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1.
Development ; 148(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081130

RESUMO

Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays in mouse astrocytic cultures, we reveal a regulatory crosstalk between PHF8 and the Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain chromatin homeostasis and limit heterochromatin formation at synaptogenic genes. Our studies provide insights into the involvement of epigenetics in intellectual disability.


Assuntos
Astrócitos/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica , Histona Desmetilases/genética , Fatores de Transcrição/genética , Animais , Astrócitos/citologia , Sítios de Ligação , Biomarcadores , Diferenciação Celular/genética , Proliferação de Células , Perfilação da Expressão Gênica , Histona Desmetilases/metabolismo , Histonas/metabolismo , Camundongos , Modelos Biológicos , Neurogênese , Neurônios/metabolismo , Ligação Proteica , Sinapses/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica
2.
Hum Mol Genet ; 29(9): 1465-1475, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32280986

RESUMO

Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as 'severe' and 'mild' from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients' iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER-mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.


Assuntos
Esclerose Lateral Amiotrófica/genética , Mitocôndrias/genética , Degeneração Neural/genética , Proteínas de Transporte Vesicular/genética , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Diferenciação Celular/genética , Retículo Endoplasmático/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Degeneração Neural/patologia , Estresse Oxidativo/genética , RNA-Seq , Proteínas de Transporte Vesicular/deficiência
3.
J Exp Biol ; 225(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34904632

RESUMO

The interaction between supraphysiological cytosolic Ca2+ levels and mitochondrial redox imbalance mediates the mitochondrial permeability transition (MPT). The MPT is involved in cell death, diseases and aging. This study compared the liver mitochondrial Ca2+ retention capacity and oxygen consumption in the long-lived red-footed tortoise (Chelonoidis carbonaria) with those in the rat as a reference standard. Mitochondrial Ca2+ retention capacity, a quantitative measure of MPT sensitivity, was remarkably higher in tortoises than in rats. This difference was minimized in the presence of the MPT inhibitors ADP and cyclosporine A. However, the Ca2+ retention capacities of tortoise and rat liver mitochondria were similar when both MPT inhibitors were present simultaneously. NADH-linked phosphorylating respiration rates of tortoise liver mitochondria represented only 30% of the maximal electron transport system capacity, indicating a limitation imposed by the phosphorylation system. These results suggested underlying differences in putative MPT structural components [e.g. ATP synthase, adenine nucleotide translocase (ANT) and cyclophilin D] between tortoises and rats. Indeed, in tortoise mitochondria, titrations of inhibitors of the oxidative phosphorylation components revealed a higher limitation of ANT. Furthermore, cyclophilin D activity was approximately 70% lower in tortoises than in rats. Investigation of critical properties of mitochondrial redox control that affect MPT demonstrated that tortoise and rat liver mitochondria exhibited similar rates of H2O2 release and glutathione redox status. Overall, our findings suggest that constraints imposed by ANT and cyclophilin D, putative components or regulators of the MPT pore, are associated with the enhanced resistance to Ca2+-induced MPT in tortoises.


Assuntos
Tartarugas , Animais , Cálcio/metabolismo , Peptidil-Prolil Isomerase F , Peróxido de Hidrogênio , Mitocôndrias Hepáticas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Necrose Dirigida por Permeabilidade Transmembrânica da Mitocôndria , Permeabilidade , Ratos , Tartarugas/metabolismo
4.
Proc Natl Acad Sci U S A ; 116(39): 19464-19473, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31488723

RESUMO

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.


Assuntos
Dano ao DNA , Histona Desmetilases/metabolismo , Proteínas de Homeodomínio/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Embrião de Galinha , Metilação de DNA , Células-Tronco Embrionárias , Epigênese Genética , Estudo de Associação Genômica Ampla , Histona Desmetilases/genética , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/enzimologia , Neurogênese/fisiologia , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismo
5.
Gen Dent ; 70(4): 67-71, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35749250

