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1.
JBMR Plus ; 2020 Aug 22.
Article in English | MEDLINE | ID: covidwho-1898823

ABSTRACT

Regulation of immune function continues to be one of the most well recognised extra-skeletal actions of vitamin D. This stemmed initially from the discovery that antigen presenting cells such as macrophages could actively metabolise precursor 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D). Parallel observation that activated cells from the immune system expressed the intracellular vitamin D receptor (VDR) for 1,25D suggested a potential role for vitamin D as a localised endogenous modulator of immune function. Subsequent studies have expanded our understanding of how vitamin D exerts effects on both the innate and adaptive arms of the immune system. At an innate level, intracrine synthesis of 1,25D by macrophages and dendritic cells (DC) stimulates expression of antimicrobial proteins such as cathelicidin, as well as lowering intracellular iron concentrations via suppression of hepcidin. By potently enhancing autophagy, 1,25D may also play an important role in combatting intracellular pathogens such as M. tuberculosis and viral infections. Local synthesis of 1,25D by macrophages and DC also appears to play a pivotal role in mediating T cell responses to vitamin D, leading to suppression of inflammatory T helper (Th)1 and Th17 cells, and concomitant induction of immunotolerogenic T regulatory (Treg) responses. The aim of this review is to provide an update on our current understanding of these prominent immune actions of vitamin D, as well as highlighting new, less well-recognised immune effects of vitamin D. The review also aims to place this mechanistic basis for the link between vitamin D and immunity with studies in vivo that have explored a role for vitamin D supplementation as a strategy for improved immune health. This has gained prominence in recent months with the global COVID-19 health crisis and highlights important new objectives for future studies of vitamin D and immune function. This article is protected by copyright. All rights reserved.

2.
Curr Opin Immunol ; 72: 126-134, 2021 10.
Article in English | MEDLINE | ID: covidwho-1606183

ABSTRACT

Membrane cofactor protein (MCP; CD46), a ubiquitously expressed complement regulatory protein, serves as a cofactor for serine protease factor I to cleave and inactivate C3b and C4b deposited on host cells. However, CD46 also plays roles in human reproduction, autophagy, modulating T cell activation and effector functions and is a member of the newly identified intracellular complement system (complosome). CD46 also is a receptor for 11 pathogens ('pathogen magnet'). While CD46 deficiencies contribute to inflammatory disorders, its overexpression in cancers and role as a receptor for some adenoviruses has led to its targeting by oncolytic agents and adenoviral-based therapeutic vectors, including coronavirus disease of 2019 (COVID-19) vaccines. This review focuses on recent advances in identifying disease-causing CD46 variants and its pathogen connections.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Membrane Cofactor Protein/metabolism , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Animals , Autophagy , Complement Activation , Host-Pathogen Interactions , Humans , Lymphocyte Activation , Membrane Cofactor Protein/genetics , Oncolytic Virotherapy , Polymorphism, Genetic , Reproduction
3.
J Virol ; 94(13)2020 06 16.
Article in English | MEDLINE | ID: covidwho-1583223

ABSTRACT

Fusion with, and subsequent entry into, the host cell is one of the critical steps in the life cycle of enveloped viruses. For Middle East respiratory syndrome coronavirus (MERS-CoV), the spike (S) protein is the main determinant of viral entry. Proteolytic cleavage of the S protein exposes its fusion peptide (FP), which initiates the process of membrane fusion. Previous studies on the related severe acute respiratory syndrome coronavirus (SARS-CoV) FP have shown that calcium ions (Ca2+) play an important role in fusogenic activity via a Ca2+ binding pocket with conserved glutamic acid (E) and aspartic acid (D) residues. SARS-CoV and MERS-CoV FPs share a high sequence homology, and here, we investigated whether Ca2+ is required for MERS-CoV fusion by screening a mutant array in which E and D residues in the MERS-CoV FP were substituted with neutrally charged alanines (A). Upon verifying mutant cell surface expression and proteolytic cleavage, we tested their ability to mediate pseudoparticle (PP) infection of host cells in modulating Ca2+ environments. Our results demonstrate that intracellular Ca2+ enhances MERS-CoV wild-type (WT) PP infection by approximately 2-fold and that E891 is a crucial residue for Ca2+ interaction. Subsequent electron spin resonance (ESR) experiments revealed that this enhancement could be attributed to Ca2+ increasing MERS-CoV FP fusion-relevant membrane ordering. Intriguingly, isothermal calorimetry showed an approximate 1:1 MERS-CoV FP to Ca2+ ratio, as opposed to an 1:2 SARS-CoV FP to Ca2+ ratio, suggesting significant differences in FP Ca2+ interactions of MERS-CoV and SARS-CoV FP despite their high sequence similarity.IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is a major emerging infectious disease with zoonotic potential and has reservoirs in dromedary camels and bats. Since its first outbreak in 2012, the virus has repeatedly transmitted from camels to humans, with 2,468 confirmed cases causing 851 deaths. To date, there are no efficacious drugs and vaccines against MERS-CoV, increasing its potential to cause a public health emergency. In order to develop novel drugs and vaccines, it is important to understand the molecular mechanisms that enable the virus to infect host cells. Our data have found that calcium is an important regulator of viral fusion by interacting with negatively charged residues in the MERS-CoV FP region. This information can guide therapeutic solutions to block this calcium interaction and also repurpose already approved drugs for this use for a fast response to MERS-CoV outbreaks.


