Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
目的:研究长期口服天麻素对SAMP8鼠记忆力的影响及与额叶Sst表达水平的关系。方法:将4月龄雄性SAMP8鼠20只随机分成2组:天麻素治疗组和对照组。治疗组每只鼠平均每日饮10ml含60μg/ml天麻素的蒸馏水,对照组每日仅饮用蒸馏水,直至12月龄...目的:研究长期口服天麻素对SAMP8鼠记忆力的影响及与额叶Sst表达水平的关系。方法:将4月龄雄性SAMP8鼠20只随机分成2组:天麻素治疗组和对照组。治疗组每只鼠平均每日饮10ml含60μg/ml天麻素的蒸馏水,对照组每日仅饮用蒸馏水,直至12月龄。然后,观察两组鼠皮毛、眼睑、运动等基本情况;并通过passive-avoidance-test实验检测两组鼠对疼痛刺激的短期记忆力;同时用QRT-PCR(quantitative real time polymerase c hain reaction)和Western Blot分别检测两组鼠额叶生长抑素(somatostatin,Sst)的转录水平和表达水平。结果:天麻素治疗组小鼠的毛发光泽好、眼睑无炎症、较活跃,而对照组小鼠脱毛明显、部分小鼠眼睑有炎症、运动少;Passive-avoidance-test实验中天麻素治疗组小鼠明室停留时间及进入暗室小鼠的比例与对照组相比具有显著性差别;QRT-PCR结果显示,天麻素治疗组小鼠额叶中Sst转录水平较对照组升高,二者比较差别具有显著性;Western Blot结果显示,天麻素治疗组小鼠额叶中Sst表达水平较对照组明显升高。结论:天麻素治疗可能通过增进额叶Sst的转录和表达水平以改善SAMP8鼠的学习记忆能力。展开更多
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
文摘目的:研究长期口服天麻素对SAMP8鼠记忆力的影响及与额叶Sst表达水平的关系。方法:将4月龄雄性SAMP8鼠20只随机分成2组:天麻素治疗组和对照组。治疗组每只鼠平均每日饮10ml含60μg/ml天麻素的蒸馏水,对照组每日仅饮用蒸馏水,直至12月龄。然后,观察两组鼠皮毛、眼睑、运动等基本情况;并通过passive-avoidance-test实验检测两组鼠对疼痛刺激的短期记忆力;同时用QRT-PCR(quantitative real time polymerase c hain reaction)和Western Blot分别检测两组鼠额叶生长抑素(somatostatin,Sst)的转录水平和表达水平。结果:天麻素治疗组小鼠的毛发光泽好、眼睑无炎症、较活跃,而对照组小鼠脱毛明显、部分小鼠眼睑有炎症、运动少;Passive-avoidance-test实验中天麻素治疗组小鼠明室停留时间及进入暗室小鼠的比例与对照组相比具有显著性差别;QRT-PCR结果显示,天麻素治疗组小鼠额叶中Sst转录水平较对照组升高,二者比较差别具有显著性;Western Blot结果显示,天麻素治疗组小鼠额叶中Sst表达水平较对照组明显升高。结论:天麻素治疗可能通过增进额叶Sst的转录和表达水平以改善SAMP8鼠的学习记忆能力。