RESUMO

Hereditary hemorrhagic telangiectasia (HHT) is a rare condition in which fragile vascular walls lead to increased risks of bleeding, cerebral abscesses, arteriovenous malformations, anemia, and thrombosis. To date, no protocol has been established for optimizing the clinical outcomes of periodontal treatment in patients with this condition. The aim of this case report is to describe a safe clinical approach to periodontal treatment in a patient with HHT. A 39-year-old woman had a history of multiple macules on the oral mucosa, and a diagnosis of HHT was made based on the Curaçao diagnostic criteria (epistaxis, telangiectases, visceral lesions, and family history). Evaluation of the patient's periodontal clinical parameters and radiographs led to a diagnosis of generalized periodontitis, stage IV, grade C. The patient underwent nonsurgical periodontal therapy consisting of supragingival and subgingival scaling and root planing under a careful and specific protocol that included antibiotic prophylaxis before each session. Two months after therapy, the periodontal reevaluation showed improvement in the clinical parameters at most sites. Sites with remaining periodontal pockets were re-treated according to the same protocol, including the antibiotic prophylaxis. The patient was enrolled in a periodontal maintenance program, and her HHT was routinely monitored by her physician. Periodontal treatment may promote secondary complications in patients with HHT if appropriate systemic care is not provided, and the periodontal treatment plan should be designed individually for each patient. Establishing the correct HHT diagnosis and coordinating care with the patient's physician are essential to safe, effective treatment.


Assuntos
Telangiectasia Hemorrágica Hereditária , Adulto , Assistência Odontológica , Feminino , Humanos , Mucosa Bucal , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/terapia , Resultado do Tratamento
6.
J Exp Biol ; 224(21)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34622285

RESUMO

Snakes are interesting examples of taxa that can overcome energy metabolism challenges, as many species can endure long periods without feeding, and their eventual meals are of reasonably large sizes, thus exhibiting dual extreme adaptations. Consequently, metabolic rate increases considerably to attend to the energetic demand of digestion, absorption and protein synthesis. These animals should be adapted to transition from these two opposite states of energy fairly quickly, and therefore we investigated mitochondrial function plasticity in these states. Herein, we compared liver mitochondrial bioenergetics of the boid snake Boa constrictor during fasting and after meal intake. We fasted the snakes for 60 days, and then we fed a subgroup with 30% of their body size and evaluated their maximum postprandial response. We measured liver respiration rates from permeabilized tissue and isolated mitochondria. From isolated mitochondria, we also measured Ca2+ retention capacity and redox status. Mitochondrial respiration rates were maximized after feeding, reaching an approximately 60% increase from fasting levels when energized with complex I-linked substrates. Interestingly, fasting and fed snakes exhibited similar respiratory control ratios and citrate synthase activity. Furthermore, we found no differences in Ca2+ retention capacity, indicating no increase in susceptibility to mitochondrial permeability transition, and no changes in mitochondrial redox state, although fed animals exhibited increases in the release of H2O2. Thus, we conclude that liver mitochondria from B. constrictor snakes increase respiration rates during the postprandial period and quickly improve the bioenergetic capacity without compromising redox balance.


Assuntos
Boidae , Animais , Metabolismo Energético , Peróxido de Hidrogênio , Fígado , Mitocôndrias
7.
J Craniofac Surg ; 32(5): e425-e427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33208703

RESUMO

ABSTRACT: Necrotizing fasciitis (NF) is an infection of the deeper tissues that results in progressive destruction of muscle fascia and overlying subcutaneous fat. It has a fast and destructive course. Moreover, it is related to immunosuppression and could be fatal. The aim of this study is to report a clinical case of a young patient, without immunosuppression, who developed NF evolution due to an erroneous diagnosis of abscess at the beginning of the disease. Patient was submitted to broad-spectrum antibiotic therapy and aggressive surgical treatment. Adequate treatment led to a satisfactory evolution in a short period of time. Early recognition and adequate treatment are essential for a favorable prognosis.


