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1.
Neural Regen Res ; 17(10): 2293-2299, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35259852

RESUMO

Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106-126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106-126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

2.
J Clin Endocrinol Metab ; 106(6): 1566-1575, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33711158

RESUMO

CONTEXT: Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown. OBJECTIVE: This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN. METHODS: A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients. RESULTS: The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders. CONCLUSION: Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN.


Assuntos
Neuropatias Diabéticas/patologia , Substância Cinzenta/ultraestrutura , Córtex Somatossensorial/ultraestrutura , Adulto , Estudos de Casos e Controles , China , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/psicologia , Neuropatias Diabéticas/diagnóstico , Neuropatias Diabéticas/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Prognóstico , Índice de Gravidade de Doença , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia
3.
Cancers (Basel) ; 12(11)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238517

RESUMO

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan-Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.

4.
J Clin Endocrinol Metab ; 104(7): 3025-3038, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30817818

RESUMO

CONTEXT: Middle-aged to elderly patients with type 2 diabetes mellitus (T2DM) exhibit reduced functional connectivity and brain atrophy underlying cognitive decrements; however, little is known about brain abnormalities in young patients. OBJECTIVE: To detect brain anatomical and functional changes in young patients with T2DM during the early disease stage. DESIGN: Case-control study. SETTING: Tertiary referral hospital. PARTICIPANTS: Thirty-five young patients with T2DM (<40 years of age) with no detectable microangiopathy and 32 nondiabetic control subjects. INTERVENTION: None. MAIN OUTCOME MEASURES: Subjects underwent neuropsychological assessments and structural and resting-state functional MRI. Both voxel-based morphometry and resting-state functional connectivity analyses were performed. RESULTS: No significant differences in brain volume were observed between the patients with T2DM and the controls after controlling for age, sex, education, and body mass index. Compared with the controls, the patients showed greater connectivity of the left hippocampus with the left inferior frontal gyrus and the left inferior parietal lobule. Moreover, the enhanced functional connectivity of left hippocampus with the left inferior frontal gyrus significantly correlated with disease severity (urinary albumin-to-creatinine ratio) (r = 0.613, P < 0.001) and executive function (completion time of Stroop Color and Word Test) (r = -0.461, P = 0.005) after false discovery rate correction. CONCLUSIONS: Our findings suggest an adaptive compensation of brain function to counteract the insidious cognitive decrements during the early stage of T2DM. Additionally, the functional alterations occurring before changes in brain structure and peripheral microangiopathy might serve as early biomarkers related to cognitive decrements.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Hipocampo/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Diabetes Mellitus Tipo 2/psicologia , Função Executiva/fisiologia , Feminino , Neuroimagem Funcional , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Tamanho do Órgão , Lobo Parietal/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Índice de Gravidade de Doença , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
5.
ACS Chem Biol ; 12(1): 63-72, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28103685

RESUMO

Fucose is an important component of many oligo- and polysaccharide structures as well as glycoproteins and glycolipids, which are often associated with a variety of physiological processes ranging from fertilization, embryogenesis, signal transduction, and disease progression, such as rheumatoid arthritis, inflammation, and cancer. The enzyme α-l-fucosidase is involved in the cleavage of the fucosidic bond in glycans and glycoconjugates, particularly the Fuc-α-1,2-Gal, Fuc-α-1,3/4-GlcNAc, and Fuc-α-1,6-GlcNAc linkages. Here, we report a highly efficient fucosidase, designated as BfFucH identified from a library of bacterial glycosidases expressed in E. coli from the CAZy database, which is capable of hydrolyzing the aforementioned fucosidic linkages, especially the α-1,6-linkage from the N-linked Fuc-α-1,6-GlcNAc residue on glycoproteins. Using BfFucH coupled with endoglycosidases and the emerging glycosynthases allows glycoengineering of IgG antibodies to provide homogeneous glycoforms with well-defined glycan structures and optimal effector functions.


Assuntos
Bactérias/enzimologia , Fucose/metabolismo , Glicoproteínas/metabolismo , Imunoglobulina G/metabolismo , alfa-L-Fucosidase/metabolismo , Bactérias/metabolismo , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Fucose/química , Glicoconjugados/química , Glicoconjugados/metabolismo , Glicoproteínas/química , Humanos , Imunoglobulina G/química , Polissacarídeos/química , Polissacarídeos/metabolismo , Especificidade por Substrato
6.
Proc Natl Acad Sci U S A ; 112(34): 10611-6, 2015 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-26253764

RESUMO

Antibodies have been developed as therapeutic agents for the treatment of cancer, infection, and inflammation. In addition to binding activity toward the target, antibodies also exhibit effector-mediated activities through the interaction of the Fc glycan and the Fc receptors on immune cells. To identify the optimal glycan structures for individual antibodies with desired activity, we have developed an effective method to modify the Fc-glycan structures to a homogeneous glycoform. In this study, it was found that the biantennary N-glycan structure with two terminal alpha-2,6-linked sialic acids is a common and optimized structure for the enhancement of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antiinflammatory activities.


Assuntos
Fragmentos Fc das Imunoglobulinas/química , Imunoglobulina G/química , Polissacarídeos/química , Rituximab/química , Acetilglucosamina/química , Acetilglucosamina/imunologia , Animais , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Proteínas de Bactérias/metabolismo , Bacteroides fragilis/enzimologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/metabolismo , Infecções por Orthomyxoviridae/prevenção & controle , Engenharia de Proteínas , Receptores de IgG/imunologia , Rituximab/imunologia , Ácidos Siálicos/química , Ácidos Siálicos/imunologia , Streptococcus pyogenes/enzimologia , Relação Estrutura-Atividade , Trastuzumab/química , Trastuzumab/imunologia , alfa-L-Fucosidase/metabolismo
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