European journal of pharmacology
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The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion channel, the GABAA receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABAA receptors, using an autoradiographic assay with [35S]TBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.e., without having affinity to the [35S]TBPS binding site. ⋯ Of the non-fenamate NSAIDs studied at 100 μM concentration, diclofenac induced the greatest inhibition of the binding, which is not surprising as it has close structural similarity with the potent fenamate meclofenamic acid. Using two-electrode voltage-clamp assays on Xenopus oocytes, the effect of niflumic acid was found to be dependent on the β subunit variant and the presence of γ2 subunit in rat recombinant α1β and α1βγ2 GABAA receptors, with the β1 allowing the niflumic acid inhibition and β3 the stimulation of the receptor-mediated currents. In summary, the fenamate NSAIDs constitute an interesting class of compounds that could be used for development of potent GABAA receptor allosteric agonists with other targets to moderate inflammation, pain and associated anxiety/depression.
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Opioids are potent analgesic drugs, but their use has been limited due to their side effects. Antinociceptive effects of D2-like receptor agonists such as quinpirole have been shown at the spinal cord level; however, their efficacy is not as high as that of opioids. Dopaminergic agonists are long-prescribed and well-tolerated drugs that have been useful to treat clinically and experimentally painful conditions. ⋯ Coadministration of 1 nmol quinpirole and 30 pmol DAMGO completely reversed hyperalgesia in the CFA model, whereas 100 pmol DAMGO plus 1 nmol quinpirole reversed the allodynia in the SLL model. This work offers evidence about a synergistic antinociceptive effect between opioidergic and dopaminergic drugs. This combination may relieve painful conditions resistant to conventional treatments, and it may reduce the adverse effects of chronic opioid administration.
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Surgery resection is the primary treatment for colorectal cancer (CRC) patients with the risk of cancer dissemination and metastasis. Sevoflurane is one inhalational anesthesia which regulates migration and invasion in varying cancers. However, the effect of sevoflurane on CRC cells and its mechanism remain poorly understood. ⋯ Notably, MMP-9, as a downstream of ERK, was involved in sevoflurane-mediated processes in CRC cells. Besides, Robo1 was indicated as a target of miR-203 and inhibited by sevoflurane treatment. These results indicated that sevoflurane suppressed cell migration and invasion through regulating ERK/MMP-9 pathway via miR-203/Robo1 in CRC cells, indicating important clinical implications for anesthetic agents to prevent metastasis in CRC.
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Meta Analysis
Does alpha-lipoic acid affect lipid profile? A meta-analysis and systematic review on randomized controlled trials.
Randomized controlled trials (RCTs) have demonstrated that alpha lipoic acid (ALA) may change lipid profile, but their results are contradictory. The aim of this study is to conduct a meta-analysis to assess the effects of ALA on lipid profile. Electronic databases including ISI web of science, Ovid, PubMed/Medline, SCOPUS, and Google Scholar were searched up to February 2018. ⋯ The overall effect of ALA on serum triglyceride did not reveal any significant change, but in subgroup analysis based on health status (diabetic vs. non-diabetic), ALA decreased serum triglyceride levels in both diabetic and non-diabetic groups compared with controls. This meta-analysis revealed that ALA might favorably affect lipid profile especially LDL and TC. However, for confirming these results, more studies particularly among hyperlipidemic patients are needed.
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Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviors. BTBR T+ Itpr3tf/J (BTBR) mice, a preclinical autistic model featuring ASD symptoms as defined by social relations, was used in this study. We evaluated the potentially protective effect of D-Ala-peptide T-amide (DAPTA), a selective C-C chemokine receptor 5 (CCR5) antagonist, in BTBR mice. ⋯ Additionally, DAPTA treatment inhibited CCR5+, CD4+CCR5+, CCR5+IL-6+, CCR5+IL-9+, CCR5+IL-17A+, CCR5+RORγT+, and upregulated CCR5+IL-10+, and CCR5+Foxp3+ production. We further observed that DAPTA downregulated IL-6, IL-9, IL-17A, and RORγT, and increased IL-10 and Foxp3 protein and mRNA expression. Therefore, our results suggest that DAPTA administration represents a potential treatment strategy for patients with ASD.