Subject(s)
Calcium/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions , Ions/metabolism , Membrane Fusion , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Internalization , Amino Acid Sequence , Amino Acid Substitution , Animals , Cell Line , Chlorocebus aethiops , Humans , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Models, Molecular , Mutation , Protein Binding , Proteolysis , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , Vero Cells , Virulence , Virus Assembly
4.
Crit Care Med ; 49(12): 2131-2136, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1522360

ABSTRACT

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.


Subject(s)
COVID-19/physiopathology , Hydrocortisone/blood , Leucine Zippers/physiology , Receptors, Glucocorticoid/biosynthesis , Academic Medical Centers , Adult , Aged , Comorbidity , Critical Illness , Female , Greece , Humans , Intensive Care Units , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Severity of Illness Index
5.
J Proteome Res ; 19(11): 4398-4406, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-1387124

ABSTRACT

Presentation of antigenic peptides by MHCI is central to cellular immune responses against viral pathogens. While adaptive immune responses versus SARS-CoV-2 can be of critical importance to both recovery and vaccine efficacy, how protein antigens from this pathogen are processed to generate antigenic peptides is largely unknown. Here, we analyzed the proteolytic processing of overlapping precursor peptides spanning the entire sequence of the S1 spike glycoprotein of SARS-CoV-2, by three key enzymes that generate antigenic peptides, aminopeptidases ERAP1, ERAP2, and IRAP. All enzymes generated shorter peptides with sequences suitable for binding onto HLA alleles, but with distinct specificity fingerprints. ERAP1 was the most efficient in generating peptides 8-11 residues long, the optimal length for HLA binding, while IRAP was the least efficient. The combination of ERAP1 with ERAP2 greatly limited the variability of peptide sequences produced. Less than 7% of computationally predicted epitopes were found to be produced experimentally, suggesting that aminopeptidase processing may constitute a significant filter to epitope presentation. These experimentally generated putative epitopes could be prioritized for SARS-CoV-2 immunogenicity studies and vaccine design. We furthermore propose that this in vitro trimming approach could constitute a general filtering method to enhance the prediction robustness for viral antigenic epitopes.


Subject(s)
Aminopeptidases/metabolism , Antigens, Viral , Epitopes , Spike Glycoprotein, Coronavirus , Antigens, Viral/chemistry , Antigens, Viral/metabolism , Chromatography, Liquid , Epitopes/chemistry , Epitopes/metabolism , HEK293 Cells , HLA Antigens/chemistry , HLA Antigens/metabolism , Humans , Peptides/analysis , Peptides/chemistry , Peptides/metabolism , Proteomics/methods , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tandem Mass Spectrometry
6.
Cell Rep ; 31(11): 107772, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-1385222

ABSTRACT

ISG15 is a ubiquitin-like modifier that also functions extracellularly, signaling through the LFA-1 integrin to promote interferon (IFN)-γ release from natural killer (NK) and T cells. The signals that lead to the production of extracellular ISG15 and the relationship between its two core functions remain unclear. We show that both epithelial cells and lymphocytes can secrete ISG15, which then signals in either an autocrine or paracrine manner to LFA-1-expressing cells. Microbial pathogens and Toll-like receptor (TLR) agonists result in both IFN-ß-dependent and -independent secretion of ISG15, and residues required for ISG15 secretion are mapped. Intracellular ISGylation inhibits secretion, and viral effector proteins, influenza B NS1, and viral de-ISGylases, including SARS-CoV-2 PLpro, have opposing effects on secretion of ISG15. These results establish extracellular ISG15 as a cytokine-like protein that bridges early innate and IFN-γ-dependent immune responses, and indicate that pathogens have evolved to differentially inhibit the intracellular and extracellular functions of ISG15.