Assuntos
Fasciite Necrosante , Abscesso , Adulto , Antibacterianos/uso terapêutico , Face , Fasciite Necrosante/diagnóstico , Fasciite Necrosante/cirurgia , Humanos , Lábio , Masculino
8.
Nucleic Acids Res ; 46(7): 3351-3365, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29438503

RESUMO

During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFß signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFß-responsive Neurog2 enhancer is essential for proper neuronal polarization.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Elementos Facilitadores Genéticos/genética , Neurogênese/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Animais , Sistemas CRISPR-Cas/genética , Linhagem da Célula/genética , Polaridade Celular/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Fatores de Transcrição/genética
9.
BMC Public Health ; 20(1): 97, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969136

RESUMO

BACKGROUND: Lifestyle changes can reduce the risk of T2D; however, no study has evaluated the effect of a lifestyle intervention involving patients´ family. The aim of this study was to compare the impact of an interdisciplinary family (FI) Vs individual intervention (II) on glucose metabolism, insulin resistance (IR), pancreatic ß-cell function and cardiovascular risk markers in patients with prediabetes, as well as to measure the impact on their families' metabolic risk. METHODS: Randomized Clinical Trial (RCT) to compare the impact of FI and II on IR and pancreatic ß-cell function in subjects with prediabetes. There were 122 subjects with prediabetes (and 101 family members) randomized to FI or II. Data were collected in 2015-2016 and analyzed in 2017-2018. FI group had the support of their family members, who also received personalized diet and exercise recommendations; patients and their family members attended monthly a lifestyle enhancement program. II group received personalized diet and exercise recommendations. The follow-up was for 12 months. Glucose, IR, pancreatic ß-cell function and secondary outcomes (body composition and lipid profile) were assessed at baseline, 6 and 12 months. RESULTS: FI group improved area under the glucose curve (AUC) (from 18,597 ± 2611 to 17,237 ± 2792, p = 0.004) and the Matsuda index (from 3.5 ± 2.3 to 4.7 ± 3.5, p = 0.05) at 12 months. II group improved Disposition Index (from 1.5 ± 0.4 to 1.9 ± 0.73, p < .0001) at 12 months. The improvements achieved in weight and lipids at 6 months, were lost in II group at 12 moths, whereas in FI persisted. Adherence up to 12 months was not different between the study groups (FI 56% Vs II 60%). CONCLUSIONS: FI intervention was more effective by improving glucose AUC, insulin sensitivity and lipid profile, besides that, metabolic risk in family members of the FI group was maintained, while the risk of II group was increased. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov on December 15, 2015 (NTC026365646).


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Família , Estilo de Vida , Educação de Pacientes como Assunto/organização & administração , Estado Pré-Diabético/fisiopatologia , Adolescente , Adulto , Biomarcadores , Glicemia , Dieta , Exercício Físico/fisiologia , Feminino , Humanos , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
10.
J Cutan Pathol ; 46(10): 778-783, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31115930

RESUMO

The low-fat and fat-free spindle cell lipomas (SCLs) are rare and often mistaken for other benign and malignant morphological mimics, because of the fact that the diagnosis relies on its non-lipogenic component analysis. Here, we report the clinicopathological features of two oral SCLs (low-fat and fat-free variants). Both lesions presented clinically as an asymptomatic nodule, which initially yielded diagnostic difficulties on the morphological analysis alone. One case was diagnosed as low-fat SCL on the lower lip in a 29-year-old man, and the other as fat-free SCL on the buccal mucosa in a 46-year-old man. In both cases, immunohistochemistry showed strong positivity for CD34 and, remarkably, retinoblastoma (Rb) protein was deficient. Mast cell (MC) tryptase and toluidine blue stain highlighted numerous MCs distributed throughout all tumor stroma. Alpha-SMA and desmin were negative. S100 evidenced scarce adipocytes only in the low-fat SCL case. Conservative surgical treatment was performed and no recurrence was noticed in about 2-year of follow-up in both cases. Because of the potential pitfalls, careful morphological analysis of the tumor stroma in the low-fat/fat-free SCL diagnosis, supported by immunohistochemistry (especially CD34, Rb and MC tryptase), is strongly recommended. To the best of our knowledge, these are the first and second cases reported of fat-free and low-fat SCL in the oral cavity.


