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1.
Artigo em Chinês | MEDLINE | ID: mdl-38433688

RESUMO

Objective:This study was to investigate the wideband acoustic immittance(WAI) characteristics of children with large vestibular aqueduct syndrome(LVAS) and to construct a diagnostic model for LVAS based on WAI and machine learning(ML) techniques. Methods:We performed a retrospective analysis of the data from 38 children(76 ears) with LVAS and 44 children(88 ears) with normal hearing. The data included conventional audiological examination, temporal bone CT scan and WAI test. We performed statistical analysis and developed multivariate diagnostic models based on different ML techniques. Results:The two groups were balanced in terms of ear, gender, and age(P>0.05). The wideband absorbance(WBA) of the LVAS group was significantly lower than that of the control group at 1 000-2 519 Hz, while the WBA of the LVAS group was significantly higher than that of the control group at 4 000-6 349 Hz(P<0.05). WBA at 5 039 Hz under ambient pressure had a certain diagnostic value(AUC=0.767). The multivariate diagnostic model had a high diagnostic value(AUC>0.8), among which the KNN model performed the best(AUC=0.961). Conclusion:The WAI characteristics of children with LVAS are significantly different from those of normal children. The diagnostic model based on WAI and ML techniques has high accuracy and reliability, and provides new ideas and methods for intelligent diagnosis of LVAS.


Assuntos
Aqueduto Vestibular , Doenças Vestibulares , Criança , Humanos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Aprendizado de Máquina , Síndrome , Acústica
2.
Antioxid Redox Signal ; 38(1-3): 115-136, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35708118

RESUMO

Aims: Noise damage to auditory hair cells is associated with oxidative stress and mitochondrial dysfunction. This study aimed to investigate the possible effect of sestrin 2 (SESN2), an endogenous antioxidant protein, on noise-induced hearing loss (NIHL) and the underlying mechanisms. Results: We identified SESN2 as a protective factor against oxidative stress in NIHL through activation of Parkin-mediated mitophagy. Consistently, SESN2 expression was increased and mitophagy was induced during the early stage after a temporary threshold shift due to noise exposure or hydrogen peroxide(H2O2) stimulation; conversely, SESN2 deficiency blocked mitophagy and exacerbated acoustic trauma. Mechanistically, SESN2 interacted with Unc-51-like protein kinase 1(ULK1), promoting ULK1 protein-level stabilization by interfering with its proteasomal degradation. This stabilization is essential for mitophagy initiation, since restoring ULK1 expression in SESN2-silenced cells rescued mitophagy defects. Innovation and Conclusion: Our results provide novel insights regarding SESN2 as a therapeutic target against noise-induced cochlear injury, possibly through improved mitophagy. Antioxid. Redox Signal. 38, 115-136.


Assuntos
Perda Auditiva Provocada por Ruído , Mitofagia , Humanos , Sestrinas , Peróxido de Hidrogênio/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética
3.
Neurosci Lett ; 793: 136990, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36455693

RESUMO

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.


Assuntos
Infecções por Citomegalovirus , Surdez , Perda Auditiva Neurossensorial , MAP Quinase Quinase Quinases , Muromegalovirus , Animais , Camundongos , Apoptose , Citomegalovirus , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/patologia , Surdez/metabolismo , Surdez/patologia , Perda Auditiva/metabolismo , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Neurônios , Proteína 3 que Contém Domínio de Pirina da Família NLR , Gânglio Espiral da Cóclea/patologia , Proteína Supressora de Tumor p53 , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinase 11 Ativada por Mitógeno
4.
Prog Neurobiol ; 221: 102399, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36581184

RESUMO

Multisensory integration plays an important role in animal cognition. Although many studies have focused on visual-auditory integration, studies on olfactory-auditory integration are rare. Here, we investigated neural activity patterns and odor decoding in the lateral entorhinal cortex (LEC) under uni-sensory and multisensory stimuli in awake, head-fixed mice. Using specific retrograde tracing, we verified that the LEC receives direct inputs from the primary auditory cortex (AC) and the medial geniculate body (MGB). Strikingly, we found that mitral/tufted cells (M/Ts) in the olfactory bulb (OB) and neurons in the LEC respond to both olfactory and auditory stimuli. Sound decreased the neural responses evoked by odors in both the OB and LEC, for both excitatory and inhibitory responses. Interestingly, significant changes in odor decoding performance and modulation of odor-evoked local field potentials (LFPs) were observed only in the LEC. These data indicate that the LEC is a critical center for olfactory-auditory multisensory integration, with direct projections from both olfactory and auditory centers.


