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1.
Otolaryngol Head Neck Surg ; 171(4): 1172-1180, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38881387

RESUMO

OBJECTIVE: To identify the prevalence of and relevant information for video head impulse test (vHIT) abnormality in a large population. STUDY DESIGN: A cross-sectional design. SETTING: Korean National Health and Nutrition Examination Survey, 2021. METHODS: The sample was representative of the Korean population, with 2237 participants aged ≥40 years. A vHIT was performed to evaluate vestibular function. The vestibulo-ocular reflex (VOR) gain and the presence of reproducible catch-up saccades was assessed in a vHIT. Participants also completed questionnaires for demographics, socioeconomic status, and basic information regarding systemic diseases and dizziness and underwent hearing tests with automated pure-tone audiometry. RESULTS: The prevalence of vHIT abnormality was 22.5%, with unilateral (14.3%) being more common than bilateral (8.2%). The prevalence of vHIT abnormality increased significantly with age, with the highest rate observed in individuals aged >70 years (42.5%). Both hearing and VOR gain deteriorated with age, but the patterns of age-related progression were different. While hearing loss (HL) deteriorated gradually and progressively throughout adulthood, VOR gain deterioration was markedly evident after 70 years of age. CONCLUSION: Considering the high prevalence of vHIT abnormality, appropriate social and medical policies are needed to prevent associated injuries and improve patients' quality of life. The distinct age-related changes in HL and objective findings of vestibular dysfunction indicate the need for different approaches to address these social problems in aging countries.


Assuntos
Teste do Impulso da Cabeça , Doenças Vestibulares , Humanos , República da Coreia/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Transversais , Idoso , Adulto , Fatores de Risco , Doenças Vestibulares/epidemiologia , Doenças Vestibulares/diagnóstico , Reflexo Vestíbulo-Ocular/fisiologia , Inquéritos Nutricionais , Gravação em Vídeo
2.
Cell Rep ; 43(2): 113752, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38341852

RESUMO

We here demonstrate that SERTAD1 is an adaptor protein responsible for the regulation of lysine 63 (K63)-linked NLRP3 polyubiquitination by the Cullin1 E3 ubiquitin ligase upon inflammasome activation. SERTAD1 specifically binds to NLRP3 but not to other inflammasome sensors. This endogenous interaction increases after inflammasome activation, interfering with the interaction between NLRP3 and Cullin1. Interleukin (IL)-1ß and IL-18 secretion, as well as the cleavage of gasdermin D, are decreased in SERTAD1 knockout bone-marrow-derived macrophages, together with reduced formation of the NLRP3 inflammasome complex. Additionally, SERTAD1-deficient mice show attenuated severity of monosodium-uric-acid-induced peritonitis and experimental autoimmune encephalomyelitis. Analysis of public datasets indicates that expression of SERTAD1 mRNA is significantly increased in the patients of autoimmune diseases. Thus, our findings uncover a function of SERTAD1 that specifically reduces Cullin1-mediated NLRP3 polyubiquitination via direct binding to NLRP3, eventually acting as a crucial factor to regulate the initiation of NLRP3-mediated inflammasome activation.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Humanos , Camundongos , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
3.
Otolaryngol Head Neck Surg ; 170(2): 515-521, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37787037

