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1.
J Appl Physiol (1985) ; 129(2): 257-262, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-670695

ABSTRACT

The emergence of COVID-19 infection (caused by the SARS-CoV-2 virus) in Wuhan, China in the latter part of 2019 has, within a relatively short time, led to a global pandemic. Amidst the initial spread of SARS-CoV-2 across Asia, an epidemiologic trend emerged in relation to high altitude (HA) populations. Compared with the rest of Asia, SARS-CoV-2 exhibited attenuated rates of expansion with limited COVID-19 infection severity along the Tibetan plateau. These characteristics were soon evident in additional HA regions across Bolivia, central Ecuador, Nepal, Bhutan, and the Sichuan province of mainland China. This mini-review presents a discussion surrounding attributes of the HA environment, aspects of HA physiology, as well as, genetic variations among HA populations which may provide clues for this pattern of SARS-CoV-2 expansion and COVID-19 infection severity. Explanations are provided in the hypothetical, albeit relevant historical evidence is provided to create a foundation for future research.


Subject(s)
Altitude , Betacoronavirus , Coronavirus Infections/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Bolivia/epidemiology , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/metabolism , Humans , Nepal/epidemiology , Pandemics/statistics & numerical data , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/metabolism
2.
Sci Rep ; 10(1): 11746, 2020 07 16.
Article in English | MEDLINE | ID: covidwho-654915

ABSTRACT

Category A and B biothreat agents are deemed to be of great concern by the US Centers for Disease Control and Prevention (CDC) and include the bacteria Francisella tularensis, Yersinia pestis, Burkholderia mallei, and Brucella species. Underscored by the impact of the 2020 SARS-CoV-2 outbreak, 2016 Zika pandemic, 2014 Ebola outbreak, 2001 anthrax letter attacks, and 1984 Rajneeshee Salmonella attacks, the threat of future epidemics/pandemics and/or terrorist/criminal use of pathogenic organisms warrants continued exploration and development of both classic and alternative methods of detecting biothreat agents. Volatile organic compounds (VOCs) comprise a large and highly diverse group of carbon-based molecules, generally related by their volatility at ambient temperature. Recently, the diagnostic potential of VOCs has been realized, as correlations between the microbial VOC metabolome and specific bacterial pathogens have been identified. Herein, we describe the use of microbial VOC profiles as fingerprints for the identification of biothreat-relevant microbes, and for differentiating between a kanamycin susceptible and resistant strain. Additionally, we demonstrate microbial VOC profiling using a rapid-throughput VOC metabolomics method we refer to as 'simultaneous multifiber headspace solid-phase microextraction' (simulti-hSPME). Finally, through VOC analysis, we illustrate a rapid non-invasive approach to the diagnosis of BALB/c mice infected with either F. tularensis SCHU S4 or Y. pestis CO92.


Subject(s)
Metabolomics/methods , Tularemia/metabolism , Volatile Organic Compounds/metabolism , Animals , Betacoronavirus/isolation & purification , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Disease Outbreaks , Drug Resistance, Microbial/drug effects , Drug Resistance, Microbial/genetics , Female , Francisella tularensis/drug effects , Francisella tularensis/isolation & purification , Francisella tularensis/metabolism , Kanamycin/pharmacology , Mice , Mice, Inbred BALB C , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Solid Phase Microextraction , Tularemia/microbiology , Tularemia/pathology , Tularemia/veterinary , Volatile Organic Compounds/analysis , Volatile Organic Compounds/isolation & purification , Yersinia pestis/drug effects , Yersinia pestis/isolation & purification , Yersinia pestis/metabolism
3.
EBioMedicine ; 58: 102887, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-684307

ABSTRACT

The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1-7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1-7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/etiology , Cytokines/metabolism , Pneumonia, Viral/etiology , Renin-Angiotensin System , Animals , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Coronavirus Infections/virology , Feedback, Physiological , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology
4.
ACS Chem Neurosci ; 11(15): 2145-2148, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-646274

ABSTRACT

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.


