| Background:Hearing loss is a common disease in clinic,which seriously affects human health and quality of life.The causes of hearing loss can be mainly classified as hereditary and non-hereditary hearing loss.Among them,the use of ear toxic drugs is the main cause of non-hereditary hearing loss.Platinum preparations are commonly used in clinical anti-tumor drugs,such as cisplatin,caplatinum and other platinum complexes are commonly used in the clinic to suppress ovarian cancer,lung cancer,esophageal cancer,head and neck squamous cancer,and osteosarcoma and other solid tumors,has a strong broad-spectrum anti-cancer effect.However,platinum complexes also have very strong ear toxicity,resulting in 90%of patients with hearing loss,tinnitus vertigo and other symptoms,but also clinically common causes of ear toxicity.It has been made clear that cisplatin and other esotaltoxic drugs cause the death of hair-making cells and spiral nerve-sectional cells.Since damaged hair cells and spiral nerve cells are not renewable,the use of cisplatin can cause permanent hearing loss and deafness.But the molecular mechanism by which cisplatin causes the death of hair cells is not yet known.Therefore,there is also a clinical lack of specific drugs to reduce the ear toxicity of cisplatin.The use of cisplatin causes hair cells to apoptosis.There have been many literatures on the process of hearing loss,noise hearing loss,age-related hearing loss caused by amino glycoglycerides,etc..The accumulation of ROS in hair cells has been found in the hair cells,and eventually lead to the death of hair cells.So the accumulation of ROS is an important cause of hair cell death.Our previous experiments also found that cisplatin also causes the accumulation of ROS in hair cells.This suggests that the ear toxicity of cisplatin is also likely to be produced by ROS-induced hairapopatosis.The accumulation of ROS causes apoptosis and has been found in a variety of organ tissues other than cochlear implants associated with the mTOR signaling pathway.ROS is able to activate the mTOR signaling pathway and regulate the proliferation,differentiation and apoptosis processes of a variety of cells in the organism.However,the current research on the mTOR signaling pathway in cochlear implants is very limited.The mTOR signaling pathway is closely related to intracellular transcription,autophagy,apoptosis and other processes,but it is not clear whether the mTOR signaling pathway is involved in hair cell damage caused by ear toxic drugs.Research purpose:This study will clarify the effect of cisplatin on the mTOR signaling pathway sonin the hair cells.It also studies how the mTOR signaling pathway causes the death of hair cells.Methods:Firstly,we used C57 newborn rats born 1-2 days to create a model of cisplatin-induced loss of hair cells,and by immunostaining to establish data on the effects of different concentrations of cisplatin on hair cells.Mito-SOX staining and NAC removal of peroxides are then used to determine whether cisplatin causes hair apoptosis by causing the accumulation of ROS in the hair cells.The changes in the expression of key signal factors in the mTOR complex 1 signal ingressin pathway in the control group and the drug group were investigated by Western Blot’s method.The relationship between mTOR signaling pathways and autophagy and cell survival in hair cells was explored.Results:Experimental data show that cisplatin can cause a large number of apoptosis in the outer hair cells of mice.In this process,cisplatin leads to a large accumulation of ROS in the hair cells,and after using NAC to remove the ROS,the wool cells survive without loss.It is shown that cisplatin causes apoptosis in hair cells due to the accumulation of ROS within the cell.Further research on its mechanism found that cisplatin can activate the mTOR complex 1 signal path,and remove the over-activation of the mTOR signal path after the accumulation of ROS due to cisplatin induction is inhibited,indicating that the mTOR signaling pathway is activated by the ROS accumulated in the hair cells.It was found that rapamycin can protect hair cells from the damage of cisplatin,further proving that the mTORCl signaling pathway is directly related to apoptosis in hair cells.After the action of cisplatin,the activation of the mTOR complex 1 pathway inhibits autophagy activity in hair cells.Autophagy activity helps hair cells clear ros from cells.Repamycin inhibits the mTOR complex 1 signaling pathway to enhance autophagy,protecting the hair cells to against the toxicity of cisplatin,and increase the survival of hair cells.Conclusions:Cisplatin can cause the accumulation of ROS in hair cells,thus activating the mTOR complex 1 signaling pathway in the hair cells,and inhibits autophagy in the hair cells,preventing the hair cells from removing the ROS in the cells,and eventually causing apoptosis in the hair cells to cause hearing loss. |
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