University of Seville

About: University of Seville is a education organization based out in Seville, Andalucía, Spain. It is known for research contribution in the topics: Population & Model predictive control. The organization has 20098 authors who have published 47317 publications receiving 947007 citations. The organization is also known as: Universidad de Sevilla.

Caspase signalling controls microglia activation and neurotoxicity

Abstract: Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-d-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves. Numerous in vivo clinical imaging and neuropathology studies suggest that activated microglia, the resident immune cells of the central nervous system, play prominent roles in the pathogenesis of neurodegenerative disorders, including PD, multiple sclerosis and AD 1,2 . Microglia are necessary for normal brain function; however, uncontrolled and over-activated microglia can trigger neurotoxicity. They are a prominent source of pro-inflammatory factors and oxidative stress such as tumour-necrosis factor (TNF)-a, nitric oxide and interleukin (IL)-1b, which are neurotoxic 2,3 . Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia 1 . Intracerebral delivery of lipopolysaccharide (LPS), the major component of Gram-negative bacterial walls and a ligand for TLR4, leads in vivo to microglia activation and neuronal injury, and is used as model for brain inflammation 4,5 . Synergistic effects between interferon-c (IFN-c) and several TLR ligands (including TLR4) have been suggested, suggesting crosstalk between these pro-inflammatory receptor signalling pathways 6 . Furthermore, IFN-c receptor-deficient mice are less susceptible to LPS-induced endotoxic shock than control mice 7 . Finally, TLR4 has been implicated in AD pathophysiology in several contexts. Thus, the upregulation of cytokines is TLR4 dependent in an AD mouse model 8 ; certain TLR4 single nucleotide polymorphisms are associated with increased risk for AD 9 ; the levels of TLR4 messenger RNA (mRNA) are upregulated in APP transgenic mice 10 ; and increased TLR4 expression is associated with amyloid plaque deposition in AD brain tissue 10 . Caspases, a family of cysteinyl-aspartate-specific proteases, are executioners of apoptotic cell death and their activation is considered a commitment to cell death 11,12 . Certain caspases, for example caspase-1, also play a pivotal role in immune-mediated inflammation. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as IL-1b, IL-18, IL-33, and not with apoptosis 13 . Inhibition of caspase activation protects against neuronal loss in several animal models of brain diseases involving activated microglia, including hypoxic ischaemia/stroke, acute bacterial meningitis, brain trauma and 6-hydroxydopamine and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonism models 2,14–17 . Currently, it is unclear whether inhibition of caspase activation specifically in microglia contributes to the neuroprotective effects of caspase inhibitors. We have now discovered that microglial activation in cell and animal models of inflammation involves caspases and that inhibition of the cascade in microglia prevents neurodegeneration. Furthermore, we demonstrate that caspase activation occurs in microglia in the brains of individuals with PD and AD, and thereby we validate the observations we made in relevant cell and animal models.

Reported Foodborne Outbreaks Due to Fresh Produce in the United States and European Union: Trends and Causes

Abstract: The consumption of fruit and vegetables continues to rise in the United States and European Union due to healthy lifestyle recommendations. Meanwhile, the rate of foodborne illness caused by the consumption of these products remains high in both regions, representing a significant public health and financial issue. This study addresses the occurrence of reported foodborne outbreaks associated with fresh fruits and vegetables consumption in the United States and European Union during the period 2004–2012, where data are available. Special attention is paid to those pathogens responsible for these outbreaks, the mechanisms of contamination, and the fresh produce vehicles involved. Norovirus is shown to be responsible for most of the produce-related outbreaks, followed by Salmonella. Norovirus is mainly linked with the consumption of salad in the United States and of berries in the European Union, as demonstrated by the Multiple Correspondence Analysis (MCA). Salmonella was the leading cause of mult...