Prenatal inflammation and risk for schizophrenia: A role for immune proteins in neurodevelopment

2018 ◽  
Vol 30 (3) ◽  
pp. 1157-1178 ◽  
Author(s):  
Dana M. Allswede ◽  
Tyrone D. Cannon
Keyword(s):  
Cognitive Deficits ◽  
Inflammatory Markers ◽  
Potential Role ◽  
Synapse Formation ◽  
Potential Candidate ◽  
Rodent Models ◽  
Cellular Mechanisms ◽  
Established Risk Factor ◽  
Prenatal Inflammation

AbstractPrenatal inflammation is an established risk factor for schizophrenia. However, the specific inflammatory pathways that mediate this association remain unclear. Potential candidate systems include inflammatory markers produced by microglia, such as cytokines and complement. Accumulating evidence suggests that these markers play a role in typical neurodevelopmental processes, such as synapse formation and interneuron migration. Rodent models demonstrate that altered marker levels during the prenatal period can cause lasting deficits in these systems, leading to cognitive deficits that resemble schizophrenia. This review assesses the potential role of prenatal cytokine and complement elevations on the etiology of schizophrenia. The current neurobiological understanding of the development of schizophrenia is reviewed to identify candidate cellular mechanisms that may be influenced by prenatal inflammation. We discuss the functions that cytokines and complement may play in prenatal neurodevelopment, review evidence that links exposure to these factors with risk for schizophrenia, and consider how these markers may interact with genetic vulnerabilities to influence the neurodevelopment of schizophrenia. We consider how prenatal inflammatory exposure may influence childhood and adolescent developmental risk trajectories for schizophrenia. Finally, we identify areas of further research needed to support the development of anti-inflammatory treatments to prevent the development of schizophrenia in at-risk neonates.

mTORC and PKCε in Regulation of Alcohol Use Disorder

2020 ◽  
Vol 20 (17) ◽  
pp. 1696-1708 ◽  
Author(s):  
Athirah Hanim ◽  
Isa Naina Mohamed ◽  
Rashidi M. Pakri Mohamed ◽  
Srijit Das ◽  
Norefrina Shafinaz Md Nor ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Alcohol Intake ◽  
Potential Role ◽  
Synaptic Proteins ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Protein Kinase C Epsilon ◽  
Seeking Behavior

Alcohol use disorder (AUD) is characterized by compulsive binge alcohol intake, leading to various health and social harms. Protein Kinase C epsilon (PKCε), a specific family of PKC isoenzyme, regulates binge alcohol intake, and potentiates alcohol-related cues. Alcohol via upstream kinases like the mammalian target to rapamycin complex 1 (mTORC1) or 2 (mTORC2), may affect the activities of PKCε or vice versa in AUD. mTORC2 phosphorylates PKCε at hydrophobic and turn motif, and was recently reported to be associated with alcohol-seeking behavior, suggesting the potential role of mTORC2-PKCε interactions in the pathophysiology of AUD. mTORC1 regulates translation of synaptic proteins involved in alcohol-induced plasticity. Hence, in this article, we aimed to review the molecular composition of mTORC1 and mTORC2, drugs targeting PKCε, mTORC1, and mTORC2 in AUD, upstream regulation of mTORC1 and mTORC2 in AUD and downstream cellular mechanisms of mTORCs in the pathogenesis of AUD.

scholarly journals Neuroinflammation and Its Impact on the Pathogenesis of COVID-19

2021 ◽  
Vol 8 ◽  
Author(s):  
Mohammed M. Almutairi ◽  
Farzane Sivandzade ◽  
Thamer H. Albekairi ◽  
Faleh Alqahtani ◽  
Luca Cucullo
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Immune Cell ◽  
Clinical Manifestations ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
Cytokine Levels

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.

A HoxD11 Homeobox Gene Mutation Associated With Congenital Absent Radius But Without The Thrombocytopenia Of The TAR Syndrome Or a HoxA11 Mutation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4837-4837
Author(s):  
Roger A. Fleischman
Keyword(s):  
Potential Role ◽  
Conflicts Of Interest ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Incomplete Penetrance ◽  
Potential Candidate ◽  
Negative Finding ◽  
Tar Syndrome ◽  
Absent Radius

