15 results on '"McGill AR"'
Search Results
2. Acetate-encapsulated Linolenic Acid Liposomes Reduce SARS-CoV-2 and RSV Infection.
- Author
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McGill AR, Markoutsa E, Mayilsamy K, Green R, Sivakumar K, Mohapatra S, and Mohapatra SS
- Subjects
- Animals, Mice, SARS-CoV-2, Liposomes, alpha-Linolenic Acid therapeutic use, Molecular Docking Simulation, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Acetates, COVID-19, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human
- Abstract
Emergent Coronaviridae viruses, such as SARS-CoV-1 in 2003, MERS-CoV in 2012, and SARS-CoV-2 (CoV-2) in 2019, have caused millions of deaths. These viruses have added to the existing respiratory infection burden along with respiratory syncytial virus (RSV) and influenza. There are limited therapies for respiratory viruses, with broad-spectrum treatment remaining an unmet need. Since gut fermentation of fiber produces short-chain fatty acids (SCFA) with antiviral potential, developing a fatty acid-based broad-spectrum antiviral was investigated. Molecular docking of fatty acids showed α-linolenic acid (ALA) is likely to interact with CoV-2-S, NL63-CoV-S, and RSV-F, and an ALA-containing liposome interacted with CoV-2 directly, degrading the particle. Furthermore, a combination of ALA and a SCFA-acetate synergistically inhibited CoV2-N expression and significantly reduced viral plaque formation and IL-6 and IL-1β transcript expression in Calu-3 cells, while increasing the expression of IFN-β. A similar effect was also observed in RSV-infected A549 cells. Moreover, mice infected with a murine-adapted SARS-CoV-2 (MA10) and treated with an ALA-liposome encapsulating acetate showed significant reductions in plaque-forming units present in lung tissue and in infection-associated lung inflammation and cytokines. Taken together, these results demonstrate that the ALA liposome-encapsulating acetate can be a promising broad antiviral therapy against respiratory infections.
- Published
- 2023
- Full Text
- View/download PDF
3. SARS-CoV-2 infection increases the gene expression profile for Alzheimer's disease risk.
- Author
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Green R, Mayilsamy K, McGill AR, Martinez TE, Chandran B, Blair LJ, Bickford PC, Mohapatra SS, and Mohapatra S
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused over 600,000,000 infections globally thus far. Up to 30% of individuals with mild to severe disease develop long COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers and whether these can precipitate the onset of Alzheimer's disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS-CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferon-inducible gene Ifi204 , and complement genes C4 and C5AR1. Brain histopathology shows AD signatures including increased tau-phosphorylation, tau-oligomerization, and α-synuclein expression in aged MA10 infected mice. The results of gene expression profiling of SARS-CoV-2-infected and AD brains and studies in the MA10 aged mouse model taken together, for the first time provide evidence suggesting that SARS-CoV-2 infection alters expression of genes in the brain associated with the development of AD. Future studies of common molecular markers in SARS-CoV-2 infection and AD could be useful for developing novel therapies targeting AD., Competing Interests: The authors have no competing interests to declare.
- Published
- 2022
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4. Targeting an evolutionarily conserved "E-L-L" motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2.
- Author
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Jana ID, Bhattacharya P, Mayilsamy K, Banerjee S, Bhattacharje G, Das S, Aditya S, Ghosh A, McGill AR, Srikrishnan S, Das AK, Basak A, Mohapatra SS, Chandran B, Bhimsaria D, Mohapatra S, Roy A, and Mondal A
- Abstract
As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key toward sustenance. Here, we identify an evolutionarily conserved "Ex
3 Lx6 L" ("E-L-L") motif present within the HR2 domain of all human and nonhuman coronavirus spike (S) proteins that play a crucial role in stabilizing its postfusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this "E-L-L" motif and impedes the formation of 6-HB, thus effectively inhibiting SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy in blocking S protein-mediated viral entry, mutations within the "E-L-L" motif rendered the protein completely resistant to the drug, establishing its specificity toward this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective toward all major variants of concerns of SARS-CoV-2, including Beta, Kappa, Delta, and Omicron. Together, we show that this conserved essential "E-L-L" motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)- Published
- 2022
- Full Text
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5. Targeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2.
