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Al-Refai, Nevin. "The role of viral advertising in increasing market penetration and building consumer awareness of products and brands". International Design Journal 12, nr 1 (1.01.2022): 283–97. http://dx.doi.org/10.21608/idj.2022.210349.
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Hernández-Sánchez, Brenda, Ericka Santacruz-Juárez, David Moore i Carmen Sánchez. "Bioactive compounds from fungi with antiviral activities: Mechanism of action and biosynthetic pathways". Mexican journal of biotechnology 6, nr 1 (11.01.2021): 165–89. http://dx.doi.org/10.29267/mxjb.2021.6.1.165.
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Viral infections have affected human health, causing critical pandemics and mortality worldwide. Viruses can also cause enormous economic problems for society globally. Bioactive compounds isolated from fungi (both edible and nonedible) have shown potential activity against viruses. In this review, we describe the fungal natural compounds that have exhibited capability to inhibit some human pathogenic viruses, such as human immunodeficiency virus, dengue virus, herpes simplex virus, bovine herpes virus, influenza virus, respiratory syndrome virus, hepatitis virus among others. We focused on the biosynthetic pathways of fungal bioactive compounds and addressed the current knowledge about their antiviral mechanisms of action and specific targets. Fungal bioactive compounds are able to inhibit viral reproduction, blocking viral penetration, replication or translation as well as integrase or protease action. Fungal compounds able to inhibit protease such as. ganodermatriol, ergosterol, terpenoids, ganoderic acid GS-2, ganoderiol, sterigmatocystin, emericellin, cordycepin, ergosterol peroxide, myristic acid among others, may have a significant value to society at present, as they may have the potential to treat severe viral respiratory infections. Fungi represent a potential natural source of bioactive molecules that can be exploited for treating viral infections, which represent one of the main causes of disease worldwide. However, extensive investigations on clinical trials are required for the introduction of new antiviral agents into the market.
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Domingues, Joana M., Marta O. Teixeira, Marta A. Teixeira, David Freitas, Samira F. da Silva, Shafagh D. Tohidi, Rui D. V. Fernandes i in. "Inhibition of Escherichia Virus MS2, Surrogate of SARS-CoV-2, via Essential Oils-Loaded Electrospun Fibrous Mats: Increasing the Multifunctionality of Antivirus Protection Masks". Pharmaceutics 14, nr 2 (27.01.2022): 303. http://dx.doi.org/10.3390/pharmaceutics14020303.
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One of the most important measures implemented to reduce SARS-CoV-2 transmission has been the use of face masks. Yet, most mask options available in the market display a passive action against the virus, not actively compromising its viability. Here, we propose to overcome this limitation by incorporating antiviral essential oils (EOs) within polycaprolactone (PCL) electrospun fibrous mats to be used as intermediate layers in individual protection masks. Twenty EOs selected based on their antimicrobial nature were examined for the first time against the Escherichia coli MS2 virus (potential surrogate of SARS-CoV-2). The most effective were the lemongrass (LGO), Niaouli (NO) and eucalyptus (ELO) with a virucidal concentration (VC) of 356.0, 365.2 and 586.0 mg/mL, respectively. PCL was processed via electrospinning, generating uniform, beadless fibrous mats. EOs loading was accomplished via two ways: (1) physisorption on pre-existing mats (PCLaEOs), and (2) EOs blending with the polymer solution prior to fiber electrospinning (PCLbEOs). In both cases, 10% v/v VC was used as loading concentration, so the mats’ stickiness and overwhelming smell could be prevented. The EOs presence and release from the mats were confirmed by UV-visible spectroscopy (≈5257–631 µg) and gas chromatography-mass spectrometry evaluations (average of ≈14.3% EOs release over 4 h), respectively. PCLbEOs mats were considered the more mechanically and thermally resilient, with LGO promoting the strongest bonds with PCL (PCLbLGO). On the other hand, PCLaNO and PCLaELO were deemed the least cohesive combinations. Mats modified with the EOs were all identified as superhydrophobic, capable of preventing droplet penetration. Air and water-vapor permeabilities were affected by the mats’ porosity (PCL < PCLaEOs < PCLbEOs), exhibiting a similar tendency of increasing with the increase of porosity. Antimicrobial testing revealed the mats’ ability to retain the virus (preventing infiltration) and to inhibit its action (log reduction averaging 1). The most effective combination against the MS2 viral particles was the PCLbLGO. These mats’ scent was also regarded as the most pleasant during sensory evaluation. Overall, data demonstrated the potential of these EOs-loaded PCL fibrous mats to work as COVID-19 active barriers for individual protection masks.
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Chung, Che-Sheng, Cheng-Yen Huang i Wen Chang. "Vaccinia Virus Penetration Requires Cholesterol and Results in Specific Viral Envelope Proteins Associated with Lipid Rafts". Journal of Virology 79, nr 3 (1.02.2005): 1623–34. http://dx.doi.org/10.1128/jvi.79.3.1623-1634.2005.
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ABSTRACT Vaccinia virus infects a wide variety of mammalian cells from different hosts, but the mechanism of virus entry is not clearly defined. The mature intracellular vaccinia virus contains several envelope proteins mediating virion adsorption to cell surface glycosaminoglycans; however, it is not known how the bound virions initiate virion penetration into cells. For this study, we investigated the importance of plasma membrane lipid rafts in the mature intracellular vaccinia virus infection process by using biochemical and fluorescence imaging techniques. A raft-disrupting drug, methyl-β-cyclodextrin, inhibited vaccinia virus uncoating without affecting virion attachment, indicating that cholesterol-containing lipid rafts are essential for virion penetration into mammalian cells. To provide direct evidence of a virus and lipid raft association, we isolated detergent-insoluble glycolipid-enriched membranes from cells immediately after virus infection and demonstrated that several viral envelope proteins, A14, A17L, and D8L, were present in the cell membrane lipid raft fractions, whereas the envelope H3L protein was not. Such an association did not occur after virions attached to cells at 4°C and was only observed when virion penetration occurred at 37°C. Immunofluorescence microscopy also revealed that cell surface staining of viral envelope proteins was colocalized with GM1, a lipid raft marker on the plasma membrane, consistent with biochemical analyses. Finally, mutant viruses lacking the H3L, D8L, or A27L protein remained associated with lipid rafts, indicating that the initial attachment of vaccinia virions through glycosaminoglycans is not required for lipid raft formation.
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Sinzger, C., M. Kahl, K. Laib, K. Klingel, P. Rieger, B. Plachter i G. Jahn. "Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus". Journal of General Virology 81, nr 12 (1.12.2000): 3021–35. http://dx.doi.org/10.1099/0022-1317-81-12-3021.
