RESUMO
Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.
Assuntos
Peso Corporal/genética , Mitocôndrias/fisiologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Células 3T3-L1 , Animais , Células Cultivadas , Regulação para Baixo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genéticaRESUMO
Spontaneous regression (SR) of cancer is very rare, especially of small cell lung cancer (SCLC). Recently, an association of paraneoplastic neurological syndrome (PNS) has been reported as a cause of SR of cancer, and onconeural antibodies are a possible factor in the SR of cancer associated with PNS. We herein report the first case of SR of SCLC combined with anti-P/Q-type of voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS), a subtype of PNS. This case report suggests that SCLC may be spontaneously reduced by an autoimmune response induced by VGCC antibodies associated with LEMS. Our finding may help elucidate the mechanisms that inhibit tumor growth and cause the regression of tumors.
RESUMO
Progressive fibrosing interstitial lung diseases (PF-ILDs) have a poor prognosis and may be resistant to corticosteroids and/or immunosuppressants, but antifibrotic therapies such as nintedanib and pirfenidone have been shown to slow the deterioration of lung function. The aim of this study was to identify the characteristic cellular profile of bronchoalveolar lavage fluid at diagnostic bronchoscopy for predicting PF-ILDs, defined as fibrotic diseases on chest high-resolution computed tomography with more than a 5% relative decline in the percent predicted value of forced vital capacity (FVC) over 6 months. The proportions of inflammatory cells, CCR6-CXCR3- T helper type 2 (Th2) cells among conventional CD4+ T cells in bronchoalveolar lavage fluid (BALF) and peripheral blood, were measured by flowcytometry. The proportion of lymphocytes in BALF was significantly higher in non-PF-ILD patients than in PF-ILD patients. The proportion of Th2 cells in BALF, but not in peripheral blood, was significantly higher in PF-ILD patients than in non-PF-ILD patients. Multivariate analysis showed that a greater population of Th2 cells in BALF was the only indicator for PF-ILDs. An increased proportion of Th2 cells in BALF is associated with greater deterioration of lung function in fibrotic interstitial lung diseases.