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The organophosphate insecticide chlorpyrifos (CPF), an acetylcholinesterase inhibitor, has raised serious concerns about human safety. Apart from inducing synaptic acetylcholine accumulation, CPF could also act at nicotinic acetylcholine receptors, like the α7-isoform (α7-nAChR), which could potentially be harmful to developing brains. Our aims were to use molecular docking to assess the binding interactions between CPF and α7-nAChR through, to test the neurocytotoxic and oxidative effects of very low concentrations of CPF on SH-SY5Y cells, and to hypothesize about the potential mediation of α7-nAChR. Docking analysis showed a significant binding affinity of CPH for the E fragment of the α7-nAChR (ΔGibbs: -5.63 to -6.85 Kcal/mol). According to the MTT- and Trypan Blue-based viability assays, commercial CPF showed concentration- and time-dependent neurotoxic effects at a concentration range (2.5-20 µM), ten-folds lower than those reported to have crucial effects for sheer CPF. A rise of the production of radical oxygen species (ROS) was seen at even lower concentrations (1-2.5 µM) of CPF after 24h. Notably, our docking analysis supports the antagonistic actions of CPF on α7-nAChR that were recently published. In conclusion, while α7-nAChR is responsible for neuronal survival and neurodevelopmental processes, its activity may also mediate the neurotoxicity of CPF.

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Acetamiprid (ACE) and Imidacloprid (IMI) are widely-used neonicotinoid insecticides (NNIs) with functional activity at human acetylcholine nicotinic receptors and, therefore, with putative toxic effects. The objective of this study was the evaluation of the interactions between NNIs and α7-nAChR, as this receptor keeps intracellular Ca2+ ([Ca2+]i) to an optimum for an adequate neuronal functioning. Possible interactions between NNIs and the cryo-EM structure of the human α-7 nAChR were identified by molecular docking. Additionally, NNI effects were analyzed in neuroblastoma SH-SY5Y cells, as they naturally express α-7 nAChRs. Functional studies included proliferative/cytotoxic effects (MTT test) in undifferentiated SH-SY-5Y cells and indirect measurements of [Ca2+]i transients in retinoic acid-differentiated SH-SY-5Y cells loaded with Fluo-4 AM. Docking analysis showed that the binding of IMI and ACE occurred at the same aromatic cage that the specific α-7 nAChR agonist EVP-6124. IMI showed a better docking strength than ACE. According to the MTT assays, low doses (10-50 µM) of IMI better than ACE stimulated neuroblastoma cell proliferation. At higher doses (250-500 µM), IMI also prevailed over ACE and dose-dependently triggered more abrupt fluorescence changes due to [Ca2+]i mobilization in differentiated SH-SY5Y neurons. Indeed, only IMI blunted nicotine-evoked intracellular fluorescence stimulation (i.e., nicotine cross-desensitization). Summarizing, IMI demonstrated a superior docking strength and more robust cellular responses compared to ACE, which were likely associated with a stronger activity at α-7nAChRs. Through the interaction with α-7nAChRs, IMI would demonstrate its high neurotoxic potential for humans. More research is needed for investigating the proliferative effects of IMI in neuroblastoma cells.

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Objective: The performance of the platelet times neutrophil-to-lymphocyte ratio, namely systemic immune inflammation (SII) index, is an inflammatory index that shows controversial results as a predicting indicator of the poor outcomes of COVID-19. In this study, this indicator was analyzed in 3280 patients admitted at a COVID-19 reference hospital in Quito (Ecuador). Methods: The Receiver Operating Characteristic (ROC) curve analysis was conducted on SII values upon admission to identify the most appropriate cut-off values in discriminating COVID-19 severity and in-hospital mortality. Results: SII was higher in both severe patients and in those who finally died (cut-off points of 757.3 and 808.5 respectively). However, the AUC-ROC analysis (0.60-0.67) demonstrated a modest discriminating performance of SII for COVID-19 severity (61.2% sensitivity and 61.5% specificity), which sensibly improved for COVID-19 mortality (AUC-ROC: 0.73-0.83, sensitivity: 80.6% specificity; 63.6%). Conclusion: SII index may well be an indicator of inflammatory conditions secondary to COVID-19 leading to a higher mortality, rather than a predictor of severe forms of the disease.

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Neonicotinoids are effective insecticides with specificity for invertebrate nicotinic acetylcholine receptors. Neonicotinoids are chemically stable and tend to remain in the environment for long so concerns about their neurotoxicity in humans do nothing but increase. Herein, we evaluated the chronic toxic effects of acetamiprid- and imidacloprid-based insecticides over the differentiation of human neuroblastoma SH-SY5Y cells, which were exposed to these insecticides at a concentration range similar to that applied to crop fields (0.01-0.5 mM). Both insecticides did not have acute cytotoxic effects in both non-differentiated and in staurosporine-differentiated SH-SY5Y cells cytotoxicity as measured by the MTT and vital-dye exclusion tests. However, after a chronic (7-day) treatment, only imidacloprid dose-dependently decreased the viability of SH-SY5Y cells (F(4,39) = 43.05, P < 0.001), largely when administered-during cell differentiation (F(4,39) = 51.86, P < 0.001). A well-defined dose-response curve was constructed for imidacloprid on day 4 (R2 = 0.945, EC50 = 0.14 mM). During differentiation, either imidacloprid or acetamiprid dose-dependently caused neurite branch retraction on day 3, likely because of oxidative stress, to the extent that cells turned into spheres without neurites after 7-day treatment. Despite their apparent safety, the neurodevelopmental vulnerability of SH-SY5Y neurons to the chronic exposure to imidacloprid and to a lesser extent to acetamiprid points to a neurotoxic risk for humans.

