Terfestatins B (1) and C (2), new p-terphenyls bearing a novel unsaturated hexuronic acid (4-deoxy-α-l-threo-hex-4-enopyranuronate), a unique β-d-glycosyl ester of 5-isoprenylindole-3-carboxylate (3) ...and the same rare sugar, and two new hygromycin precursors, were characterized as metabolites of the coal mine fire isolate Streptomyces sp. RM-5–8. EtOH damage neuroprotection assays using rat hippocampal-derived primary cell cultures with 1, 2, 3 and echoside B (a terfestatin C-3′-β-d-glucuronide from Streptomyces sp. RM-5–8) revealed 1 as potently neuroprotective, highlighting a new potential application of the terfestatin scaffold.
Highlights • The present studies examine the role of mGluR signaling in ethanol dependence. • Hippocampal explants are effective as a high-throughout screen of toxicity. • Group 1 metabotrophic ...receptor antagonism attenuates hippocampal cytotoxicity. • Blocking these receptors prior to withdrawal reduces development of dependence.
Highlights • We model kindling-like effects of repeated ethanol intoxication and withdrawal. • We examine behavioral indices of withdrawal and hypothalamic–adrenal-axis activity. • Selective ...antagonism of glucocorticoid receptors attenuates withdrawal severity. • Acute antagonism of these receptors reduces hypothalamic–adrenal-axis activation.
The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated Streptomyces sp. RM-14-6 is reported. Using the ...engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of 4, while glycosylation of the structurally related inactive spoxazomicin C (3) remarkably invoked neuroprotective activity.
Chronic, intermittent ethanol (CIE) exposure is known to produce neuroadaptive alterations in excitatory neurotransmission that contribute to the development of dependence. Although activation of ...protein kinases (e.g., cyclic AMP cAMP-dependent protein kinase) is implicated in the synaptic trafficking of these receptors following CIE exposure, the functional consequences of these effects are yet to be fully understood. The present study sought to delineate the influence of protein kinase in regulating cytotoxicity following CIE exposure, as well as to examine the relative roles of ethanol exposure and ethanol withdrawal (EWD) in promoting these effects. Rat hippocampal explants were exposed to a developmental model of CIE with or without co-application of broad-spectrum protein kinase inhibitor KT-5720 (1 μM) either during ethanol exposure or EWD. Hippocampal cytotoxicity was assessed via immunofluorescence (IF) of neuron-specific nuclear protein (NeuN) with thionine staining of Nissl bodies to confirm IF findings. Concomitant application of ethanol and KT-5720 restored the loss of NeuN/Fox-3 IF in pyramidal CA1 and granule DG cell layers produced by CIE, but there was no restoration in CA3. Application of KT-5720 during EWD failed to significantly alter levels of NeuN IF, implying that ethanol exposure activates protein kinases that, in part, mediate the effects of EWD. KT-5720 application during EWD also restored thionine staining in CA1, suggesting kinase regulation of both neurons and non-neuronal cells. These data demonstrate that CIE exposure alters protein kinase activity to promote ethanol withdrawal-associated loss of NeuN/Fox-3 and highlight the influence of kinase signaling on distinct cell types in the developing hippocampus.
•Effects of protein kinase activity on hippocampal cytotoxicity following CIE are assessed.•Protein kinase inhibition prior to EWD spared the loss of NeuN/Fox-3 produced by CIE.•Protein kinase inhibition prior to EWD also attenuated losses of thionine staining.•Kinases regulate both neurons and non-neuronal cells.•CIE alters protein kinase activity to produce cytotoxic effects of CIE.
Highlights • Midbrain and striatal cultures functionally reintegrate synaptic contacts ex vivo. • Corticosterone causes glutamate receptor-dependent cell loss in midbrain neurons. • Ventral striatum ...is insensitive to effects of either corticosterone or an excitotoxin.
Multisite, course-based undergraduate research experiences (CUREs) in the Ecological Research as Education Network (EREN) were assessed for impacts on student learning of collaborative science skills ...using a survey that could serve as a starting point for a validated assessment instrument for multisite CUREs. Pretests/posttests were administered across multiple courses and institutions, capturing effects of diverse EREN projects and pedagogies on collaborative knowledge. Students' scientific collaboration and data management skills improved most in small, upper-level courses. The amount of EREN content in a course was positively associated with posttest scores for 60 to 86 percent of assessment survey questions. However, no learning gains were seen for some questions, and some cases of low competency and effects of timing and place of assessment testing were observed in student scores. EREN CUREs need further development to maximize their potential.
The aim was to conduct a systematic review and meta-analysis analyzing the impact of up to 24 h of prolonged sitting on postprandial glucose, insulin and triglyceride responses, blood pressure and ...vascular function, in comparison to sitting interrupted with light- to moderate-intensity physical activity.
To be included, studies had to examine the impact of prolonged sitting lasting < 24 h in apparently healthy males or females of any age. Studies were identified from searches of the MEDLINE, CINAHL and SportDISCUS databases on July 6, 2016. Study quality was assessed using the Downs and Black Checklist; publication bias was assessed via funnel plot.
Forty-four studies met the inclusion criteria for the systematic review; of these, 20 were included in the meta-analysis, which compared prolonged sitting to the effects of interrupting sitting with regular activity breaks on postprandial glucose, insulin and triglycerides. When compared to prolonged sitting, regular activity breaks lowered postprandial glucose (d = - 0.36, 95% confidence interval CI - 0.50 to - 0.21) and insulin (d = - 0.37, 95% CI - 0.53 to - 0.20), but not triglyceride responses (d = 0.06, 95% CI - 0.15 to 0.26). Subgroup analyses indicated reductions in postprandial triglyceride responses only occurred 12-16 h after the intervention. The magnitude of the reductions in glucose, insulin or triglyceride response was not modified by the intensity of the activity breaks, the macronutrient composition of the test meal, or the age or body mass index of participants.
Prolonged sitting results in moderate elevations in postprandial glucose and insulin responses when compared to sitting interrupted with activity breaks.
CRD42015020907.
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