Assuntos
Córtex Entorrinal , Olfato , Camundongos , Animais , Córtex Entorrinal/fisiologia , Olfato/fisiologia , Odorantes , Bulbo Olfatório/fisiologia , Potenciais Evocados
5.
Int Immunopharmacol ; 113(Pt A): 109305, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36244217

RESUMO

Cytomegalovirus (CMV) infection causes newborn deafness, and the death of the spiral ganglion neurons (SGNs) is crucial in determining the degree of CMV-related hearing loss. Therefore, understanding the psychopathology of CMV-related SGN loss is important for identifying targets and exploring treatment strategies. In this study, we found that pyroptosis and apoptosis, two inflammasome-related programmed cell death pathways, are involved in CMV-induced SGN death and are mainly regulated by activated caspase-1 and caspase-8. Moreover, suppressing inflammasome assembly by blocking apoptosis-associated speck-like protein containing a CARD (ASC) interaction inhibited the activation of both caspase-1 and caspase-8, rescued SGN death, and improved hearing loss in CMV-infected newborn mice. Therefore, we propose that ASC inflammasome might be a promising target for treating CMV-related SGN death and newborn hearing loss by inhibiting caspase-1 and caspase-8 activated pyroptosis and apoptosis.


Assuntos
Infecções por Citomegalovirus , Perda Auditiva , Animais , Camundongos , Caspase 1/metabolismo , Inflamassomos/metabolismo , Piroptose , Caspase 8/metabolismo , Apoptose/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
6.
Signal Transduct Target Ther ; 7(1): 175, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35680846

RESUMO

Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide. However, the presence of the blood-labyrinth barrier (BLB) on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability, which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue. Here, we report the finding of a novel receptor, low-density lipoprotein receptor-related protein 1 (LRP1), that is expressed on the BLB, as a potential target for shuttling therapeutics across this barrier. As a proof-of-concept, we developed an LRP1-binding peptide, IETP2, and covalently conjugated a series of model small-molecule compounds to it, including potential drugs and imaging agents. All compounds were successfully delivered into the inner ear and inner ear lymph, indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB. The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.


Assuntos
Orelha Interna , Perda Auditiva , Sistemas de Liberação de Medicamentos , Orelha Interna/irrigação sanguínea , Orelha Interna/metabolismo , Perda Auditiva/metabolismo , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Preparações Farmacêuticas/metabolismo
7.
Mol Immunol ; 149: 66-76, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35749835

RESUMO

Aminoglycoside antibiotic drugs induce hearing loss in children and adults every year; however, the pathological mechanisms remain unknown. Previous studies have shown that the accumulation of reactive oxygen species (ROS) and inflammation in the inner ear may be responsible for kanamycin (KM)-induced hair cell death and hearing loss. Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) is a specific ROS sensor that initiates inflammasome assembly as well as activates caspase-1 and downstream inflammatory factors. Therefore, this study aimed to determine whether NLRP3 inflammasomes are involved in KM-related hearing loss in mice. Compared with the control (saline) group, increased levels of activated caspase-1, interleukin (IL)-1ß, IL-18, N-terminal fragment of gasdermin D (GSDMD-N), and NLRP3 were detected by immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) in the KM-plus-furosemide (LASIX)-treated group. Moreover, we also found that the NLRP3 inhibitor oridonin (Ori) could significantly rescue KM-related hearing loss by inhibiting NLRP3-inflammasome activation and caspase-1/GSDMD-related hair cell pyroptosis. These findings demonstrate that apoptosis, as well as pyroptosis, may be involved in KM-related hearing loss and that the NLRP3/caspase-1/GSDMD pathway may be a new target for treating aminoglycoside-induced hearing loss.


Assuntos
Perda Auditiva , Piroptose , Animais , Caspase 1/metabolismo , Diterpenos do Tipo Caurano , Cabelo/metabolismo , Perda Auditiva/induzido quimicamente , Perda Auditiva/tratamento farmacológico , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Canamicina , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Front Immunol ; 13: 852700, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603157

RESUMO

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.


