Bungo Nishimura

Early Detection of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a unique disease with a clinical presentation, epidemiology, and histopathology differing from other squamous cell carcinomas of the head and neck. NPC is an Epstein-Barr virus-associated malignancy with a marked racial and geographic distribution. Specifically, it is highly prevalent in southern China, Southeast Asia, and the Middle East. To date, most NPC patients have been diagnosed in the advanced stage, but the treatment results for advanced NPC are not satisfactory. This paper provides a brief overview regarding NPC, with the focus on the early detection of initial and recurrent NPC lesions.

Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity

Expression of antioxidant enzymes is regulated by transcription factor NF-E2-related factor (Nrf2) and induced by oxidative stress. Reactive oxygen species contribute to the formation of several types of cochlear injuries, including age-related hearing loss and gentamicin ototoxicity. In this study, we examined the roles of Nrf2 in age-related hearing loss and gentamicin ototoxicity by measuring auditory brainstem response thresholds in Nrf2-knockout mice. Although Nrf2-knockout mice maintained normal auditory thresholds at 3 months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11 months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11 months of age. To examine the importance of Nrf2 in protecting against gentamicin-induced ototoxicity, 3-day-old mouse organ of Corti explants were cultured with gentamicin. Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. Furthermore, the expressions of some Nrf2-target genes were activated by gentamicin treatment in wild-type mice but not in Nrf2-knockout mice. The present findings indicate that Nrf2 protects the inner ear against age-related hearing injuries and gentamicin ototoxicity by up-regulating antioxidant enzymes and detoxifying proteins.

Estradiol protects the cochlea against gentamicin ototoxicity through inhibition of the JNK pathway

Gentamicin induces outer hair cell death through the apoptotic pathway. It has been reported that this death pathway of outer hair cells is mediated by specific apoptotic enzymes including c-jun N-terminal kinase (JNK) and caspases. 17beta-Estradiol (E2), the most potent estrogen, is known to function as an antiapoptotic agent to prevent the death of various cell types. The purpose of the present study was to examine the effects of E2 on gentamicin-induced apoptotic cell death in outer hair cells. The basal turn organ of Corti explants from p3 or p4 rats were maintained in a tissue culture and exposed to 100muM gentamicin for 48h. The effects of E2 on gentamicin-induced outer hair cell loss, JNK activation, and staining for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL) were examined. E2 significantly decreased gentamicin-induced outer hair cell loss in a dose-dependent manner. JNK activation and TUNEL staining were observed in organ of Corti explants exposed to gentamicin, and staining levels were significantly decreased by E2 treatment. The results indicate that, through the inhibition of JNK and subsequent apoptotic reactions, E2 decreases outer hair cell loss induced by gentamicin ototoxicity.

Ischemia-Reperfusion Injury of the Cochlea: Pharmacological Strategies for Cochlear Protection and Implications of Glutamate and Reactive Oxygen Species

A large amount of energy produced by active aerobic metabolism is necessary for the cochlea to maintain its function. This makes the cochlea vulnerable to blockade of cochlear blood flow and interruption of the oxygen supply. Although certain forms of human idiopathic sudden sensorineural hearing loss reportedly arise from ischemic injury, the pathological mechanism of cochlear ischemia-reperfusion injury has not been fully elucidated. Recent animal studies have shed light on the mechanisms of cochlear ischemia-reperfusion injury. It will help in the understanding of the pathology of cochlear ischemia-reperfusion injury to classify this injury into ischemic injury and reperfusion injury. Excitotoxicity, mainly observed during the ischemic period, aggravates the injury of primary auditory neurons. On the other hand, oxidative damage induced by hydroxyl radicals and nitric oxide enhances cochlear reperfusion injury. This article briefly summarizes the generation mechanisms of cochlear ischemia-reperfusion injury and potential therapeutic targets that could be developed for the effective management of this injury type.

Cochlear protection from acoustic injury by inhibitors of p38 mitogen-activated protein kinase and sequestosome 1 stress protein

This study evaluated the protective role of p38 mitogen-activated protein kinase (p38 MAPK) inhibitors and sequestosome 1 (Sqstm1/A170/p62), a stress-induced signal modulator, in acoustic injury of the cochlea in mice. Two weeks after the exposure of mice to acoustic stress, threshold shifts of the auditory brainstem response (ABR) from the pre-exposure level and hair cell loss were evaluated. The activation of p38 MAPK was observed in cochlea by immunostaining 4 h after acoustic stress. To examine the role of p38 MAPK in tissue injury, its inhibitors were i.p. injected into male wild-type C57BL mice before the acoustic overexposure. The inhibitors SB202190 and SB203580 but not the inactive analogue SB202474 dose-dependently decreased the auditory threshold shift and outer hair cell loss induced by acoustic overexposure, suggesting the involvement of p38 MAPK in ototoxicity. We found that acoustic overexposure induced the up-regulation of Sqstm1 mRNA expression in the cochlea of wild-type mice and that SQSTM1-deficient mice exhibited an enhanced ABR threshold shift and hair cell loss, suggesting a role of SQSTM1 in the protection of tissue from acoustic stress.

