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1.
Viruses ; 14(12) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2200869

ABSTRACT

Fundamental key processes in viral infection cycles generally occur in distinct cellular sites where both viral and host factors accumulate and interact. These sites are usually termed viral replication organelles, or viral factories (VF). The generation of VF is accompanied by the synthesis of viral proteins and genomes and involves the reorganization of cellular structure. Recently, rVSV-DELTAG-spike (VSV-S), a recombinant VSV expressing the SARS-CoV-2 spike protein, was developed as a vaccine candidate against SARS-CoV-2. By combining transmission electron microscopy (TEM) tomography studies and immuno-labeling techniques, we investigated the infection cycle of VSV-S in Vero E6 cells. RT-real-time-PCR results show that viral RNA synthesis occurs 3-4 h post infection (PI), and accumulates as the infection proceeds. By 10-24 h PI, TEM electron tomography results show that VSV-S generates VF in multi-lamellar bodies located in the cytoplasm. The VF consists of virus particles with various morphologies. We demonstrate that VSV-S infection is associated with accumulation of cytoplasmatic viral proteins co-localized with dsRNA (marker for RNA replication) but not with ER membranes. Newly formed virus particles released from the multi-lamellar bodies containing VF, concentrate in a vacuole membrane, and the infection ends with the budding of particles after the fusion of the vacuole membrane with the plasma membrane. In summary, the current study describes detailed 3D imaging of key processes during the VSV-S infection cycle. Copyright © 2022 by the authors.

2.
NeuroQuantology ; 20(17):1438-1450, 2022.
Article in English | EMBASE | ID: covidwho-2206884

ABSTRACT

This review focuses on the management of Novel Corona Virus with antiviral drugs and antibiotics and therefore the worldwide dissemination of COVID-19 has been accompanied by increased use of antibiotics, according to this review, which focuses on the therapy of Novel Corona Virus with antiviral medicines and antiviral. This is linked to COVID-19 patients' priority of viral infections. In low-and middle-income countries, identifying viruses is difficult because to a lack of medical or cheap infrastructure that is easily accessible and inexpensive among diseases and pathogens. The possibility of COVID-19 spreading has increased public awareness of the need of antibiotic management systems, as well as infection control and control measures that can minimize microbial load. In underdeveloped nations, these measures are commonly employed. During the COVID-19 pandemic, studies were conducted as a test for worldwide antibiotic resistance. Respiratory problems are being blamed on the Novel Corona Virus that Include pneumonia, colds, sneezing and coughing, and other respiratory diseases. Humans are infected with the Coronavirus by airborne droplets. The World Health Organization has warned against visiting public areas and avoiding close contact with an infected individual. First, on December 31, 2019, the Coronavirus (2019-nCoV) was separated from the Wuhan market in China, resulting in the COVID-19 pandemic of extremely complicated viral illnesses. Patients with risk factors are more prone to develop secondary infections, which necessitate the use of antibiotics. Attempts to duplicate the medication, on the other hand, raised knowledge of the antibiotics' significance beyond infection management. Antiviral, immunomodulatory action, and unique pharmacokinetic profile of antibiotics play a significant part in the therapy of pneumonia;other benefits include cardiac safety, improved lung tissue access, and possible antiviral, and immunomodulation, but some adverse effects by usage. SARS-CoV-2 has generated an epidemic of the highly infectious new coronavirus 2019 (COVID-19), which poses a severe public health concern. Given the potential for a COVID-19 outbreak, a better knowledge of the virus is critical in the event of therapeutic alternatives. We offer a thorough analysis of antimicrobials and antiviral COVID-19 in this review. We also go about COVID-19's current treatments. Copyright © 2022, Anka Publishers. All rights reserved.