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Marked interstrain differences in the endothelial cell (EC) tropism of human cytomegalovirus (HCMV) isolates have been described. This study aimed to define the step during the replicative cycle of HCMV that determines this phenotype. The infection efficiency of various HCMV strains in EC versus fibroblasts was quantified by immunodetection of immediate early (IE), early and late viral antigens. Adsorption and penetration were analysed by radiolabelled virus binding assays and competitive HCMV-DNA-PCR. The translocation of penetrated viral DNA to the nucleus of infected cells was quantified by competitive HCMV-DNA-PCR in pure nuclear fractions. The intracytoplasmic translocation of capsids that had penetrated was followed by immunostaining of virus particles on a single particle level; this was correlated with the initiation of viral gene expression by simultaneous immunostaining of viral IE antigens. The infectivity of nonendotheliotropic HCMV strains in EC was found to be 100–1000-fold lower when compared to endotheliotropic strains. The manifestation of this phenotype at the level of IE gene expression indicated the importance of initial replication events. Surprisingly, no interstrain differences were detected during virus entry. However, dramatic interstrain differences were found regarding the nuclear translocation of penetrated viral DNA. With nonendotheliotropic strains, the content of viral DNA in the cell nucleus was 100–1000-fold lower in EC when compared to endotheliotropic strains, thereby reflecting the strain differences in IE gene expression. Simultaneous staining of viral particles and viral IE antigen revealed that interstrain differences in the transport of penetrated capsids towards the nucleus of endothelial cells determine the EC tropism of HCMV.
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Kaufman, Gil, Benjamin A. Horwitz, Ruthi Hadar, Yehuda Ullmann i Israela Berdicevsky. "Green fluorescent protein (GFP) as a vital marker for pathogenic development of the dermatophyte Trichophyton mentagrophytes". Microbiology 150, nr 8 (1.08.2004): 2785–90. http://dx.doi.org/10.1099/mic.0.27094-0.
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Skin infections by dermatophytes of the genus Trichophyton are widespread, but methods to investigate the molecular basis of pathogenicity are only starting to be developed. The initial stages of growth on the host can only be studied by electron microscopy, which requires fixing the tissue. This paper shows that restriction-enzyme-mediated integration (REMI) provides stable expression of the green fluorescent protein (GFP) in a clinical isolate of Trichophyton mentagrophytes. Under control of a constitutively active fungal promoter, GFP renders the hyphae fluorescent both in culture and in a recently developed model using human skin explants. Stages of infection and penetration into the skin layers were visualized by confocal microscopy. The stages of infection can thus be followed using GFP as a vital marker, and this method will also provide, for the first time, a means to follow gene expression during infection of skin by dermatophyte fungi.
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Bisseneva, Anar Kazbekovna, Gayane Pogossyan, Konstantin Li i Michael Danilenko. "Analysis of the interaction of ACE2, TMPRSS2 genes and their polymorphisms with the SARS-CoV-2 virus". Bulletin of the Karaganda University. “Biology, medicine, geography Series” 105, nr 1 (30.03.2022): 42–48. http://dx.doi.org/10.31489/2022bmg1/42-48.
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Host genes act as a factor related to susceptibility and resistance to viral infections. The article provides a description of modern scientific studies devoted to the study of the role of the ACE2, TMPRSS2 genes, and their single-nucleotide polymorphisms in infection with the SARS-CoV-2 virus. SNPs of the ACE2 gene, TMPRSS2 can affect the penetration of SARS-CoV-2 into the cell. In addition, the study of these polymorphisms will determine the predisposition of an individual to the disease COVID–19, or the nature of its course. Based on the literature sources, the role of angiotensin-converting enzyme 2 and transmembrane proteases in the participation of the SARS-CoV-2 virus penetration process with the body cells is noted. Other functions that ACE2 and TMPRSS2 receptors perform in the human body are also described. The characteristics of two genes and their fairly well-known polymorphisms are given. The tissues and organs in which genes are expressed are marked. Information on the frequency of alleles of genetic variants of genes in different populations is shown. In addition to describing the relationship of gene polymorphisms with the disease caused by SARSCoV-2, information is provided on the association of these genetic variations with diseases of the blood vascular system and oncological diseases.
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Gerdts, Volker, Jörg Beyer, Béla Lomniczi i Thomas C. Mettenleiter. "Pseudorabies Virus Expressing Bovine Herpesvirus 1 Glycoprotein B Exhibits Altered Neurotropism and Increased Neurovirulence". Journal of Virology 74, nr 2 (15.01.2000): 817–27. http://dx.doi.org/10.1128/jvi.74.2.817-827.2000.
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ABSTRACT Herpesvirus glycoproteins play dominant roles in the initiation of infection of target cells in culture and thus may also influence viral tropism in vivo. Whereas the relative contribution of several nonessential glycoproteins to neurovirulence and neurotropism ofPseudorabies virus (PrV), an alphaherpesvirus which causes Aujeszky's disease in pigs, has recently been uncovered in studies using viral deletion mutants, the importance of essential glycoproteins is more difficult to assess. We isolated an infectious PrV mutant, PrV-9112C2, which lacks the gene encoding the essential PrV glycoprotein B (gB) but stably carries in its genome and expresses the homologous gene of bovine herpesvirus 1 (BHV-1) (A. Kopp and T. C. Mettenleiter, J. Virol. 66:2754–2762, 1992). Apart from exhibiting a slight delay in penetration kinetics, PrV-9112C2 was similar in its growth characteristics in cell culture to wild-type PrV. To analyze the effect of the exchange of these homologous glycoproteins in PrV's natural host, swine, 4-week-old piglets were intranasally infected with 106 PFU of either wild-type PrV strain Kaplan (PrV-Ka), PrV-9112C2, or PrV-9112C2R, in which the PrV gB gene was reinserted instead of the BHV-1 gB gene. Animals infected with PrV-Ka and PrV-9112C2R showed a similar course of disease, i.e., high fever, marked respiratory symptoms but minimal neurological disorders, and excretion of high amounts of virus. All animals survived the infection. In contrast, animals infected with PrV-9112C2 showed no respiratory symptoms and developed only mild fever. However, on day 5 after infection, all piglets developed severe central nervous system (CNS) symptoms leading to death within 48 to 72 h. Detailed histological analyses showed that PrV-9112C2R infected all regions of the nasal mucosa and subsequently spread to the CNS preferentially by the trigeminal route. In contrast, PrV-9112C2 primarily infected the olfactory epithelium and spread via the olfactory route. In the CNS, more viral antigen and significantly more pronounced histological changes resulting in more severe encephalitis were found after PrV-9112C2 infection. Thus, our results demonstrate that replacement of PrV gB by the homologous BHV-1 glycoprotein resulted in a dramatic increase in neurovirulence combined with an alteration in the route of neuroinvasion, indicating that the essential gB is involved in determining neurotropism and neurovirulence of PrV.
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Chu, J. J. H., i M. L. Ng. "Infectious Entry of West Nile Virus Occurs through a Clathrin-Mediated Endocytic Pathway". Journal of Virology 78, nr 19 (1.10.2004): 10543–55. http://dx.doi.org/10.1128/jvi.78.19.10543-10555.2004.
