RESUMO
Structural diversity of complex sphingolipids is important for maintenance of various cellular functions; however, the overall picture of the significance of this structural diversity remains largely unknown. To investigate the physiological importance of the structural diversity of complex sphingolipids, we here constructed a complex sphingolipid structural diversity disruption library in budding yeast, which comprises 11 mutants including with combinations of deletions of sphingolipid-metabolizing enzyme genes. The sensitivity of the mutants to various environmental stresses revealed that the more the structural variation of complex sphingolipids is limited, the more stress sensitivity tends to increase. Moreover, it was found that in mutant cells with only one subtype of complex sphingolipid, Slt2 MAP kinase and Msn2/4 transcriptional factors are essential for maintenance of a normal growth and compensation for reduced tolerance of multiple stresses caused by loss of complex sphingolipid diversity. Slt2 and Msn2/4 are involved in compensation for impaired integrity of cell walls and plasma membranes caused by loss of complex sphingolipid diversity, respectively. From these findings, it was suggested that loss of structural diversity of complex sphingolipids affects the environment of the cell surface, including both plasma membranes and cell walls, which could cause multiple environmental stress hypersensitivity.
Assuntos
Proteínas de Saccharomyces cerevisiae , Esfingolipídeos , Membrana Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Esfingolipídeos/metabolismo , Estresse Fisiológico , Fatores de Transcrição/metabolismoRESUMO
Sphingoid long-chain bases are essential intermediates of ceramides and complex sphingolipids, and function in the regulation of various signal transduction systems. Previously, we found that, in budding yeast, intracellularly accumulated dihydrosphingosine (DHS) causes mitochondrial reactive-oxygen species (ROS)-mediated cytotoxicity, which is much stronger than phytosphingosine. In this study, we screened for suppressor mutations that confer resistance to DHS, and identified RTG2, which encodes upregulation of the mitochondrial retrograde signaling pathway (RTG pathway). Deletion of RTG3 encoding transcriptional factor for the RTG pathway suppressed the cytotoxicity of DHS, whereas deletion of MKS1 or point mutation of LST8, both of which cause increased activity of the RTG pathway, enhanced the cytotoxicity. Moreover, the deletion of RTG3 also suppressed the DHS-induced increases in ROS levels. Finally, it was found that the RTG pathway is activated on DHS treatment. These results suggested that the cytotoxicity of DHS is partially mediated through activation of the RTG pathway.
Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Esfingolipídeos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Esfingosina/farmacologiaRESUMO
Previously, we found that yeast exhibits a strong growth defect with the combination of a lack of gene involved in structural modification of sphingolipids and repression of the phosphatidylserine synthase gene. Here we found that the double gene mutation causes reactive oxygen species-mediated cell growth defect, which is suppressed by deletion of LEM3 encoding the subunit of phospholipid flippase.
Assuntos
Fosfatidilserinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Saccharomycetales/crescimento & desenvolvimento , Saccharomycetales/metabolismo , Esfingolipídeos/metabolismoRESUMO
We present a case of cryptococcosis with adrenal insufficiency and meningitis in a healthy host without any risk factors. Antifungal therapy did not reduce the cryptococcal antigen titers of the cerebrospinal fluid and serum or the bilateral adrenal gland enlargement. It was suggested that the adrenal glands were the focus of persistent fungemia. Removal of both adrenal glands brought about a response to antifungal therapy. We conclude that if antifungal therapy is ineffective, bilateral adrenalectomy is an effective measure for treatment of such patients. Cryptococcosis is a possible cause of primary adrenal insufficiency in immunocompetent patients.
Assuntos
Doença de Addison/diagnóstico , Doença de Addison/tratamento farmacológico , Antifúngicos/uso terapêutico , Criptococose/diagnóstico , Criptococose/tratamento farmacológico , Meningite/diagnóstico , Meningite/tratamento farmacológico , Doença de Addison/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Povo Asiático , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Fungemia/diagnóstico , Fungemia/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do TratamentoRESUMO
Lipomatous angiomyofibroblastoma is extremely rare, with only 16 cases reported to date. We herein describe an additional case arising in the left vulvar region of a 49-year-old woman. The resected 5.3-cm yellowish tumor predominantly consisted of fat cells (85% of the tumor), together with medium- and small-sized vessels, multifocal fibrotic areas and pseudoangiomatous spaces. Spindle, rounded, and/or epithelioid tumor cells proliferated in a nest and/or cord-like pattern, or singly within perivascular fibrous tissues and between fat cells. The tumor cells were positive for vimentin, estrogen receptor, progesterone receptor, B-cell lymphoma 2, and CD10, but were negative for desmin, cytokeratin, epithelial membrane antigen, S-100 protein, human melanoma black 45, C-kit and p40. Ultrastructural examination revealed that these tumor cells exhibited fibroblastic characteristics. Lipomatous angiomyofibroblastoma should be discriminated from other lipomatous tumors, including spindle cell lipoma, angiomyolipoma and cellular angiofibroma containing numerous fat cells.
RESUMO
AIMS: To elucidate the histopathological findings of classical Lambl excrescences (LEs) and non-exophytic LEs (non-ex LEs) without excrescent papillary features. METHODS AND RESULTS: We examined 126 aortic valves (AVs) and revealed LEs (non-ex and/or classical), non-ex LEs and classical LEs in 106, 78 and 88 AVs, respectively. The detection of non-ex LEs was challenging, but elastica van Gieson stain highlighted their presence. Non-ex and classical LEs chiefly involved the ventricular regions, favoured posterior cusps and coexisted in the same areas of 31 AVs. A possible transformation of classical LEs into non-ex LEs was suggested histologically in 39 AVs. Non-ex LEs were associated with age of >70 years (P < 0.001) and marked deformity (P = 0.007). Classical LEs were associated inversely with marked deformity (P < 0.001), but not with age of >70 years. Compared with age- and sex-matched control AVs, non-ex LEs and marked deformity in dysfunctional AVs were more common (P = 0.037 and P < 0.001, respectively), but classical LEs were less common (P = 0.021). CONCLUSIONS: Non-ex LEs have subtle features but are a common form of LEs, and seem to develop from classical LEs. AV dysfunction-related marked deformity can promote non-ex LEs.