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Age-related hearing loss (ARHL) is an auditory disease characterized by gradual loss of high-frequency hearing sensitivity. Excessive reactive oxygen species trigger NLRP3-inflammasome activation that may be crucial for ARHL pathogenesis. The antioxidant factor Sestrin2 (SESN2) has been reported to be involved in the remission of oxidative stress and ARHL. However, the mechanism by which SESN2 protects auditory cells in the aging mouse cochlea remains unknown. Here, we observed that ectopic overexpression of SESN2 delayed ARHL, whereas SESN2 knockdown accelerated it. Importantly, we elucidated that SESN2 exerts a hearing-protective effect by inhibiting the production of NLRP3 by acting as a mitophagy agonist. Our study proposes a new theoretical basis for SESN2 prevention of ARHL and provides a novel therapeutic strategy for maintaining SESN2 activity in the aging cochlea.

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Cytomegalovirus (CMV)-induced sensorineural hearing loss (SNHL) is a worldwide epidemic. Recent studies have shown that the degree of spiral ganglion neuron (SGN) loss is correlated with hearing loss after CMV infection. We aimed to better understand the pathological mechanisms of CMV-related SGN death and to search for intervention measures. We found that both apoptosis and pyroptosis are involved in CMV-induced SGN death, which may be caused by the simultaneous activation of the p53/JNK and NLRP3/caspase-1 signaling pathways, respectively. Moreover, considering that mixed lineage kinase family (MLK1/2/3) are host restriction factors against viral infection and upstream regulators of the p53/JNK and inflammatory (including NLRP3-caspase1) signaling pathways, we further demonstrated that the MLKs inhibitor URMC-099 exhibited a protective effect against CMV-induced SGN death and hearing loss. These results indicate that MLKs signaling may be a key regulator and promising novel target for preventing apoptosis and even pyroptosis during the CMV infection of SGN cells and for treating hearing loss.

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CD147, a glycosylated transmembrane protein in the immunoglobulin superfamily, is overexpressed on the surfaces of various tumor cells and promotes cancer cell proliferation, invasion, and metastasis. Nanobodies, characterized by small sizes, high affinities and specificities, and low immunogenicities, are promising diagnostic and therapeutic tools. However, there are few reports on nanobodies that specifically target CD147. In this work, a specific anti-CD147 nanobody has been successfully identified using phage display technology. The tumor target and antitumor effects have also been detected in different CD147-positive tumors in in vitro and in vivo assays, respectively. Meanwhile, it has a synergistic effect for inhibiting 4T1-bearing mice through conjugating doxorubicin. It may afford new strategies for cancer therapies.

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In rodents, massive initial synapses are formed in the auditory peripheral nervous system at the early postnatal stage, and one of the major phenomena is that the number of afferent synapses in the cochlea is significantly reduced in the duration of development. This raises the hypothesis that the number of cochlear ribbon synapses are dramatically changed with hearing development and maturation. In this study, several tracers identifying activities of autophagy were applied to estimate the level of autophagy activity in the process of ribbon synapse development in mice; further, changes in the synaptic number and spiral ganglion nerve (SGN) fibers were quantitatively measured. We found robust expression of LC3B and lysosomal-associated membrane protein 1 as well as LysoTracker in or near inner hair cells and cochlear ribbon synapses in the early stage of postnatal development. Moreover, we found a significant loss in the intensity of SGN fibers at ribbon synaptic development and hearing onset. Thus, this study demonstrates that ribbon synaptic refinement and SGN fibers pruning are closely associated with the morphological and functional maturation of ribbon synapses and that synaptic refinement and SGN fiber pruning are regulated by the robust activities of autophagy in the earlier stages of auditory development.

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Laryngeal carcinoma is one of the most common malignant tumors of the head, neck, and respiratory tract. The aim of the present study is to explore the biological function of SRY-related HMG-box 18 (SOX18) in laryngeal carcinoma cells and study the molecular mechanism involved. Initial findings indicate that the expression of SOX18 was increased in laryngeal carcinoma cell lines and tissues. The effect of SOX18 on laryngeal carcinoma cell proliferation, cell cycle, apoptosis, invasion, and migration was also identified. The results indicated that down-regulation of SOX18 significantly inhibited cell proliferation, migration, and invasion, and induced cell-cycle arrest in G0/G1 phase and apoptosis of laryngeal carcinoma cells. However, overexpression of SOX18 promoted cell proliferation, invasion, and migration, and inhibited cell apoptosis. The expression of cyclin D1, active-caspase-3, N-cadherin, MTA1, MMP-2, and MMP-7 was also regulated by the overexpression of siSOX18 or SOX18. In addition, it was found that SOX18 could also accelerate the phosphorylation of JAK2/STAT3 signaling in laryngeal carcinoma cells. Furthermore, our study indicated that SOX18 could stimulate cell proliferation, migration, and invasion of laryngeal carcinoma cells via regulation of JAK2/STAT3 signaling, which could provide a new strategy for laryngeal carcinoma diagnosis and molecular therapies.