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ABSTRACT The pathway of West Nile flavivirus early internalization events was mapped in detail in this study. Overexpression of dominant-negative mutants of Eps15 strongly inhibits West Nile virus (WNV) internalization, and pharmacological drugs that blocks clathrin also caused a marked reduction in virus entry but not caveola-dependent endocytosis inhibitory agent, filipin. Using immunocryoelectron microscopy, WNV particles were seen within clathrin-coated pits after 2 min postinfection. Double-labeling immunofluorescence assays and immunoelectron microscopy performed with anti-WNV envelope or capsid proteins and cellular markers (EEA1 and LAMP1) revealed the trafficking pathway of internalized virus particles from early endosomes to lysosomes and finally the uncoating of the virus particles. Disruption of host cell cytoskeleton (actin filaments and microtubules) with cytochalasin D and nocodazole showed significant reduction in virus infectivity. Actin filaments are shown to be essential during the initial penetration of the virus across the plasma membrane, whereas microtubules are involved in the trafficking of internalized virus from early endosomes to lysosomes for uncoating. Cells treated with lysosomotropic agents were largely resistant to infection, indicating that a low-pH-dependent step is required for WNV infection. In situ hybridization of DNA probes specific for viral RNA demonstrated the trafficking of uncoated viral RNA genomes to the endoplasmic reticulum.
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Pikuza, O. I., R. A. Fayzullina, A. M. Zakirova, Z. Ya Suleymanova, E. L. Rashitova i E. V. Volyanyuk. "Bactericidal capacity of oral neutrophils as a marker for clinical course of inflammatory respiratory diseases in children". Kazan medical journal 101, nr 5 (27.10.2020): 740–48. http://dx.doi.org/10.17816/kmj2020-740.
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Aim. To study the number of neutrophils in the oral cavity, their bactericidal potential, to assess as an indicator for predicting the course of recurrent bronchitis (J40) and community-acquired focal pneumonia in children.
Methods. 87 children between 5 and 10 years old, including 52 children with recurrent bronchitis and 35 with focal community-acquired pneumonia were observed. The control group consisted of 37 conditionally healthy children of a similar age. Viral antigens were studied by chemiluminescence immunoassay. Oral neutrophil counts and functional activity were determined. Antibacterial antibodies were measured by an enzyme-linked immunosorbent assay (ELISA).
Results. 70.11% of patients had a viral antigen, and 57.47% had immunoglobulins M and G against bacterial pathogens. Oral neutrophil counts increased in the main group compared to the control group: up to 163.826.5 cells (p 0.001) in recurrent bronchitis, to 110.925.5 (p 0.05) in community-acquired pneumonia. By the recovery period, the number of oral neutrophils counts decreased in recurrent bronchitis (1.7 times higher compared to the control group, p 0.01) and remained practically unchanged in community-acquired pneumonia (115.026.9, p 0.05). Myeloperoxidase level had opposite changes for the groups compared to the control group: with recurrent bronchitis, it was 1.610.09 to the level in the control group (p 0.05), with community-acquired pneumonia 0.730.09 to the level in the control group (p 0.001). The level of lysosomal cationic proteins decreased to 0.770.09 to the level in the control group (p 0.05) in recurrent bronchitis, and to 0.800.09 (p 0.05) in pneumonia.
Conclusion. In inflammation of the respiratory tract, neutrophil migration to the oral cavity, as well as myeloperoxidase level, increases, indicators of spontaneous luminol-dependent chemiluminescence are activated, and a deficiency of lysosomal cationic proteins occurs; this prevents the penetration of the pathogen into the lower respiratory tract.
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Odegard, Amy L., Maggie H. Kwan, Hanna E. Walukiewicz, Manidipa Banerjee, Anette Schneemann i John E. Johnson. "Low Endocytic pH and Capsid Protein Autocleavage Are Critical Components of Flock House Virus Cell Entry". Journal of Virology 83, nr 17 (24.06.2009): 8628–37. http://dx.doi.org/10.1128/jvi.00873-09.
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ABSTRACT The process by which nonenveloped viruses cross cell membranes during host cell entry remains poorly defined; however, common themes are emerging. Here, we use correlated in vivo and in vitro studies to understand the mechanism of Flock House virus (FHV) entry and membrane penetration. We demonstrate that low endocytic pH is required for FHV infection, that exposure to acidic pH promotes FHV-mediated disruption of model membranes (liposomes), and particles exposed to low pH in vitro exhibit increased hydrophobicity. In addition, FHV particles perturbed by heating displayed a marked increase in liposome disruption, indicating that membrane-active regions of the capsid are exposed or released under these conditions. We also provide evidence that autoproteolytic cleavage, to generate the lipophilic γ peptide (4.4 kDa), is required for membrane penetration. Mutant, cleavage-defective particles failed to mediate liposome lysis, regardless of pH or heat treatment, suggesting that these particles are not able to expose or release the requisite membrane-active regions of the capsid, namely, the γ peptides. Based on these results, we propose an updated model for FHV entry in which (i) the virus enters the host cell by endocytosis, (ii) low pH within the endocytic pathway triggers the irreversible exposure or release of γ peptides from the virus particle, and (iii) the exposed/released γ peptides disrupt the endosomal membrane, facilitating translocation of viral RNA into the cytoplasm.
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Romanescu, Constantin, Thomas Gabriel Schreiner i Ilya Mukovozov. "The Role of Human Herpesvirus 6 Infection in Alzheimer’s Disease Pathogenicity—A Theoretical Mosaic". Journal of Clinical Medicine 11, nr 11 (29.05.2022): 3061. http://dx.doi.org/10.3390/jcm11113061.
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Alzheimer’s disease (AD), a neurodegenerative disorder generally affecting older adults, is the most common form of dementia worldwide. The disease is marked by severe cognitive and psychiatric decline and has dramatic personal and social consequences. Considerable time and resources are dedicated to the pursuit of a better understanding of disease mechanisms; however, the ultimate goal of obtaining a viable treatment option remains elusive. Neurodegenerative disease as an outcome of gene–environment interaction is a notion widely accepted today; a clear understanding of how external factors are involved in disease pathogenesis is missing, however. In the case of AD, significant effort has been invested in the study of viral pathogens and their role in disease mechanisms. The current scoping review focuses on the purported role HHV-6 plays in AD pathogenesis. First, early studies demonstrating evidence of HHV-6 cantonment in either post-mortem AD brain specimens or in peripheral blood samples of living AD patients are reviewed. Next, selected examples of possible mechanisms whereby viral infection can directly or indirectly contribute to AD pathogenesis are presented, such as autophagy dysregulation, the interaction between miR155 and HHV-6, and amyloid-beta as an antimicrobial peptide. Finally, closely related topics such as HHV-6 penetration in the CNS, HHV-6 involvement in neuroinflammation, and a brief discussion on HHV-6 epigenetics are examined.
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Choo, Hyunah, James R. Beadle, Earl R. Kern, Mark N. Prichard, Kathy A. Keith, Caroll B. Hartline, Julissa Trahan, Kathy A. Aldern, Brent E. Korba i Karl Y. Hostetler. "Antiviral Activities of Novel 5-Phosphono-Pent-2-en-1-yl Nucleosides and Their Alkoxyalkyl Phosphonoesters". Antimicrobial Agents and Chemotherapy 51, nr 2 (27.11.2006): 611–15. http://dx.doi.org/10.1128/aac.00444-06.
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ABSTRACT Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailability and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphono-pent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-1-yl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.
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Vijakumaran, Ubashini, Fazlina Nordin, Zariyantey Abdul Hamid, Maha Abdullah i Jun Tye Gee. "TAT Κappa (TATΚ): A Novel Cell Penetrating Peptide for Delivery of Pluripotent Proteins into Target Cells". Sains Malaysiana 51, nr 2 (28.02.2022): 567–76. http://dx.doi.org/10.17576/jsm-2022-5102-20.