HoxA11 and HoxD11 are homeobox genes critical for normal development of the forearm and thus are potential candidate genes for involvement in the pathogenesis of the thrombocytopenia/absent radius (TAR) syndrome. However, we previously reported an absence of coding sequence mutations in either HoxA11 or HoxD11 in a series of 10 unrelated TAR syndrome patients (Fleischman RA et al., Br J Haematol., 116:367-75, 2002). Despite this negative finding, interest in the potential role of homeobox genes in the TAR syndrome has been supported by a report of a HoxA11 mutation occurring in two kindreds with amegakaryocytic thrombocytopenia and radio-ulnar synostosis, a less pronounced more proximal pattern of radial malformation (Thompson AA and Nguyen LT. Nat Genet., 26:397-8, 2000). Unlike HoxA11, however, no mutations in the human HoxD11 gene have been described thus far that would help elucidate the potential role of this paralogous gene in megakaryopoiesis or the TAR syndrome. We now describe a novel mutation in human HoxD11 that results in a polyalanine sequence expansion, (GCG)6→ (GCG)8, and report that this mutation is associated with a unilateral absent radius in the affected propositus. A familial syndrome is suggested in this kindred, moreover, by the prior observation of a bilateral absent radius in a deceased maternal aunt. This mutation was not present in more than 100 unrelated normal subjects or 8 other unrelated individuals with sporadic absence of the radius. Two other living maternal relatives also carried the mutation but did not exhibit any radial defects, a finding consistent with autosomal dominance with incomplete penetrance, an inheritance pattern reported for short polyalanine expansion mutations in the related homeobox gene HoxD13 which cause synpolydactyly. In contrast to the reported HoxA11 mutation, however, neither the propositus nor the mutation carriers of this HoxD11 mutation exhibited thrombocytopenia or any other cytopenias or congenital defect. The results suggest that at least one class of mutation in human HoxD11 may be sufficient to cause an absent radius syndrome but unlike the reported HoxA11 mutation, does not adversely affect megakaryopoiesis. The findings further suggest that additional studies of the TAR syndrome may be necessary to exclude as yet undetected non-coding mutations in promoter or enhancer sequences that alter the expression of HoxA11, HoxD11 or other homeobox genes critical for radial development and/or megakaryopoiesis. This work was supported by a VA Merit Award. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Potential Role of Therapeutic Dose of Low Molecular Weight Heparin (LWMH) to Attenuate Hyper-Inflammatory State in Hospitalized COVID-19 Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Mohsin Sheraz Mughal ◽  
Ikwinder Preet Kaur ◽  
Ali R. Jaffery ◽  
Chang Wang ◽  
Muhammad Asif ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Disease Severity ◽  
Inflammatory Markers ◽  
Potential Role ◽  
Hospitalized Patients ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
D Dimer ◽  
Inflammatory Effect

Introduction:The underlying pathophysiology of severe COVID-19 involves cytokine storm syndrome that is associated with an elevation of immunoinflammatory cytokines [1]. This hyper-inflammatory state has been implicated with coagulopathy among severely sick patients with COVID-19. Inflammation and coagulopathy are interlinked processes [2]. Coagulopathy has been associated with high mortality in COVID-19 patients [3]. LMWH is traditionally used for its anticoagulant and antithrombotic properties, however, its anti-inflammatory effect has not been fully elucidated. A study done by Shastri et al. suggested that LMWH can inhibit the release of different cytokines (IL-4, IL-5, IL-13, and TNF-α) [4]. Recent retrospective studies on COVID-19 illustrated that the LMWH (40-60 mg, subcutaneously every day) was associated with better prognosis as measured by (28 days of survival) in severely sick patients meeting sepsis-induced coagulopathy (SIC≥4) criteria compared to nonusers [5]. The potential role of escalated/therapeutic LMWH (1mg/kg/subcutaneously every 12 hours) remains unclear. This study involves a retrospective analysis of the potential role of an escalated dose of LMWH to alter the hyper-inflammatory state in hospitalized patients with COVID-19 and compared outcomes to those patients who received a low dose (40-60 mg, subcutaneously every day) of LMWH. Methods:Adult patients with confirmed SARS-CoV-2 infection by nasopharyngeal (NP) polymerase chain reaction (PCR) who were hospitalized from March 1st to April 20, 2020, were included. They were divided into two cohorts based on the dose of LMWH; cohort 1 (40-60 mg, subcutaneously every day) and cohort 2 (1mg/kg/subcutaneously every 12 hours). Categorical variables were compared by conducting a chi-square test or Fisher's exact test while continuous ones were compared by conducting a median two-sample test. Results:The median values of PT, PTT, INR, CRPmax, LDHmax, ferritinmax, D-dimermax, are mentioned in table 1. Incidence of thrombotic events (deep venous thrombosis, ischemic stroke, pulmonary embolism) was higher in cohort 1 (n=3, 4.8%) compared to cohort 2 (n=1, 2.6%). Cohort 2 had a higher number of patients who received ICU level of care (n=24) compared to the 6 patients in cohort 1. Out of 24 patients in cohort 2, 18 patients received invasive mechanical ventilation. The median value of length of stay in the hospital (10.0 days) and all-cause mortality (31.6 %) were higher in cohort 2 as compared to cohort 1 (p<0.05). Discussion:Infections have the ability to trigger systemic inflammation [6]. The interplay between the host system and its response to foreign pathogens can lead to the activation of coagulation pathways. SARS-CoV-2 entry via ACE-2 receptors on endothelial cells is likely associated with endothelial dysfunction. This endotheliopathy plays a significant role in COVID-19 related microcirculatory changes [7]. Severe COVID-19, a hyperinflammatory state, is marked by elevated inflammatory markers including D-dimer, ferritin, IL-6, LDH, and CRP levels. Elevated D-dimer levels have been correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 [8]. The incidence of VTE and pulmonary embolism among COVID-19 ICU patients was higher in a study from France [9]. The patient population who received the escalated dose of LMWH in our study either had SIC score ≥ 4 or D-dimer ≥ 2.2 (FEU). This data indicated that the median value of peak inflammatory markers in cohort 1 was lower (p<0.05) when compared to cohort 2. Patients in cohort 2 were sicker than cohort 1, as evidenced by a statistically significant longer length of hospital stay and a higher rate of ICU admission. However, the potential dose-dependent anti-inflammatory effect of LMWH was not observed. Additional studies evaluating comorbidities and disease severity in both cohorts may yield different results. Conclusion:Aside from the known anticoagulant benefit of LMWH, there was no additional anti-inflammatory role with higher doses (1mg/kg/subcutaneously every 12 hours) of LMWH. Disclosures No relevant conflicts of interest to declare.

