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
目的通过比较噪声暴露后基底膜不同区域内毛细胞(IHCs)带状突触损伤差异,探讨带状突触损伤易感性的相关因素。方法将28只C57BL/6J雄性小鼠随机分为噪声暴露组和对照组,每组14只。噪声暴露组小鼠给予强度103 dB SPL、频率2~20 kHz、持续...目的通过比较噪声暴露后基底膜不同区域内毛细胞(IHCs)带状突触损伤差异,探讨带状突触损伤易感性的相关因素。方法将28只C57BL/6J雄性小鼠随机分为噪声暴露组和对照组,每组14只。噪声暴露组小鼠给予强度103 dB SPL、频率2~20 kHz、持续2 h的宽带噪声暴露,对照组小鼠则饲养于安静环境中。噪声暴露前及噪声暴露后第一天进行ABR测试及毛细胞带状突触免疫荧光染色实验。使用全细胞膜片钳技术比较不同区域IHCs的钙离子流入。通过免疫荧光染色比较噪声暴露后的耳蜗基底膜顶回、中回、底回IHCs钙蛋白酶(Calpain)表达水平,并用蛋白质印迹实验验证钙蛋白酶对IHCs带状突触蛋白CtBP2的损伤作用。结果噪声暴露后一天,噪声暴露组在11.3、16.0、22.6、32.0 kHz的ABR阈值较对照组显著上升(均为P<0.001),中回、底回IHCs带状突触数量明显减少(P<0.05)。全细胞膜片钳实验结果表明耳蜗基底膜中回IHCs有较多的钙离子通道(P<0.01),但其单通道电流较小(P<0.01),顶回、中回IHCs钙离子通道开放率无显著差异(P>0.05)。噪声暴露后,耳蜗基底膜中回、底回IHCs的Calpain表达水平显著高于顶回(P<0.001),蛋白质印迹实验结果表明Calpain以钙离子依赖的方式降解带状突触蛋白CtBP2。结论钙蛋白酶是基底膜高频区内毛细胞带状突触噪声损伤易感的重要因素。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.
文摘目的探讨吸烟、饮酒、职业性噪声暴露对工人听力的影响。方法选取某重型装备制造厂中噪声暴露环境下工人作为研究对象,问卷调查其噪声暴露史、吸烟史、饮酒史等,并在隔音室内进行纯音测听检查,将PTA0.25-3>25d BHL记为低频听力损失,PTA4-8>40d B HL记为高频听力损失。根据吸烟史、饮酒史将受试者分为不吸烟不饮酒组(C0A0)、吸烟不饮酒组(C1A0)、饮酒不吸烟组(C0A1)、吸烟饮酒组(C1A1),以不吸烟不饮酒组(C0A0)为对照组统计分析各组听力情况的区别。并应用Logistic回归分析吸烟、饮酒、噪声的不同暴露时间(0-5年、5-10年、10-15年、≥15年)对听力的影响。结果 C1A0、C0A1、C1A1各组中听力损失工人的听力阈值及各组听力损失率与C0A0组的差异无统计学意义。Logistic回归分析显示相对于噪声暴露0-5年的工人,噪声暴露5-10年、10-15年、≥15年的工人发生低频听力损失的优势比分别为1.736、1.954、3.975,发生高频听力损失的优势比分别为1.517、2.257、1.627;相对于不饮酒人群,不同饮酒时间工人发生高频听力损失的优势比为1.777、1.814、2.402、3.134。结论饮酒可能会增加噪声暴露下工人听力受损的危险性,应在加强工人个人防护的基础上劝诫工人养成良好的生活习惯;而吸烟可能并不是造成听力损失的主要危险因素。
