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Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a Type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice, and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in mouse sepsis models. Using cultured peritoneal and bone marrow-derived macrophages we demonstrated that Pnpt1 regulated NLRP3 inflammasome dependent IL-1β release in response to lipopolysaccharides (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS, and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on both increased glycolysis and expression of the mitochondrial antiviral-signaling protein (MAVS), but not NF-κB signaling. Collectively, these data strengthen the concept that Pnpt1 is an important mediator of inflammation as shown by activation of the NLRP3 inflammasome in mouse sepsis and cultured macrophages.

Pyroptosis is a form of cell death triggered by the innate immune system that has been implicated in the pathogenesis of sepsis and acute lung injury. At the cellular level, pyroptosis is characterized by cell swelling, membrane rupture, and release of inflammatory cytokines, such as IL-1β. However, the role of endogenous lipids in pyroptosis remains underappreciated. We discovered that 4-hydroxynonenal (HNE), a major endogenous product of lipid peroxidation, inhibited pyroptosis and inflammasome activation. HNE at physiological concentrations (3 µM) blocked nigericin and ATP-induced cell death, as well as secretion of IL-1β, by mouse primary macrophages and human peripheral blood mononuclear cells. Treatment with HNE, or an increase of endogenous HNE by inhibiting glutathione peroxidase 4, reduced inflammasome activation in mouse models of acute lung injury and sepsis. Mechanistically, HNE inhibited the NLRP3 inflammasome activation independently of Nrf2 and NF-κB signaling, and had no effect on the AIM2 inflammasome. Furthermore, HNE directly bound to NLRP3 and inhibited its interaction with NEK7. Our findings identify HNE as a novel, endogenous inhibitor of the NLRP3 inflammasome.

PURPOSE: investigate the existence of dysfunctional temporomandibular disorders, and as a predisposing factor to investigate tubal dysfunction in patients with cleft palate. METHOD: 10 individuals (20 temporomandibular joints), operated of cleft palate had been evaluated, that were in treatment in the Clinical Center of Fonoaudiologia of the PUC-MG, with age varying between 8 and 18 years, of both gender, and that they presented history of middle otitis in first infancy. The same ones had been submitted to the meatoscopia, imitanciometria, research of the tube function, examination of feel of the face muscle and examinations of image (x-rays transcraniana in 6 positions and AP of Town). Being compared for the Accurate Test of Fisher (p

OBJETIVO: investigar, em indivíduos com fissura palatina, a existência de disfunções temporomandibulares, tendo como fator predisponente a disfunção tubária. MÉTODO: foram avaliados 10 indivíduos (20 articulações temporomandibulares), operados de fissura de palato, que estavam em tratamento no Centro Clínico de Fonoaudiologia da PUC Minas, com idade variando entre 8 e 18 anos, de ambos os sexos, e que apresentavam história de otite média na primeira infância. Esses foram submetidos à meatoscopia, imitanciometria, pesquisa da função tubária, exame de palpação da musculatura orofacial e exames de imagem (radiografias transcraniana em seis posições e Ap de Town). RESULTADOS: foi observado que a maioria da amostra apresentava disfunção da tuba auditiva, correspondendo a 80% do total. Em relação à articulação temporomandibular nove indivíduos (90%) não apresentaram disfunção, em apenas um indivíduo (10%) foi verificado presença de desordem temporomandibular. CONCLUSÃO: ao analisar a relação entre a disfunção tubária e disfunção temporomandibular, não foram observados resultados significantes de acordo com o Teste Exato de Fisher, evidenciando que a articulação temporomandibular dos fissurados de palato, não sofre alterações provenientes do funcionamento ineficiente da tuba auditiva. PURPOSE: investigate the existence of dysfunctional temporomandibular disorders, and as a predisposing factor to investigate tubal dysfunction in patients with cleft palate. METHOD: 10 individuals (20 temporomandibular joints), operated of cleft palate had been evaluated, that were in treatment in the Clinical Center of Fonoaudiologia of the PUC-MG, with age varying between 8 and 18 years, of both gender, and that they presented history of middle otitis in first infancy. The same ones had been submitted to the meatoscopia, imitanciometria, research of the tube function, examination of feel of the face muscle and examinations of image (x-rays transcraniana in 6 positions and AP of Town). Being compared for the Accurate Test of Fisher (p