Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway / 药物分析学报

This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5(PRMT5)in cisplatin-induced hearing loss.The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry,apoptosis assays,and auditory brainstem response.The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction(CUT&Tag-qPCR)analyses in the HEI-OC1 cell line.Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species.CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene,thus activating the expression of Pik3ca.These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo

Astaxanthine (AST) has important biological activities including antioxidant and anti-inflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss (CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2 (NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathway using quantitative PCR and Western blotting. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction. Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

Function study of non-syndromic deafness associated mitochondrial 12S rRNA A839G mutation / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the correlation between nonsyndromic deafness and mitochondrial 12s rRNA A839G mutation.</p><p><b>METHODS</b>According to the clinical manifestations of mitochondrial DNA sequencing and analysis to find and determine family containing mitochondrial 12s rRNA A839G mutation. Harvested its family members blood and transferred their lymphocytes into lymphoblastoid cell lines, followed by cells cultured, cell doubling experiment, susceptibility testing, cellular oxygen consumption rate experiment, ROS and mitochondrial membrane potential experimental tests were progressed to explore the correlation between the A839G mutation and nonsyndromic deafness.</p><p><b>RESULTS</b>The mitochondrial 12s rRNA A839G mutation pedigrees were determined through the full sequence detections of the Mitochondrial DNA, further phylogenetic analysis showed that 839 point conservative index (CI) up to 78.6%; in RPMI-galactose medium containing A839G gene mutant cell line, the doubling time was significantly longer than the control group, and the difference was significant (P = 0.033). The effect to cell lines containing the A839G mutation of aminoglycoside drugs was not obvious. When compared with the control group, cell lines containing the A839G mutation significantly reduced cellular oxygen consumption rate(P = 0.033); compared with the control group, the ROS levels of cell lines containing the A839G mutation appeared more substantial elevated with significan difference (P < 0.01). The mitochondrial membrane potential of cells of experimental group was significantly reduced than the control group.</p><p><b>CONCLUSION</b>The present study proved that the mitochondria 12s rRNA A839G mutations affect the function of the mitochondrial respiratory chain at the cell level, which might reduce the growth rate of the mutant cell lines, result in hearing.</p>

Juvenile onset respiratory papillomatosis: risk factors for severity / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#This study was designed to explore the risk factors associated with severity of juvenile onset recurrent respiratory papillomatosis.@*METHOD@#A retrospective study was conducted to study determinants of severe forms of juvenile recurrent onset respiratory papillomatosis. The patients were separated into different groups based on the onset age, the first recurrence of age, the first recurrence of period, gender and incision of tracheal respectively. The relationship among the lesion severity score,the involvement of the subregion, operation period and the next operation period were also explored.@*RESULT@#It was observed that some children who recurred before 4 years old required more surgery, shorter operation period(the average, longest or shortest operation period) than those elder children, the differences were statistically (P=0. 029, 0. 003, 0. 010, 0. 039, respectively). The severity score of lesion was correlated positively with the involvement of the subregion and negatively with operation period (r=0. 914, -0. 451, respectively). Some children who diagnosed before 4 years old had to endure more severity score and shorter operation period than those older children, the differences were statistically (P= 0. 036, 0. 000, respectively). 8 cases accepted incision of tracheal, they accepted more surgery too. But the differences in the onset age, the first recurrence of age, and the operation period were not statistically.@*CONCLUSION@#The results showed that the clinical course of juvenile onset recurrent respiratory papillomatosis was closely related to the first recurrence age and period, while the severity of disease was associated to the onset age and the involvement of the subregion.

Levels of serum IL-4, IFN-gamma, IL-32 in children with juvenile-onset recurrent respiratory papillomatosis / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To explore the relationship between serum IL-4, IFN-gamma, IL-10 levels and the aetiology of juvenile-onset recurrent respiratory papillomatosis.@*METHOD@#Serum IL-4, IFN-gamma, IL-32 levels of 15 JORRP children were detected by use of enzyme-linked immunosorbent assay (ELISA) and compared with those of healthy control group.@*RESULT@#Serum IL-4 levels were significantly higher in the JORRP children (P<0.01): (524.65 +/- 147.77)pg/ml in the JORRP children and (213.27 +/- 87.48) pg/ml in the healthy control group. Serum IFN-gamma levels were significantly lower in the JORRP children (P<0.01): (2.87 +/- 0.84) pg/ml in the JORRP children and (10.63 +/- 5.09) pg/ml in the healthy control group. Serum IL-32 levels were significantly lower in the JORRP children (P< 0.01): (2.47 +/- 1.60) pg/ml in the JORRP children and (9.08 +/- 2.66) pg/ml in the healthy control group.@*CONCLUSION@#1) While the concentration of Th2 like cytokine IL-4 in children with JORRP was higher than that in control group, the concentration of Th1 like cytokine IFN-gamma in children with JORRP was lower than that in controls, indicating that the polarization of Th1 /Th2 T cell in children with JORRP; 2) The polarization of Th1/Th2 T cell may cause the reduction of the serum IL-32 as a proinflammatory role in host immunity system that could not eradicate HPVs because of lacking enough inflammatory stimulation.