Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Her...Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.展开更多
目的探讨血小板体积相关指数(PVIs)、Sestrin2、泛连接蛋白1(Pannexin1)与急性脑梗死患者美国国立卫生研究院卒中量表(NIHSS)评分关系及对溶栓预后的预测效能。方法选取2020年1月—2022年10月莆田九十五医院收治急性脑梗死患者82例,均...目的探讨血小板体积相关指数(PVIs)、Sestrin2、泛连接蛋白1(Pannexin1)与急性脑梗死患者美国国立卫生研究院卒中量表(NIHSS)评分关系及对溶栓预后的预测效能。方法选取2020年1月—2022年10月莆田九十五医院收治急性脑梗死患者82例,均给予静脉溶栓治疗,根据溶栓预后分为良好组49例、较差组33例。比较2组治疗前及治疗后5 d、7 d PVIs、Sestrin2、Pannexin1、NIHSS评分,Pearson分析治疗后5 d、7 d PVIs、Sestrin2、Pannexin1与NIHSS评分的关系,多因素Logistic回归分析急性脑梗死患者溶栓预后的相关影响因素,受试者工作特征曲线(ROC)分析治疗后5 d、7 d PVIs、Sestrin2、Pannexin1及不同联合方案对溶栓预后的预测效能。结果治疗后5 d、7 d较差组PVIs、Sestrin2、Pannexin1、NIHSS评分均高于良好组(治疗后5 d:t/P=5.171/<0.001、6.043/<0.001、8.291/<0.001、6.215/<0.001;治疗后7 d:t/P=10.877/<0.001、6.496/<0.001、7.253/<0.001、11.834/<0.001);治疗后5 d、7 d PVIs、Sestrin2、Pannexin1与NIHSS评分呈正相关(治疗后5 d:r/P=0.818/<0.001、0.762/<0.001、0.806/<0.001;治疗后7 d:r/P=0.832/<0.001、0.796/<0.001、0.810/<0.001);Logistic回归分析结果显示,PVIs高、Sestrin2高、Pannexin1高均是影响溶栓预后的相关危险因素[OR(95%CI)=13.672(2.954~63.282)、8.742(1.628~46.944)、9.857(1.021~95.168),P<0.05];治疗后7 d PVIs、Sestrin2、Pannexin1及三者联合预测急性脑梗死患者溶栓预后的AUC大于治疗后5 d对应的预测方案(Z/P=2.115/0.031、2.102/0.036、4.207/0.030、2.056/0.040),且治疗后5 d三项指标联合的AUC大于各自单独预测(Z/P=3.289/0.002、3.387/0.001、3.562/<0.001),治疗后7 d三项指标联合的AUC大于各自单独预测(Z/P=3.115/0.005、2.896/0.018、3.402/0.001)。结论PVIs、Sestrin2、Pannexin1与急性脑梗死患者神经缺损程度及溶栓预后有关,联合检测治疗后7 d三者水平有望为临床早期预测溶栓预后提供一个有效方案。展开更多
基金supported by the National Key Research and Development Program of China,No.2022YFC2402701(to WC)Key International(Regional)Joint Research Program of the National Natural Science Foundation of China,No.81820108009(to SY)+5 种基金the National Natural Science Foundation of China,Nos.81970890(to WC)and 82371148(to WG)Fujian Provincial Healthcare Young and Middle-aged Backbone Talent Training Project,No.2023GGA035(to XC)Spring City Planthe High-level Talent Promotion and Training Project of Kunming,No.2022SCP001(to SY)the Natural Science Foundation of Hainan Province of China,No.824MS052(to XS)the Sixth Medical Center of Chinese PLA General Hospital Innovation Cultivation,No.CXPY202116(to LX)。
文摘Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction.However,there are currently no effective pharmacological interventions for patients with noise-induced hearing loss.Here,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory mechanisms.We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 hours.We found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine.The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with saline.These findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell loss.Additionally,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway.Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)production.In conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing function.These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.
文摘目的探讨血小板体积相关指数(PVIs)、Sestrin2、泛连接蛋白1(Pannexin1)与急性脑梗死患者美国国立卫生研究院卒中量表(NIHSS)评分关系及对溶栓预后的预测效能。方法选取2020年1月—2022年10月莆田九十五医院收治急性脑梗死患者82例,均给予静脉溶栓治疗,根据溶栓预后分为良好组49例、较差组33例。比较2组治疗前及治疗后5 d、7 d PVIs、Sestrin2、Pannexin1、NIHSS评分,Pearson分析治疗后5 d、7 d PVIs、Sestrin2、Pannexin1与NIHSS评分的关系,多因素Logistic回归分析急性脑梗死患者溶栓预后的相关影响因素,受试者工作特征曲线(ROC)分析治疗后5 d、7 d PVIs、Sestrin2、Pannexin1及不同联合方案对溶栓预后的预测效能。结果治疗后5 d、7 d较差组PVIs、Sestrin2、Pannexin1、NIHSS评分均高于良好组(治疗后5 d:t/P=5.171/<0.001、6.043/<0.001、8.291/<0.001、6.215/<0.001;治疗后7 d:t/P=10.877/<0.001、6.496/<0.001、7.253/<0.001、11.834/<0.001);治疗后5 d、7 d PVIs、Sestrin2、Pannexin1与NIHSS评分呈正相关(治疗后5 d:r/P=0.818/<0.001、0.762/<0.001、0.806/<0.001;治疗后7 d:r/P=0.832/<0.001、0.796/<0.001、0.810/<0.001);Logistic回归分析结果显示,PVIs高、Sestrin2高、Pannexin1高均是影响溶栓预后的相关危险因素[OR(95%CI)=13.672(2.954~63.282)、8.742(1.628~46.944)、9.857(1.021~95.168),P<0.05];治疗后7 d PVIs、Sestrin2、Pannexin1及三者联合预测急性脑梗死患者溶栓预后的AUC大于治疗后5 d对应的预测方案(Z/P=2.115/0.031、2.102/0.036、4.207/0.030、2.056/0.040),且治疗后5 d三项指标联合的AUC大于各自单独预测(Z/P=3.289/0.002、3.387/0.001、3.562/<0.001),治疗后7 d三项指标联合的AUC大于各自单独预测(Z/P=3.115/0.005、2.896/0.018、3.402/0.001)。结论PVIs、Sestrin2、Pannexin1与急性脑梗死患者神经缺损程度及溶栓预后有关,联合检测治疗后7 d三者水平有望为临床早期预测溶栓预后提供一个有效方案。
