NAADP (nicotinic acid-adenine dinucleotide phosphate) is an unusual second messenger thought to mobilize acidic Ca(2+) stores, such as lysosomes or lysosome-like organelles, that are functionally coupled to the ER (endoplasmic reticulum). Although NAADP-sensitive Ca(2+) stores have been described in neurons, the physiological cues that recruit them are not known. Here we show that in both hippocampal neurons and glia, extracellular application of glutamate, in the absence of external Ca(2+), evoked cytosolic Ca(2+) signals that were inhibited by preventing organelle acidification or following osmotic bursting of lysosomes. The sensitivity of both cell types to glutamate correlated well with lysosomal Ca(2+) content. However, interfering with acidic compartments was largely without effect on the Ca(2+) content of the ER or Ca(2+) signals in response to ATP. Glutamate but not ATP elevated cellular NAADP levels. Our results provide evidence for the agonist-specific recruitment of NAADP-sensitive Ca(2+) stores by glutamate. This links the actions of NAADP to a major neurotransmitter in the brain.
Clinical observations on the potential of pre-hospital antiplatelet therapy in preventing ARDS have been inconsistent. To further the correlation between antiplatelet therapy and ARDS, we conducted a meta-analysis to evaluate the effects of pre-hospital antiplatelet therapy on subjects with ARDS.
METHODS:
A literature search in major data banks was performed. We included prospective and retrospective cohorts, case-control trials, and randomized controlled trials that compared the ARDS incidence in subjects with or without pre-hospital antiplatelet agents.
RESULTS:
Meta-analysis of 7 studies (a total of 30,291 subjects) showed significantly lower odds of ARDS in the pre-hospital antiplatelet therapy group compared with subjects with no pre-hospital antiplatelet therapy (odds ratio 0.68, 95% CI 0.56–0.83; P < .001). However, ARDS mortalities in the hospital and ICUs were not affected.
CONCLUSIONS:
These findings indicated that pre-hospital antiplatelet therapy was associated with a reduced rate of ARDS but had no effect on the mortality in the subjects at high risk.
This study was designed to examine the potential involvement of reactive oxygen species in skeletal muscle dysfunction linked with stretching in a mouse model and to explore the effects of combined antioxidant intake on peripheral leukocyte apoptosis following eccentrically-biased downhill runs in human subjects. In the mouse model, diaphragmatic muscle was stretched by 30% of its optimal length, followed by 5-min contraction. Muscle function and extracellular reactive oxygen species release was measured ex vivo. In human models, participants performed two trials of downhill running either with or without antioxidant supplementation, followed by apoptotic assay of inflammatory cells in the blood. The results showed that stretch led to decreased muscle function and prominent ROS increase during muscle contraction. In human models, we observed an elevation in circulating leukocyte apoptosis 24–48 hours following acute downhill runs. However, there is an attenuated leukocyte apoptosis following the second bout of downhill run. Interestingly, the combination of ascorbic acid (vitamin C) and α-tocopherol (vitamin E) supplementation attenuated the decrease in B-cell lymphoma 2 (Bcl-2) at 24 hours following acute downhill running. These data collectively suggest that significant ROS formation can be induced by muscle-lengthening associated with eccentric exercise, which is accompanied by compromised muscle function. The combination of antioxidants supplementation appears to have a protective role via the attenuation of decrease in anti-apoptotic protein.
Aim. Skeletal muscle subjected to hypoxia followed by reoxygenation is susceptible to injury and subsequent muscle function decline. This phenomenon can be observed in the diaphragm during strenuous exercise or in pulmonary diseases such as chronic obstructive pulmonary diseases (COPD). Previous studies have shown that PO2 cycling or hypoxic preconditioning (HPC), as it can also be referred to as, protects muscle function via mechanisms involving reactive oxygen species (ROS). However, this HPC protection has not been fully elucidated in pulmonary TNF- overexpressing (Tg+) mice (a COPD-like model). We hypothesize that HPC can exert protection on the diaphragms of Tg+ mice through pathways involving ROS-PI3K-Akt-ERK, as well as the mitochondrial ATP-sensitive potassium channel (mitoKATP) and permeability transition pore (mPTP). Methods. Isolated Tg+ diaphragm muscle strips were either non-treated, or treated with HPC, incubated with signaling cascade inhibitors, or incubated with mitochondrial channel enhancers/blockers， followed by 30-min hypoxia and 15-min reoxygenation periods. Data were analyzed by multi-way ANOVA and expressed as means ± SE. Results. Muscle treated with HPC showed improved muscle function during reoxygenation (n = 5, p < 0.05). Inhibition of ROS, PI3K, Akt, ERK, as well as mitochondrial mediators, abolished the protective effect of HPC. Individual regulation of mitochondrial channels with either the opening of mitoKATP channel or the closure of mPTP alleviated muscle function decline, suggesting that mitochondria play a role in HPC initiation (n = 5; p < 0.05). Conclusion. HPC may protect respiratory skeletal muscle function in Tg+ mice during reoxygenation through cell signaling cascades and regulations of mitochondrial channels.
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