3.
Journal of the American Society of Nephrology ; 33:72, 2022.
Article in English | EMBASE | ID: covidwho-2125201

ABSTRACT

Background: AKI is a common complication of COVID-19. The peripheral blood molecular signatures are unknown and could unveil potential therapeutic targets. Method(s): We enrolled a prospective patient cohort of 283 patients with COVID-19 (Mar 24-Aug 26, 2020), with blood samples from Mount Sinai Biobank. We determined AKI severity using KDIGO criteria on admission parameters. 31 patients with severe AKI (AKI 2-3) were defined as cases. We then performed bulk peripheral RNA sequencing and fit a multivariate linear regression model adjusting for key covariates. We also performed cell-type deconvolution following to adjust for neutrophils, and whole blood cells. We considered a significant p-value (0.05) after Bonferroni correction and then used ingenuity pathway analysis (IPA) to analyze differentially expressed genes. Result(s): Patients who developed AKI were significantly older (67 vs. 60 yrs.) and had a greater prevalence of type 2 diabetes (37% vs 20%), and chronic kidney disease (20% vs 4%) vs. controls. Of the 18539 genes in the analysis, 1597 were upregulated and 1267 were downregulated after Bonferroni correction. Top canonical pathways (Fig 1) showed significantly downregulated genes including EIF2, eIF4, and p70S6K via activation of ATF6, a marker of ER stress. Potential mechanisms displayed by our analyses include upregulation of the NF-KB inhibitor and IL6 pathways. Genes involved in oxidative Phosphorylation and mitochondrial dysfunction were heavily downregulated and there was upregulation of markers of kidney cell necrosis. In contrast, upregulated genes CRK and TIMP2 have been previously implicated in kidney injury and progression. Downregulated mTOR pathway is responsible for the activation of the ER stress response via the eIF2/4 complex which is also supported by our finding of upregulated NRF2- transcriptional pathway. Conclusion(s): Transcriptomic analysis of AKI in COVID-19 revealed evidence of mitochondrial dysfunction driven by ER stress and immune-mediated pathways. Addressing these pathways could aide development of targeted therapies. (Figure Presented).

4.
Diabetologia ; 2022 Nov 19.
Article in English | MEDLINE | ID: covidwho-2128530

ABSTRACT

AIMS/HYPOTHESIS: Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-ßH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. METHODS: We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8-12 weeks (including training at home during the COVID-19 pandemic). EndoC-ßH1 cells were treated with 'exercised' serum or with the exerkine clusterin to ascertain cytoprotection from ER stress. RESULTS: The exercise interventions were effective and improved [Formula: see text] values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera. CONCLUSIONS/INTERPRETATION: These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle-beta cell crosstalk.

5.
Chinese Journal of Virology ; 38(1):41-56, 2022.
Article in Chinese | GIM | ID: covidwho-2112068

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV -2) is a highly pathogenic and rapidly spreading pathogen. It can invade and infect cells by recognizing receptors on the surface of host cells with spike (5) glycoprotein. Systematic bioinformatics analysis and prokaryotic expression of the S protein can aid understanding of its function and clarify the molecular mechanism of viral infection mediated by this protein. The physicochemical properties, subcellular localization, post - translational modifications and protein - interaction network of the S protein were analyzed systematically using Protparam. Pfam, TMHMM ExPASy - ProtScale, PSORT II, SignalP, UniProt, NetPhos 3.1. NetNGlyc 1.0, NetOGlyc 4.0. BLAST and other bioinformatics software and databases. In addition. Clustal X2 and MEGA7.0 were used to analyze the homology and phylogeny of S glycoproteins based on amino-acid sequences. Finally, recombinant expression vector of the S glycoprotein was constructed by molecular cloning technology and expressed in Escherichia call. Results showed that the S glycoprotein is composed of 1,273 amino acids, with a molecular weight of 141.2 kD and an isoelectric point of 6.24. It had two coiled helical structures and one transmembrane helix region. It was a hydrophobic protein, contained a spike receptor-binding domain and 52 glycoprotein domain. This protein was distributed mainly in the endoplasmic-reticulum membrane (39.1%) and cell membrane (21.7%) of host cells. and contained 136 potential phosphorylation sites and 20 possible glycosylation sites. SARS-CoV, SARS-Coy WI-120 and bat coronavirus HKU3 showed the highest sequence identity with the spike-glycoprotein sequence of SARS-CoV-2 (76%). SARS-CoV-2, SARS-CoV and bat coronavirus clustered into a large branch. suggesting that they may have a common ancestor. The S protein was expressed mainly in the precipitate after centrifugation of bacterial lysates, which lays a foundation for future structural analysis and vaccine development. The S glycoprotein was highly conserved between SARS-CoV and bat coronavirus, suggesting that this glycoprotein has a vital role in viral invasion into host cells. SARS-CoV-2 may have a common ancestor with SARS-CoV and bat coronavirus. Our study provides an important data basis for expression. purification. structural and functional analysis of the S glycoprotein of SARS-CoV-2. Our data may help to reveal the biological functions of the S glycoprotein, and provide a scientific basis for the design and screening of new antiviral drugs targeting this protein.