Assuntos
Neoplasias , Anticorpos de Domínio Único , Animais , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Anticorpos de Domínio Único/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Eur Arch Otorhinolaryngol ; 279(11): 5207-5214, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35438345

RESUMO

OBJECTIVE: To detect the expression of Epac1 and Epac2 in the inner ear of guinea pigs and its association with microcirculation in the inner ear. METHODS: The temporal bones of 30 healthy red-eye guinea pigs (60 ears) weighing 200-350 g were collected, then the surrounding bone wall of the cochlea was removed under a dissection microscope. Real-time quantitative PCR (RT-qPCR) and Western blot were used to detect mRNA and protein expression, respectively, of Epac1 and Epac2 in the inner ear and to compare their expression in heart, liver, kidney, intestine, and lung tissues. The specimens of the cochlea included the stria vascularis, basilar membrane, saccule, and utricles isolated under a microscope to detect the localization of Epac1 and Epac2 proteins in various parts of the inner ear through immunofluorescence staining. RESULTS: The RT-qPCR and Western blot results showed that Epac1 mRNA was universally expressed in the inner ear, heart, liver, kidneys, intestines, and lungs, and was highly expressed in the liver, kidneys, and intestines (p < 0.05 vs heart, liver, kidney, intestine; p > 0.05 vs lung). Epac2 mRNA was expressed in the inner ear and heart, but not in the liver, kidneys, intestines, or lungs (p < 0.05 vs Heart). Epac1 and Epac2 proteins were both expressed in the inner ear, heart, liver, kidneys, intestines, and lungs. The relative expression of Epac1 proteins in the inner ear was significantly different from the liver, kidneys, intestines, and lungs (p < 0.05). The relative expression of Epac2 proteins in the inner ear was significantly different from the liver, kidneys, and lungs (p < 0.05), but not from the heart (p = 0.127) or intestines (p = 0.274). Immunofluorescence staining observed under confocal microscopy indicated that Epac1 and Epac2 proteins were expressed in the stria vascularis, basilar membrane, saccule, and utricles of the inner ear. They were expressed in maginal cells, intermediate cells, and basal cells of the stria vascularis, and highly expressed in capillary endothelial cells. CONCLUSIONS: Epac1 and Epac2 mRNA and proteins were both expressed in the inner ear of guinea pigs and evenly expressed in the spiral ganglion, basilar membrane, saccule, and utricles. However, their expression in capillary endothelial cells of the stria vascularis was more obvious, suggesting that cyclic adenosine monophosphate-Epac1 signaling may play an important role in maintaining the function of the blood-labyrinth barrier and regulating the stability of microcirculation in the inner ear.


Assuntos
Cóclea , Células Endoteliais , Monofosfato de Adenosina , Animais , Membrana Basilar , Cobaias , RNA Mensageiro
10.
BMC Geriatr ; 22(1): 280, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35382747

RESUMO

OBJECTIVE: This study explores the relationship between nutritional status and oral health quality of life, the self-efficacy of older inpatients and the correlative factors. METHODS: In this study, the convenience sampling method was used to select 307 older inpatients in the southern section of the Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October to December 2020 as the main research participants. A mini nutritional assessment questionnaire was used to assess nutritional status, and the Chinese version of a geriatric oral health assessment index questionnaire was used to determine the oral health quality of life. Self-efficacy was assessed by a general self-efficacy scale questionnaire. Descriptive statistics were used to analyse data using the SPSS 22.0 software. Pearson correlation and multiple linear regression analysis were applied to explore the correlation between variables and factors concerned with nutritional status, respectively. RESULTS: The results of this study showed that the self-efficacy and oral health quality of life of older inpatients were at a moderate level. Among the patients, 263 had one or more tooth defects, and only 128 had oral restorations or wore dentures. The risk of malnutrition in hospitalised older patients was 37.1%, and the incidence of malnutrition was 13.4%. The risk factors of nutritional status of older patients were age, oral-related quality of life, prealbumin index, self-efficacy, chronic disease, monthly income and tooth defect (P < 0.05). CONCLUSION: The incidence of malnutrition and malnutrition risk in hospitalised older patients is relatively high. The main associated factors include age, tooth defect, oral health quality of life, self-efficacy, chronic disease status and monthly income. Therefore, older inpatients, especially those with prosthodontic problems, should carry out nutritional assessments, intervention and graded management as soon as possible to improve their self-efficacy, improve their nutrition and health status and reduce the incidence of a poor prognosis.