Subject(s)
Cytokines/metabolism , Signal Transduction , Ubiquitins/metabolism , Animals , HEK293 Cells , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Jurkat Cells , Mice , Mice, Inbred C57BL , Mycobacterium Infections/immunology , Mycobacterium Infections/metabolism , Pathogen-Associated Molecular Pattern Molecules , Typhoid Fever/immunology , Typhoid Fever/metabolism , Viral Nonstructural Proteins/metabolism
8.
Int J Mol Sci ; 22(7)2021 Mar 30.
Article in English | MEDLINE | ID: covidwho-1299437

ABSTRACT

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.


Subject(s)
Glutathione/metabolism , Virus Diseases/drug therapy , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , Humans , NF-kappa B/metabolism , Oxidation-Reduction/drug effects , Protein Disulfide-Isomerases/metabolism , Reactive Oxygen Species/metabolism , Virus Diseases/metabolism
9.
J Antimicrob Chemother ; 76(8): 2121-2128, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1254771

ABSTRACT

OBJECTIVES: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5'-triphosphate (FAVI-RTP)]. METHODS: Published in vitro data for intracellular production and elimination of FAVI-RTP in Madin-Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions. RESULTS: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of ∼1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of ∼2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. CONCLUSIONS: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.


Subject(s)
COVID-19 , SARS-CoV-2 , Amides , Animals , Antiviral Agents/therapeutic use , Dogs , Humans , Polyphosphates , Pyrazines
10.
J Chem Inf Model ; 61(6): 2780-2787, 2021 06 28.
Article in English | MEDLINE | ID: covidwho-1246311

ABSTRACT

In the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) genome, open reading frames (ORFs) encode for viral accessory proteins. Among these, Orf7a structurally resembles the members of the immunoglobulin (Ig) superfamily and intracellular adhesion molecules (ICAMs), in particular. ICAMs are involved in integrin binding through lymphocyte function-associated antigen 1 (LFA-1). Based on such considerations and on previous findings on SARS-CoV, it has been postulated that the formation of the LFA-1/Orf7a complex could contribute to SARS-CoV-2 infectivity and pathogenicity. With the current work, we aim at providing insight into this macromolecular assembly, taking advantage of the recently reported SARS-CoV-2 Orf7a structure. Protein-protein docking, molecular dynamics (MD) simulations, and a Molecular Mechanical-Generalized Born Surface Area (MM-GBSA)-based stage were enrolled to provide refined models.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Lymphocyte Function-Associated Antigen-1 , Molecular Docking Simulation , Viral Proteins
12.
Immunity ; 54(6): 1290-1303.e7, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1237724

ABSTRACT

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibody Formation/genetics , B-Lymphocytes/metabolism , Computational Biology/methods , Cross Reactions/immunology , Epitope Mapping , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/genetics , Humans , Immunodominant Epitopes/genetics , Immunologic Memory , Male , Neutralization Tests , Single-Cell Analysis/methods , Spike Glycoprotein, Coronavirus/immunology , Transcriptome
13.
Cells ; 10(5)2021 05 06.
Article in English | MEDLINE | ID: covidwho-1223960

ABSTRACT

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5'-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid ß-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Antiviral Agents/pharmacology , Signal Transduction/immunology , Virus Diseases/immunology , Antiviral Agents/therapeutic use , Autophagy/drug effects , Autophagy/immunology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , Cell Proliferation/drug effects , Drug Development , Humans , Pandemics/prevention & control , SARS-CoV-2/immunology , Signal Transduction/drug effects , Virus Diseases/drug therapy , Virus Replication/drug effects , Virus Replication/immunology
14.
Pathog Immun ; 6(1): 55-74, 2021.
Article in English | MEDLINE | ID: covidwho-1222332

