RGC-5 cell lines.RGC-5 cell lines were pre-treated with imipramine 30 minutes before exposure to H_2O_2.Western blot assay showed that in H_2O_2-damaged RGC-5 cells,imipramine activated Trk B pathways through extracellular signal-regulated protein kinase/Trk B phosphorylation.TUNEL staining assay also demonstrated that imipramine ameliorated H_2O_2-induced apoptosis in RGC-5 cells.Finally,Trk B-Ig G intervention was able to reverse the protective effect of imipramine on H_2O_2-induced RGC-5 apoptosis.Imipramine therefore protects RGCs from oxidative stress-induced apoptosis through the Trk B signaling pathway.
基金Supported by The European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TáMOP 4.2.4.A/2-11-1-2012-0001 National Excellence Program
文摘Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation,the hexosamine pathway,the polyol pathway and diacylglycerol-protein kinase C.Oxidative stress may lead to the production of hydroxyl free radicals,which can attack macromolecules,such as lipids,nucleic acids or amino acids.Phenylalanine(Phe) can be enzymatically converted to the physiological para-tyrosine(p-Tyr);however,a hydroxyl free radical attack on Phe may yield meta-and ortho-tyrosine(m-and o-Tyr,respectively) in addition to p-Tyr.Hence,m-and o-Tyr may be regarded as markers of hydroxyl free radical-induced damage.Their accumulation has been described;e.g.,this accumulation has been found in the urine of patients with diabetes mellitus(DM) and/or chronic kidney disease,in cataract lenses,in vessel walls,in irradiated food and in amniotic fluid,and it may serve as an indicator of oxidative stress.The use of resveratrol to treat patients with type 2 DM led to a decrease in the urinary excretion of o-Tyr and concomitantly led to an improvement in insulin signaling and insulin sensitivity.Literature data also suggest that m-and o-Tyr may interfere with intracellular signaling.Our group has shown that erythropoietin(EPO) has insulin-like metabolic effects on fat cells in addition to its ability to promote the proliferation of erythroid precursor cells.We have shown that the supplementation of cell culture medium with m-and o-Tyr inhibits erythroblast cell proliferation,which could be ameliorated by p-Tyr.Additionally,in vivo,the o-Tyr/p-Tyr ratio is higher in patients with renal replacement therapy and a greater need for EPO.However,the o-Tyr/p-Tyr ratio was an independent determinant of EPO-resistance indices in our human study.The o-Tyr content of blood vessel walls inversely correlates with insulin-and acetylcholineinduced vasodilation,which could be further impaired by artificial oxidative stress and improved by the use of antioxidants.In rats that receive o-Tyr supplements,decreased vasorelaxation is detected in response to insulin.Additionally,o-Tyr supplementation led to the incorporation of the unnatural amino acid into cellular proteins and caused a decrease in the insulin-induced phosphorylation of endothelial nitric oxide synthase.Our data suggest that m-and o-Tyr may not only be markers of oxidative stress;instead,they may also be incorporated into cellular proteins,leading to resistance to insulin,EPO and acetylcholine.
文摘目的探讨左旋多巴对帕金森病(PD)大鼠模型结肠平滑肌收缩性和神经递质的影响。方法 6-羟多巴胺损毁制备偏侧PD大鼠模型。动物分为对照组、PD组、左旋多巴组、PD+左旋多巴组4组;左旋多巴组和PD+左旋多巴组给予左旋多巴灌胃治疗35 d,对照组和PD组给予生理盐水灌胃治疗35 d;采用生物信号采集分析系统记录各组结肠平滑肌收缩频率和幅度;免疫组织化学SP法观察结肠肌间神经丛神经元型一氧化氮合酶(nN O S)、酪氨酸羟化酶(TH)和乙酰胆碱转移酶(C hAT)的变化;R T-PC R检测nN O S、TH、C hAT m R-N A在结肠的表达。结果①与对照组比较,PD组和PD+左旋多巴组收缩频率和幅度明显下降(P<0.05);与PD组比较,PD+左旋多巴组收缩频率和幅度增加(P<0.05)。②与对照组比较,PD组和PD+左旋多巴组nN O S免疫阳性产物积分光密度(IO D)和nN O S m R N A表达明显升高(P<0.05),TH免疫阳性产物IO D和TH m R N A表达明显降低(P<0.05);与PD组比较,PD+左旋多巴组nN O S免疫阳性产物IO D和m R N A表达降低(P<0.05),TH免疫阳性产物IO D和m R N A表达升高(P<0.05);各组C hAT免疫阳性产物IO D和C hAT m R N A表达无明显差异。结论 PD大鼠结肠收缩性下降,其机制可能与nN O S的增多和多巴胺的减少有关。左旋多巴可改善PD大鼠结肠收缩功能,可能与nN O S的减少和多巴胺的增多有关。
基金supported by the Fundamental Research Funds for the Central Universities, No. lzujbky-2011-83Project of the International Cooperation and Communion Department of Chinese Education Ministry (46th batch)the Science Foundation of Key Laboratory of Preclinical Study for New Drugs of Gansu Province, No. GSKFKT-0804
文摘Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in the pathogenesis of Parkinson＇s disease. A Parkinson＇s disease model was produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into C57BL/6 mice. Real-time reverse transcription-PCR, western blot analysis and colorimetric assay showed that the levels of thioredoxin reductase 1 mRNA and protein were decreased, along with a significant reduction in thioredoxin reductase activity, in the midbrain of Parkinson＇s disease mice compared with normal mice. Immunohistochemical staining revealed that the number of thioredoxin reductase 1-positive neurons in the substantia nigra pars compacta of Parkinson＇s disease mice was significantly decreased compared with normal mice. These experimental findings suggest that the expression of thioredoxin reductase 1 in the substantia nigra pars compacta of Parkinson＇s disease mice is significantly decreased, and that the enzyme may be associated with disease onset.