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Nasopharyngeal carcinoma (NPC) is a respiratory malignant epithelial carcinoma. Research has indicated that bactericidal/permeability-increasing fold-containing protein B1 (BPIFB1), mostly secreted by nasopharyngeal epithelia, is dysregulated in patients with NPC. This study aimed to explore the effects of BPIFB1 inviability, proliferation, apoptosis and its molecular mechanism. To confirm the effects of BPIFB1 on NPC cells, BPIFB1 was overexpressed or silenced in NPC-KT cells after being transfected with BPIFB1 or siBPIFB1 plasmids. The results showed that BPIFB1 overexpression could induce apoptosis and DNA damage in NPC-KT cells, and silenced BPIFB1 had the opposite effects. BPIFB1 overexpression can inhibit the cell cycle by being arrested at the G0/G1 phase and by regulating the MEK/ERK signaling pathway. MEK inhibitor U0126 was used to confirm the effects of BPIFB1 on the MEK/ERK pathway, and U0126 can inverse the effects of siBPIFB1. Additionally, BPIFB1 can enhance the anti-proliferative effect of chemotherapy drugs on NPC-KT cells. All the results indicated that BPIFB1 could be a potential target for the treatment of NPC.

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CONCLUSION: Ototoxic gentamicin exposure does not disrupt the expression of myosin VIIa in the inner hair cells (IHCs) of mice, whereas gentamicin ototoxicity causes altered expression of otoferlin in IHCs, as well as parallel hearing threshold shifts. OBJECTIVE: To explore whether myosin VIIa and otoferlin in IHCs have different responses to gentamicin ototoxicity. METHODS: Lower dose treatment (100 mg/kg): adult C57 mice were continuously injected intraperitoneally with gentamicin once a day for 14 consecutive days. Dose-dependent gentamicin treatment: mice were injected intraperitoneally with differing doses (100, 200, and 300 mg/kg) once a day for 2 consecutive days. The hearing thresholds were detected by auditory brainstem response (ABR). Immunostaining and Western blotting were utilized to measure the manner of expression of myosin VIIa and otoferlin in IHCs. RESULTS: Lower dose treatment: There were no significant differences among the control (day 0), and 4, 7, and 14 days after the ototoxicity exposure (p > 0.05). Dose-dependent gentamicin treatment: There were no significant differences among the control, 100, 200, and 300 mg/kg groups after the ototoxicity exposure (p > 0.05). In contrast, we found an altered expression of otoferlin in IHCs among the control (day 0), and 4, 7, and 14 days of exposure, when the mice were exposed to gentamicin ototoxicity (p > 0.05).

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CONCLUSION: Dynamic distribution of ototoxic gentamicin entry into inner hair cells (IHCs) may cause an interruption of cochlear ribbon synapse. OBJECTIVE: To explore the pattern of uptake of gentamicin into IHCs, as well as its possible contribution to hearing loss. METHODS: Adult C57 mice were injected intraperitoneally with gentamicin (100 mg/kg, conjugated with Texas Red ester) continuously for 14 days. The hearing thresholds were detected by auditory brainstem response (ABR) examinations. Immunostaining and confocal microscopy were utilized to trace gentamicin distribution, as well as the expression of RIBEYE/CtBP2 in mouse IHCs. Scanning electron microscopy (SEM) observation was used to find possible alterations of stereocilia. RESULTS: The distribution of gentamicin in IHCs was first found on the 4th day and the accumulation of gentamicin was increased significantly on the 7th day after treatment, corresponding to the maximal elevation of the hearing threshold. However, the accumulation of gentamicin on the 14th day did not show significant differences compared with the level found on the 7th day. In addition, the uptake of gentamicin was excessively identified at or near the synaptic ribbons of IHCs throughout the 4th, 7th, and 14th days after the treatment, suggesting that cochlear ribbon synapses could be affected by ototoxic gentamicin exposure.

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The ribbon synapses of inner hair cells (IHCs) play an important role in sound encoding and neurotransmitter release. However, it remains unclear whether IHC ribbon synapse plasticity can be interrupted by ototoxic aminoglycoside stimuli. Here, we report that quantitative changes in the number of IHC ribbon synapses and hearing loss occur in response to gentamicin treatment in mice. Using 3D reconstruction, we were able to calculate the number of IHC ribbon synapses after ototoxic gentamicin exposure. Mice were injected intraperitoneally with a low dose of gentamicin (100 mg/kg) once a day for 14 days. Double immunostaining was used to identify IHC ribbon synapses; histopathology and scanning electron microscopy were used to observe the morphology of cochlear hair cells and spiral ganglion neurons (SGNs), the hearing threshold shifts were recorded by auditory brainstem response examinations. Our study shows that the maximal number of IHC ribbon synapses appeared at the 7th day after treatment, followed by a significant reduction after the 7th day regardless of ongoing treatment. Correspondingly, the maximal elevation of hearing threshold was observed at the 7th day after treatment. Meanwhile, additional cochlear components included OHCs, IHCs, and SGNs were unaffected, suggesting that IHC ribbon synapses are more susceptible to ototoxic aminoglycoside stimulation. Our study indicated that quantitative changes in the number of IHC ribbon synapses is critical response to lower dose of ototoxic stimulation, and may contribute to moderate hearing loss. Additionally, our data indcated that ribbon synaptic plasticity may require the quantitative changes to play self-protective role adapted to ototoxic aminoglycoside stimuli.

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