6.
Res Vet Sci ; 152: 236-244, 2022 Dec 20.
Article in English | MEDLINE | ID: covidwho-2069657

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) envelope protein (E) is recognized as a viroporin that plays important functions in virus budding, assembly and virulence. Our previous study found that PEDV E protein induces endoplasmic reticulum stress (ERS), as well as suppresses the type I interferon (IFN) response, but their link and underlying mechanism remain obscure. To better understand this relationship, we investigated the roles of PEDV E protein-induced ERS in regulating cellular type I IFN production. Our results showed that PEDV E protein localized in the ER and triggered ERS through activation of PERK/eIF2α branch, as revealed by the up-regulated phosphorylation of PERK and eIF2α. PEDV E protein also significantly inhibited both poly(I:C)-induced and RIG-I signaling-mediated type I interferon production. The PERK/eIF2α branch of ERS activated by PEDV E protein led to the translation attenuation of RIG-I signaling-associated antiviral proteins, resulting in the suppression of type I IFN production. However, PEDV E protein had no effect on the mRNA transcription of RIG-I-associated molecules. Moreover, suppression of ERS with 4-PBA, a widely used ERS inhibitor, restored the expression of RIG-I-signaling-associated antiviral proteins and mRNA transcription of IFN-ß and ISGs genes to their normal levels, suggesting that PEDV E protein blocks the production of type I IFN through inhibiting expression of antiviral proteins caused by ERS-mediated translation attenuation. This study elucidates the mechanism by which PEDV E protein specifically modulates the ERS to inhibit type I IFN production, which will augment our understanding of PEDV E protein-mediated virus evasion of host innate immunity.


Subject(s)
Coronavirus Infections , Interferon Type I , Porcine epidemic diarrhea virus , Swine Diseases , Swine , Animals , Antiviral Agents , Endoplasmic Reticulum Stress , Cell Line , Eukaryotic Initiation Factor-2 , RNA, Messenger , Coronavirus Infections/veterinary
7.
Chest ; 162(4):A1192, 2022.
Article in English | EMBASE | ID: covidwho-2060788