RESUMO

OBJECTIVE: To evaluate the older adults with chronic dizziness using the Barany Society's presbyvestibulopathy (PVP) diagnostic criteria and to assess the clinical usability of the criteria. STUDY DESIGN: Retrospective study. SETTING: Single tertiary medical center. METHODS: Among a total of 1964 patients aged 60 years or older, 55 patients who had symptoms suitable for the PVP criteria and who underwent all 3 vestibular function tests were analyzed. Of these 55 patients, 13 patients were diagnosed with PVP based on the peripheral vestibular hypofunction criteria; the remaining 42 patients were categorized as patients without PVP. RESULTS: In both patients with PVP and patients without PVP, postural imbalance or unsteadiness was the most frequently reported vestibular symptom. The rotatory chair test contributed the most to the quantitative diagnosis of PVP (6 of 13), followed by the caloric response test (3 of 13) and video head impulse test (vHIT; 2 of 13). When we included the presence of catch-up saccades in addition to the vHIT gain in the diagnostic criteria, 5 patients without PVP were additionally diagnosed with PVP. Furthermore, when accounting for the inclusion of catch-up saccades, patients who experienced recurrent falls demonstrated a significantly higher rate of impairments in the lateral and posterior semicircular canals according to the multivariate analysis. CONCLUSION: Considering the catch-up saccades in addition to vHIT gain seemed to contribute to the diagnosis of PVP and prediction of recurrent fall risks in older adults. Further studies are needed to solidify the diagnostic criteria for PVP.


Assuntos
Tontura , Testes de Função Vestibular , Humanos , Idoso , Tontura/diagnóstico , Tontura/etiologia , Estudos Retrospectivos , Testes Calóricos , Teste do Impulso da Cabeça , Canais Semicirculares , Reflexo Vestíbulo-Ocular/fisiologia
4.
Otolaryngol Head Neck Surg ; 169(6): 1573-1581, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37418229

RESUMO

OBJECTIVE: To investigate the impairment patterns in peripheral vestibular organs in sudden sensorineural hearing loss (SSNHL) with and without vertigo. STUDY DESIGN: Retrospective study. SETTING: Single tertiary medical center. METHODS: Data from 165 SSNHL patients in a tertiary referral center from January 2017 to December 2022 were retrospectively analyzed. All patients underwent a video head impulse test, vestibular evoked myogenic potential test, and pure-tone audiometry. Hierarchical cluster analysis was performed to investigate vestibular impairment patterns. The prognosis of the hearing was determined using American Academy of Otolaryngology-Head and Neck Surgery recommendations. RESULTS: After excluding patients with vestibular schwannoma and Meniere's disease, 152 patients were included in this study. A total of 73 of 152 patients were categorized as SSNHL with vertigo (SSNHL_V) and showed an independent merge of the posterior semicircular canal (PSCC) in cluster analysis. A total of 79 of 152 patients were categorized as SSNHL without vertigo (SSNHL_N) and showed an independent merge of saccule in cluster analysis. The PSCC (56.2%) and saccule (20.3%) were the most frequently impaired vestibular organs in SSNHL_V and SSNHL_N, respectively. In terms of prognosis, 106 of 152 patients had partial/no recovery and showed an independent merge of the PSCC in cluster analysis. A total of 46 of 152 patients had a complete recovery and showed an independent merge of the saccule in cluster analysis. CONCLUSION: A tendency of isolated PSCC dysfunction was seen in SSNHL_V and partial/no recovery. A tendency of isolated saccular dysfunction was seen in SSNHL_N and complete recovery. Different treatments might be needed in SSNHL depending on the presence of vertigo.


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Vestíbulo do Labirinto , Humanos , Estudos Retrospectivos , Vertigem/etiologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Súbita/diagnóstico , Perda Auditiva Súbita/etiologia , Audiometria de Tons Puros
5.
Exp Mol Med ; 55(6): 1218-1231, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37258579