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Induced pluripotent stem cell (iPSC) holds a magnificent place in the medical revolution. Its emergence is expected to instigate development of novel therapies for regenerative medicine and treatment of malignant diseases. Moreover, iPSC usage also resolved a long-time ethical controversy on the usage of the embryo as a pluripotent stem cells source. Since Yamanaka’s iPSC discovery in 2006, several pieces of research have proven that the enforced expression of transcription factors Oct-3/4, KLF4, and Sox2 can induce the reprogramming of previously differentiated cells, to generate iPSC. However, the conventional method using viral vectors leads to genetic modification due to exogene integration and subsequently tumorigenicity, which is unsafe for clinical application. Therefore, our study utilised an improved novel protein transduction domain, trans-activator of transcription kappa (TAT), a synthetic TAT-HIV to deliver these transcription factors gene as an alternative method for iPSC generation via non-viral reprogramming. With this new strategy, we have established a stable clone of 293T cells expressing TATk fusion proteins (TATκ-GFP, TATκ-KLF4, TATκ-Sox2, and TATκ-Oct-3/4) that expresses and secretes their respective cloned reprogramming proteins. These stable clones successfully transduced our target cell (U937) monocyte cell line. TATκ-GFP, a marker protein and fusion proteins TATκ-KLF4, TATκ-Sox2, and TATκ-Oct-3/4 transduced the targeted (U937) monocyte cell line, proving that this novel TATκ possesses an ability to translocate across the cell membrane. Morphological changes were successfully observed in U937 cells after 20 days of transduction, however the presence of bonifide iPSC colonies were unable to be elicited. This might be due to the incomplete reprogramming or insufficient duration of protein transduction to generate iPSC cells.
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Ma, Henry, Joseph R. Albe, Theron Gilliland, Cynthia M. McMillen, Christina L. Gardner, Devin A. Boyles, Emily L. Cottle i in. "Long-term persistence of viral RNA and inflammation in the CNS of macaques exposed to aerosolized Venezuelan equine encephalitis virus". PLOS Pathogens 18, nr 6 (13.06.2022): e1009946. http://dx.doi.org/10.1371/journal.ppat.1009946.
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Venezuelan equine encephalitis virus (VEEV) is a positively-stranded RNA arbovirus of the genus Alphavirus that causes encephalitis in humans. Cynomolgus macaques are a relevant model of the human disease caused by VEEV and are useful in exploring pathogenic mechanisms and the host response to VEEV infection. Macaques were exposed to small-particle aerosols containing virus derived from an infectious clone of VEEV strain INH-9813, a subtype IC strain isolated from a human infection. VEEV-exposed macaques developed a biphasic fever after infection similar to that seen in humans. Maximum temperature deviation correlated with the inhaled dose, but fever duration did not. Neurological signs, suggestive of virus penetration into the central nervous system (CNS), were predominantly seen in the second febrile period. Electroencephalography data indicated a statistically significant decrease in all power bands and circadian index during the second febrile period that returned to normal after fever resolved. Intracranial pressure increased late in the second febrile period. On day 6 post-infection macaques had high levels of MCP-1 and IP-10 chemokines in the CNS, as well as a marked increase of T lymphocytes and activated microglia. More than four weeks after infection, VEEV genomic RNA was found in the brain, cerebrospinal fluid and cervical lymph nodes. Pro-inflammatory cytokines & chemokines, infiltrating leukocytes and pathological changes were seen in the CNS tissues of macaques euthanized at these times. These data are consistent with persistence of virus replication and/or genomic RNA and potentially, inflammatory sequelae in the central nervous system after resolution of acute VEEV disease.
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Kowalska, Klaudia, Zofia Sabatowska, Joanna Forycka, Ewelina Młynarska, Beata Franczyk i Jacek Rysz. "The Influence of SARS-CoV-2 Infection on Lipid Metabolism—The Potential Use of Lipid-Lowering Agents in COVID-19 Management". Biomedicines 10, nr 9 (18.09.2022): 2320. http://dx.doi.org/10.3390/biomedicines10092320.
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Several studies have indicated lipid metabolism alterations during COVID-19 infection, specifically a decrease in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations and an increase in triglyceride (TG) levels during the infection. However, a decline in triglycerides can also be observed in critical cases. A direct correlation can be observed between a decrease in serum cholesterol, HDL-C, LDL-C and TGs, and the severity of the disease; these laboratory findings can serve as potential markers for patient outcomes. The transmission of coronavirus increases proportionally with rising levels of cholesterol in the cell membrane. This is due to the fact that cholesterol increases the number of viral entry spots and the concentration of angiotensin-converting enzyme 2 (ACE2) receptor, crucial for viral penetration. Studies have found that lower HDL-C levels correspond with a higher susceptibility to SARS-CoV-2 infection and infections in general, while higher HDL-C levels were related to a lower risk of developing them. However, extremely high HDL-C levels in serum increase the risk of infectious diseases and is associated with a higher risk of cardiovascular events. Low HDL-C levels are already accepted as a marker for risk stratification in critical illnesses, and higher HDL-C levels prior to the infection is associated with a lower risk of death in older patients. The correlation between LDL-C levels and disease severity is still unclear. However, TG levels were significantly higher in non-surviving severe patients compared to those that survived; therefore, elevated TG-C levels in COVID-19 patients may be considered an indicator of uncontrolled inflammation and an increased risk of death.
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Liu, Xiaoqiu, Jinxiang Yuan, Allen W. Wu, Patrick W. McGonagill, Courtney S. Galle i Jeffery L. Meier. "Phorbol Ester-Induced Human Cytomegalovirus Major Immediate-Early (MIE) Enhancer Activation through PKC-Delta, CREB, and NF-κB Desilences MIE Gene Expression in Quiescently Infected Human Pluripotent NTera2 Cells". Journal of Virology 84, nr 17 (26.05.2010): 8495–508. http://dx.doi.org/10.1128/jvi.00416-10.
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ABSTRACT The ways in which human cytomegalovirus (HCMV) major immediate-early (MIE) gene expression breaks silence from latency to initiate the viral replicative cycle are poorly understood. A delineation of the signaling cascades that desilence the HCMV MIE genes during viral quiescence in the human pluripotent N-Tera2 (NT2) cell model provides insight into the molecular mechanisms underlying HCMV reactivation. In this model, we show that phorbol 12-myristate 13-acetate (PMA) immediately activates the expression of HCMV MIE RNA and protein and greatly increases the MIE-positive (MIE+) NT2 cell population density; levels of Oct4 (pluripotent cell marker) and HCMV genome penetration are unchanged. Decreasing PKC-delta activity (pharmacological, dominant-negative, or RNA interference [RNAi] method) attenuates PMA-activated MIE gene expression. MIE gene activation coincides with PKC-delta Thr505 phosphorylation. Mutations in MIE enhancer binding sites for either CREB (cyclic AMP [cAMP] response element [CRE]) or NF-κB (κB) partially block PMA-activated MIE gene expression; the ETS binding site is negligibly involved, and κB does not confer MIE gene activation by vasoactive intestinal peptide (VIP). The PMA response is also partially attenuated by the RNAi-mediated depletion of the CREB or NF-κB subunit RelA or p50; it is not diminished by TORC2 knockdown or accompanied by TORC2 dephosphorylation. Mutations in both CRE and κB fully abolish PMA-activated MIE gene expression. Thus, PMA stimulates a PKC-delta-dependent, TORC2-independent signaling cascade that acts through cellular CREB and NF-κB, as well as their cognate binding sites in the MIE enhancer, to immediately desilence HCMV MIE genes. This signaling cascade is distinctly different from that elicited by VIP.