ABSTRACT

SESSION TITLE: Rare Genetic Mutations and Anatomical Variants SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal disease affecting older adults that results in progressive scarring of the lung parenchyma. Familial IPF (FPF), defined by disease in two or more first-degree relatives, is estimated to occur in 2–20% of all IPF cases and can present with varying phenotypes which may be difficult to diagnose. Inherited gene variation as well as environmental factors predispose a patient to disease development. Additionally, rare genetic variants in the genes encoding surfactant A (SFTPA1, and SFTPA2) that affect alveolar stability and endoplasmic reticulum stress have been reported in less than 1% of FPF cases. Understanding these genetic variants is essential in the diagnosis and management of patients with FPF. CASE PRESENTATION: A 47-year-old Hispanic male with a history of COVID-19 one year ago (not requiring hospitalization) presented to the hospital for a two-day history of subjective fever and shortness of breath. He was hypoxic requiring oxygen via high flow nasal cannula. He was admitted four months ago for shortness of breath and treated for pneumonia. Since then, he has had chronic dyspnea with exertion. Computed tomography of the chest showed extensive ground glass opacities, worse in the right lung, with basilar and upper lobe honeycombing, and air bronchograms in the bilateral lower lobes. Family history was significant for a mother, maternal aunt, maternal grandfather, and maternal cousin who all died from pulmonary fibrosis. His maternal cousin was treated at our facility, in which genetic sequencing revealed a mutation in SFTPA2, c.697T>C. Our patient was found to have the same genetic mutation. DISCUSSION: The genetic basis of IPF remains poorly understood. Prior studies suggest only 20-30% of FPF cases harbor an identifiable causative genetic variant. Rare variants in two biologic pathways contribute to the known heritability of FPF including pathologic variants in surfactant related genes which cause improper protein trafficking leading to endoplasmic reticulum stress, defects in autophagy, and type II alveolar cell toxicity. SFTPA1 and SFTPA2 variants have been associated with FPF and lung adenocarcinoma in a small number of families and there are few reported cases. While currently the SFTPA2, c.697T>C mutation, previously reported by our group in 2016, is considered a variant of unknown significance, its occurrence in two relatives with serious progressive interstitial lung diseases suggests that it is indeed pathogenic. CONCLUSIONS: Gene sequencing should be considered for all patients with a family history of pulmonary fibrosis as identification of a rare genetic variant may offer guidance to diagnosis, prognostication, and risk stratification when considering lung transplantation as well as identify additional relatives who may be affected by IPF. Reference #1: Kropski JA, Young LR, Cogan JD, et al. Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017;195(11):1423-1428. doi:10.1164/rccm.201609-1820PP Reference #2: Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009 Jan;84(1):52-9. doi: 10.1016/j.ajhg.2008.11.010. Epub 2008 Dec 18. PMID: 19100526;PMCID: PMC2668050. Reference #3: Pulmonary Fibrosis Due to a Novel Surfactant Protein Mutation R.A. Arciniegas Flores, I.A. Vital, K. Medepalli, D. DeMarzo, M.K. Glassberg Csete, R.A. Alvarez. https://doi.org/10.1164/ajrccm-conference.2019.199.1_Meetings.A5437 DISCLOSURES: No relevant relationships by Roger Alvarez No relevant relationships by Eduardo Lopez Gonzalez No relevant relationships by Anita Singh