Subject(s)
Alzheimer Disease/drug therapy , Betacoronavirus , Calcium Channel Blockers/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Calcium/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/psychology , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/psychology , Treatment Outcome
6.
Zhonghua Yan Ke Za Zhi ; 56(6): 438-446, 2020 Jun 11.
Article in Chinese | MEDLINE | ID: covidwho-742856

ABSTRACT

This article was published ahead of print on the official website of Chinese Journal of Ophthalmolog on Apirl 22,2020. Objective: Angiotensin converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2) are the key proteins for 2019-nCoV entry into host cells. To evaluate the potential infection risk of 2019-nCoV on ocular surface, we compared ACE2 and TMPRSS2 expression among different eye tissues. Methods: Experimental study. Thirty mice were assigned to male, female, aged, diabetic and non-diabetic groups, with 6 mice in each group. Real-time PCR was performed to quantify ACE2 and TMPRSS2 gene expression in conjunctiva, cornea, lacrimal gland, iris, lens, retina, lung, heart, kidney, and liver from male mice. Immunohistochemistry staining was applied to visualize the distribution of the two proteins in different mice tissues, and in human corneal and conjunctival sections. Published transcriptome datasets were extracted to generate the expression comparasion of ACE2 and TMPRSS2 between human conjunctival and corneal tissues, and results were analyzed using Mann-Whitney U test. Female mice, aged mice, STZ-induced diabetic mice, diabetic group control mice were also subjected to ACE2 expression analysis. Results were analyzed using Student's t-test. Results: The expression of ACE2 and TMPRSS2 genes were the highest in conjunctiva among all the six mice eye tissues explored. The expression of these two genes in conjunctiva were lower than that in kidney and lung. ACE2 and TMPRSS2 shared similar expression pattern with the staining concentrated in corneal epithelium, conjunctival epithelium and lacrimal gland serous cells. The expression levels of ACE2 showed gender difference. Female mice had lower ACE2 in conjunctiva and cornea than male mice, with the expression levels being only 43% (t=3.269, P=0.031) and 63% (t=4.080, P=0.015) of that in the male conjunctiva and cornea, respectively. Diabetic mice expressed more ACE2 in conjunctiva (1.21-fold, P>0.05) and lacrimal gland (1.10-fold, P>0.05) compared with the control group. No significant difference on ACE2 expression was found between the aged and young adult mice. The expression level of human conjunctiva ACE2 and TMPRSS2 were significantly higher than that in the cornea (P=0.007), with 5.74-fold and 12.84-fold higher in the conjunctiva than in the corneal epithelium cells, which resembled the situation in mice. Conclusion: The observation of high-level ACE2 and TMPRSS2 expression in conjunctiva among the 6 eye tissues examined suggests that conjunctiva serves as an infection target tissue of 2019-nCoV. (Chin J Ophthalmol, 2020, 56:438-446).


Subject(s)
Conjunctiva/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Serine Endopeptidases/metabolism , Animals , Betacoronavirus , Conjunctiva/virology , Cornea/metabolism , Cornea/virology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/virology , Epithelial Cells/metabolism , Epithelial Cells/virology , Female , Humans , Male , Mice , Pandemics
7.
Int J Mol Sci ; 21(17)2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-742800

ABSTRACT

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Susceptibility/immunology , Host-Pathogen Interactions/immunology , Immunity, Innate , Killer Cells, Natural/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Autoimmunity , Coronavirus Infections/metabolism , Humans , Immunomodulation , Killer Cells, Natural/metabolism , Pandemics , Pneumonia, Viral/metabolism
8.
Sci Rep ; 10(1): 14179, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741695

ABSTRACT

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.


Subject(s)
Betacoronavirus/immunology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Host-Pathogen Interactions/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Viral Proteins/immunology , Amino Acid Sequence , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/classification , Betacoronavirus/genetics , Betacoronavirus/metabolism , Computational Biology/methods , Coronavirus Infections/metabolism , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Genome, Viral , Genomics/methods , Humans , Models, Molecular , Pandemics , Peptides/chemistry , Peptides/immunology , Phylogeny , Pneumonia, Viral/metabolism , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Vaccines, Subunit/immunology , Viral Proteins/chemistry , Viral Vaccines/immunology
9.
Chaos ; 30(8): 081104, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-740056

ABSTRACT

The coronavirus 2019 (COVID-19) respiratory disease is caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which uses the enzyme ACE2 to enter human cells. This disease is characterized by important damage at a multi-organ level, partially due to the abundant expression of ACE2 in practically all human tissues. However, not every organ in which ACE2 is abundant is affected by SARS-CoV-2, which suggests the existence of other multi-organ routes for transmitting the perturbations produced by the virus. We consider here diffusive processes through the protein-protein interaction (PPI) network of proteins targeted by SARS-CoV-2 as an alternative route. We found a subdiffusive regime that allows the propagation of virus perturbations through the PPI network at a significant rate. By following the main subdiffusive routes across the PPI network, we identify proteins mainly expressed in the heart, cerebral cortex, thymus, testis, lymph node, kidney, among others of the organs reported to be affected by COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Models, Biological , Pneumonia, Viral/physiopathology , Protein Interaction Mapping , Protein Interaction Maps , Proteome , Biomarkers/metabolism , Coronavirus Infections/metabolism , Diffusion , Humans , Pandemics , Pneumonia, Viral/metabolism , Time Factors
10.
Sci Rep ; 10(1): 14214, 2020 08 26.
Article in English | MEDLINE | ID: covidwho-733506