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Rauch, Daniel A., Nilda Rodriguez i Richard J. Roller. "Mutations in Herpes Simplex Virus Glycoprotein D Distinguish Entry of Free Virus from Cell-Cell Spread". Journal of Virology 74, nr 24 (15.12.2000): 11437–46. http://dx.doi.org/10.1128/jvi.74.24.11437-11446.2000.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) glycoprotein D (gD) is an essential component of the entry apparatus that is responsible for viral penetration and subsequent cell-cell spread. To test the hypothesis that gD may serve distinguishable functions in entry of free virus and cell-cell spread, mutants were selected for growth on US11cl19.3 cells, which are resistant to both processes due to the lack of a functional gD receptor, and then tested for their ability to enter as free virus and to spread from cell to cell. Unlike their wild-type parent, HSV-1(F), the variants that emerged from this selection, which were named SP mutants, are all capable of forming macroscopic plaques on the resistant cells. This ability is caused by a marked increase in cell-cell spread without a concomitant increase in efficiency of entry of free virus. gD substitutions that arose within these mutants are sufficient to mediate cell-cell spread in US11cl19.3 cells but are insufficient to overcome the restriction to entry of free virions. These results suggest that mutations in gD (i) are sufficient but not necessary to overcome the block to cell-cell spread exhibited by US11cl19.3 cells and (ii) are insufficient to mediate entry of free virus in the same cells.
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Einsele, Hermann, Michael Bonin, Florian Gebhardt, Tobias Kessler, Susanne Riegler, Ziad Haddad, Holger Hebart i Juergen Loeffler. "Toll-Like Receptor 3 Is a Mediator of the Innate Immune Response to Cytomegalovirus in Immature Dendritic Cells." Blood 104, nr 11 (16.11.2004): 731. http://dx.doi.org/10.1182/blood.v104.11.731.731.
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Abstract Dendritic cells (DCs), contribute to the initiation of immune responses to viral infection. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and initiate antimicrobial immune responses. TLR3 in DCs recognizes viral double-stranded RNA and triggers downstream signals to activate the NF?B and the interferon ß promoter. Double-stranded RNA may also be produced by double-stranded DNA viruses, such as HCMV, through bidirectional transcription from the genome during infection. Here we investigated whether TLR3 mediates the interaction between monocyte-derived immature DCs (iDCs) and HCMV after either active viral replication or viral penetration. We observed that HCMV strains differ in their interactions with iDCs. Strains that show no tropism for DCs, such as AD169, only penetrate iDCs, whereas the DC-tropic strains, e.g. TB40-E, actively replicate in iDCs. This difference provides an opportunity to study different forms of virus-DC interaction. Genome-wide expression array analysis showed that although 23 genes encoding cytokines, chemokines, and transcription factors are upregulated in iDCs after incubation with either strain, subsets of genes are induced specifically by DC-tropic or DC-nontropic strains. Only interaction with the DC-tropic HCMV strain TB40E, which replicates and produces mature virions, led to up-regulation of the TLR3 gene as well as genes downstream of TLR3 in the TLR3-signaling pathway, including class I interferon genes, NF?B, TRAF family member-associated NFKB activator (TANK), TANK-binding kinase 1 (TBK1), CXCL10, and CXCL11. The DC-nontropic HCMV strain AD169, which penetrates iDCs without replicating, did not upregulate genes of the TLR3 pathways. For selected genes, array data were confirmed by quantitative real-time PCR assay and ELISA to detect the gene products. To further confirm that the DC-tropic HCMV strain TB40E interacts with iDCs via TLR3, we transfected DCs with TLR3-specific siRNA prior to infection. TLR3 gene expression was potently silenced, while levels of the hALAS housekeeping gene mRNA remained normal. After these transfected DCs were infected with TB40E, HCMV-induced TLR3 gene expression was still markedly downregulated (−219 x), as were the downstream genes of the TLR3-signaling pathway (IFNa, −2.8 x; IFNß, −12.8 x; NF?B, −7.7 x; CCL5, −14.4 x; CXCL10, −16.5 x; CXCL11, −10.9 x). In contrast, TLR3 siRNA alone did not significantly modulate the expression of NF?B, CCL5, CXCL10, and class I interferons. Our results are consistent with those of McWirther et al., who reported that mice with a deficiency of TBK1 which is downstream of TLR3 show marked defects in IFNa and IFNß gene expression after viral infection or after engagement of TLR3 by double-stranded RNA. Thus, a key mediator of HCMV-DC interaction, which activates both a MyD88-dependent pathway that leads to early NF?B activation and a MyD88-independent pathway that leads to a class I interferon response (IFNa and IFNß) via interferon regulatory factor 3 (IRF3). This activation of the TLR3 signalling pathway was not observed when the DC-nontropic HCMV strain AD169 penetrated DCs without replicating. The identification of pathways that enhance innate antiviral immune responses may provide new avenues of therapeutic intervention for viral infections.
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Brabec, Marianne, Daniela Schober, Ernst Wagner, Nora Bayer, Robert F. Murphy, Dieter Blaas i Renate Fuchs. "Opening of Size-Selective Pores in Endosomes during Human Rhinovirus Serotype 2 In Vivo Uncoating Monitored by Single-Organelle Flow Analysis". Journal of Virology 79, nr 2 (15.01.2005): 1008–16. http://dx.doi.org/10.1128/jvi.79.2.1008-1016.2005.
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ABSTRACT The effect of virus uncoating on endosome integrity during the early steps in viral infection was investigated. Using fluid-phase uptake of 10- and 70-kDa dextrans labeled with a pH-dependent fluorophore (fluorescein isothiocyanate [FITC]) and a pH-independent fluorophore (cyanine 5 [Cy5]), we determined the pHs of labeled compartments in intact HeLa cells by fluorescence-activated cell sorting analysis. Subsequently, the number and pH of fluorescent endosomes in cell homogenates were determined by single-organelle flow analysis. Cointernalization of adenovirus and 70-kDa FITC- and Cy5-labeled dextran (FITC/Cy5-dextran) led to virus-induced endosomal rupture, resulting in the release of the marker from the low-pH environment into the neutral cytosol. Consequently, in the presence of adenovirus, the number of fluorescent endosomes was reduced by 40% compared to that in the control. When human rhinovirus serotype 2 (HRV2) was cointernalized with 10-and 70-kDa FITC/Cy5-dextrans, the 10-kDa dextran was released, whereas the 70-kDa dextran remained within the endosomes, which also maintained their low pH. These data demonstrate that pores are generated in the membrane during HRV2 uncoating and RNA penetration into the cytosol without gross damage of the endosomes; 10-kDa dextran can access the cytosol through these pores. Whereas rhinovirus-mediated pore formation was prevented by the vacuolar ATPase inhibitor bafilomycin A1, adenovirus-mediated endosomal rupture also occurred in the presence of the inhibitor. This finding is in keeping with the low-pH requirement of HRV2 infection; for adenovirus, no pH dependence for endosomal escape was found with this drug.