ABSTRACT

BACKGROUND: Host proteases have been suggested to be crucial for dissemination of MERS, SARS-CoV, and SARS-CoV-2 coronaviruses, but the relative contribution of membrane versus intracellular proteases remains controversial. Transmembrane serine protease 2 (TMPRSS2) is regarded as one of the main proteases implicated in the coronavirus S protein priming, an important step for binding of the S protein to the angiotensin-converting enzyme 2 (ACE2) receptor before cell entry. METHODS: We developed a cell-based assay to identify TMPRSS2 inhibitors. Inhibitory activity was established in SARS-CoV-2 viral load systems. RESULTS: We identified the human extracellular serine protease inhibitor (serpin) alpha 1 anti-trypsin (A1AT) as a novel TMPRSS2 inhibitor. Structural modeling revealed that A1AT docked to an extracellular domain of TMPRSS2 in a conformation that is suitable for catalysis, resembling similar serine protease inhibitor complexes. Inhibitory activity of A1AT was established in a SARS-CoV-2 viral load system. Notably, plasma A1AT levels were associated with COVID-19 disease severity. CONCLUSIONS: Our data support the key role of extracellular serine proteases in SARS CoV-2 infections and indicate that treatment with serpins, particularly the FDA-approved drug A1AT, may be effective in limiting SARS-CoV-2 dissemination by affecting the surface of the host cells.

15.
J Med Virol ; 93(4): 2476-2486, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217395

ABSTRACT

The coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro-inflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.


Subject(s)
COVID-19/virology , RNA, Messenger/genetics , RNA, Viral/metabolism , SARS-CoV-2/metabolism , Toll-Like Receptors/metabolism , Binding Sites , COVID-19/immunology , COVID-19/metabolism , Computer Simulation , Genome, Viral , Humans , Molecular Docking Simulation , Protein Binding , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics , Toll-Like Receptors/chemistry , Toll-Like Receptors/genetics
16.
Int J Biol Macromol ; 183: 549-563, 2021 Jul 31.
Article in English | MEDLINE | ID: covidwho-1208539

ABSTRACT

Biological polyesters of hydroxyacids are known as polyhydroxyalkanoates (PHA). They have proved to be an alternative, environmentally friendly and attractive candidate for the replacement of petroleum-based plastics in many applications. Many bacteria synthesize these compounds as an intracellular carbon and energy compound usually under unbalanced growth conditions. Biodegradability and biocompatibility of different PHA has been studied in cell culture systems or in an animal host during the last few decades. Such investigations have proposed that PHA can be used as biomaterials for applications in conventional medical devices such as sutures, patches, meshes, implants, and tissue engineering scaffolds as well. Moreover, findings related to encapsulation capability and degradation kinetics of some PHA polymers has paved their way for development of controlled drug delivery systems. The present review discusses about bio-plastics, their characteristics, examines the key findings and recent advances highlighting the usage of bio-plastics in different medical devices. The patents concerning to PHA application in biomedical field have been also enlisted that will provide a brief overview of the status of research in bio-plastic. This would help medical researchers and practitioners to replace the synthetic plastics aids that are currently being used. Simultaneously, it could also prove to be a strong step in reducing the plastic pollution that surged abruptly due to the COVID-19 medical waste.


Subject(s)
Biocompatible Materials/chemistry , COVID-19 , Polyhydroxyalkanoates/chemistry , SARS-CoV-2 , Animals , Biodegradation, Environmental , Humans , Medical Waste , Medical Waste Disposal
17.
Int J Mol Sci ; 22(8)2021 Apr 17.
Article in English | MEDLINE | ID: covidwho-1206368

ABSTRACT

Viral infections cause a host of fatal diseases and seriously affect every form of life from bacteria to humans. Although most viral infections can receive appropriate treatment thereby limiting damage to life and livelihood with modern medicine and early diagnosis, new types of viral infections are continuously emerging that need to be properly and timely treated. As time is the most important factor in the progress of many deadly viral diseases, early detection becomes of paramount importance for effective treatment. Aptamers are small oligonucleotide molecules made by the systematic evolution of ligands by exponential enrichment (SELEX). Aptamers are characterized by being able to specifically bind to a target, much like antibodies. However, unlike antibodies, aptamers are easily synthesized, modified, and are able to target a wider range of substances, including proteins and carbohydrates. With these advantages in mind, many studies on aptamer-based viral diagnosis and treatments are currently in progress. The use of aptamers for viral diagnosis requires a system that recognizes the binding of viral molecules to aptamers in samples of blood, serum, plasma, or in virus-infected cells. From a therapeutic perspective, aptamers target viral particles or host cell receptors to prevent the interaction between the virus and host cells or target intracellular viral proteins to interrupt the life cycle of the virus within infected cells. In this paper, we review recent attempts to use aptamers for the diagnosis and treatment of various viral infections.