Assuntos
Adipócitos , Lipoma , Neoplasias Bucais , Sarcoma , Adipócitos/metabolismo , Adipócitos/patologia , Adulto , Humanos , Lipoma/metabolismo , Lipoma/patologia , Masculino , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Sarcoma/metabolismo , Sarcoma/patologia
11.
J Neurochem ; 147(5): 663-677, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30281804

RESUMO

Among mitochondrial NADP-reducing enzymes, nicotinamide nucleotide transhydrogenase (NNT) establishes an elevated matrix NADPH/NADP+ by catalyzing the reduction of NADP+ at the expense of NADH oxidation coupled to inward proton translocation across the inner mitochondrial membrane. Here, we characterize NNT activity and mitochondrial redox balance in the brain using a congenic mouse model carrying the mutated Nnt gene from the C57BL/6J strain. The absence of NNT activity resulted in lower total NADPH sources activity in the brain mitochondria of young mice, an effect that was partially compensated in aged mice. Nonsynaptic mitochondria showed higher NNT activity than synaptic mitochondria. In the absence of NNT, an increased release of H2 O2 from mitochondria was observed when the metabolism of respiratory substrates occurred with restricted flux through relevant mitochondrial NADPH sources or when respiratory complex I was inhibited. In accordance, mitochondria from Nnt-/- brains were unable to sustain NADP in its reduced state when energized in the absence of carbon substrates, an effect aggravated after H2 O2 bolus metabolism. These data indicate that the lack of NNT in brain mitochondria impairs peroxide detoxification, but peroxide detoxification can be partially counterbalanced by concurrent NADPH sources depending on substrate availability. Notably, only brain mitochondria from Nnt-/- mice chronically fed a high-fat diet exhibited lower activity of the redox-sensitive aconitase, suggesting that brain mitochondrial redox balance requires NNT under the metabolic stress of a high-fat diet. Overall, the role of NNT in the brain mitochondria redox balance especially comes into play under mitochondrial respiratory defects or high-fat diet.


Assuntos
Química Encefálica/fisiologia , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Mitocôndrias/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/metabolismo , Envelhecimento , Animais , Química Encefálica/efeitos dos fármacos , Complexo I de Transporte de Elétrons , Metabolismo Energético/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , NADP/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/genética , Oxirredução , Consumo de Oxigênio/genética , Consumo de Oxigênio/fisiologia , Sinaptossomos/metabolismo
12.
Cell Biol Int ; 42(6): 742-746, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29424467

RESUMO

Mitochondrial redox imbalance and high Ca2+ uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy-linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)-transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca2+ -induced PTP. We highlight the aggravation of high fat diet-induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria.


Assuntos
Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , NADP Trans-Hidrogenases/genética , Animais , Dieta Hiperlipídica , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/veterinária , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial , NADP Trans-Hidrogenases/metabolismo , Permeabilidade/efeitos dos fármacos , Ubiquinona/análogos & derivados , Ubiquinona/química , Ubiquinona/metabolismo
13.
J Oral Pathol Med ; 47(1): 3-10, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28600896

RESUMO

BACKGROUND: Several studies investigate the prognostic value of squamous cell carcinoma antigen (SCC-Ag) in head and neck squamous cell carcinoma (HNSCC) patients, with contradicting findings. Considering this, the aim of this study was to evaluate the prognostic value of high SCC-Ag levels and its association with clinicopathological features of HNSCC. MATERIAL AND METHODS: PubMed, SCOPUS, and Cochrane Library were searched for relevant studies up to December 2015. English-language publications assessing clinicopathological features of HNSCC and the prognostic significance of SCC-Ag in this disease were included. A meta-analysis was performed using Review Manager 5.3 and STATA version 14 software to clarify a possible association between SCC-Ag and clinical outcomes. RESULTS: A total of 11 studies met inclusion criteria, comprising 1901 cases of HNSCC. The results of the meta-analysis showed that there was significant correlation between high SCC-Ag levels and males (odds ratio [OR]=2.99, 95% CI: 1.18-7.57, P=.02 fixed-effect), and advanced TNM stages (OR=3.18, 95% CI: 1.88-5.38, P<.0001 random-effect). The survival meta-analysis showed a pooled hazard ratio for disease-free survival (DFS) and overall survival (OS) of 1.01 (95% CI: 0.70-1.31) and 0.86 (95% CI: 0.54-1.17), respectively. CONCLUSION: Our meta-analysis suggests that elevated SCC-Ag levels have a significant correlation with males and TNM stage, but may not be used as predictive marker for OS and DFS in HNSCC patients.