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Akbasheva, O. E., L. V. Spirina, D. A. Dyakov i N. V. Masunova. "Proteolysis and deficiency of α1-proteinase inhibitor in SARS-CoV-2 infection". Biomeditsinskaya Khimiya 68, nr 3 (2022): 157–76. http://dx.doi.org/10.18097/pbmc20226803157.
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The SARS-CoV-2 pandemia had stimulated the numerous publications emergence on the α1-proteinase inhibitor (α1-PI, α1-antitrypsin), primarily when it was found that high mortality in some regions corresponded to the regions with deficient α1-PI alleles. By analogy with the last century's data, when the root cause of the α1-antitrypsin, genetic deficiency leading to the elastase activation in pulmonary emphysema, was proven. It is evident that proteolysis hyperactivation in COVID-19 may be associated with α1-PI impaired functions. The purpose of this review is to systematize scientific data, critical directions for translational studies on the role of α1-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a target in therapy. This review describes the proteinase-dependent stages of a viral infection: the reception and virus penetration into the cell, the plasma aldosterone-angiotensin-renin, kinins, blood clotting systems imbalance. The ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases role in the virus tropism, proteolytic cascades activation in blood, and the COVID-19-dependent complications is presented. The analysis of scientific reports on the α1-PI implementation in the SARS-CoV-2-induced inflammation, the links with the infection severity, and comorbidities were carried out. Particular attention is paid to the acquired α1-PI deficiency in assessing the patients with the proteolysis overactivation and chronic non-inflammatory diseases that are accompanied by the risk factors for the comorbidities progression, and the long-term consequences of COVID-19 initiation. Analyzed data on the search and proteases inhibitory drugs usage in the bronchopulmonary cardiovascular pathologies therapy are essential. It becomes evident the antiviral, anti-inflammatory, anticoagulant, anti-apoptotic effect of α1-PI. The prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders are presented.
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Daud, Adil I., Ronald C. DeConti, Stephanie Andrews, Patricia Urbas, Adam I. Riker, Vernon K. Sondak, Pamela N. Munster i in. "Phase I Trial of Interleukin-12 Plasmid Electroporation in Patients With Metastatic Melanoma". Journal of Clinical Oncology 26, nr 36 (20.12.2008): 5896–903. http://dx.doi.org/10.1200/jco.2007.15.6794.
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Purpose Gene-based immunotherapy for cancer is limited by the lack of safe, efficient, reproducible, and titratable delivery methods. Direct injection of DNA into tissue, although safer than viral vectors, suffers from low gene transfer efficiency. In vivo electroporation, in preclinical models, significantly enhances gene transfer efficiency while retaining the safety advantages of plasmid DNA. Patients and Methods A phase I dose escalation trial of plasmid interleukin (IL)-12 electroporation was carried out in patients with metastatic melanoma. Patients received electroporation on days 1, 5, and 8 during a single 39-day cycle, into metastatic melanoma lesions with six 100-μs pulses at a 1,300-V/cm electric field through a penetrating six-electrode array immediately after DNA injection. Pre- and post-treatment biopsies were obtained at defined time points for detailed histologic evaluation and determination of IL-12 protein levels. Results Twenty-four patients were treated at seven dose levels, with minimal systemic toxicity. Transient pain after electroporation was the major adverse effect. Post-treatment biopsies showed plasmid dose proportional increases in IL-12 protein levels as well as marked tumor necrosis and lymphocytic infiltrate. Two (10%) of 19 patients with nonelectroporated distant lesions and no other systemic therapy showed complete regression of all metastases, whereas eight additional patients (42%) showed disease stabilization or partial response. Conclusion This report describes the first human trial, to our knowledge, of gene transfer utilizing in vivo DNA electroporation. The results indicated this modality to be safe, effective, reproducible, and titratable.
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Pohodenko-Chudakova, I. O. "Substantiation of Targeted Research on the Development of Diagnostic and Differential-Diagnostic Tests Used in Chronic Sialoadenitis. Literature review". Ukraïnsʹkij žurnal medicini, bìologìï ta sportu 6, nr 4 (18.09.2021): 22–27. http://dx.doi.org/10.26693/jmbs06.04.022.
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The last decades in maxillofacial surgery and surgical dentistry are marked by the fact that one of the most popular and frequently encountered research topics is the pathology of the salivary glands. Patients with this pathology make up 2.3-5.2% of the total number of persons hospitalized during the year in specialized inpatient departments. The spectrum of these diseases is wide and includes: malformations, traumatic injuries, inflammatory processes of both viral and bacterial nature, reactive dystrophic lesions, salivary stone disease, benign and malignant neoplasms. Sialoadenitis can occur in both acute and chronic forms. At the same time, the ways of penetration of the infectious agent were determined: hematogenic, lymphogenic, contact, intraductal. The most frequently diagnosed inflammatory pathology of the salivary glands is chronic sialoadenitis. The purpose of the study is to identify unsolved problems and determine the directions of further research based on the analysis of available domestic and foreign specialized literature on epidemiology, diagnosis and differential diagnosis of chronic sialoadenitis. Materials and methods. The analysis of specialized literature containing information on the epidemiology, diagnosis and differential diagnosis of chronic sialoadenitis was carried out. The article analyzes periodicals for the last 10 years, as well as basic manuals, monographs, and textbooks without a statute of limitations. The descriptive method is used for the analysis. Results and discussion. Chronic sialoadenitis and sialosis account for 42.0-54.4% of the total pathology of the salivary glands. This is due to: an increase in the number of neoplasms, including malignant ones both in the maxillofacial region and in the salivary glands; an increase in the number of patients with thyroid diseases who use radioactive iodine for therapeutic purposes, which also accumulates in the salivary glands, which causes the appearance of symptoms of xerostomia and sialoadenitis; a significant share of publications indicating the complexity of the differential diagnosis of chronic sialoadenitis and a large number of diagnostic errors. Conclusion. The presented material proves that the task of developing diagnostic and differential-diagnostic tests used in chronic sialoadenitis is socially significant and belongs to the category of priority and determines the need for its early effective solution. The development and implementation of new diagnostic and differential-diagnostic tests developed and scientifically based on the principles of evidence-based medicine, used in patients with chronic sialoadenitis, will reduce the number of complications, improve the quality of life of patients, and increase the level of specialized medical care to the population
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Netiazhenko, V. Z. "Infusion therapy for cardiovascular diseases: the allowed limits". Infusion & Chemotherapy, nr 3.2 (15.12.2020): 227–30. http://dx.doi.org/10.32902/2663-0338-2020-3.2-227-230.
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Background. Analysis of the mortality structure of patients with coronavirus disease (COVID-19) had found that 69.2 % of non-survivors had hypertension. Comorbid diabetes mellitus (31.8 %) and coronary heart disease (28.2 %) were also common. During pandemic, it is necessary to maintain optimal cardiovascular therapy by continuing to administer its main drugs (acetylsalicylic acid, statins, β-blockers, angiotensin-converting enzyme inhibitors – ACEI).