RESUMO

The signaling pathways governing acetaminophen (APAP)-induced liver injury have been extensively studied. However, little is known about the ubiquitin-modifying enzymes needed for the regulation of APAP-induced liver injury. Here, we examined whether the Pellino3 protein, which has E3 ligase activity, is needed for APAP-induced liver injury and subsequently explored its molecular mechanism. Whole-body Peli3-/- knockout (KO) and adenovirus-mediated Peli3 knockdown (KD) mice showed reduced levels of centrilobular cell death, infiltration of immune cells, and biomarkers of liver injury, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), upon APAP treatment compared to wild-type (WT) mice. Peli3 deficiency in primary hepatocytes decreased mitochondrial and lysosomal damage and reduced the mitochondrial reactive oxygen species (ROS) levels. In addition, the levels of phosphorylation at serine 9 in the cytoplasm and mitochondrial translocation of GSK3ß were decreased in primary hepatocytes obtained from Peli3-/- KO mice, and these reductions were accompanied by decreases in JNK phosphorylation and mitochondrial translocation. Pellino3 bound more strongly to GSK3ß compared with JNK1 and JNK2 and induced the lysine 63 (K63)-mediated polyubiquitination of GSK3ß. In rescue experiments, the ectopic expression of wild-type Pellino3 in Peli3-/- KO hepatocytes restored the mitochondrial translocation of GSK3ß, but this restoration was not obtained with expression of a catalytically inactive mutant of Pellino3. These findings are the first to suggest a mechanistic link between Pellino3 and APAP-induced liver injury through the modulation of GSK3ß polyubiquitination.


Assuntos
Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Animais , Camundongos , Acetaminofen/efeitos adversos , Fosforilação , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Fígado/metabolismo , Hepatócitos/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Camundongos Endogâmicos C57BL
6.
Eur Arch Otorhinolaryngol ; 280(12): 5251-5258, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37210462

RESUMO

PURPOSE: To observe vestibular impairment patterns in patients with Ramsay Hunt syndrome with dizziness (RHS_D) and sudden sensorineural hearing loss with dizziness (SSNHL_D) using hierarchical cluster analysis (HCA) to interpret results with possible mechanisms. METHODS: The data of 30 RHS_D and 81 SSNHL_D patients from January 2017 to August 2022 in a single tertiary referral center were retrospectively analyzed. Video head impulse test (vHIT) and vestibular evoked myogenic potential (VEMP) were used for vestibular analysis of peripheral vestibular organs, and the results of vHIT and VEMP were analyzed. HCA was used to analyze vestibular impairment patterns. RESULTS: In RHS_D patients, the lateral semicircular canal (LSCC) was the most impaired semicircular canal (SCC), followed by the anterior semicircular canal (ASCC) and the posterior semicircular canal (PSCC), and the utricle was more impaired than the saccule. In SSNHL_D patients, the PSCC was the most impaired SCC, followed by the LSCC and the ASCC, and the utricle was more impaired than the saccule. In HCA of RHS_D patients, the ASCC and utricle were initially clustered, followed by the LSCC, PSCC and saccule in order. In the HCA of SSNHL_D patients, the PSCC was solely merged and independently clustered. CONCLUSION: There were different patterns of vestibular impairments between RHS_D and SSNHL_D patients. The vestibular analysis and HCA results of SSNHL_D showed tendency of skip lesion, which could be explained by vascular pathophysiology.


Assuntos
Perda Auditiva Neurossensorial , Perda Auditiva Súbita , Herpes Zoster da Orelha Externa , Potenciais Evocados Miogênicos Vestibulares , Humanos , Tontura , Herpes Zoster da Orelha Externa/complicações , Herpes Zoster da Orelha Externa/diagnóstico , Estudos Retrospectivos , Vertigem , Perda Auditiva Neurossensorial/diagnóstico , Canais Semicirculares , Perda Auditiva Súbita/diagnóstico
7.
J Audiol Otol ; 27(1): 45-50, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35405063

RESUMO

Congenital middle ear cholesteatoma (CMEC) accounts for 2%-5% of all cases of middle ear cholesteatoma. CMEC is rare and diagnostically challenging; therefore, only a few cases are reported in the literature, and the pathophysiology of this condition remains largely unclear. Currently, epidermoid formation, amniotic fluid contamination, lack of the tympanic ring, and squamous metaplasia are among the mechanisms implicated in the pathogenesis of CMEC; however, no single theory satisfactorily explains the pathophysiology of this disorder. We report a case of CMEC in a young male patient, who showed a symmetric, binaural whitish mass posterior to the anterosuperior quadrant of the tympanic membrane. A few reports have described bilateral CMEC; however, no study has reported symmetrical CMEC as observed in this case. Bilateral tympanoplasty concomitant with cholesteatoma removal was performed, and histopathological evaluation of the resected specimen showed closed-type cholesteatoma. In this report, we describe a rare case of symmetric CMEC, which supports the epidermoid formation theory associated with CMEC, together with a literature review.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33859705