The influence of sphingosine-1-phosphate receptor antagonists on gentamicin-induced hair cell loss of the rat cochlea

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates various critical biological processes, such as cell proliferation, survival, migration, and angiogenesis. The action of S1P is exerted by its binding to 5 specific G protein-coupled S1P receptors (S1PR), S1PR1-S1PR5. Aminoglycoside antibiotics including gentamicin induce cochlear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this type of cochlear injury. S1P acts as a cochlear protectant against gentamicin ototoxicity. In the present study, expression of S1PRs in the cochlea was examined. In addition, the effects of S1PR antagonists on gentamicin ototoxicity were investigated using tissue culture techniques. Cochleas were dissected from Sprague-Dawley rats on postnatal days 3-5. Basal turn organ of Corti explants were exposed to 35 μM gentamicin for 48 h with or without S1PR antagonists. S1PR(1-3) were expressed in the organ of Corti and spiral ganglion. The S1PR2 antagonist increased gentamicin-induced hair cell loss, while the S1PR1 and S1PR3 antagonists did not affect gentamicin ototoxicity. These results indicate the possibility that S1P act as a cochlear protectant against gentamicin ototoxicity via activation of S1PR2.

The influences of sphingolipid metabolites on gentamicin-induced hair cell loss of the rat cochlea

Sphingolipid metabolites inducing ceramide, sphingosine, and sphingosine-1-phosphate (S1P) play important roles in the regulation of cell proliferation, survival, and death. Aminoglycoside antibiotics including gentamicin induce inner ear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this injury. The present study was designed to investigate the possible involvement of ceramide and S1P in hair cell death due to gentamicin. In addition, the effects of other metabolites of ceramide, gangliosides GM1 (GM1) and GM3 (GM3), on gentamicin ototoxicity were also investigated. Basal turn organ of Corti explants from p3 to p5 rats were maintained in tissue culture and exposed to 20 or 35μM gentamicin for 48h. The effects of ceramide, S1P, GM1, and GM3 on gentamicin-induced hair cell loss were examined. Gentamicin-induced hair cell loss was increased by ceramide but was decreased by S1P. GM1 and GM3 exhibited protective effects against gentamicin-induced hair cell death at the limited concentrations. These results indicate that ceramide enhances gentamicin ototoxicity by promoting apoptotic hair cell death, and that S1P, GM1, and GM3 act as cochlear protectants. In conclusion, sphingolipid metabolites influence the apoptotic reaction of hair cells to gentamicin ototoxicity.

Epiglottic cyst in an infant.

Epiglottic cyst is a rare cause of stridor and respiratory distress in newborns and infants. A 2-year-old girl was referred to our department for the treatment of an epiglottic cyst causing inspiratory stridor. Flexible fiberoptic laryngoscopy and a computed tomography (CT) scan revealed a cystic lesion on the lingual surface of the epiglottis. Frequent episodes of sleep apnea accompanied by desaturation had been observed during her sleep. Endoscopic deroofing was performed under general anesthesia. After the operation, stridor and sleep apnea disappeared.

Protective Effects of Corticosteroids and Neurosteroids on Cochlear injury

Dysfunction of the cochlea causes sensorineural hearing loss. Glucocorticoids have been clinically applied for sensorineural hearing loss of sudden onset, including idiopathic sudden sensorineural hearing loss, acoustic injury, Menieres disease, and immune-mediated hearing loss. However, clinical studies on sudden sensorineural hearing loss have revealed conflicting results regarding the efficacy of glucocorticoids. The findings obtained from animal experiments have demonstrated that glucocorticoids exhibited protective effects on some types of cochlear injury, but there were limitations regarding glucocorticoid therapy. Recently, the actions of neurosteroids in the cochlea have drawn much attention from auditory researchers. Clinical and experimental studies of the auditory system have indicated that estrogens affect auditory perception. Furthermore, estrogens and dehydroepiandrosterone (DHEA) exhibit protective effects on cochlear injury. This article was aimed to give an overview of steroid treatment for protection of the inner ear against various cochlear injuries. Findings obtained from animal studies are focused on.

Effects of neuroactive steroids on cochlear hair cell death induced by gentamicin.

As neuroactive steroids, sex steroid hormones have non-reproductive effects. We previously reported that 17β-estradiol (βE2) had protective effects against gentamicin (GM) ototoxicity in the cochlea. In the present study, we examined whether the protective action of βE2 on GM ototoxicity is mediated by the estrogen receptor (ER) and whether other estrogens (17α-estradiol (αE2), estrone (E1), and estriol (E3)) and other neuroactive steroids, dehydroepiandrosterone (DHEA) and progesterone (P), have similar protective effects. The basal turn of the organ of Corti was dissected from Sprague-Dawley rats and cultured in a medium containing 100 μM GM for 48h. The effects of βE2 and ICI 182,780, a selective ER antagonist, were examined. In addition, the effects of other estrogens, DHEA and P were tested using this culture system. Loss of outer hair cells induced by GM exposure was compared among groups. βE2 exhibited a protective effect against GM ototoxicity, but its protective effect was antagonized by ICI 182,780. αE2, E1, and E3 also protected hair cells against gentamicin ototoxicity. DHEA showed a protective effect; however, the addition of ICI 182,780 did not affect hair cell loss. P did not have any effect on GM-induced outer hair cell death. The present findings suggest that estrogens and DHEA are protective agents against GM ototoxicity. The results of the ER antagonist study also suggest that the protective action of βE2 is mediated via ER but that of DHEA is not related to its conversion to estrogen and binding to ER. Further studies on neuroactive steroids may lead to new insights regarding cochlear protection.