8.
Chest ; 162(4):A462, 2022.
Article in English | EMBASE | ID: covidwho-2060600

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Mucormycosis is an angio-invasive fungal infection with substantial morbidity and mortality. While diabetes and immune suppression remain well-known risk factors for mucormycosis, COVID-19 is now emerging as its independent predictor. CASE PRESENTATION: A 43-year-old male, with a history of hyperlipidemia and alcoholism, presented to the hospital with complaints of progressive dyspnea on exertion, productive cough, intermittent fever, anorexia, and chest pain over the course of 2 weeks. About 5 weeks prior to the current presentation, he was tested positive for COVID-19 by a polymerase chain reaction (PCR) based test and remained in quarantine at home. He was not vaccinated against COVID-19. He had no known immunosuppressive disease. On initial examination, he was ill-appearing and had a temperature of 101 F, blood pressure 138/83 mmHg, respiratory rate 22/minute, pulse 102/minute, and saturation of 91% on 2 L nasal cannula oxygen. A computerized tomography (CT) scan of the chest revealed small bilateral pneumothorax (2 cm and 5mm) along with extensive ground-glass opacifications in all lobes. In the next 24 hours, the right-sided pneumothorax progressed to tension pneumothorax requiring pigtail pleural drainage catheter placement. The drained pleural fluid had more than 100,000/uL total nucleated cells (91% neutrophils, 2% lymphocytes, and 1% eosinophils) and ultimately cultures grew Rhizopus spp. He was started on intravenous liposomal amphotericin-B infusion (5 mg/kg daily). On hospital discharge, he was switched to oral posaconazole (started with loading 300 mg delayed-release tablet twice a day, followed by 300 mg dosing of delayed-release posaconazole tablets daily) to complete the long term treatment course. DISCUSSION: Most of the reported cases of mucormycosis in COVID-19 were in patients with either diabetes or receiving steroids. This is a rare presentation of COVID-19–associated pulmonary mucormycosis (CAPM) as spontaneous pneumothorax, in the absence of known immunosuppression history. COVID-19 results in a considerable increase in cytokines, particularly interleukin-6 (IL-6), which increase free iron by increasing ferritin levels due to increased synthesis and decreased iron transport. Also, concomitant acidosis increases free iron by reducing the ability of transferrin to chelate iron and this available iron becomes a considerable resource for mucormycosis. [1] Also, Mucorales adheres to and invades endothelial cells by specific recognition of the host receptor glucose-regulator protein 78 (GRP-78). Acidosis associated with severe COVID-19 triggers GRP-78 and fungal ligand spore coating homolog (CotH) protein expression on endothelial cells, both contributing to angioinvasion, hematogenous dissemination, and tissue necrosis. [2] CONCLUSIONS: Mucormycosis can present as spontaneous pneumothorax after recent COVID-19 and clinicians should be aware of rare clinical presentation. Reference #1: Singh AK, Singh R, Joshi SR, et al. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr Clin Res Rev 2021;15:102146. doi:10.1016/j.dsx.2021.05.019 Reference #2: Baldin C, Ibrahim AS. Molecular mechanisms of mucormycosis—The bitter and the sweet. PLOS Pathog 2017;13:e1006408. doi:10.1371/journal.ppat.1006408 DISCLOSURES: No relevant relationships by Faran Ahmad No relevant relationships by AYESHA BATOOL No relevant relationships by Zachary DePew No relevant relationships by Neil Mendoza

9.
Journal of Clinical and Experimental Medicine ; 282(4):253-257, 2022.
Article in Japanese | Ichushi | ID: covidwho-2057978
10.
Pharmacol Res ; 185: 106477, 2022 11.
Article in English | MEDLINE | ID: covidwho-2049743

ABSTRACT

Receptor expression-enhancing proteins (REEPs) are an evolutionarily conserved protein family that is pivotal to the structure and function of the endoplasmic reticulum (ER). The REEP family can be classified into two major subfamilies in higher species, the REEP1-4 and REEP5-6 subfamilies. Within the REEP1-4 subfamily, REEP1 and REEP2 are closely related, and REEP3 and REEP4 are similarly related. The REEP family is widely distributed in various tissues. Recent studies indicate that the REEP family is involved in many pathological and physiological processes, such as ER morphogenesis and remodeling, microtubule cytoskeleton regulation, and the trafficking and expression of G protein-coupled receptors (GPCRs). Moreover, the REEP family plays crucial roles in the occurrence and development of many diseases, including neurological diseases, diabetes, retinal diseases, cardiac diseases, infertility, obesity, oligoarticular juvenile idiopathic arthritis (OJIA), COVID-19, and cancer. In the present review, we describe the distribution and structure of the REEP family. Furthermore, we summarize the functions and the associated diseases of this family. Based on the pleiotropic actions of the REEP family, the study of its family members is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.


Subject(s)
COVID-19 , Humans , Endoplasmic Reticulum/metabolism , Carrier Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Cytoskeleton/metabolism , Membrane Transport Proteins/metabolism
11.
Biochemistry (Mosc) ; 87(9): 916-931, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2038256