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple 500 ns or 1 µs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV-2 and SARS-CoV utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 S protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493 and Gln498 of SARS-CoV-2 and Asp38, Glu35 and Lys353 of ACE2 were observed, which were absent in the ACE2-SARS-CoV interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS Virus/physiology , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Binding Sites , Conserved Sequence , Host-Pathogen Interactions , Humans , Models, Molecular , Pandemics , Peptidyl-Dipeptidase A/chemistry , Protein Binding , Protein Conformation , Spike Glycoprotein, Coronavirus/chemistry
13.
Biosensors (Basel) ; 10(9)2020 Aug 24.
Article in English | MEDLINE | ID: covidwho-727396

ABSTRACT

Cytokines are a family of proteins which play a major role in the regulation of the immune system and the development of several diseases, from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being developed to improve therapy and diagnosis, as well as to produce inhibitory drugs and biosensors for a rapid, minimally invasive, and effective detection. In this regard, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of IL-6 cytokine receptors, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an idealized experimental setup.


Subject(s)
Biosensing Techniques/methods , Interleukin-6/analysis , Receptors, Interleukin-6/analysis , Antibodies, Monoclonal/analysis , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized/chemistry , Antibodies, Monoclonal, Humanized/immunology , Aptamers, Nucleotide/chemistry , Betacoronavirus/isolation & purification , Coronavirus Infections/diagnosis , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Immunoglobulin Fab Fragments/analysis , Immunoglobulin Fab Fragments/immunology , Interleukin-6/immunology , Limit of Detection , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Receptors, Interleukin-6/immunology
14.
PLoS Pathog ; 16(8): e1008762, 2020 08.
Article in English | MEDLINE | ID: covidwho-727333

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a newly emerging, highly transmissible, and pathogenic coronavirus in humans that has caused global public health emergencies and economic crises. To date, millions of infections and thousands of deaths have been reported worldwide, and the numbers continue to rise. Currently, there is no specific drug or vaccine against this deadly virus; therefore, there is a pressing need to understand the mechanism(s) through which this virus enters the host cell. Viral entry into the host cell is a multistep process in which SARS-CoV-2 utilizes the receptor-binding domain (RBD) of the spike (S) glycoprotein to recognize angiotensin-converting enzyme 2 (ACE2) receptors on the human cells; this initiates host-cell entry by promoting viral-host cell membrane fusion through large-scale conformational changes in the S protein. Receptor recognition and fusion are critical and essential steps of viral infections and are key determinants of the viral host range and cross-species transmission. In this review, we summarize the current knowledge on the origin and evolution of SARS-CoV-2 and the roles of key viral factors. We discuss the structure of RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and its significance in drug discovery and explain the receptor recognition mechanisms of coronaviruses. Further, we provide a comparative analysis of the SARS-CoV and SARS-CoV-2 S proteins and their receptor-binding specificity and discuss the differences in their antigenicity based on biophysical and structural characteristics.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Coronavirus Infections/metabolism , Humans , Pandemics , Pneumonia, Viral/metabolism , Receptors, Virus/immunology , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization
15.
BMC Pregnancy Childbirth ; 20(1): 481, 2020 Aug 24.
Article in English | MEDLINE | ID: covidwho-727268

ABSTRACT

BACKGROUND: The world's understanding of COVID-19 continues to evolve as the scientific community discovers unique presentations of this disease. This case report depicts an unexpected intraoperative coagulopathy during a cesarean section in an otherwise asymptomatic patient who was later found to have COVID-19. This case suggests that there may be a higher risk for intrapartum bleeding in the pregnant, largely asymptomatic COVID-positive patient with more abnormal COVID laboratory values. CASE: The case patient displayed D-Dimer elevations beyond what is typically observed among this hospital's COVID-positive peripartum population and displayed significantly more oozing than expected intraoperatively, despite normal prothrombin time, international normalized ratio, fibrinogen, and platelets. CONCLUSION: There is little published evidence on the association between D-Dimer and coagulopathy among the pregnant population infected with SARS-CoV-2. This case report contributes to the growing body of evidence on the effects of COVID-19 in pregnancy. A clinical picture concerning for intraoperative coagulopathy may be associated with SARS-CoV-2 infection during cesarean sections, and abnormal COVID laboratory tests, particularly D-Dimer, may help identify the patients in which this presentation occurs.