Assuntos
Desnutrição , Qualidade de Vida , Idoso , China , Estudos Transversais , Avaliação Geriátrica/métodos , Humanos , Pacientes Internados , Desnutrição/epidemiologia , Avaliação Nutricional , Estado Nutricional , Saúde Bucal , Autoeficácia
11.
Artigo em Chinês | MEDLINE | ID: mdl-34886618

RESUMO

Objective:To explore the wideband absorbance characteristics of patients with Meniere's disease(MD). Methods:Wideband acoustic immittance was performed in 52 patients with unilateral Meniere's disease(UMD) and 30 control subjects with normal hearing. All UMD patients underwent pure tone audiometry, 226 Hz acoustic immittance, wideband acoustic immittance, and gadolinium contrast MRI. Sixteen frequency points were chosen to analyze the wideband absorbance at ambient and peak pressure, and the subjects were grouped as UMD group vs. control group and asymptomatic group. The student's t-test was used to compare the absorbance difference between them. Results:Both at peak and ambient pressure, there was a significant difference between the MD group and control group at 1587 Hz, 2000 Hz, 2519 Hz, 3174 Hz, and 4000 Hz; the MD group was lower than the control group(P<0.05); there were no differences between the asymptomatic group and the symptomatic group, there also was a significant difference between the asymptomatic group and control group at 1587-4000 Hz(P<0.05). Conclusion:The wideband absorbance in MD patients was significantly reduced within the frequency range of 1587-4000 Hz, and wideband acoustic immittance seems to be cost-effective in predicting MD.


Assuntos
Doença de Meniere , Testes de Impedância Acústica , Acústica , Audiometria de Tons Puros , Humanos
12.
Int Immunopharmacol ; 95: 107576, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33770730

RESUMO

Inflammation is involved in noise-induced hearing loss (NIHL), but the mechanism is still unknown. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which triggers the inflammatory cascade, has been implicated in several inflammatory diseases in response to oxidative stress. However, whether the NLRP3 inflammasome is a key factor for permanent NIHL is still unknown. In this study, quantitative real-time polymerase chain reaction (qPCR), western blot, and enzyme-linked immunosorbent assays (ELISAs) demonstrated that the expression levels of activated caspase-1, interleukin (IL)-1ß, IL-18, and NLRP3 were significantly increased in the cochleae of mice exposed to broadband noise (120 dB) for 4 h, compared with the control group. These results indicate that the activation of inflammasomes in the cochleae of mice during the pathological process of NIHL as well as NLRP3, a sensor protein of reactive oxygen species (ROS), may be key factors for inflammasome assembly and subsequent inflammation in cochleae. Moreover, many recent studies have revealed that NEK7 is an important component and regulator of NLRP3 inflammasomes by interacting with NLRP3 directly and that these interactions can be interrupted by oridonin. Here, we further determined that treatment with oridonin could indeed interrupt the interaction between NLRP3 and NEK7 as well as inhibit the downstream inflammasome activation in mouse cochleae after noise exposure. Furthermore, we tested anakinra, another inflammatory inhibitor, and it was shown to partially alleviate the degree of hearing impairment in some frequencies in an NIHL mouse model. These discoveries suggest that inhibiting NLRP3 inflammasomes and the downstream signaling pathway may provide a new strategy for the clinical treatment of NIHL.


Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos do Tipo Caurano/uso terapêutico , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Cóclea/efeitos dos fármacos , Cóclea/imunologia , Citocinas/imunologia , Diterpenos do Tipo Caurano/farmacologia , Perda Auditiva Provocada por Ruído/imunologia , Inflamassomos/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia
13.
ACS Appl Mater Interfaces ; 13(6): 7102-7114, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33528239

RESUMO

Overproduction of reactive oxygen species (ROS) and inflammation are two key pathogeneses of noise-induced hearing loss (NIHL), which leads to outer hair cell (OHC) damage and hearing loss. In this work, we successfully developed ROS-responsive nanoparticles as berberine (BBR) carriers (PL-PPS/BBR) for OHC-targeted therapy of NIHL: Prestin-targeting peptide 2 (PrTP2)-modified nanoparticles (PL-PPS/BBR), which effectively accumulated in OHC areas, and poly(propylene sulfide)120 (PPS120), which scavenged ROS and converted to poly(propylene sulfoxide)120 in a ROS environment to disintegrate and provoke the rapid release of BBR with anti-inflammatory and antioxidant effects. In this study, satisfactory anti-inflammatory and antioxidant effects of PL-PPS/BBR were confirmed. Immunofluorescence and scanning electron microscopy (SEM) images showed that PL-PPS/BBR effectively accumulated in OHCs and protected the morphological integrity of OHCs. The auditory brainstem response (ABR) results demonstrated that PL-PPS/BBR significantly improved hearing in NIHL guinea pigs after noise exposure. This work suggested that PL-PPS/BBR may be a new potential treatment for noise-associated injury with clinical application.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Berberina/farmacologia , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Perda Auditiva Provocada por Ruído/tratamento farmacológico , Espécies Reativas de Oxigênio/química , Animais , Anti-Inflamatórios não Esteroides/química , Antioxidantes/química , Berberina/química , Modelos Animais de Doenças , Portadores de Fármacos/química , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Cobaias , Estrutura Molecular , Nanopartículas/química , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície
14.
Onco Targets Ther ; 11: 8107-8115, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532552

RESUMO

BACKGROUND: Follicle-stimulating hormone (FSH) has multiple biological functions. It is currently considered that FSH can inhibit cervical cancer, and our aim was to explore the underlying molecular mechanisms. MATERIALS AND METHODS: An in vivo experiment using nude mice injected with HeLa cells was performed. Flow cytometry, western blotting, and real-time quantitative PCR analyses were done. RESULTS: Twenty one days after injection of HeLa cells, the subcutaneous tumor mass was significantly lower (P<0.01) in mice treated with 20 mIU/mL FSH, but did not disappear. In vitro observations indicated that FSH might inhibit cell proliferation and activate cell apoptosis to induce the reduction of HeLa cells. The mRNA and protein levels of Cyclin D1, Cyclin E1, and Caspase 3 changed accordingly as expected in vivo and in vitro. Moreover, FSH inactivated the nuclear factor-kappa B (NF-κB) pathway in subcutaneous tumors; the NF-κB(p65) activity in HeLa cells was significantly decreased using 20 mIU/mL FSH and was increased when FSH was administered along with lipopolysaccharide, accompanied by the same change of cell number. Further, FSH accelerated protein kinase A (PKA) activity, but inactivated glycogen synthase kinase 3 beta (GSK-3ß) activity. Specific inhibition of PKA and/or GSK-3ß provided in vitro evidence that directly supported the FSH-mediated inhibition of GSK-3ß to inactivate NF-κB via the promotion of PKA activity. CONCLUSION: Our data are the first description of the molecular regulatory mechanisms of FSH-mediated inhibition of the development of cervical cancer by decreasing the cell cycle and activating cell apoptosis via the PKA/GSK-3ß/NF-κB pathway.

15.
Med Sci Monit ; 24: 3557-3563, 2018 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-29806954

RESUMO

BACKGROUND The aim of this study was to explore the value of the spectral ripple discrimination test in speech recognition evaluation among a deaf (post-lingual) Mandarin-speaking population in China following cochlear implantation. MATERIAL AND METHODS The study included 23 Mandarin-speaking adult subjects with normal hearing (normal-hearing group) and 17 deaf adults who were former Mandarin-speakers, with cochlear implants (cochlear implantation group). The normal-hearing subjects were divided into men (n=10) and women (n=13). The spectral ripple discrimination thresholds between the groups were compared. The correlation between spectral ripple discrimination thresholds and Mandarin speech recognition rates in the cochlear implantation group were studied. RESULTS Spectral ripple discrimination thresholds did not correlate with age (r=-0.19; p=0.22), and there was no significant difference in spectral ripple discrimination thresholds between the male and female groups (p=0.654). Spectral ripple discrimination thresholds of deaf adults with cochlear implants were significantly correlated with monosyllabic recognition rates (r=0.84; p=0.000). CONCLUSIONS In a Mandarin Chinese speaking population, spectral ripple discrimination thresholds of normal-hearing individuals were unaffected by both gender and age. Spectral ripple discrimination thresholds were correlated with Mandarin monosyllabic recognition rates of Mandarin-speaking in post-lingual deaf adults with cochlear implants. The spectral ripple discrimination test is a promising method for speech recognition evaluation in adults following cochlear implantation in China.