ABSTRACT

Endoplasmic reticulum (ER) is a multifunctional membrane-enclosed organelle. One of the major ER functions is cotranslational transport and processing of secretory, lysosomal, and transmembrane proteins. Impaired protein processing caused by disturbances in the ER homeostasis results in the ER stress. Restoration of normal ER functioning requires activation of an adaptive mechanism involving cell response to misfolded proteins, the so-called unfolded protein response (UPR). Besides controlling protein folding, UPR plays a key role in other physiological processes, in particular, differentiation of cells of connective, muscle, epithelial, and neural tissues. Cell differentiation is induced by the physiological levels of ER stress, while excessive ER stress suppresses differentiation and can result in cell death. So far, it remains unknown whether UPR activation induces cell differentiation or if UPR is initiated by the upregulated synthesis of secretory proteins during cell differentiation. Cell differentiation is an important stage in the development of multicellular organisms and is tightly controlled. Suppression or excessive activation of this process can lead to the development of various pathologies in an organism. In particular, impairments in the differentiation of connective tissue cells can result in the development of fibrosis, obesity, and osteoporosis. Recently, special attention has been paid to fibrosis as one of the major complications of COVID-19. Therefore, studying the role of UPR in the activation of cell differentiation is of both theoretical and practical interest, as it might result in the identification of molecular targets for selective regulation of cell differentiation stages and as well as the potential to modulate the mechanisms involved in the development of various pathological states.


Subject(s)
COVID-19 , Endoplasmic Reticulum Stress , Cell Differentiation , Fibrosis , Humans , Unfolded Protein Response
12.
Iranian Journal of Pharmaceutical Research ; 21(1), 2022.
Article in English | EMBASE | ID: covidwho-2033387

ABSTRACT

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

13.
Cell J ; 24(8): 427-433, 2022 Aug 28.
Article in English | MEDLINE | ID: covidwho-2026220

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may adversely affect male reproductive tissues and male
fertility. This concern is elicited by the higher susceptibility and mortality rate of men to the SARS-CoV-2 mediated coronavirus disease-19 (COVID-19), compared to the women. SARS-CoV-2 enters host cells after binding to a functional receptor named angiotensin-converting enzyme-2 (ACE2) and then replicates in the host cells and gets released into the plasma. SARS-CoVs use the endoplasmic reticulum (ER) as a site for viral protein synthesis and processing, as well as glucose-regulated protein 78 (Grp78) is a key ER chaperone involved in protein folding by preventing newly synthesized proteins from aggregation.
Therefore, we analyzed Grp78 expression in various human organs, particularly male reproductive organs, using Broad
Institute Cancer Cell Line Encyclopedia (CCLE), the Genotype-Tissue Expression (GTEx), and Human Protein Atlas online
datasets. Grp78 is expressed in male reproductive tissues such as the testis, epididymis, prostate, and seminal vesicle. It can facilitate the coronavirus entry into the male reproductive tract, providing an opportunity for its replication. This link between the SARS-CoV-2 and the Grp78 protein could become a therapeutic target to mitigate its harmful effects on male fertility.

14.
Cell Biol Int ; 46(12): 2257-2261, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1999839

ABSTRACT

Vascular barrier dysfunction due to endothelial hyperpermeability has been associated with the pathophysiology of sepsis and severe lung injury, which may inflict acute respiratory distress syndrome (ARDS). Our group is focused on the mechanisms operating towards the regulation of endothelial permeability, to contribute in the development of efficient and targeted countermeasures against ARDS. Unfortunately, the number of ARDS-related deaths in the intensive care units has dramatically increased during the COVID-19 era. The findings described herein inform the corresponding scientific and medical community on the relation of P53 and stress responses in barrier function.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Sepsis , Humans , Tumor Suppressor Protein p53/metabolism , Unfolded Protein Response , Sepsis/metabolism , Lung/metabolism
15.
Biomolecules ; 12(9)2022 08 24.
Article in English | MEDLINE | ID: covidwho-1997508