Subject(s)
Blood Coagulation Disorders/blood , Blood Loss, Surgical , Breech Presentation/surgery , Cesarean Section , Coronavirus Infections/blood , Pneumonia, Viral/blood , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Infectious/blood , Adult , Antifibrinolytic Agents/therapeutic use , Betacoronavirus , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/metabolism , C-Reactive Protein/metabolism , Cautery , Coronavirus Infections/diagnosis , Coronavirus Infections/metabolism , Female , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Hemostasis, Surgical , Humans , International Normalized Ratio , Methylergonovine/therapeutic use , Oligohydramnios , Oxytocics/therapeutic use , Oxytocin/therapeutic use , Pandemics , Platelet Count , Pneumonia, Viral/diagnosis , Pneumonia, Viral/metabolism , Pregnancy , Pregnancy Complications, Hematologic/drug therapy , Pregnancy Complications, Hematologic/metabolism , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/metabolism , Prothrombin Time , Tranexamic Acid/therapeutic use , Uterine Inertia/drug therapy
16.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Article in English | MEDLINE | ID: covidwho-725491

ABSTRACT

The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Drug Evaluation, Preclinical/methods , Pneumonia, Viral/metabolism , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus Infections/virology , Hydroxychloroquine/pharmacology , Imatinib Mesylate/pharmacology , Lysosomes/drug effects , Pandemics , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacology , RNA, Viral/drug effects , Vero Cells , Viral Load/drug effects
17.
Int J Mol Sci ; 21(17)2020 Aug 20.
Article in English | MEDLINE | ID: covidwho-725462

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and furin, which promote entry of the virus into the host cell, have been identified as determinants of SARS-CoV-2 infection. Dorsal tongue and gingiva, saliva, and tongue coating samples were examined to determine the presence of these molecules in the oral cavity. Immunohistochemical analyses showed that ACE2 was expressed in the stratified squamous epithelium of the dorsal tongue and gingiva. TMPRSS2 was strongly expressed in stratified squamous epithelium in the keratinized surface layer and detected in the saliva and tongue coating samples via Western blot. Furin was localized mainly in the lower layer of stratified squamous epithelium and detected in the saliva but not tongue coating. ACE2, TMPRSS2, and furin mRNA expression was observed in taste bud-derived cultured cells, which was similar to the immunofluorescence observations. These data showed that essential molecules for SARS-CoV-2 infection were abundant in the oral cavity. However, the database analysis showed that saliva also contains many protease inhibitors. Therefore, although the oral cavity may be the entry route for SARS-CoV-2, other factors including protease inhibitors in the saliva that inhibit viral entry should be considered.


Subject(s)
Betacoronavirus/metabolism , Furin/metabolism , Mouth Mucosa/metabolism , Peptidyl-Dipeptidase A/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Coronavirus Infections/metabolism , Gingiva/metabolism , Humans , Pandemics , Pneumonia, Viral/metabolism , Saliva/metabolism , Tongue/metabolism , Virus Internalization
18.
Eur Rev Med Pharmacol Sci ; 24(15): 8219-8225, 2020 08.
Article in English | MEDLINE | ID: covidwho-724284

ABSTRACT

OBJECTIVE: At the end of 2019, the Novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), spread rapidly from China to the whole world. Circadian rhythms can play crucial role in the complex interplay between viruses and organisms, and temporized schedules (chronotherapy) have been positively tested in several medical diseases. We aimed to compare the possible effects of a morning vs. evening antiviral administration in COVID patients. PATIENTS AND METHODS: We retrospectively evaluated all patients admitted to COVID internal medicine units with confirmed SARS-CoV-2 infection, and treated with darunavir-ritonavir (single daily dose, for seven days). Age, sex, length of stay (LOS), pharmacological treatment, and timing of antiviral administration (morning or evening), were recorded. Outcome indicators were death or LOS, and laboratory parameters, e.g., variations in C-reactive protein (CRP) levels, ratio of arterial oxygen partial pressure (PaO2, mmHg) to fractional inspired oxygen (FiO2) (PaO2/FiO2), and leucocyte count. RESULTS: The total sample consisted of 151 patients, 33 (21.8%) of whom were selected for antiviral treatment. The mean age was 61.8±18.3 years, 17 (51.5%) were male, and the mean LOS was 13.4±8.6 days. Nine patients (27.3%) had their antiviral administration in the morning, and 24 (72.7%) had antiviral administration in the evening. No fatalities occurred. Despite the extremely limited sample size, morning group subjects showed a significant difference in CRP variation, compared to that in evening group subjects (-65.82±33.26 vs. 83.32±304.89, respectively, p<0.032). No significant differences were found for other parameters. CONCLUSIONS: This report is the first study evaluating temporized morning vs. evening antiviral administration in SARS-CoV-2 patients. The morning regimen was associated with a significant reduction in CRP values. Further confirmations with larger and multicenter samples of patients could reveal novel potentially useful insights.