RESUMO

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

9.
Environ Chall (Amst) ; 3: 100042, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37521158

RESUMO

Plastic pollution has been a significant and widespread global issue, and the recent COVID-19 pandemic has been attributed to its worsening effect as plastics have been contaminated with the deadly infectious virus. Microplastics (MPs) may have played a role as a vector that carries hazardous microbes such as emerging bacterial threats (i.e. antibiotic resistant bacteria) and deadly viruses (e.g., coronavirus); this causes great concern over microplastics contaminated with emerging contaminants. Mitigation and treatment of MPs are challenging because of a range of factors including but not limited to physicochemical properties and composition of MPs and pH and salinity of the solution. Despite the heterogeneous nature of aquatic systems, research has overlooked interactions between contaminants and MPs under environmental conditions, degradation pathways of MPs with adsorbed contaminants, and, especially, the role of adsorbed contaminants in the efficiency of MP treatment through membrane filtration, in comparison with other treatment methods. This review aims to (1) analyze an assortment of factors that could influence the removal of MPs and mechanisms of contaminant adsorption on MPs, (2) identify mechanisms influencing membrane filtration of MPs, (3) examine the fate and transport of MPs with adsorbed contaminants, (4) evaluate membrane filtration of contaminant-adsorbing MPs in comparison to other treatment methods, and (5) draw conclusions and the future outlook based on a literature analysis.

10.
Int J Mol Sci ; 21(9)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32354117

RESUMO

p62/sequestosome-1 is a scaffolding protein involved in diverse cellular processes such as autophagy, oxidative stress, cell survival and death. It has been identified to interact with atypical protein kinase Cs (aPKCs), linking these kinases to NF-κB activation by tumor necrosis factor α (TNFα). The diverse functions of p62 are regulated through post-translational modifications of several domains within p62. Among the enzymes that mediate these post-translational modifications, little is known about the deubiquitinating enzymes (DUBs) that remove ubiquitin chains from p62, compared to the E3 ligases involved in p62 ubiquitination. In this study, we first demonstrate a role of ubiquitin-specific protease USP20 in regulating p62 stability in TNFα-mediated NF-κB activation. USP20 specifically binds to p62 and acts as a positive regulator for NF-κB activation by TNFα through deubiquitinating lysine 48 (K48)-linked polyubiquitination, eventually contributing to cell survival. Furthermore, depletion of USP20 disrupts formation of the atypical PKCζ-RIPK1-p62 complex required for TNFα-mediated NF-κB activation and significantly increases the apoptosis induced by TNFα plus cycloheximide or TNFα plus TAK1 inhibitor. These findings strongly suggest that the USP20-p62 axis plays an essential role in NF-κB-mediated cell survival induced by the TNFα-atypical PKCζ signaling pathway.


Assuntos
Lisina/metabolismo , Proteína Sequestossoma-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina Tiolesterase/metabolismo , Benzamidas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cicloeximida/farmacologia , Regulação da Expressão Gênica , Células HEK293 , Células HT29 , Células HeLa , Humanos , NF-kappa B/metabolismo , Piperazinas/farmacologia , Proteína Quinase C/metabolismo , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Piridinas/farmacologia , Pirróis/farmacologia , Proteína Sequestossoma-1/química , Transdução de Sinais , Ubiquitina Tiolesterase/genética
11.
EBioMedicine ; 49: 55-71, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31685442