- Author
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Jana ID, Bhattacharya P, Mayilsamy K, Banerjee S, Bhattacharje G, Das S, Aditya S, Ghosh A, McGill AR, Srikrishnan S, Das AK, Basak A, Mohapatra SS, Chandran B, Bhimsaria D, Mohapatra S, Roy A, and Mondal A
- Abstract
As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved E-L-L motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing the post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this E-L-L motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated viral entry, mutations within the E-L-L motif rendered the protein completely resistant to the drug, establishing its specificity towards this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective towards all major variants of concerns of SARS-CoV-2 including beta, kappa, delta, and omicron. Together, we show that this conserved essential E-L-L motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.
- Published
- 2022
- Full Text
- View/download PDF
6. Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity.
- Author
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Ramadan AA, Mayilsamy K, McGill AR, Ghosh A, Giulianotti MA, Donow HM, Mohapatra SS, Mohapatra S, Chandran B, Deschenes RJ, and Roy A
- Subjects
- Humans, Lipoylation, Spike Glycoprotein, Coronavirus, COVID-19, SARS-CoV-2
- Abstract
The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment of palmitate on cysteine residues on the cytoplasmic facing tail of the protein. The role of spike protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target of novel antivirals. Here, we report that palmitoylation of the first five cysteine residues of the C-terminal cysteine-rich domain of the SARS-CoV-2 S protein are indispensable for infection, and palmitoylation-deficient spike mutants are defective in membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 S protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.
- Published
- 2022
- Full Text
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7. Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.
- Author
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Howell MC, Green R, McGill AR, Kahlil RM, Dutta R, Mohapatra SS, and Mohapatra S
- Subjects
- COVID-19 immunology, COVID-19 virology, Gene Regulatory Networks genetics, Humans, Intracellular Space genetics, Lung immunology, Lung microbiology, Lymphocyte Count, SARS-CoV-2 physiology, T-Lymphocyte Subsets metabolism, COVID-19 genetics, Complement Activation genetics, Complement System Proteins genetics, Gene Expression Profiling methods, Lung metabolism, T-Lymphocytes metabolism
- Abstract
A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanisms, we examined publicly available RNA-Sequencing data using CIBERSORTx and conducted a Ingenuity Pathway Analysis to address this knowledge gap. In complement to these findings, we used bioinformatics tools to analyze publicly available RNA sequencing data and found that upregulation of complement may be leading to a downregulation of T-cell activity in lungs of severe COVID-19 patients. Thus, targeting treatments aimed at the modulation of classical complement and T-cell activity may help alleviate the proinflammatory effects of COVID-19, reduce lung pathology, and increase the survival of COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Howell, Green, McGill, Kahlil, Dutta, Mohapatra and Mohapatra.)
- Published
- 2021
- Full Text
- View/download PDF
8. SARS-CoV-2-Induced Gut Microbiome Dysbiosis: Implications for Colorectal Cancer.
- Author
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Howell MC, Green R, McGill AR, Dutta R, Mohapatra S, and Mohapatra SS
- Abstract
The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), in December 2019 led to a worldwide pandemic with over 170 million confirmed infections and over 3.5 million deaths (as of May 2021). Early studies have shown higher mortality rates from SARS-CoV-2 infection in cancer patients than individuals without cancer. Herein, we review the evidence that the gut microbiota plays a crucial role in health and has been linked to the development of colorectal cancer (CRC). Investigations have shown that SARS-CoV-2 infection causes changes to the gut microbiota, including an overall decline in microbial diversity, enrichment of opportunistic pathogens such as Fusobacterium nucleatum bacteremia, and depletion of beneficial commensals, such as the butyrate-producing bacteria. Further, these changes lead to increased colonic inflammation, which leads to gut barrier disruption, expression of genes governing CRC tumorigenesis, and tumor immunosuppression, thus further exacerbating CRC progression. Additionally, a long-lasting impact of SARS-CoV-2 on gut dysbiosis might result in a greater possibility of new CRC diagnosis or aggravating the condition in those already afflicted. Herein, we review the evidence relating to the current understanding of how infection with SARS-CoV-2 impacts the gut microbiota and the effects this will have on CRC carcinogenesis and progression., Competing Interests: The authors declare no potential conflict of interest.