Assuntos
Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias de Cabeça e Pescoço/sangue , Serpinas/sangue , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metanálise como Assunto , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida
14.
J Craniofac Surg ; 28(3): 794-797, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28468168

RESUMO

Osteoblastomas are benign bone tumors, which are unusual in the craniofacial skeleton, being most often observed in the axial skeleton and long bones. The most common site in the maxillofacial region is the mandible and the involvement of the maxilla and paranasal sinuses is extremely rare. Although it is a benign lesion, the aggressive variant raises concerns due to its huge local destructive potential and tendency to relapse. In this clinical case, an aggressive osteoblastoma is described in a 7-year-old patient. The lesion was large and fully involved the left maxilla, including the maxillary sinus and the nasal cavity. Recurrent volume increase was observed 2 months following enucleation of the lesion and en bloc resection of the maxillary segment was performed. Histological and immunohistochemical evaluation associated with clinical and imaging findings allowed to define the tumor as an aggressive variant of osteoblastoma and not osteosarcoma, despite the aggressive behavior. The patient recovered well and no relapses were observed after 12 months following maxillary resection.


Assuntos
Neoplasias Ósseas/cirurgia , Maxila/patologia , Neoplasias Maxilares/diagnóstico , Estadiamento de Neoplasias , Procedimentos Cirúrgicos Bucais/métodos , Osteoblastoma/diagnóstico , Neoplasias Ósseas/diagnóstico , Criança , Humanos , Imageamento por Ressonância Magnética , Masculino , Maxila/cirurgia , Neoplasias Maxilares/cirurgia
15.
Int J Paediatr Dent ; 27(3): 231-235, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27914098

RESUMO

BACKGROUND: Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a distinct subtype of inflammatory gingival hyperplasia that shows lack of response to traditional periodontal treatment, and after surgical excision, recurrence rate of 6-16% has been reported. CASE REPORT: Two girls (11- and 9-year-old) with multifocal red patches along the maxillary and mandibular labial gingiva showed no regression of the lesions after basic periodontal treatment. Surgical excision of focal lesion in each case was performed, which showed typical features of LJSGH. In both cases, the lesions presented recurrence. Hence, cryotherapy sessions in all lesions were performed. CONCLUSION: Cryotherapy appears to be successfully in LJSGH and well received by paediatric patients.


Assuntos
Criocirurgia/métodos , Hiperplasia Gengival/cirurgia , Criança , Feminino , Gengivite/cirurgia , Humanos , Mandíbula/cirurgia , Maxila/cirurgia , Recidiva , Reoperação
16.
J Craniofac Surg ; 27(8): 2084-2087, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28005758

RESUMO

This article describes the occurrence of diffuse large B-cell lymphoma in a 39-year-old human immunodeficiency virus-positive patient. The patient sought medical care complaining of increased volume in the right mandibular angle and imaging tests showed an extensive radiolucency with undefined boundaries compromising the mandibular border. After the incisional biopsy, the patient had a pathological fracture in the region, which was properly treated in a second surgical procedure using a 2.4-mm reconstruction plate. Immunohistochemical analysis revealed positive marking for CD3, CD79a, Ki67, and Epstein-Barr virus-encoded RNA. The treatment consisted of concurrent antiretroviral therapy with chemotherapy with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone. Examinations of images (2 years postoperatively) revealed complete bone repair and absence of injury recurrence. This work is important because it describes an unusual location of diffuse large B-cell lymphoma and shows the importance of diagnosis and treatment of the injury at an early stage in order to promote the prognosis and survival of patients.


Assuntos
Fixação Interna de Fraturas/métodos , Fraturas Espontâneas/etiologia , Infecções por HIV/complicações , Soropositividade para HIV/complicações , HIV , Linfoma Difuso de Grandes Células B/complicações , Fraturas Mandibulares/etiologia , Adulto , Biópsia , Placas Ósseas , Parafusos Ósseos , Feminino , Fraturas Espontâneas/diagnóstico , Fraturas Espontâneas/cirurgia , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Fraturas Mandibulares/diagnóstico , Fraturas Mandibulares/cirurgia , Radiografia Panorâmica
17.
Free Radic Biol Med ; 222: 569-578, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39009245