RESUMO

BACKGROUND: Although bone morphogenetic protein 6 (BMP6) signaling pathway has been implicated in many types of cancer, its role of tumorigenesis seems to be controversial and its ubiquitin-modifying mechanisms have not been fully addressed. Our study was designed to investigate how BMP6 signaling pathway is regulated by ubiquitin-modifying systems and to address molecular and clinical significance in colorectal cancers. METHODS: Human deubiquitnase (DUB) siRNA library was used to screen the specific DUB, named PSMD14, involved in BMP6 signaling pathway. Immunoblot, immunoprecipitation and ubiquitination assays were used to analyze targets of the PSMD14. A role of PSMD14-mediated BMP6 signaling pathway for malignant cancer progression was investigated using in vitro and in vivo model of colorectal cancers as well as clinical samples of colorectal cancer patients. FINDINGS: The deubiquitinase PSMD14 acts as a positive regulator for the initiation of the BMP6 signaling pathway through deubiquitinating K48-linked ALK2 type I receptor ubiquitination mediated by Smurf1 E3 ligase, resulting in increased stability of the ALK2. This role of PSMD14 is independent of its intrinsic role in the 26S proteasome system. Furthermore, either PSMD14 or ALK2 depletion significantly decreases tumorigenesis of HCT116 colorectal cancer cells in a xenograft model as well as cancer stemness/chemoresistance, and expression of the PSMD14 and ALK2 gene are correlated with malignant progression and the survival of colorectal cancer patients. INTERPRETATION: These findings suggest that the PSMD14-ALK2 axis plays an essential role in initiation of the BMP6 signaling pathway and contributes to tumorigenesis and chemoresistance of colorectal cancers.


Assuntos
Receptores de Ativinas Tipo I/metabolismo , Proteína Morfogenética Óssea 6/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Lisina/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Poliubiquitina/metabolismo , Prognóstico , Ligação Proteica , Estabilidade Proteica , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
12.
Otolaryngol Head Neck Surg ; 160(5): 894-901, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30665325

RESUMO

OBJECTIVE: To analyze acute vertigo showing spontaneous nystagmus with negative video head impulse test (vHIT). STUDY DESIGN: Retrospective chart analysis. SETTING: Tertiary referral hospital. SUBJECTS AND METHODS: Over 16 months, 155 patients were identified with acute vertigo with spontaneous nystagmus. Of these 155, 30 (19.4%) were enrolled in this study because they did not show gain loss or catch-up saccades in both sides of the horizontal vHIT. Results of vestibular function tests (videonystagmography, horizontal vHIT, caloric test, and cervical vestibular-evoked myogenic potential [cVEMP]) and pure tone audiometry were analyzed. For all cases, magnetic resonance imaging with diffusion-weighted imaging was checked. RESULTS: Patients consisted of 17 with Ménière's disease and 7 with sudden sensorineural hearing loss with vertigo (SSNHL_V), and only 3 patients were finally diagnosed as having acute vascular stroke. Except for the loss of hearing on the lesion side, the direction of nystagmus or cVEMP asymmetry showed very different results. All 7 patients with SSNHL_V did not have canal paresis in the caloric test, but cVEMP amplitude was smaller on the lesion side for 6 patients. CONCLUSIONS: For patients with acute vertigo presenting spontaneous nystagmus with negative horizontal vHIT, it is important not only to focus on the diagnosis of acute vascular stroke but also to evaluate hearing because of the high possibility of Ménière's disease or SSNHL_V.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Doença de Meniere/diagnóstico , Nistagmo Patológico/etiologia , Vertigem/etiologia , Neuronite Vestibular/diagnóstico , Adulto , Idoso , Audiometria de Tons Puros , Feminino , Teste do Impulso da Cabeça , Perda Auditiva Neurossensorial/complicações , Humanos , Masculino , Doença de Meniere/complicações , Pessoa de Meia-Idade , Estudos Retrospectivos , Potenciais Evocados Miogênicos Vestibulares , Testes de Função Vestibular , Neuronite Vestibular/complicações , Vestíbulo do Labirinto , Adulto Jovem
13.
Stem Cells ; 37(3): 368-381, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30444564

RESUMO

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-ß signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-peroxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368-381.