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In the epidemiological COVID-19 research, artificial intelligence is a unique approach to make predictions about disease severity to manage COVID-19 patients. A limitation of artificial intelligence is, however, the high risk of bias. We investigated the skill of data mining and machine learning, two advanced forms of artificial intelligence, to predict severe COVID-19 pneumonia based on routine laboratory tests. A sample of 4009 COVID-19 patients was divided into Severe (PaO2< 60 mmHg, 489 cases) and Non-Severe (PaO2 ≥ 60 mmHg, 3520 cases) groups according to blood hypoxemia on admission and their laboratory datasets analyzed by the R software and WEKA workbench. After curation, data were processed for the selection of the most influential features including hemogram, pCO2, blood acid-base balance, prothrombin time, inflammation biomarkers, and glucose. The best fit of variables was successfully confirmed by either the Multilayer Perceptron, a feedforward neural network algorithm that performed machine recognition of severe COVID-19 with 96.5% precision, or by the C4.5 software, a supervised learning algorithm based on an objective-predefined variable (severity) that generated a decision tree with 89.4% precision. Finally, a complex bivariate Pearson's correlation matrix combined with advanced hierarchical clustering (dendrograms) were conducted for knowledge discovery. The hidden structure of the datasets revealed shift patterns related to the development of COVID-19-induced pneumonia that involved the lymphocyte-to-C-reactive protein and leukocyte-to-C-protein ratios, neutrophil %, pH and pCO2. The data mining approaches to the hematological fluctuations associated with severe COVID-19 pneumonia could not only anticipate adverse clinical outcomes, but also reveal putative therapeutic targets.

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Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the flux of nerve impulses across corticolimbic areas and the excitatory projections to mesolimbic pathways. At the basal striatum, CCK modulates the excitability of glutamate, the release of inhibitory GABA, and the discharge of dopamine. Here we focus on how CCK may reduce rather than trigger anxiety by regulating its cognitive component. Adequate levels of CCK release in the basal striatum may control the interplay between cognition and reward circuitry, which is critical in schizophrenia. Hence, it is proposed that disturbances in the excitatory/ inhibitory interplay modulated by CCK may contribute to the imbalanced interaction between corticolimbic and mesolimbic neural activity found in anxiety and schizophrenia.

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Exposure to hypoxic environments when ascending at high altitudes may cause life-threatening pulmonary edema (HAPE) due to a rapid accumulation of extracellular fluid flooding in the pulmonary alveoli. In Andeans, high-altitude adaptation occurs at the expense of being more prone to chronic mountain sickness: relative hypoventilation, excess pulmonary hypertension, and secondary polycythemia. Because HAPE prevalence is high in the Andes, we posit the hypothesis that a high hemoglobine mass may increase HAPE risk. In support of it, high intrapulmonary hypertension along with hyperviscosity produced by polycytemia may enhance sear forces and intravascular hemolysis, thus leading to increased acellular hemoglobin and the subsequent damage of the alveolar and endothelial barrier. It is proposed to investigate the relationship between the vaso-endothelial homeostasis and erythropoiesis in the maladaptation to high altitude and HAPE. This research is especially important when reentry HAPE, since rheologic properties of blood changes with rapid ascent to high altitudes.

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Cyclooxygenases are a group of heme-containing isozymes (namely Cox-1 and Cox-2) that catalyze the conversion of arachidonic acid to largely bioactive prostaglandins (PGs). Cox-1 is the ubiquitous housekeeping enzyme, and the mitogen-inducible Cox-2 is activated to cause inflammation. Interestingly, Cox-2 is constitutively expressed in the brain at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Neuronal Cox-2 is activated in response to synaptic excitation to yield PGE2, the predominant Cox-2 metabolite in the brain, which in turn stimulates the release of glutamate and neuronal firing in a retrograde fashion. Cox-2 is also engaged in the metabolism of new endocannabinoids from 2-arachidonoyl-glycerol to modulate their actions at presynaptic terminals. In addition to these interactions, the induction of neuronal Cox-2 is coupled to the trans-synaptic activation of the dopaminergic mesolimbic system and some serotoninergic receptors, which might contribute to the development of emotional behavior. Although much of the focus regarding the induction of Cox-2 in the brain has been centered on neuroinflammation-related neurodegenerative and psychiatric disorders, some evidence also suggests that Cox-2 release during neuronal signaling may be pivotal for the fine tuning of cortical networks to regulate behavior. This review compiles the evidence supporting the homeostatic role of neuronal Cox-2 in synaptic transmission and plasticity, since neuroinflammation is originally triggered by the induction of glial Cox-2 expression. The goal is to provide perspective on the roles of Cox-2 beyond neuroinflammation, such as those played in memory and anxiety, and whose evidence is still scant.

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