Subject(s)
Antiviral Agents/administration & dosage , Coronavirus Infections/drug therapy , Darunavir/administration & dosage , Drug Chronotherapy , Hospital Mortality , Length of Stay/statistics & numerical data , Pneumonia, Viral/drug therapy , Ritonavir/administration & dosage , Adult , Aged , Aged, 80 and over , Betacoronavirus , Blood Gas Analysis , C-Reactive Protein , Coronavirus Infections/metabolism , Drug Therapy, Combination , Humans , Italy , Leukocyte Count , Middle Aged , Oxygen/metabolism , Pandemics , Partial Pressure , Pneumonia, Viral/metabolism , Retrospective Studies
19.
Commun Biol ; 3(1): 466, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-723561

ABSTRACT

Chinese herbal formulas including the lung-cleaning and toxicity-excluding (LCTE) soup have played an important role in treating the ongoing COVID-19 pandemic (caused by SARS-CoV-2) in China. Applying LCTE outside of China may prove challenging due to the unfamiliar rationale behind its application in terms of Traditional Chinese Medicine. To overcome this barrier, a biochemical understanding of the clinical effects of LCTE is needed. Here, we explore the chemical compounds present in the reported LCTE ingredients and the proteins targeted by these compounds via a network pharmacology analysis. Our results indicate that LCTE contains compounds with the potential to directly inhibit SARS-CoV-2 and inflammation, and that the compound targets proteins highly related to COVID-19's main symptoms. We predict the general effect of LCTE is to affect the pathways involved in viral and other microbial infections, inflammation/cytokine response, and lung diseases. Our work provides a biochemical basis for using LCTE to treat COVID-19 and its main symptoms.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional , Pandemics , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Calcium Sulfate , China/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Drug Delivery Systems , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Gastrointestinal Tract/drug effects , Humans , Metabolic Networks and Pathways/drug effects , Phytotherapy , Plants, Medicinal/chemistry , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Respiratory System/drug effects , Viral Proteins/antagonists & inhibitors
20.
Diabetes Metab J ; 44(4): 602-613, 2020 08.
Article in English | MEDLINE | ID: covidwho-721570

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic that had affected more than eight million people worldwide by June 2020. Given the importance of the presence of diabetes mellitus (DM) for host immunity, we retrospectively evaluated the clinical characteristics and outcomes of moderate-to-severe COVID-19 in patients with diabetes. METHODS: We conducted a multi-center observational study of 1,082 adult inpatients (aged ≥18 years) who were admitted to one of five university hospitals in Daegu because of the severity of their COVID-19-related disease. The demographic, laboratory, and radiologic findings, and the mortality, prevalence of severe disease, and duration of quarantine were compared between patients with and without DM. In addition, 1:1 propensity score (PS)-matching was conducted with the DM group. RESULTS: Compared with the non-DM group (n=847), patients with DM (n=235) were older, exhibited higher mortality, and required more intensive care. Even after PS-matching, patients with DM exhibited more severe disease, and DM remained a prognostic factor for higher mortality (hazard ratio, 2.40; 95% confidence interval, 1.38 to 4.15). Subgroup analysis revealed that the presence of DM was associated with higher mortality, especially in older people (≥70 years old). Prior use of a dipeptidyl peptidase-4 inhibitor or a renin-angiotensin system inhibitor did not affect mortality or the clinical severity of the disease. CONCLUSION: DM is a significant risk factor for COVID-19 severity and mortality. Our findings imply that COVID-19 patients with DM, especially if elderly, require special attention and prompt intensive care.


Subject(s)
Coronavirus Infections/mortality , Diabetes Mellitus/epidemiology , Pneumonia, Viral/mortality , Adult , Aged , Aged, 80 and over , Alanine Transaminase/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Aspartate Aminotransferases/metabolism , Betacoronavirus , C-Reactive Protein/metabolism , Case-Control Studies , Comorbidity , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Female , Humans , Length of Stay/statistics & numerical data , Logistic Models , Lymphocytosis , Male , Middle Aged , Multivariate Analysis , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , Prognosis , Propensity Score , Proportional Hazards Models , Quarantine/statistics & numerical data , Republic of Korea/epidemiology , Risk Factors , Severity of Illness Index , Thrombocytopenia
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