Assuntos
Adipogenia , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Diferenciação Celular , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Proteína Smad4/genética , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
14.
Nat Cell Biol ; 19(10): 1260-1273, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28892081

RESUMO

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-ß1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3ß (GSK3ß), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-ß1-induced EMT and metastasis of basal-like breast cancers.


Assuntos
Neoplasias da Mama/enzimologia , Movimento Celular , Neoplasias Pulmonares/enzimologia , Fatores de Transcrição da Família Snail/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Lisina , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Fosforilação , Estabilidade Proteica , Interferência de RNA , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/farmacologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitinação/efeitos dos fármacos
15.
Phytother Res ; 29(3): 434-43, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25583173

RESUMO

Several studies have demonstrated that deregulated activation of signal transducer and activator of transcription 3 (STAT3) has been associated with survival, proliferation, chemoresistance and angiogenesis of tumour cells. Thus, inhibition of STAT3 expression could be a potent therapeutic approach for cancer treatment. Using several leukaemia cell lines, the effect of the hydrolysed-catalpol (H-catalpol) and hydrolysed-aucubin (H-aucubin) products on the STAT3 signalling pathway, inhibition of BCR-ABL activation, cellular proliferation and potentiation of imatinib mesylate-induced apoptosis was investigated. We found that iridoid glycosides (catalpol and aucubin) did not exert any cytotoxicity in the tumour cells, whereas both H-catalpol and H-aucubin exhibited significant cytotoxic effects on K562 human myeloid leukaemia cells. Indeed, H-catalpol and H-aucubin down-regulated BCR-ABL phosphorylation and inhibited constitutive STAT3 activation through abrogating upstream JAK2 and c-Src and constitutive STAT5 activation leading to apoptosis through caspase-3 activation. Hydrolysed-catalpol enhanced the apoptosis induced by imatinib mesylate and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1), and cell survival (Bcl-2, Bcl-xL and survivin); all known to be regulated by the STAT3. Overall, our results provide novel insight into the role of hydrolysed iridoids in potentially treating leukaemia through the modulation of STAT3 signalling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Glicosídeos Iridoides/farmacologia , Leucemia Mieloide/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Proteína Tirosina Quinase CSK , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Mesilato de Imatinib , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Glicosídeos Iridoides/química , Janus Quinase 2/metabolismo , Células K562/efeitos dos fármacos , Fosforilação , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo
16.
Clin Exp Otorhinolaryngol ; 3(4): 203-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21217961

RESUMO

OBJECTIVES: The aim of this study was to compare the hearing outcomes between canal wall up mastoidectmy (CWUM) and canal wall down mastoidectmy (CWDM). METHODS: One hundred seventy one chronic suppurative otitis media (CSOM) patients were enrolled in this retrospective study. The patients who underwent the second staged ossiculoplasty at least 6 months after mastoidectomy and who had an intact, well aerated tympanic cavity as well as intact mobile stapes at the time of operation were selected from the medical record. Based on the type of mastoid surgery, the patients were categorized into two groups: the CWUM (n=38) and CWDM groups (n=133). The hearing results of the CWUM and CWDM groups were compared using the pre- and post-operative air-bone gap (ABG) at 3 months after ossiculoplasty. RESULTS: The preoperative ABG in both groups (CWUM and CWDM) were 28.4±15.6 dB and 31.8±14.5 dB, respectively (P=0.18). Both groups didn't show any significant difference (10.9 dB vs. 13.5 dB, respectively) (P=0.21) for the postoperative ABG closure. The proportion of patients with an ABG less than 20 dB was 58.6% of the CWDM patients and 68.4% of the CWUM patients (P=0.25). CONCLUSION: The type of mastoid surgery (CWUM and CWDM) did not affect the hearing results of CSOM patients. When choosing the type of mastoidectomy procedure for CSOM surgery, the hearing outcomes are basically the same for both types of procedure.