ABSTRACT

SARS-CoV-2 receptor-binding domain (RBD) is a major target for the development of diagnostics, vaccines and therapeutics directed against COVID-19. Important efforts have been dedicated to the rapid and efficient production of recombinant RBD proteins for clinical and diagnostic applications. One of the main challenges is the ongoing emergence of SARS-CoV-2 variants that carry mutations within the RBD, resulting in the constant need to design and optimise the production of new recombinant protein variants. We describe here the impact of naturally occurring RBD mutations on the secretion of a recombinant Fc-tagged RBD protein expressed in HEK 293 cells. We show that mutation E484K of the B.1.351 variant interferes with the proper disulphide bond formation and folding of the recombinant protein, resulting in its retention into the endoplasmic reticulum (ER) and reduced protein secretion. Accumulation of the recombinant B.1.351 RBD-Fc fusion protein in the ER correlated with the upregulation of endogenous ER chaperones, suggestive of the unfolded protein response (UPR). Overexpression of the chaperone and protein disulphide isomerase PDIA2 further impaired protein secretion by altering disulphide bond formation and increasing ER retention. This work contributes to a better understanding of the challenges faced in producing mutant RBD proteins and can assist in the design of optimisation protocols.


Subject(s)
COVID-19 , Viral Vaccines , Disulfides , HEK293 Cells , Humans , Mutation , Protein Disulfide-Isomerases/genetics , Recombinant Fusion Proteins/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
16.
Russian Journal of Genetics ; 58(7):814-822, 2022.
Article in English | EMBASE | ID: covidwho-1986344

ABSTRACT

: Lung cancer is the most commonly occurring cancer in men worldwide. To search for new biological markers of this pathology, the transcriptome of the blood mononuclear cells from patients and healthy donors (residents of Kemerovo oblast, Russia) was studied using SurePrint G3 Human Gene Expression microarray technology. A total of 288 differentially expressed genes were identified, including 108 up-regulated genes and 180 down-regulated genes. Functional enrichment analysis using the WebGestalt resource and different databases (Gene Ontology, KEGG, and Reactome) indicated changes in the expression profiles of genes involved in the processes of immune response, protein synthesis, cell cycle control, and apoptosis. Analysis of protein–protein interactions using the STRING algorithm made it possible to identify functional clusters of gene products with different expression levels.

17.
Bulletin of Russian State Medical University ; - (3):38-41, 2022.
Article in English | Web of Science | ID: covidwho-1979882

ABSTRACT

Despite the extensive research spurred by the catastrophic effects of COVID-19 pandemic. precise molecular mechanisms of some stages in SARS-CoV-2 life cycle remain elusive. One of such stages is the detachment of viral particles during budding. Using confocal fluorescence microscopy, we observed formation of specific structures by endoplasmic reticulum in human cells expressing SARS-CoV-2 M-protein, implicating oligomerization of M-protein across parallel membranes. In our opinion, such intermembrane oligomerization may provide a driving forts for pinching off the viral particles during SARS-CoV-2 budding.

18.
Gastroenterology ; 162(7):S-364, 2022.
Article in English | EMBASE | ID: covidwho-1967299

ABSTRACT

Background: Diarrhea is present in up to 36.6% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte-enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of Damage Associated Molecular Patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. The influence of ER stress and enteric neuronderived vasoactive intestinal peptide (VIP) on the expression of Na+/H+ exchanger 3 (NHE3), an important transporter that mediates intestinal Na+/fluid absorption, was further examined. Methods: SARS-CoV-2 propagated in Vero-E6 cells was used to infect Caco-2, a human colon epithelial cell line that expresses SARS-CoV-2 entry receptor ACE2. The expression of ER stress markers, phospho-PERK, Xbp1s, and DAMP proteins, was examined by Western blotting. Primary mouse enteric neurons were treated with a conditioned medium of Caco- 2 cells that were infected with SARS-CoV-2 or treated with tunicamycin. VIP expression by cultured enteric neurons was assessed by RT-qPCR, Western blotting, and ELISA. Membrane expression of NHE3 was determined by surface biotinylation. Results: SARS-CoV-2 infection of Caco-2 cells led to increased expression of phospho-PERK and Xbp1s indicating increased ER stress. Infected Caco-2 cells secreted DAMP proteins, including HSP70 and calreticulin, as revealed by proteomic and Western analyses. The expression of VIP mRNA in enteric neurons was up-regulated after treatment with a conditioned medium of SARS-CoV-2- infected Caco-2 cells (Mock, 1 ± 0.0885;and SARS-CoV-2, 1.351 ± 0.020, P=.005). CD91, a receptor for HSP70 and calreticulin, is abundantly expressed in cultured mouse and human enteric neurons and was up-regulated by a conditioned medium of SARS-CoV-2-infected Caco-2 cells. Tunicamycin, an inducer of ER stress, also induced the secretion of HSP70 and calreticulin, mimicking SARS-CoV-2 infection. Moreover, co-culture of enteric neurons with tunicamycin-treated Caco-2 cells stimulated VIP production as determined by ELISA. Co-treatment of Caco-2 cells with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in the membrane expression of NHE3. Conclusions: Our findings demonstrate that SARS-CoV-2 infection of enterocytes leads to ER stress and the release of DAMPs that up-regulate the expression and release of VIP by enteric neurons. The presence of ER stress together with the secreted VIP, in turn, inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in the enterocytes. These data highlight epithelial-neuronal crosstalk in COVID-19 related diarrhea. (Figure Presented)

