Iron-and aluminum-sulfate together, at nanomolar concentrations, trigger the production of reactive oxygen species (ROS) in cultures of human brain cells. Previous studies have shown that following ROS induction, a family of pathogenic brain genes that promote inflammatory signalling, cellular apoptosis and brain cell death is significantly over-expressed. Notably, iron-and aluminum-sulfate induce genes in cultured human brain cells that exhibit expression patterns similar to those observed to be up-regulated in moderate-to late-stage Alzheimer's disease (AD). In this study we have extended our investigations to analyze the expression of micro RNA (miRNA) populations in ironand aluminum-sulfate treated human neural cells in primary culture. The main finding was that these ROS-generating neurotoxic metal sulfates also up-regulate a specific set of miRNAs that includes miR-9, miR-125b and miR-128. Notably, these same miRNAs are up-regulated in AD brain. These findings further support the idea that iron-and aluminum-sulfates induce genotoxicity via a ROS-* Corresponding Author: Walter J. Lukiw, MS, PhD, e-mail: wlukiw@lsuhsc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. FOOTNOTE 1 -Experimental detailsIn the construction of brain cell-specific miRNA array panels, 13 individual brain-enriched miRNAs and human 5S ribosomal RNA (5S rRNA) were spotted onto GeneScreen Plus nylon membranes using a Biomek® 2000 laboratory automation workstation (Beckmann, Fullerton, CA) and were crosslinked, baked, hybridized and probed according to the manufacturer's protocol (NEN® Research Products, Boston MA) [7,[10][11][12]. A guanidine isothiocyanate-and silica gel-based membrane total RNA purification system and miRNA isolation kit (PureLink™ Invitrogen, Carlsbad, CA) were used to isolate total small RNAs (5S rRNA, tRNA and miRNA) from magnesium-, aluminum-and iron-plus aluminum-sulfate treated HN cells. Total RNA concentrations and spectral purity were quantified using RNA 6000 Nano LabChip analysis and a 2100 Spectral Analyzer (Caliper Technologies, Mountainview, CA; Agilent Technologies, Palo Alto, CA) [1,4,5,7]. 28S/18S ratios consistently exceeded 1.4 and the A 260/280 of total RNA (based on peak area) was typically ≥1.8. Poly A+ messenger RNA was found to range in size from 0.5−8 kilobases. In a preliminary screen, miRNA arrays were probed with total labeled miRNAs isolated from 3 week old HN cells that had been exposed to 100 nM magnesium-sulfate (control), or aluminum-sulfate, or aluminum-plus iron-sulfate, for 7 days, or about one-third of their in vitro life-span [1]. ...

The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin-and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell-and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.

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Micro RNA-146a (miRNA-146a) is an inducible, 22 nucleotide, small RNA over-expressed in Alzheimer’s disease (AD) brain. Up-regulated miRNA-146a targets several inflammation-related and membrane-associated messenger RNAs (mRNAs), including those encoding complement factor-H (CFH) and the interleukin-1 receptor associated kinase-1 (IRAK-1), resulting in significant decreases in their expression (p < 0.05, ANOVA). In this study we assayed miRNA-146a, CFH, IRAK-1 and tetraspanin-12 (TSPAN12), abundances in primary human neuronal-glial (HNG) co-cultures, in human astroglial (HAG) and microglial (HMG) cells stressed with Aβ42 peptide and tumor necrosis factor alpha (TNFα). The results indicate a consistent inverse relationship between miRNA-146a and CFH, IRAK-1 and TSPAN12 expression levels, and indicate that HNG, HAG and HMG cell types each respond differently to Aβ42-peptide + TNFα-triggered stress. While the strongest miRNA-146a-IRAK-1 response was found in HAG cells, the largest miRNA-146a-TSPAN12 response was found in HNG cells, and the most significant miRNA-146a-CFH changes were found in HMG cells, the ‘resident scavenging macrophages’ of the brain.