RESUMO

Mitophagy is a mechanism that maintains mitochondrial integrity and homeostasis and is thought to promote longevity and reduce the risk of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Here, we investigate the abundance of mitochondrial reactive oxygen species (ROS), mitochondrial function, and mitophagy in primary fibroblasts from patients with sporadic AD (sAD) and normal healthy controls. The results show increased levels of mitochondrial ROS, changes in mitochondrial morphology, altered bioenergetic properties, and defects in autophagy, mitophagy, and lysosome-mediated degradation pathways in sAD fibroblasts relative to control fibroblasts. Interestingly, lysosome abundance and the staining of lysosomal markers remained high, while the capacity of lysosome-dependent degradation was lower in sAD fibroblasts than in controls fibroblasts. Nicotinamide riboside supplementation decreased mitochondrial ROS, while capacity for lysosomal degradation remained unchanged in sAD fibroblasts relative to healthy control fibroblasts. These findings provide insight into molecular mechanisms involving the dysregulation of lysosome and autophagy/mitophagy pathways that may contribute significantly to clinical signs and pathological features of sAD.


Assuntos
Doença de Alzheimer , Autofagia , Fibroblastos , Lisossomos , Mitocôndrias , Mitofagia , Espécies Reativas de Oxigênio , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Lisossomos/metabolismo , Lisossomos/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Células Cultivadas , Estudos de Casos e Controles , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Piridínio
18.
Exp Gerontol ; 193: 112465, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38795789

RESUMO

Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt-/-) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt-/- mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt-/- mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt-/- mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.


Assuntos
Envelhecimento , Metabolismo Energético , Mitocôndrias Musculares , Músculo Esquelético , Animais , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Camundongos , Músculo Esquelético/metabolismo , Mitocôndrias Musculares/metabolismo , Masculino , NADP Trans-Hidrogenase Específica para A ou B/metabolismo , NADP Trans-Hidrogenase Específica para A ou B/genética , Consumo de Oxigênio/fisiologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais
19.
Eur J Endocrinol ; 190(2): 130-138, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38261461

RESUMO

BACKGROUND: Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. OBJECTIVE: Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. DESIGN: The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). METHODS: NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. RESULTS: NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. CONCLUSIONS: The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.


Assuntos
Doença de Addison , NADP Trans-Hidrogenases , Animais , Humanos , Camundongos , Leucócitos Mononucleares/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , NAD , NADP Trans-Hidrogenase Específica para A ou B/genética , NADP Trans-Hidrogenase Específica para A ou B/metabolismo , NADP Trans-Hidrogenases/genética , NADP Trans-Hidrogenases/metabolismo
20.
J Funct Morphol Kinesiol ; 8(2)2023 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-37367241

RESUMO

Advanced knee osteoarthritis patients' gait usually undergoes alterations leading to decreased mobility and lower functional performance, which can result in a worsening of their quality of life (QoL). While several authors have reported a moderate correlation between gait parameters and QoL assessed by generic questionnaires, the literature is scarce. This study aimed to explore the relationship between gait and QoL parameters assessed by a generic and a disease-specific questionnaire in patients with advanced knee osteoarthritis. In this single-centre, prospective, observational study, 129 patients with advanced knee osteoarthritis scheduled for elective total knee replacement were selected. The patients' gait was evaluated by means of a validated wireless device while they walked 30 m at a comfortable speed. Patient function was also analysed using the Knee Society Score (KSS). QoL was measured with the EQ-5D and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaires. Patients showed a mean walking speed of 0.95 ± 0.19 m/s, a mean cadence of 105.6 ± 9.9 steps/min, and a mean stride length of 1.25 ± 0.17 m on both legs. They presented poor knee status (KSS < 60) and poor QoL, with an EQ-5D of 0.44 ± 0.24 and a total KOOS of 29.77 ± 13.99. Positive low correlations (r <0.5, p <0.5) were found only between the speed, propulsion and stride length of both legs, and the overall and ADLs subscale scores of the total KOOS questionnaire. In conclusion, several gait parameters have a significant low correlation with the QoL of patients with advanced knee osteoarthritis, as assessed by an osteoarthritis-specific questionnaire.

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