- Published
- 2021
- Full Text
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9. SARS-CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges.
- Author
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McGill AR, Kahlil R, Dutta R, Green R, Howell M, Mohapatra S, and Mohapatra SS
- Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that emerged from Wuhan, China in late 2019 causing coronavirus disease-19 (COVID-19). SARS-CoV-2 infection begins by attaching to angiotensin-converting enzyme 2 receptor (ACE2) via the spike glycoprotein, followed by cleavage by TMPRSS2, revealing the viral fusion domain. Other presumptive receptors for SARS-CoV-2 attachment include CD147, neuropilin-1 (NRP1), and Myeloid C-lectin like receptor (CLR), each of which might play a role in the systemic viral spread. The pathology of SARS-CoV-2 infection ranges from asymptomatic to severe acute respiratory distress syndrome, often displaying a cytokine storm syndrome, which can be life-threatening. Despite progress made, the detailed mechanisms underlying SARS-CoV-2 interaction with the host immune system remain unclear and are an area of very active research. The process's key players include viral non-structural proteins and open reading frame products, which have been implicated in immune antagonism. The dysregulation of the innate immune system results in reduced adaptive immune responses characterized by rapidly diminishing antibody titers. Several treatment options for COVID-19 are emerging, with immunotherapies, peptide therapies, and nucleic acid vaccines showing promise. This review discusses the advances in the immunopathology of SARS-CoV-2, vaccines and therapies under investigation to counter the effects of this virus, as well as viral variants.
- Published
- 2021
- Full Text
- View/download PDF
10. A multifunctional nanoparticle as a prophylactic and therapeutic approach targeting respiratory syncytial virus.
- Author
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Markoutsa E, McGill AR, Singer A, Jadhav H, Mohapatra S, and Mohapatra SS
- Subjects
- Animals, Cytokines metabolism, Drug Liberation, Female, Inflammation Mediators metabolism, Intercellular Adhesion Molecule-1 metabolism, Mice, Inbred BALB C, Multifunctional Nanoparticles ultrastructure, Peptides pharmacology, Plasmids genetics, RNA, Small Interfering metabolism, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Virus, Human drug effects, Transfection, Viral Fusion Proteins metabolism, Mice, Multifunctional Nanoparticles therapeutic use, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus, Human physiology
- Abstract
Respiratory Syncytial Virus (RSV) has been a major health concern globally for decades, yet no effective prophylactic or treatment regimen is available. The key viral proteins responsible for RSV pathology include the fusion protein (F), the immunomodulatory non-structural-protein 1 (NS1) and the phosphoprotein (P) involved in viral replication. Herein, we developed a novel shell-core multifunctional nanosystem with dual payload: a plasmid construct encoding for shRNAs against NS1 and P, and an anti-fusion peptide (HR2D). Anti-ICAM1 antibody conjugated on the nanoparticle (NP) surface is used to target RSV infected cells. Our data show the potential of this nanosystem as a prophylactic and/or a therapeutic regimen against RSV infection. Furthermore, therapy of RSV infected mice with this nanosystem, in addition to reducing viral load, modulated expression of Th2 and allergy-associated cytokines such as IL4, IL-13 and IL-17 indicating a direct role of this nanosystem in the mechanisms involved in the immunoregulation of disease pathogenesis., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
11. Molecular mechanism-driven new biomarkers and therapies for atopic dermatitis.
- Author
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Mohapatra SS, Mohapatra S, McGill AR, and Green R
- Subjects
- Biomarkers, Cytokines, Humans, NF-kappa B, Dermatitis, Atopic diagnosis, Dermatitis, Atopic drug therapy, Dermatitis, Atopic genetics, Eczema, MicroRNAs
- Published
- 2020
- Full Text
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12. Advances in Translational Nanotechnology: Challenges and Opportunities.