17.
Int J Pediatr Otorhinolaryngol ; 72(1): 103-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18022702

RESUMO

OBJECTIVES: To evaluate the chronic bony changes in the paranasal sinuses of longstanding chronic rhinosinusitis (CRS) in pediatric patients and to compare them with normal controls. STUDY DESIGN: A single-institution retrospective analysis. METHOD: Thirty 15- and 16-year-old children with longstanding CRS, for more than 2 years, despite maximal medical treatment and had a Lund CT score over 20 were enrolled as the CRS group. They were compared with 45 age and gender matched randomly selected normal controls without CRS. No enrolled patient had a history of nasal or adenoid surgery. The volume of the maxillary sinus was measured using a three-dimensional CT reconstruction program (V-works 4.0). The bony thickness of the maxillary (MS) and ethmoid sinuses (ES) and the middle turbinate (MT) was measured and compared. In addition, we evaluated the effect of disease duration on the sinus volume and bony thickness. RESULTS: The mean volume of the MS was 22.5+/-4.4 cm(3) in the normal group and 20.0+/-4.1 cm(3) in the CRS group; this difference was statistically significant (p=0.02). However, there was no correlation found between the disease duration and maxillary sinus volume (r=-0.07, p=0.69). The mean thicknesses of the bony walls were 1.0+/-0.4 mm (MS), 0.8+/-0.4 mm (ES) and 1.8+/-0.5 mm (MT) in the normal group and 1.2+/-0.3 mm (MS), 1.2+/-0.4 mm (ES) and 2.4+/-0.5 mm (MT) in the CRS group; these differences were significant (p<0.01). In addition, the bony thickness of the ES was significantly correlated with the duration of symptoms (r=0.44, p=0.03). CONCLUSION: The volume of the maxillary sinuses decreased and the bony thickness of the paranasal sinuses increased with longstanding pediatric CRS.


Assuntos
Seio Maxilar/patologia , Seios Paranasais/patologia , Sinusite/patologia , Adolescente , Doença Crônica , Seio Etmoidal/patologia , Feminino , Humanos , Masculino , Seio Maxilar/diagnóstico por imagem , Tamanho do Órgão , Radiografia , Estudos Retrospectivos , Conchas Nasais/patologia
18.
Otolaryngol Head Neck Surg ; 137(4): 569-75, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17903572

RESUMO

OBJECTIVE: The authors aimed to assess the effect of vocal hygiene education for patients suffering with vocal polyp and to discover the meaningful factors that can predict better outcomes with performing vocal hygiene. STUDY DESIGN AND SETTING: Voice evaluation and vocal hygiene education were provided to 340 consecutive patients with vocal polyp. Three months later, 175 of the 340 patients completed a follow-up evaluation. According to the change in polyp size, these patients were divided into two groups: the "improvement" and the "no improvement." The effect of vocal hygiene was assessed. Eight parameters were compared between these two groups. RESULTS: The "improvement" group was composed of 20% of the 340 patients and 38% of the 175 patients. Multivariate analyses demonstrated that nonsmokers with a small polyp had the greatest possibility of improvement with vocal hygiene and so avoid unnecessary surgery. CONCLUSION: Patients who do not smoke and who have a polyp that is small in size have a much better chance to improve their voice by performing vocal hygiene.


Assuntos
Neoplasias Laríngeas/complicações , Educação de Pacientes como Assunto , Pólipos/complicações , Prega Vocal/patologia , Distúrbios da Voz/prevenção & controle , Adulto , Idoso , Meio Ambiente , Comportamento Alimentar , Feminino , Seguimentos , Previsões , Hábitos , Comportamentos Relacionados com a Saúde , Rouquidão/prevenção & controle , Humanos , Neoplasias Laríngeas/classificação , Neoplasias Laríngeas/terapia , Masculino , Pessoa de Meia-Idade , Pólipos/classificação , Pólipos/terapia , Autocuidado , Fala/fisiologia , Resultado do Tratamento , Distúrbios da Voz/etiologia , Qualidade da Voz/fisiologia , Treinamento da Voz
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