Subject(s)
Antiviral Agents/therapeutic use , Aptamers, Nucleotide/therapeutic use , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Animals , DNA Viruses/drug effects , Humans , RNA Viruses/drug effects , Viral Proteins/drug effects , Virion/drug effects
18.
Mater Today Proc ; 2021 Apr 13.
Article in English | MEDLINE | ID: covidwho-1179880

ABSTRACT

Ferritin is an intracellular blood protein that contains iron, covid-19 diseases is an infectious disease caused by a virus called corona virus, the infected person mostly experiences mild to moderate respiratory illness ferritin level in blood mostly depend on severity of the covid-19 disease. Ferritin level could be used as an indicator for the covid-19 disease. Within 120 corona virus patients that used as individual in this study, the ferritin level in the blood were tested, also each of (D-Dimer, ESR, C.R protein) Depend on the results, the patients with over 60 years have a high ferritin level also the d-dimer were abnormal with 65% higher than normal range.

19.
Nat Commun ; 12(1): 1676, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1135664

ABSTRACT

The recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. How this novel beta-coronavirus virus, and coronaviruses more generally, alter cellular metabolism to support massive production of ~30 kB viral genomes and subgenomic viral RNAs remains largely unknown. To gain insights, transcriptional and metabolomic analyses are performed 8 hours after SARS-CoV-2 infection, an early timepoint where the viral lifecycle is completed but prior to overt effects on host cell growth or survival. Here, we show that SARS-CoV-2 remodels host folate and one-carbon metabolism at the post-transcriptional level to support de novo purine synthesis, bypassing viral shutoff of host translation. Intracellular glucose and folate are depleted in SARS-CoV-2-infected cells, and viral replication is exquisitely sensitive to inhibitors of folate and one-carbon metabolism, notably methotrexate. Host metabolism targeted therapy could add to the armamentarium against future coronavirus outbreaks.


Subject(s)
COVID-19/metabolism , Carbon/metabolism , Folic Acid/metabolism , SARS-CoV-2/physiology , Virus Replication , A549 Cells , Animals , COVID-19/virology , Chlorocebus aethiops , Cytopathogenic Effect, Viral , Folic Acid Antagonists/pharmacology , Glucose/metabolism , Humans , Methotrexate/pharmacology , RNA, Viral/biosynthesis , SARS-CoV-2/drug effects , Serine/metabolism , Transcription, Genetic , Vero Cells , Viral Proteins/genetics , Virus Replication/drug effects
20.
Drug Dev Res ; 82(6): 784-788, 2021 09.
Article in English | MEDLINE | ID: covidwho-1120208

ABSTRACT

Over the recent decades, a number of new pathogens have emerged within specific and diverse populations across the globe, namely, the Nipah virus, the Ebola virus, the Zika virus, and coronaviruses (CoVs) to name a few. Recently, a new form of coronavirus was identified in the city of Wuhan, China. Interestingly, the genomic architecture of the virus did not match with any of the existing genomic sequencing data of previously sequenced CoVs. This had led scientists to confirm the emergence of a new CoV strain. Originally, named as 2019-nCoV, the strain is now called as SARS-CoV-2. High serum levels of proinflammatory mediators, namely, interleukin-12 (IL-12), IL-1ß, IL-6, interferon-gamma (IFNγ), chemoattractant protein-1, and IFN-inducible protein, have been repeatedly observed in subjects who were infected with this virus. In addition, the virus demonstrated strong coagulation activation properties, leading to further the understanding on the SARS-CoV2. To our understanding, these findings are unique to the published literature. Numerous studies have reported anomalies, namely, decline in the number of lymphocytes, platelets and albumins; and a rise in neutrophil count, aspartate transaminase, alanine aminotransaminase, lactate dehydrogenase, troponins, creatinine, complete bilirubin, D-dimers, and procalcitonin. Supplementation of calcium during the SARS CoV-2 associated hyperactive stage of calcium-sensing receptors (CaSR) may be harmful to the cardio-renal system. Thus, pharmacological inhibition of CaSR may prevent the increase in the levels of intracellular calcium, oxidative, inflammatory stress, and cardio-renal cellular apoptosis induced by high cytokines level in COVID-19 infection.


Subject(s)
COVID-19/metabolism , Coronavirus Envelope Proteins/metabolism , Receptors, Calcium-Sensing/metabolism , SARS-CoV-2/metabolism , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Calcium/metabolism , Humans , Molecular Targeted Therapy , Receptors, Calcium-Sensing/drug effects
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