- Author
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Mohapatra SS, Frisina RD, Mohapatra S, Sneed KB, Markoutsa E, Wang T, Dutta R, Damnjanovic R, Phan MH, Denmark DJ, Biswal MR, McGill AR, Green R, Howell M, Ghosh P, Gonzalez A, Ahmed NT, Borresen B, Farmer M, Gaeta M, Sharma K, Bouchard C, Gamboni D, Martin J, Tolve B, Singh M, Judy JW, Li C, Santra S, Daunert S, Zeynaloo E, Gelfand RM, Lenhert S, McLamore ES, Xiang D, Morgan V, Friedersdorf LE, Lal R, Webster TJ, Hoogerheide DP, Nguyen TD, D'Souza MJ, Çulha M, Kondiah PPD, and Martin DK
- Abstract
The burgeoning field of nanotechnology aims to create and deploy nanoscale structures, devices, and systems with novel, size-dependent properties and functions. The nanotechnology revolution has sparked radically new technologies and strategies across all scientific disciplines, with nanotechnology now applied to virtually every area of research and development in the US and globally. NanoFlorida was founded to create a forum for scientific exchange, promote networking among nanoscientists, encourage collaborative research efforts across institutions, forge strong industry-academia partnerships in nanoscience, and showcase the contributions of students and trainees in nanotechnology fields. The 2019 NanoFlorida International Conference expanded this vision to emphasize national and international participation, with a focus on advances made in translating nanotechnology. This review highlights notable research in the areas of engineering especially in optics, photonics and plasmonics and electronics; biomedical devices, nano-biotechnology, nanotherapeutics including both experimental nanotherapies and nanovaccines; nano-diagnostics and -theranostics; nano-enabled drug discovery platforms; tissue engineering, bioprinting, and environmental nanotechnology, as well as challenges and directions for future research., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.
- Published
- 2020
- Full Text
- View/download PDF
13. The effects of diet on high density lipoprotein cholesterol.
- Author
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Flanagan M, Little C, Milliken J, Wright E, McGill AR, Weir DG, and O'Moore RR
- Subjects
- Adult, Colonic Diseases, Functional therapy, Female, Humans, Male, Middle Aged, Time Factors, Varicose Veins therapy, Cellulose therapeutic use, Cholesterol blood, Diet, Dietary Fiber therapeutic use, Energy Intake, Lipoproteins, HDL blood
- Abstract
Twenty-nine patients with normal blood lipids were placed on diets. Thirteen, mainly attending hospital for varicose veins, were prescribed low-energy diets: HDL-cholesterol was raised after one month and significantly after three months (P less than 0.02); total cholesterol was lowered (P less than 0.05). Sixteen patients, mainly with irritable bowel symptoms, were prescribed high-fibre diet: HDL-C was raised after one month (P less than 0.05), but not significantly so after three months; total cholesterol was unchanged.
- Published
- 1980
- Full Text
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14. The effect of apple fibre on diabetic control and plasma lipids.
- Author
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Mayne PD, McGill AR, Gormley TR, Tomkin GH, Julian TR, and O'Moore RR
- Subjects
- Adult, Blood Glucose, Female, Fruit, Humans, Lipids blood, Male, Diet, Diabetic, Dietary Fiber therapeutic use
- Published
- 1982
- Full Text
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15. Serum cholesterol and HDL cholesterol in childhood.
- Author
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Kelly DA, Hooey H, Neale G, McGill AR, and Stuart M
- Subjects
- Child, Child, Preschool, Cholesterol, HDL, Female, Humans, Infant, Male, Reference Values, Cholesterol blood, Lipoproteins, HDL blood
- Published
- 1981
- Full Text
- View/download PDF
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