Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. ⋯ Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated. Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT). Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.
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Necrosis with inflammation plays a crucial role in acute respiratory distress syndrome (ARDS). Receptor-interacting protein 3 (RIPK3) regulates a newly discovered programmed form of necrosis called necroptosis. However, the underlying mechanism of necroptosis in ARDS remains unknown. ⋯ KEY MESSAGES: Lung injury in high-dose LPS-induced severe ARDS is mainly due to RIP3-MLKL-mediated necroptosis and endothelial dysfunction. Chaperone HSP90/p23 is a novel RIP3- and MLKL-interacting complex in HPAECs. HSP90/p23 is a novel RIP3- and MLKL-interacting complex in RIP-MLKL-mediated necroptosis, inflammation and endothelial dysfunction.
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Here we report a novel role for TRPC6, a member of the transient receptor potential (TRPC) channel family, in the CXCL1-dependent recruitment of murine neutrophil granulocytes. Representing a central element of the innate immune system, neutrophils are recruited from the blood stream to a site of inflammation. The recruitment process follows a well-defined sequence of events including adhesion to the blood vessel walls, migration, and chemotaxis to reach the inflammatory focus. ⋯ Mechanistically, TRPC6-/- neutrophils exhibited lower Ca2+ transients during the initial adhesion leading to diminished Rap1 and β2 integrin activation and thereby reduced ICAM-1 binding. In summary, our study reveals that TRPC6 channels in neutrophils are crucial signaling modules in their recruitment from the blood stream in response to CXCL1. KEY POINT: Neutrophil TRPC6 channels are crucial for CXCL1-triggered activation of integrins during the initial steps of neutrophil recruitment.
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The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. ⋯ Systems biology-based analysis revealed distinct molecular signature in CHDs. Gene expression modules specifically associated with cyanotic TOF were uncovered. Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.
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In an earlier study, a novel Sendai virus-vectored anti-tuberculosis vaccine encoding Ag85A and Ag85B (SeV85AB) was constructed and shown to elicit antigen-specific T cell responses and protection against Mycobacterium tuberculosis (Mtb) infection in a murine model. In this study, we evaluate whether the immune responses induced by this novel vaccine might be elevated by a recombinant DNA vaccine expressing the same antigen in a heterologous prime-boost vaccination strategy. The results showed that both SeV85AB prime-DNA boost (SeV85AB-DNA) and DNA prime-SeV85AB boost (DNA-SeV85AB) vaccination strategies significantly enhanced the antigen-specific T cell responses induced by the separate vaccines. ⋯ KEY MESSAGES: A heterologous prime-boost regimen with a novel recombinant SeV85AB and a DNA vaccine increase the T cell responses above those from a single vaccine. The heterologous prime-boost regimen provided protection against Mtb infection. The DNA vaccine might be included in a novel SeV85AB immunization strategy designed to enhance the immune protection against Mtb.