Assuntos
Implantes Cocleares , Idioma , Testes de Discriminação da Fala , Fala/fisiologia , Adulto , Limiar Auditivo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Free Radic Biol Med ; 121: 127-135, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29715550

RESUMO

Cytomegalovirus (CMV) is the leading cause of sensorineural hearing loss (SNHL) in children because of its damage to the cochlea and spiral ganglion cells. Therefore, it has become a top priority to devise new methods to effectively protect spiral ganglion cells from damage. Berberine (BBR) has gained attention for its vast beneficial biological effects through immunomodulation, and its anti-inflammatory and anti-apoptosis properties. However, the effect of BBR on spiral ganglion cells and molecular mechanisms are still unclear. This study aims to investigate whether BBR has an anti-apoptosis effect in CMV-induced apoptosis in cultured spiral ganglion cells and explore the possible mechanism. In this study, TUNEL and MTT assays significantly demonstrated that low doses of BBR did not promote cell apoptosis and they also inhibited the CMV-induced cultured spiral ganglion cell apoptosis. Immunofluorescence and Western blot assays indicated that the anti-apoptosis effect of BBR was related to Nox3. Mitochondrial calcium and Western blot assays revealed that NMDAR1 mediated this anti-apoptosis effect. Our results demonstrated that BBR exerted an anti-apoptosis effect against CMV in cultured spiral ganglion cells, and the mechanism is related to NMDAR1/Nox3-mediated mitochondrial reactive oxygen species (ROS) generation.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Berberina/farmacologia , Infecções por Citomegalovirus/complicações , Citomegalovirus/patogenicidade , Substâncias Protetoras/farmacologia , Gânglio Espiral da Cóclea/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Células Cultivadas , Infecções por Citomegalovirus/virologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo , Transdução de Sinais , Gânglio Espiral da Cóclea/patologia , Gânglio Espiral da Cóclea/virologia
17.
Mol Cancer ; 17(1): 86, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29716593

RESUMO

Abnormal expression of non-coding circular RNAs (circRNAs) have been reported in many types of tumors. circRNA have been suggested to be an ideal candidate biomarker for diagnostic and therapeutic implications in cancers. The aim of this study was to assess the circRNA expression profile of laryngeal squamous cell carcinomas (LSCC). The biopsy samples from patients with LSCC were obtained intra-operatively. The circRNA expression was performed using secondary sequencing. Among 10 patients with LSCC, 2 were well differentiated, 3 were moderately differentiated and 5 were adjunctive samples with normal and LSCC tissues. A total of 21,444 distinct circRNA candidates were detected. Among them, we defined the statistical criteria for selecting aberrant-expressed circRNA using a q-value of < 0.001 with a fold change of > 2.0 or < 0.5. A total of 29 circRNA were upregulated and 19 circRNA were downregulated significantly in the LSCC tissues. The intersection of these dysregulated circRNAs of normal-well differentiated set and normal-moderately differentiated set was then assessed to narrow the upregulated and downregulated circRNAs down to 18 and 5 respectively. Furthermore, an association of the circRNA-miRNA-mRNA was investigated, showing that 20 dysregulated circRNA successfully predicted an interaction with several cancer-related miRNAs. Finally, a further KEGG analysis showed that PPAR, Axon guidance, Wnt and Cell cycle signaling pathway were key putative pathways in the process of LSCC. hsa_circ:chr20:31876585-31,897,648 was found to be able to differentiate most of LSCC from the matching normal tissues. This observational study demonstrated dysregulation of circRNA in LSCC, which may have an impact on development of potential biomarkers in this disease. Validation of down-regulation of hsa_circ:chr20:31876585-31,897,648 in LSCC compared to each adjunctive tissue by Q-RT-PCR, indicating that hsa_circ:chr20:31876585-31,897,648 may be a novel promising tumor suppresser in LSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Laríngeas/genética , RNA/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/genética , RNA Circular , RNA Mensageiro/genética , Análise de Sequência de RNA
18.
J Clin Lab Anal ; 32(7): e22444, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29665173

