Physiology - Journal Articles

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    Role of Ca2+ stores in metabotropic L-glutamate receptor-mediated supralinear Ca2+ signaling in rat hippocampal neurons
    (Society for Neuroscience, 2000-12-01) Rae, Mark G.; Martin, Duncan J.; Collingridge, Graham L.; Irving, Andrew J.; Wellcome Trust
    The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca2+ signaling was investigated in cultured hippocampal cells using Ca2+ imaging techniques and whole-cell voltage-clamp recording. In neurons, but not glia, global supralinear Ca2+ release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K+ levels (10.8 mm), moderate depolarization (15–30 mV), or NMDA (3 μm). There was a delay (2–8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu5 receptor subtype. The L-type voltage-gated Ca2+ channel antagonist nifedipine (10 μm) substantially reduced responses to DHPG obtained in the presence of elevated extracellular K+ but not NMDA. This suggests that the Ca2+ that is required to load the stores can enter either through L-type voltage-gated Ca2+ channels or directly through NMDA receptors. The findings that both depolarization and NMDA receptor activation can facilitate mGlu receptor Ca2+ signaling adds considerable flexibility to the processes that underlie activity-dependent changes in synaptic strength. In particular, a temporal separation between the store-loading stimulus and the activation of mGlu receptors could be used as a recency detector in neurons.
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    Development of novel therapeutics for all individuals with CF (the future goes on)
    (Elsevier B.V., 2022-10-30) Amaral, Margarida D.; Harrison, Patrick T.; Science Foundation Ireland; Horizon 2020; Fundação para a Ciência e a Tecnologia; Ministério da Ciência, Tecnologia e Ensino Superior; Cystic Fibrosis Trust; Cystic Fibrosis Foundation
    Despite the major advances and successes in finding and establishing new treatments that tackle the basic defect in Cystic Fibrosis (CF), there is still an unmet need to bring these potentially curative therapies to all individuals with CF. Here, we review aspects of what is still missing to treat all individuals with CF by such approaches. On the one hand, we discuss novel holistic (high-throughput) approaches to elucidate mechanistic defects caused by distinct classes of mutations to identify novel drug targets. On the other hand, we examine therapeutic approaches to correct the gene in its own environment, i.e., in the genome.
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    Influence of innate immune activation on endocrine and metabolic pathways in infancy
    (American Physiological Society, 2021-04-26) O'Connor, Karen M.; Ashoori, Minoo; Dias, M. L.; Dempsey, Eugene M.; O'Halloran, Ken D.; McDonald, Fiona B.
    Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.
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    N-acetylcysteine decreases fibrosis and increases force-generating capacity of mdx diaphragm
    (MDPI AG, 2019-11-24) Burns, David P.; Drummond, Sarah E.; Bolger, Dearbhla; Coiscaud, Amélie; Murphy, Kevin H.; Edge, Deirdre; O'Halloran, Ken D.; Trinity College Dublin; University College Cork; The Physiological Society
    Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.
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    Gene and base editing as a therapeutic option for cystic fibrosis—learning from other diseases
    (MDPI, 2019-05-21) Mention, Karen; Santos, Lúcia; Harrison, Patrick T.; Cystic Fibrosis Trust; Fundação para a Ciência e a Tecnologia
    Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations is CFTR cDNA-based therapy, but clinical trials to date have only been able to stabilise rather than improve lung function disease in patients. While cDNA-based therapy is already a clinical reality for a number of diseases, some animal studies have clearly established that precision genome editing can be significantly more effective than cDNA addition. These observations have led to a number of gene-editing clinical trials for a small number of such genetic disorders. To date, gene-editing strategies to correct CFTR mutations have been conducted exclusively in cell models, with no in vivo gene-editing studies yet described. Here, we highlight some of the key breakthroughs in in vivo and ex vivo gene and base editing in animal models for other diseases and discuss what might be learned from these studies in the development of editing strategies that may be applied to cystic fibrosis as a potential therapeutic approach. There are many hurdles that need to be overcome, including the in vivo delivery of editing machinery or successful engraftment of ex vivo-edited cells, as well as minimising potential off-target effects. However, a successful proof-of-concept study for gene or base editing in one or more of the available CF animal models could pave the way towards a long-term therapeutic strategy for this disease.