1,721,076 research outputs found
Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases
No full textAutophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear. © 2014 Springer-Verlag Berlin Heidelberg
Temporal changes in co-morbidities and mortality in patients hospitalized for COVID-19 in Italy
No full textCausative and common PHOX2B variants define a broad phenotypic spectrum
No full textPaired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non‐PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine‐contractions, gene deletions may influence the occurrence of either apparent life‐threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity
Correspondence regarding: Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes
No full textTumor necrosis factor in congestive heart failure: A mechanism of disease for the new millennium?
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Bradykinin and coronary artery disease
No full textAlthough the benefits of angiotensin-converting enzyme (ACE) inhibitors in limiting the progression of a variety of cardiovascular diseases are well known, their mechanisms of action have not been completely discovered. A reduction in the synthesis of the potent vasoconstricting agent angiotensin II has for a long time been considered to be the leading mechanism to account for the effects of ACE inhibitors. However, another action of these relatively old drugs is emerging: the increased availability of bradykinin. This kinin, which is broken down by ACE, has potent cardioprotective, antithrombotic antitrophic and vasodilator effects occurring through the stimulation of specific receptors on several cells. The recent development of a specific bradykinin-receptor blocking agent, icatibant, has allowed better understanding of the therapeutic properties of ACE inhibitors mediated by bradykinin both in experimental and clinical studies
Correspondence regarding: Alexander disease mutant glial fibrillary acidic protein compromises glutamate transport in astrocytes J Neuropathol Exp Neurol 2010;69:335-45
No full textSpecies-specific modulation of the nitric oxide pathway following acute experimentally-induced endotoxemia
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