Docosahexaenoic acid (DHA) and neuroprotectin D1 (NPD1) are neuroprotective after experimental ischemic stroke. To explore underlying mechanisms, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo) and treated with DHA (5 mg/kg, IV) or NPD1 (5 μg/per rat, ICV) and vehicles 1 h after. Neuro-behavioral assessments was conducted on days 1, 2, and 3, and on week 1, 2, 3, or 4. BrdU was injected on days 4, 5, and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7, and lipidomic analysis at 4 and 5 h after onset of stroke. DHA improved short- and long-term behavioral functions and reduced cortical, subcortical, and total infarct volumes (by 42, 47, and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU/Ki-67, BrdU/DCX, and BrdU/NeuN cells in the cortex, subventricular zone, and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5 h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71-positive cells and vessels, axonal regeneration in the penumbra, and attenuated blood-brain barrier (BBB) after MCAo. We conclude that docosanoid administration increases neurogenesis and angiogenesis, activates NPD1 synthesis in the penumbra, and diminishes BBB permeability, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.

: Oxidative stress has been implicated in a large number of human degenerative diseases, including epilepsy. Levetiracetam (LEV) is a new antiepileptic agent with broad-spectrum effects on seizures and animal models of epilepsy. Recently, it was demonstrated that the mechanism of LEV differs from that of conventional antiepileptic drugs. Objectifying to investigate if LEV mechanism of action involves antioxidant properties, lipid peroxidation levels, nitrite-nitrate formation, catalase activity, and glutathione (GSH) content were measured in adult mice brain. The neurochemical analyses were carried out in hippocampus of animals pretreated with LEV (200 mg/kg, i.p.) 60 min before pilocarpine-induced seizures (400 mg/kg, s.c.). The administration of alone pilocarpine, 400 mg/kg, s.c. (P400) produced a significant increase of lipid peroxidation level in hippocampus. LEV pretreatment was able to counteract this increase, preserving the lipid peroxidation level in normal value. P400 administration also produced increase in the nitrite-nitrate formation and catalase activity in hippocampus, beyond a decrease in GSH levels. LEV administration before P400 prevented the P400-induced alteration in nitrite-nitrate levels and preserved normal values of catalase activity in hippocampus. Moreover, LEV administration prevented the P400-induced loss of GSH in this cerebral area. The present data suggest that the protective effects of LEV against pilocarpine-induced seizures can be mediated, at least in part, by reduction of lipid peroxidation and hippocampal oxidative stress.

ATV reduced inflammation, oxidative stress, and bone loss in rats with EP and GIOP, with participation of the WNT signaling pathway.

The effects of the protease inhibitors saquinavir, darunavir, ritonavir, and indinavir on growth inhibition, protease and phospholipase activities, as well as capsule thickness of Cryptococcus neoformans were investigated. Viral protease inhibitors did not reduce fungal growth when tested in concentrations ranging from 0.001 to 1.000 mg/L. A tendency toward increasing phospholipase activity was observed with the highest tested drug concentration in a strain-specific pattern. However, these drugs reduced protease activity as well as capsule production. Our results confirm a previous finding that antiretroviral drugs affect the production of important virulence factors of C. neoformans.

Temporomandibular joint (TMJ) disorders show inflammatory components, heavily impacting on quality of life. Abelmoschus esculentus is largely cultivated in Northeastern Brazil for medicinal purposes, having it shown anti-inflammatory activity. We evaluated A. esculentus lectin (AEL) efficacy in reducing zymosan-induced temporomandibular joint inflammatory hypernociception in rats along with the mechanism of action through which it exerts anti-inflammatory activity. Animals were pre-treated with AEL (0.01, 0.1 or 1mg/kg) before zymosan (Zy) injection in the TMJ to determine anti-inflammatory activity. To analyse the possible effect of the hemeoxygenase-1 (HO-1) and the nitric oxide (NO) pathways on AEL efficacy, animals were pre-treated with ZnPP-IX (3mg/kg), a specific HO-1 inhibitor, or aminoguanidine (30mg/kg), a selective iNOS inhibitor, before AEL administration. Von Frey test evaluated inflammatory hypernociception, synovial fluid collection was performed to determine leukocyte counting and myeloperoxidase (MPO) activity 6h after Zy injection, and Evans Blue extravasation determined vascular permeability. TMJ tissue was collected for histopathological analysis (H&E) and immunohistochemistry (TNF-α, IL-1β, HO-1). In addition, TMJ tissue and trigeminal ganglion collection was performed for TNF-α and IL-1β dosage (ELISA). AEL increased inflammatory nociceptive threshold, reduced leukocyte influx along with MPO activity, leukocyte influx into the synovial membrane, and Evans Blue extravasation. It promoted HO-1 overexpression whilst decreased TNF-α and IL-1β expression in the TMJ tissue. AEL reduced TNF-α and IL-1β levels in TMJ tissue and trigeminal ganglion. AEL effects, however, were not observed in the presence of ZnPP-IX. These findings suggest that AEL efficacy depends on TNF-α/IL-1β inhibition and HO-1 pathway integrity.

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Corona virus disease 2019 (COVID-19) pathogenesis is intimately linked to the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and disease severity has been associated with compromised induction of type I interferon (IFN-I) cytokines which coordinate the innate immune response to virus infections. Here we identified the SARS-CoV-2 encoded protein, Spike, as an inhibitor of IFN-I that antagonizes viral RNA pattern recognition receptor RIG-I signaling. Ectopic expression of SARS-CoV-2 Spike blocked RIG-I mediated activation of IFNβ and downstream induction of interferon stimulated genes. Consequently, SARS-CoV-2 Spike expressing cells harbored increased RNA viral burden compared to control cells. Co-immunoprecipitation experiments revealed SARS-CoV-2 Spike associated with interferon regulatory factor 3 (IRF3), a key transcription factor that governs IFN-I activation. Co-expression analysis via immunoassays further indicated Spike specifically suppressed IRF3 expression as NF-κB and STAT1 transcription factor levels remained intact. Further biochemical experiments uncovered SARS-CoV-2 Spike potentiated proteasomal degradation of IRF3, implicating a novel mechanism by which SARS-CoV-2 evades the host innate antiviral immune response to facilitate COVID-19 pathogenesis.

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