Objective. To describe infusion therapy (IT) for cerebrovascular and cardiovascular diseases in settings of the COVID-19 pandemic.
Materials and methods. Analysis of the literature on this topic.
Results and discussion. Although the spike proteins of the new coronavirus have the tropism to ACE-2, discontinuation of ACEI is unwarranted and may worsen the course of cardiovascular disease (CVD). Particular attention should be paid to the diagnosis of acute coronary syndrome (ACS) in COVID-19. In myocardial infarction, myocarditis or cardiomyopathy on the background of COVID-19, there is a moderate increase in troponin, brain natriuretic peptide and N-terminal pro-B-type natriuretic peptide. An increase in D-dimers is a prognostic marker of the unfavorable prognosis. The algorithm for the ACS diagnosis includes the detection of typical clinical symptoms, ECG analysis, detection of disorders of local contractility of the left ventricle. Determination of troponin in patients without clinical manifestations of ACS with nonspecific manifestations of COVID-19 is not recommended. As for reperfusion therapy strategies, it is indicated in patients with symptoms of ischemia lasting >12 hours and a persistent increase in ST in two adjacent leads. In the absence of prior testing for coronavirus infection, all patients should be managed according to the tactics for COVID-positive patients. In non-STEMI, patients should be stratified according to their risk level (very high, high, moderate, low). In case of high risk, the early (<24 hours) invasive strategy is reasonable, in case of intermediate risk it is reasonable to consider noninvasive treatment. It should be remembered that the use of certain drugs for the treatment of COVID-19 (azithromycin, chloroquine, hydroxychloroquine, lopinavir, ritonavir) is associated with a risk of cardiotoxicity and life-threatening arrhythmias. Cardiotoxicity monitoring (determination of the corrected QT interval) should be performed before the start of therapy and then once in 5 days, primarily in risk groups (men >55 years, women >65 years and people with the CVD history). Lopinavir and ritonavir may also decrease the levels of active metabolites of clopidogrel and increase – of ticagrelor, so prasugrel is the antiplatelet drug of choice for COVID-19. Amiodarone also interacts with a large number of antiviral drugs. In turn, statins have multiple immunomodulatory effects including increase of the innate antiviral immune response. It is recommended to continue taking those statins that were prescribed earlier. If co-administration with lopinavir and ritonavir is required, the minimum dose of rosuvastatin or atorvastatin should be started. These antivirals are able to interact with calcium channel blockers and increase their concentration, so the dose of amlodipine and diltiazem can be reduced by 50 %. Endothelial dysfunction (ED) caused by a viral infection leads to the excessive thrombin formation and inhibition of fibrinolysis, increasing the risk of thrombotic complications. Nitric oxide (NO) plays an important role in counteracting ED. NO also inhibits the replication of the acute severe respiratory syndrome coronavirus and improves the survival of infected cells. L-arginine (Tivortin, “Yuria-Pharm”) is the only substrate for NO synthase that catalyzes the formation of NO in endothelial cells. According to the results of the own study, Tivortin helped to reduce the content of fibrinogen and soluble fibrin-monomer complexes, as well as to increase the thromboplastin time. Endothelium-dependent vasodilation also improved after administration of Tivortin. Tivorel (“Yuria-Pharm”) contains L-arginine and L-carnitine, which allows this drug to increase the survival of cardiomyocytes and endothelial cells, to restore homeostasis in the affected areas of the myocardium, and to counteract the progression of atherogenesis and thrombosis. In case of COVID-19, it is also advisable to prescribe edaravone (Ksavron, “Yuria-Pharm”), which neutralizes the cytokine storm, inhibits lipid peroxidation, protects against endothelial damage and, penetrating the blood-brain barrier, counteracts cerebral edema. In case of the need in IT, it is advisable to choose Reosorbilact (“Yuria-Pharm”), which has anti-shock, rheological, detoxifying, alkalizing and osmodiuretic effects. In hypovolemic shock and intracranial hemorrhage, the use of isotonic low-molecular-weight gelatin preparations (Volutenz, “Yuria-Pharm”) has been shown.
Conclusions. 1. In the absence of prior testing for coronavirus infection, all patients should be managed following the tactics for COVID-positive patients. 2. The use of azithromycin, chloroquine, hydroxychloroquine, lopinavir, ritonavir is associated with a risk of cardiotoxicity and life-threatening arrhythmias. 3. ED, caused by a viral infection, increases the risk of thrombotic complications. 4. It is reasonable to include the required solutions (Tivortin, Tivorel, Ksavron, Reosorbilact, Volutenz) into the combined IT of COVID-19 patients.
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Krishnan, Sushmita, Darshini Subramanian i Sri Sakthi Priyadarshini Rajamani. "A Review on Catastrophic Evolution of SARS-CoV to SARS-CoV2-A Global Pandemic". Coronaviruses 01 (17.09.2020). http://dx.doi.org/10.2174/2666796701999200917125700.
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: The coronaviruses belonging to the family Coronaviridae have caused a massive pandemic in December 2019 af-ter its previous outbreaks as SARS-CoV and MERS. The outbreak is believed to have originated from the seafood and live market in Hubei province of China. The Rhinolophus species are the natural hosts of this virus. The unknown virus caus-ing pneumonia took away so many lives before recognising it as the novel Coronavirus. Very little information is known about the biology and nature of the current outbreak. This article reviews multiple aspects encompassing its origin, epide-miology, pathogenesis, symptoms and the global statistics of spread. Acute respiratory distress syndrome (ARDS) is the key symptom of this condition. Angiotensin converting enzyme 2 (ACE2) helps in the penetration of the virus into the tar-get cells. Deeper research and understanding is essential for identification of antibodies that inhibit ACE2 and can prevent viral replication. Drug design and control of disease is crucial. In countries like India where plant diversity is extensive, it is wise to focus on plant based alternative drugs. Many attempts have been made to review and curate the drug discovery attempts using immune-informatics and bioinformatics tools.
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Classen, J. Bart. "Review of COVID-19 Vaccines and the Risk of Chronic Adverse Events Including Neurological Degeneration". Journal of Medical - Clinical Research & Reviews 5, nr 3 (30.03.2021). http://dx.doi.org/10.33425/2639-944x.1202.
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Many have argued that the outbreak of COVID-19 is the result of the release of a viral based bioweapon. Vaccines to COVID-19 have been developed and a policy of universal immunization has been initiated with total disregard to the fact that the virus may be a bioweapon. The potential risk of a catastrophe exists in part because all the vaccines contain the spike protein and or the mRNA/DNA encoding for the COVID-19 associated spike protein. These vaccines were designed and placed on the market with little knowledge of how the spike protein or its nucleic acid causes disease and without knowledge of long-term adverse effects of the vaccines. This paper reviews many of the potential long-term risks that could result from receiving one of the COVID-19 vaccines. The potential for the spike protein and its mRNA to cause prion disease is reviewed as well as reasons why the vaccine could be much more dangerous than the natural infection. Adenoviral derived COVID-19 vaccines are particularly risky because of their potential to recombine with human DNA or viruses already in the human recipient. The result could be new infectious adenoviral species containing spike proteins that could infect humans and farm animals used for food. Some of the COVID-19 vaccines utilize novel technology including nanotechnology and novel adjuvants that increase intracellular penetration of cells and can potentially exacerbate chronic toxicity from the spike protein. Governments should consider suspending sale of the COVID-19 vaccines until they have a better understanding of their risks.
