Gene expression analysis of oxidative stress-related genes in the apical, middle, and basal turns of the cochlea.

It can be observed from aminoglycoside-induced hair cell damage that the cochlea basal turn is more susceptible to trauma than the apex. Drug-induced hearing loss is closely related to oxidative damage. The basilar membrane directly exposed to these ototoxic drugs exhibits differences in damage, indicating that there is an inherent difference in the sensitivity to oxidative damage from the apex to the base of the cochlea. It has been reported that the morphology and characteristics of the cochlea vary from the apex to the base. Therefore, we investigated oxidative stress-related gene expression profiles in the apical, middle, and basal turns of the cochlea. The Oxidative Stress RT2 Profiler™ PCR Array revealed that three of the 84 genes (Mb, Mpo, and Ncf1) were upregulated in the middle turn compared to their level in the apical turn. Moreover, eight genes (Mb, Duox1, Ncf1, Ngb, Fmo2, Gpx3, Mpo, and Gstk1) were upregulated in the basal turn compared to their level in the apical turn. The qPCR verification data were similar to that of the PCR Array. We found that MPO was expressed in the rat cochlea and protected against gentamicin-induced hair cell death. This study summarized the data for the gradient of expression of oxidative stress-related genes in the cochlea and found potential candidate targets for prevention of ototoxic deafness, which may provide new insights for cochlear pathology.

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α2A-adrenergic receptor.

BACKGROUND: The cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats. METHODS: We explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL. RESULTS: We found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H2O2-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α2A-AR. CONCLUSION: These results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

Expression and localization of α2A-adrenergic receptor in the rat post-natal developing cochlea.

Lots of adrenergic receptors (ARs) are widely present across the auditory pathways and are positioned to affect auditory and vestibular functions. However, noradrenergic regulation in the cochlea has not been well characterized. In this study, a rat model of noise-induced hearing loss was developed to investigate the expression of α2A-adrenergic receptor (AR) after acoustic trauma, then, we investigated the expression of α2A-AR in the developing rat cochlea using immunofluorescence, qRT-PCR, and Western blotting. We found that the expression of α2A-AR significantly increased in rats exposed to noise compared with controls. Immunofluorescence analysis demonstrated that α2A-AR is localized on hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV) in the postnatal developing cochlea from post-natal day (P) 0 to P28. Furthermore, we observed α2A-AR mRNA reached a maximum level at P14 and P28 when compared with P0, while no significant differences in α2A-AR protein levels at the various stages when compared with P0. This study provides direct evidence for the expression of α2A-AR in HCs, SGNs, and the SV of the cochlea, indicating that norepinephrine might play a vital role in hearing function within the cochlea through α2A-AR.

VDR Regulates BNP Promoting Neurite Growth and Survival of Cochlear Spiral Ganglion Neurons through cGMP-PKG Signaling Pathway.

Spiral ganglion neurons (SGNs) are important for hearing, and their peripheral and central processes connect sensory cells of the Corti organ to the central nervous system. The resulting network forms a point-to-point auditory conduction. As a cardiac hormone, brain natriuretic peptide (BNP) binds to natriuretic peptide receptor type A leading to diuresis, vasodilatation, inhibition of renin and aldosterone production, and cardiac and vascular myocyte growth. This study primarily aimed to explore the expression and function of BNP in the rat's inner ear and elucidate its regulatory mechanism. We determined the expression and function of BNP and found that the vitamin D receptor (VDR) could upregulate the expression of BNP and enhance its function. In SGNs of the rat inner ear, BNP promotes neuron survival and prolongs neurite length through the cGMP-PKG signaling pathway, which could be regulated by VDR and provide a novel approach for neuronal regeneration therapy. To the best of our knowledge, this is the first study to report this potential transcriptional regulatory relationship and will act as a reference for research on neuronal regeneration therapy for SGNs injury.

Heme Oxygenase-1 Protects Hair Cells From Gentamicin-Induced Death.

Gentamicin ototoxicity can generate free radicals within the inner ear, leading to permanent damage to sensory hair cells (HCs) and eventually hearing loss. The following study examined the alterations of oxidative damage-related genes in the cochlea and important molecules responsible for oxidation following gentamicin injury in vitro. The RT2 Profiler polymerase chain reaction (PCR) array was used to screen candidate targets for treatment to prevent hearing loss caused by gentamicin. We found that during gentamicin-induced death in HCs, Heme oxygenase-1 (HO-1) had a high fold change in the HCs of the cochlea. Moreover, the use of CoPPIX to induce HO-1 inhibited gentamicin-induced HC death, while HO-1 inhibitors ZnPPIX after CoPPIX reversed this process. Furthermore, the inhibitors of NF-E2-related factor-2 (Nrf2) reduced the expression of HO-1 and inhibited the protective effect of HO-1 after gentamicin, thus suggesting that the Nrf2/HO-1 axis might regulate gentamicin-associated ototoxicity. We further demonstrated that induction of HO-1 up-regulated the expression of Nrf2 in both cochlear and HEI-OC1 cells. In summary, these findings indicated that HO-1 protects HCs from gentamicin by up-regulating its expression in HCs and interacting with Nrf2 to inhibit reactive oxygen species (ROS).

Sympathetic Nervous System Regulation of Auditory Function.

BACKGROUND: The auditory system processes how we hear and understand sounds within the environment. It comprises both peripheral and central structures. Sympathetic nervous system projections are present throughout the auditory system. The function of sympathetic fibers in the cochlea has not been studied extensively due to the limited number of direct projections in the auditory system. Nevertheless, research on adrenergic and noradrenergic regulation of the cochlea and central auditory system is growing. With the rapid development of neuroscience, auditory central regulation is an extant topic of focus in research on hearing. SUMMARY: As such, understanding sympathetic nervous system regulation of auditory function is a growing topic of interest. Herein, we review the distribution and putative physiological and pathological roles of sympathetic nervous system projections in hearing. KEY MESSAGES: In the peripheral auditory system, the sympathetic nervous system regulates cochlear blood flow, modulates cochlear efferent fibers, affects hair cells, and influences the habenula region. In central auditory pathways, norepinephrine is essential for plasticity in the auditory cortex and affects auditory cortex activity. In pathological states, the sympathetic nervous system is associated with many hearing disorders. The mechanisms and pathways of sympathetic nervous system modulation of auditory function is still valuable for us to research and discuss.

[Evaluation of clinical application of new remote radar monitoring equipment for obstructive sleep apnea].

Objective:The result consistency between the new remote radar monitoring equipment and PSG detection is compared. Methods:The monitoring results of 71 patients were randomly selected to observe and compare the difference of monitoring data of the same patient with two kinds of detection equipment. Results:Using AHI≥5 as the diagnostic criteria, compared with PSG monitoring results, the sensitivity, specificity and Youden index of the new remote radar monitoring equipment were 96.2%, 89.5% and 0.857（P<0.01） respectively. Compared with PSG monitoring results, when LSaO2≤90% in PSG monitoring, the sensitivity, specificity and Youden index of the new remote radar monitoring equipment were 94.3%, 88.9% and 0.832（P<0.01） respectively. Conclusion: There the new remote radar monitoring device can be used to monitor OSA.

A Shared Susceptibility Locus in the p53 Gene for both Gastric and Esophageal Cancers in a Northwestern Chinese Population.

Background: Upper gastrointestinal tract cancers are the leading causes of cancer-related deaths in Northwest China and they share many similarities in terms of histological type, risk factors, and genetic variants. We hypothesized that shared common single-nucleotide polymorphisms (SNPs) in the p53 pathway exist between patients with gastric and esophageal cancer (EC) patients. Materials and Methods: A case-control study to examine genetic variants in the p53 pathway was conducted with subjects from a high-incidence area for upper gastrointestinal cancers of China. Multiple logistic regression analyses were used to estimate the association of genotypes with gastric cancer and EC risks. Median survival was estimated by using the Kaplan-Meier method and compared by using the log-rank test. Results: Compared with the rs1042522 Pro allele, the rs1042522 Arg allele was associated with an increased risk of gastric cancer (1.810×) and an increased risk of EC (2.285×). The rs1042522 Arg allele carriers who also smoked or consumed alcohol had a further increased risk for gastric cancer odds ratios (ORsmoking = 2.422, ORdrinking = 5.152) and EC (ORsmoking = 5.310, ORdrinking = 8.359). No association was found between the rs1042522 genotypes and survival (p > 0.05). Conclusion: The p53 rs1042522 arg allele together with tobacco smoking and alcohol drinking, was associated with an increased risk, for gastric cancer and EC, but not the survival among northwestern Chinese patients. These associations warrant confirmatory studies.

Comparison of Genetic Variants in Cancer-Related Genes between Chinese Hui and Han Populations.

BACKGROUND: The Chinese Hui population, as the second largest minority ethnic group in China, may have a different genetic background from Han people because of its unique demographic history. In this study, we aimed to identify genetic differences between Han and Hui Chinese from the Ningxia region of China by comparing eighteen single nucleotide polymorphisms in cancer-related genes. METHODS: DNA samples were collected from 99 Hui and 145 Han people from the Ningxia Hui Autonomous Region in China, and SNPs were detected using an improved multiplex ligase detection reaction method. Genotyping data from six 1000 Genomes Project population samples (99 Utah residents with northern and western European ancestry (CEU), 107 Toscani in Italy (TSI), 108 Yoruba in Ibadan (YRI), 61 of African ancestry in the southwestern US (ASW), 103 Han Chinese in Beijing (CHB), and 104 Japanese in Tokyo (JPT)) were also included in this study. Differences in the distribution of alleles among the populations were assessed using χ2 tests, and FST was used to measure the degree of population differentiation. RESULTS: We found that the genetic diversity of many SNPs in cancer-related genes in the Hui Chinese in Ningxia was different from that in the Han Chinese in Ningxia. For example, the allele frequencies of four SNPs (rs13361707, rs2274223, rs465498, and rs753955) showed different genetic distributions (p<0.05) between Chinese Ningxia Han and Chinese Ningxia Hui. Five SNPs (rs730506, rs13361707, rs2274223, rs465498 and rs753955) had different FST values (FST>0.000) between the Hui and Han populations. CONCLUSIONS: These results suggest that some SNPs associated with cancer-related genes vary among different Chinese ethnic groups. We suggest that population differences should be carefully considered in evaluating cancer risk and prognosis as well as the efficacy of cancer therapy.

Evaluating the Association of Eight Polymorphisms with Cancer Susceptibility in a Han Chinese Population.

BACKGROUND: The identification of susceptibility genes for specific types of cancer can provide necessary information for the complete characterization of cancer syndromes. Eight single nucleotide polymorphisms (SNPs), rs465498, rs17728461, rs4488809, rs753955, rs13361707, rs9841504, rs2274223, and rs13042395, were reported by genome wide association studies (GWASs) to be closely related to the susceptibility of lung cancer (LC), gastric cancer (GC) or esophageal cancer (EC) in Han population from northern or southern China. However, Chinese Han people from different geographic areas may have different genetic backgrounds. This study aims to assess the genetic associations of the eight SNPs mentioned above with three cancers risk in a Han population from northwest China. METHODS: A total of 186 cancer-free controls and 436 cases with non-small cell lung cancer (NSCLC) (159 cases), non-cardia GC (167 cases) or EC (110 cases) were enrolled in this study. Chi-square test and polytomous logistic regression analyses were used to estimate the association between eight cancer-related SNPs and three cancers in a Han Chinese population from northwest China. The logistic regression results were adjusted for confounding factors and Benjamini and Hochberg False Discovery Rate (FDR) method was used to adjust the multiple hypothesis tests. Association analyses by cigarette smoking or alcohol drinking status were analyzed by crossover analyses. RESULTS: One of the eight SNPs, rs17728461 was associated with NSCLC susceptibility (in a heterozygous model, OR = 0.44, 95% CI = 0.27-0.72, p = 0.001). Two SNPs, rs753955 and rs13042395, were associated with the risk of non-cardia GC in different genetic models (p < 0.05). No SNPs were associated with EC. The crossover analyses showed that the rs13042395 CT genotype, combined with cigarette smoking or alcohol drinking, could further increase the risk for non-cardia GC (p < 0.05). CONCLUSIONS: These results indicated that rs17728461 may be specifically associated with the risk of NSCLC. rs753955 and rs13042395 were specifically associated with susceptibility to non-cardia GC in Ningxia Han Chinese. Susceptibility-associated polymorphisms in the northwestern Han Chinese were not very consistent with those in the northern Han Chinese or southern Han Chinese. The validation of these findings with a functional evaluation and a larger population is still required.