RESUMO

OBJECTIVE: To investigate whether a novel compound heterozygous mutations c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) in GJB2 result in hearing loss. METHODS: Allele-specific PCR-based universal array (ASPUA) screening and sequence analysis were applied to identify these mutations. 3D model was built to perform molecular dynamics (MD) simulation to verify the susceptibility of the mutations. Furthermore, WT- and Mut-GJB2 DNA fragments, containing the mutation of c.257C>G and c.176del16 were respectively cloned and transfected into HEK293 and spiral ganglion neuron cell (SGNs) by lenti-virus delivery system to indicate the subcellular localization of the WT- and Mut-CX26 protein. RESULTS: A novel compound heterozygous mutation c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) in GJB2 was identified in a Chinese family, in which 4 siblings with profound hearing loss, but the fifth child is normal. By ASPUA screening and sequencing, a compound heterozygote mutations in GJB2 c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) were identified in these four deaf children, each of the mutated GJB2 gene were inherited from their parents. There is no mutation of GJB2 gene identified in the normal child. Besides, the compound heterozygous mutation GJB2 c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) could lead to the alterations of the subcellular localization of each corresponding mutated CX26 protein and could cause the hearing loss, which has been predicted by MD simulation and verified in both 293T and SGNs cell line. CONCLUSION: The c.257C>G (p.T86R)/c.176del16 (p.G59A fs*18) compound mutations in GJB2 detected in this study are novel, and which may be associated with hearing loss in this Chinese family.


Assuntos
Povo Asiático/genética , Conexinas , Perda Auditiva Neurossensorial/genética , Mutação/genética , Animais , Células Cultivadas , Estudos de Coortes , Conexina 26 , Conexinas/química , Conexinas/genética , Conexinas/metabolismo , Feminino , Gânglios Espinais/citologia , Células HEK293 , Humanos , Masculino , Camundongos , Simulação de Dinâmica Molecular
19.
Int J Mol Med ; 41(6): 3448-3456, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512778

RESUMO

Congenital cytomegalovirus (CMV) infection is the most common infectious cause of sensorineural hearing loss in children. While the importance of CMV­induced SNHL has been described, the mechanisms underlying its pathogenesis and the role of inflammatory responses remain elusive. The present study established an experimental model of hearing loss after systemic infection with murine CMV (MCMV) in newborn mice. Auditory brainstem responses were tested to evaluate hearing at 3 weeks, expression of inflammasome­-associated factors was assessed by immunofluorescence, western blot analysis, reverse transcription­quantitative polymerase chain reaction and ELISA. MCMV sequentially induced inflammasome­associated factors. Furthermore, the inflammasome­associated factors were also increased in cultured spiral ganglion neurons infected with MCMV for 24 h. In addition, MCMV increased the content of reactive oxygen species (ROS). These results suggest that hearing loss caused by MCMV infection may be associated with ROS­induced inflammation.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gânglio Espiral da Cóclea/citologia , Animais , Células Cultivadas , Orelha Interna/citologia , Orelha Interna/fisiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imunofluorescência , Perda Auditiva/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo
20.
J Med Genet ; 55(5): 298-306, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29453195

RESUMO

Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G>A (p.Arg99His) in the gene encoding interferon lambda receptor 1 (IFNLR1) - a protein that functions in the Jak/ STAT pathway- are associated with ADNSHL Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. ConclusionIFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.


Assuntos
Predisposição Genética para Doença , Perda Auditiva Neurossensorial/genética , Receptores de Citocinas/genética , Receptores de Interferon/genética , Animais , Técnicas de Silenciamento de Genes , Ligação Genética , Perda Auditiva Neurossensorial/fisiopatologia , Heterozigoto , Humanos , Janus Quinase 1/genética , Camundongos , Morfolinas , Mutação de Sentido Incorreto/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Sequenciamento do Exoma , Peixe-Zebra/genética
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