Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/− mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders

Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood–brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.

Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism

Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.

Associative influence of new coronavirus infection SARS-CoV-2 during pregnancy on formation of neurological disorders in newborns: clinical case

The Severe Acute Respiratory Syndrome caused by Coronavirus-2 (SARS-CoV-2) has a destructive impact on the population all over the world. In this scenario, the extent, to which the disease will affect more vulnerable individuals, such as pregnant women, is a major concern. Since pregnancy can be a risk factor for respiratory viral infections, there are significant differences regarding the severity of COVID-19 between pregnant and non-pregnant women. In these circumstances, there arises a serious problem associated with the possibility of harm to the health and neuropsychiatric development of the posterity of infected mothers. The acute inflammatory response observed during the disease can lead to several types of nervous system disorders in the newborn. In the light of neuroimmune interactions on the mother-fetus hematoplacental relationship, a clinical case is described that reflects the consequences for the nervous and psychoneurological development of the newborn from SARS-CoV-2 infected mother.

COVID-19 and Autoimmunity: A Single Center Prospective Follow-Up Study

Background: Various factors, such as viral infections, can act as triggers for the development of autoimmune diseases.In our recent study we reported the presence of autoantibodies in patients diagnosed with COVID-19. To verify whether these autoantibodies persisted over time and led to the development of chronic autoimmune diseases, we conducted a follow-up study at 3 and 6 months after admission.Methods:Thirteen of 40 patients enrolled in the previous study gave their consent to the analysis. The same autoimmunity tests performed at the time of diagnosis were carried out in these patients during follow up.Results:We showed, compatibly with an acute inflammatory response, that two patients were negative 6 months after diagnosis. In nine patients, autoantibodies were still present at follow-up. Among them, one patient had only ENA positivity. Another patient developed strong positivity for ANA and M2-β and Ku antigens. Currently, the symptoms do not meet full diagnostic criteria for diagnosis of polymyositis, but the patient is closely monitored to check its possible onset.Three patients developed: transient alopecia, autoimmune thrombocytopenia and hearing loss. Other four patients did not show any clinical symptoms.Conclusions:In conclusion, our data show that after 6 months, the autoantibodies are still present in the majority of patients. Further investigations will be necessary to check whether these patients will become negative over time or may develop clinical symptoms compatible with the onset of longer-term chronic autoimmune diseases.

Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.

In silico and gene expression analysis of the acute inflammatory response of gilthead seabream (Sparus aurata) after subcutaneous administration of carrageenin

Inflammation is one of the main causes of loss of homeostasis at both the systemic and molecular levels. The aim of this study was to investigate in silico the conservation of inflammation-related proteins in the gilthead seabream (Sparus aurata L.). Open reading frames of the selected genes were used as input in the STRING database for protein–protein interaction network analysis, comparing them with other teleost protein sequences. Proteins of the large yellow croaker (Larimichthys crocea L.) presented the highest percentages of identity with the gilthead seabream protein sequence. The gene expression profile of these proteins was then studied in gilthead seabream specimens subcutaneously injected with carrageenin (1%) or phosphate-buffered saline (control) by analyzing skin samples from the injected zone 12 and 24 h after injection. Gene expression analysis indicated that the mechanisms necessary to terminate the inflammatory response to carrageenin and recover skin homeostasis were activated between 12 and 24 h after injection (at the tested dose). The gene analysis performed in this study could contribute to the identification of the main mechanisms of acute inflammatory response and validate the use of carrageenin as an inflammation model to elucidate these mechanisms in fish.

Association of Circulating, Inflammatory-Response Exosomal mRNAs With Acute Myocardial Infarction

Background: Although many cardiovascular disease studies have focused on the microRNAs of circulating exosomes, the profile and the potential clinical diagnostic value of plasma exosomal long RNAs (exoLRs) are unknown for acute myocardial infarction (AMI).Methods: In this study, the exoLR profile of 10 AMI patients, eight stable coronary artery disease (CAD) patients, and 10 healthy individuals was assessed by RNA sequencing. Bioinformatic approaches were used to investigate the characteristics and potential clinical value of exoLRs.Results: Exosomal mRNAs comprised the majority of total exoLRs. Immune cell types analyzed by CIBERSORT showed that neutrophils and monocytes were significantly enriched in AMI patients, consistent with clinical baseline values. Biological process enrichment analysis and co-expression network analysis demonstrated neutrophil activation processes to be enriched in AMI patients. Furthermore, two exosomal mRNAs, ALPL and CXCR2, were identified as AMI biomarkers that may be useful for evaluation of the acute inflammatory response mediated by neutrophils.Conclusions: ExoLRs were assessed in AMI patients and found to be associated with the acute inflammatory response mediated by neutrophils. Exosomal mRNAs, ALPL and CXCR2, were identified as potentially useful biomarkers for the study of AMI.