19.
INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES ; 84:190-201, 2022.
Article in English | Web of Science | ID: covidwho-1939749

ABSTRACT

Phellodendrine is a Phellodendri Cortex-derived isoquinoline alkaloids, has been shown to have various activities, especially hypoglycemic effect in mice, predicting its medicinal value on diabetes mellitus. To further understand the pharmacological effect of phellodendrine on diabetes mellitus, network pharmacological techniques have been used to elaborate the involved mechanisms. 84 common target molecules were screened, based on the chemical structure of phellodendrine molecule and disease database. These proteins were enriched in insulin resistance, insulin secretion and inflammatory response, mainly focus on the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, mitogen-activated protein kinase signaling pathway and interleukin-17 signaling pathway. Moreover, enrichment analysis suggested that the targets of phellodendrine such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha and mitogen-activated protein kinases 8 were associated with coronavirus disease 2019. To verify the results, molecular docking technique was used to evaluate the interaction between phellodendrine and key targets in the signaling pathway. The calculated binding energy indicates that phellodendrine can form stable complex with insulin receptor, mitogen-activated protein kinases 8, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha and glycogen synthase kinase 3 beta. These data suggest that phellodendrine should be beneficial for treatment of diabetes mellitus.

20.
European Journal of Inflammation ; 20, 2022.
Article in English | EMBASE | ID: covidwho-1938133

ABSTRACT

Objectives: The development of effective targeted therapy and drug-design approaches against the SARS-CoV-2 is a universal health priority. Therefore, it is important to assess possible therapeutic strategies against SARS-CoV-2 via its most interaction targets. The present study aimed to perform a systematic review on clinical and experimental investigations regarding SARS-COV-2 interaction targets for human cell entry. Methods: A systematic search using relevant MeSH terms and keywords was performed in PubMed, Scopus, Embase, and Web of Science (ISI) databases up to July 2021. Two reviewers independently assessed the eligibility of the studies, extracted the data, and evaluated the methodological quality of the included studies. Additionally, a narrative synthesis was done as a qualitative method for data gathering and synthesis of each outcome measure. Results: A total of 5610 studies were identified, and 128 articles were included in the systematic review. Based on the results, spike antigen was the only interaction protein from SARS-CoV-2. However, the interaction proteins from humans varied including different spike receptors and several cleavage enzymes. The most common interactions of the spike protein of SARS-CoV-2 for cell entry were ACE2 (entry receptor) and TMPRSS2 (for spike priming). A lot of published studies have mainly focused on the ACE2 receptor followed by the TMPRSS family and furin. Based on the results, ACE2 polymorphisms as well as spike RBD mutations affected the SARS-CoV-2 binding affinity. Conclusion: The included studies shed more light on SARS-CoV-2 cellular entry mechanisms and detailed interactions, which could enhance the understanding of SARS-CoV-2 pathogenesis and the development of new and comprehensive therapeutic approaches.

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