scholarly journals Regulation of the unfolded protein response by microRNAs

2013 ◽  
Vol 18 (4) ◽  
Author(s):  
Sylwia Bartoszewska ◽  
Kinga Kochan ◽  
Piotr Madanecki ◽  
Arkadiusz Piotrowski ◽  
Renata Ochocka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Potential Role ◽  
Recovery Phase ◽  
Cellular Mechanisms ◽  
Unfolded Protein ◽  
Critical Components ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe unfolded protein response (UPR) is an adaptive response to the stress that is caused by an accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). It is an important component of cellular homeostasis. During ER stress, the UPR increases the protein-folding capacity of the endoplasmic reticulum to relieve the stress. Failure to recover leads to apoptosis. Specific cellular mechanisms are required for the cellular recovery phase after UPR activation. Using bioinformatics tools, we identified a number of microRNAs that are predicted to decrease the mRNA expression levels for a number of critical components of the UPR. In this review, we discuss the potential role of microRNAs as key regulators of this pathway and describe how microRNAs may play an essential role in turning off the UPR after the stress has subsided.

scholarly journals Detection of MicroRNAs in Extracellular Vesicles Secreted by Umbilical Cord-derived Mesenchymal Stem Cells

2021 ◽  
Vol 37 (3) ◽  
Author(s):  
Nguyen Thu Huyen ◽  
Duong Minh Chau ◽  
Do Thi Xuan Phuong ◽  
Nguyen Thanh Liem ◽  
Than Thi Trang Uyen
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Potential Role ◽  
Culture Media ◽  
Therapeutic Effects ◽  
Potential Candidate ◽  
Disease Treatment

Extracellular vesicles (EVs) are emerging as a potential candidate for disease treatment due to their bioactive cargoes. Recently, mesenchymal stem cells (MSC)-derived EVs have shown their capacity to replace parental cells as their similar functions to MSCs. The therapeutic effects of EVs depend on their cargo, such as DNA, miRNA, proteins, and lipids. In this study, we expanded umbilical cord-derived MSCs (UCMSCs) for EV release. Additionally, we evaluated the expression level of several microRNAs in three EV populations, including apoptotic bodies (AB), microvesicles (MV), and exosomes (EX). Results showed that UCMSCs released three EV types: AB, MV, and EX into culture media. The three EV populations were different in morphology and size. Three EVs were detected to carry microRNAs, such as hsa-miR-320, hsa-miR-181b, and hsa-miR-140. Among these microRNAs, hsa-miR-140 expressed with the greatest level, followed by hsa-miR-181b and hsa-miR-320. The results of this study provide more knowledge about UCMSC-derived EV miRNAs in addition to reveal the potential role of UCMSC-EVs associated with detected miRNAs.

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