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Siaw Fui, Kiew, Razauden Mohamed Zulkifli i Mohd Bakri Bakar. "Synthesis of Cationic Porphyrins as Potential Gene Transfection Carriers". Malaysian Journal of Fundamental and Applied Sciences 8, nr 4 (17.06.2012). http://dx.doi.org/10.11113/mjfas.v8n4.166.
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Porphyrins are found having strong but reversible interaction with nucleic acid and thus can be used as complementary to other non-viral vectors in gene transfection delivery. Amphiphilic porphyrins with combination of hydrophobic and hydrophilic substituents along the peripheral of porphyrin macrocycle were synthesized with an attempt to facilitate the membrane penetration as well as better accumulation on the targeted cells. Besides, their fluorescent properties can be used as marker to identify their localization in the intracellular domain. Adler-Longo condensation method was employed to synthesize basic cationic porphyrins and novel asymmetrical amphiphilic cationic porphyrins. All compounds were characterized using 1H-NMR, 13C-NMR, Ultraviolet (UV) and Infrared (IR) spectroscopy.
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Ellan, Kavithambigai, Ravindran Thayan, Jegadeesh Raman, Kazuya I. P. J. Hidari, Norizah Ismail i Vikineswary Sabaratnam. "Anti-viral activity of culinary and medicinal mushroom extracts against dengue virus serotype 2: an in-vitro study". BMC Complementary and Alternative Medicine 19, nr 1 (18.09.2019). http://dx.doi.org/10.1186/s12906-019-2629-y.
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Abstract Background Dengue is a mosquito-borne viral infection that has become a major public health concern worldwide. Presently, there is no specific vaccine or treatment available for dengue viral infection. Methods Lignosus rhinocerotis, Pleurotus giganteus, Hericium erinaceus, Schizophyllum commune and Ganoderma lucidium were selected for evaluation of their in-vitro anti-dengue virus serotype 2 (DENV-2) activities. Hot aqueous extracts (HAEs), ethanol extracts (EEs), hexane soluble extracts (HSEs), ethyl acetate soluble extracts (ESEs) and aqueous soluble extracts (ASEs) were prepared from the selected mushrooms. The cytotoxic effects of the extracts were evaluated by the MTT assay. The anti-DENV-2 activities of the extracts were evaluated in three different assays: simultaneous, attachment and penetration assays were perfomed using plaque reduction assays and RT-qPCR assays. The effect of the addition time on viral replication was assessed by the time of addition assay, and a virucidal assay was carried out to evaluate the direct effect of each mushroom extract on DENV-2. The chemical composition of glucans, and the protein and phenolic acid contents in the extracts were estimated. Results We found that the HAEs and ASEs of L. rhinocerotis, P. giganteus, H. erinaceus and S. commune were the least toxic to Vero cells and showed very prominent anti-DENV2 activity. The 50% inhibitory concentration (IC50) values of the ASEs ranged between 399.2–637.9 μg/ml, while for the HAEs the range was 312.9–680.6 μg/ml during simultaneous treatment. Significant anti-dengue activity was also detected in the penetration assay of ASEs (IC50: 226.3–315.4 μg/ml) and HAEs (IC50: 943.1–2080.2 μg/ml). Similarly, we observed a marked reduction in the expression levels of the ENV and NS5 genes in the simultaneous and penetration assays of the ASEs and HAEs. Time-of-addition experiments showed that the highest percent of anti-DENV2 activity was observed when the mushroom extracts were added immediately after virus adsorption. None of the extracts exhibited virucidal effect. Chemical composition analysis showed that the major components in the mushroom HAEs and ASEs were glucan (beta D-glucan) and proteins, however, there was no significant correlation between the anti-dengue activity and the concentration of glucans and proteins. Conclusion These findings demonstrated the potential of mushroom extracts as anti-dengue therapeutic agents with less toxic effects.
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Jung, Keunok, Min-Jeong Son, Se-Young Lee, Jeong-Ah Kim, Deok-Han Ko, Sojung Yoo, Chul-Ho Kim i Yong-Sung Kim. "Antibody-mediated delivery of a viral MHC-I epitope into the cytosol of target tumor cells repurposes virus-specific CD8+ T cells for cancer immunotherapy". Molecular Cancer 21, nr 1 (22.04.2022). http://dx.doi.org/10.1186/s12943-022-01574-0.
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Abstract Background Redirecting pre-existing virus-specific cytotoxic CD8+ T lymphocytes (CTLs) to tumors by simulating a viral infection of the tumor cells has great potential for cancer immunotherapy. However, this strategy is limited by lack of amenable method for viral antigen delivery into the cytosol of target tumors. Here, we addressed the limit by developing a CD8+T cell epitope-delivering antibody, termed a TEDbody, which was engineered to deliver a viral MHC-I epitope peptide into the cytosol of target tumor cells by fusion with a tumor-specific cytosol-penetrating antibody. Methods To direct human cytomegalovirus (CMV)-specific CTLs against tumors, we designed a series of TEDbodies carrying various CMV pp65 antigen-derived peptides. CMV-specific CTLs from blood of CMV-seropositive healthy donors were expanded for use in in vitro and in vivo experiments. Comprehensive cellular assays were performed to determine the presentation mechanism of TEDbody-mediated CMV peptide-MHC-I complex (CMV-pMHCI) on the surface of target tumor cells and the recognition and lysis by CMV-specific CTLs. In vivo CMV-pMHCI presentation and antitumor efficacy of TEDbody were evaluated in immunodeficient mice bearing human tumors. Results TEDbody delivered the fused epitope peptides into target tumor cells to be intracellularly processed and surface displayed in the form of CMV-pMHCI, leading to disguise target tumor cells as virally infected cells for recognition and lysis by CMV-specific CTLs. When systemically injected into tumor-bearing immunodeficient mice, TEDbody efficiently marked tumor cells with CMV-pMHCI to augment the proliferation and cytotoxic property of tumor-infiltrated CMV-specific CTLs, resulting in significant inhibition of the in vivo tumor growth by redirecting adoptively transferred CMV-specific CTLs. Further, combination of TEDbody with anti-OX40 agonistic antibody substantially enhanced the in vivo antitumor activity. Conclusion Our study offers an effective technology for MHC-I antigen cytosolic delivery. TEDbody may thus have utility as a therapeutic cancer vaccine to redirect pre-existing anti-viral CTLs arising from previously exposed viral infections to attack tumors.
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Yunis, Joseph, Helen E. Farrell, Kimberley Bruce, Clara Lawler, Orry Wyer, Nicholas Davis-Poynter, Ilija Brizić, Stipan Jonjić, Barbara Adler i Philip G. Stevenson. "Murine Cytomegalovirus Glycoprotein O Promotes Epithelial Cell InfectionIn Vivo". Journal of Virology 93, nr 3 (7.11.2018). http://dx.doi.org/10.1128/jvi.01378-18.
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ABSTRACTCytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a nonessential fusion complex component of both human CMV (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract.In vitro, MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact, but penetration was delayed. In contrast, myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c+myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, the tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization.IMPORTANCEHuman cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focused on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore, targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections.