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1.
iScience ; 24(6): 102523, 2021 Jun 25.
Article in English | MEDLINE | ID: covidwho-1385758

ABSTRACT

Nucleocapsid (N) protein of the SARS-CoV-2 virus packages the viral genome into well-defined ribonucleoprotein particles, but the molecular pathway is still unclear. N-protein is dimeric and consists of two folded domains with nucleic acid (NA) binding sites, surrounded by intrinsically disordered regions that promote liquid-liquid phase separation. Here, we use biophysical tools to study N-protein interactions with oligonucleotides of different lengths, examining the size, composition, secondary structure, and energetics of the resulting states. We observe the formation of supramolecular clusters or nuclei preceding growth into phase-separated droplets. Short hexanucleotide NA forms compact 2:2 N-protein/NA complexes with reduced disorder. Longer oligonucleotides expose additional N-protein interactions and multi-valent protein-NA interactions, which generate higher-order mixed oligomers and simultaneously promote growth of droplets. Phase separation is accompanied by a significant change in protein secondary structure, different from that caused by initial NA binding, which may contribute to the assembly of ribonucleoprotein particles within macromolecular condensates.

2.
Materials (Basel) ; 14(11)2021 May 30.
Article in English | MEDLINE | ID: covidwho-1266753

ABSTRACT

A series of pure and doped TiO2 nanomaterials with different Zr4+ ions content have been synthesized by the simple sol-gel method. Both types of materials (nanopowders and nanofilms scratched off of the working electrode's surface) have been characterized in detail by XRD, TEM, and Raman techniques. Inserting dopant ions into the TiO2 structure has resulted in inhibition of crystal growth and prevention of phase transformation. The role of Zr4+ ions in this process was explained by performing computer simulations. The three structures such as pure anatase, Zr-doped TiO2, and tetragonal ZrO2 have been investigated using density functional theory extended by Hubbard correction. The computational calculations correlate well with experimental results. Formation of defects and broadening of energy bandgap in defected Zr-doped materials have been confirmed. It turned out that the oxygen vacancies with substituting Zr4+ ions in TiO2 structure have a positive influence on the performance of dye-sensitized solar cells. The overall photoconversion efficiency enhancement up to 8.63% by introducing 3.7% Zr4+ ions into the TiO2 has been confirmed by I-V curves, EIS, and IPCE measurements. Such efficiency of DSSC utilizing the working electrode made by Zr4+ ions substituted into TiO2 material lattice has been for the first time reported.

3.
Antibiotics (Basel) ; 10(3)2021 Mar 22.
Article in English | MEDLINE | ID: covidwho-1167400

ABSTRACT

Industrial hemp is characterized by a huge amount of by-products, such as inflorescences, that may represent high-quality sources of biomolecules with pharmaceutical interest. In the present study, we have evaluated the phytochemical profile, including terpene and terpenophenolic compounds, of the essential oils (EOs) of Futura 75, Carmagnola selezionata and Eletta campana hemp varieties. The EOs were also tested for antifungal properties toward Trichophyton mentagrophytes, Trichophyton rubrum, Arthroderma crocatum, Arthroderma quadrifidum, Arthroderma gypseum, Arthroderma curreyi, and Arthroderma insingulare. In parallel, we investigated the inhibitory effects of the EOs against tyrosinase, and the production of prostaglandin E2 in isolated mouse skin exposed to hydrogen peroxide. In human H1299 lung adenocarcinoma cells, we also evaluated the influence of the EOs on the gene expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which are involved in SARS-CoV-2 entry in human host. E-caryophyllene and α-pinene were the prominent terpenes in the EOs, whereas the cannabidiolic acid was the terpenophenol present at higher concentration. The EOs inhibited the growth of all tested dermatophytes species. In isolated skin specimens, EOs prevented the hydrogen-peroxide-induced synthesis of prostaglandin E2, consistent with the intrinsic antityrosinase activity. Finally, in H1299 cells, all tested EOs reduced the gene expression of ACE-2 and TMPRSS2, as well. Therefore, the present findings highlight the rationale for the use of the present EOs against infectious diseases.

4.
ACS Chem Neurosci ; 12(8): 1299-1312, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1160454

ABSTRACT

Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 Spike protein interferes with pain signaling. Here, we report confirmed hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physicochemical properties. Using ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Further, two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.


Subject(s)
COVID-19 , Neuropilin-1 , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vascular Endothelial Growth Factor A , Virus Internalization
5.
Clin Transl Immunology ; 10(3): e1240, 2021.
Article in English | MEDLINE | ID: covidwho-1144230

ABSTRACT

The new coronavirus SARS-CoV-2 is a global pandemic and a severe public health crisis. SARS-CoV-2 is highly contagious and shows high mortality rates, especially in elderly and patients with pre-existing medical conditions. At the current stage, no effective drugs are available to treat these patients. In this review, we analyse the rationale of targeting RGD-binding integrins to potentially inhibit viral cell infection and to block TGF-ß activation, which is involved in the severity of several human pathologies, including the complications of severe COVID-19 cases. Furthermore, we demonstrate the correlation between ACE2 and TGF-ß expression and the possible consequences for severe COVID-19 infections. Finally, we list approved drugs or drugs in clinical trials for other diseases that also target the RGD-binding integrins or TGF-ß. These drugs have already shown a good safety profile and, therefore, can be faster brought into a trial to treat COVID-19 patients.

6.
Int J Mol Sci ; 22(5)2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1129733

ABSTRACT

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic ß-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Metformin/pharmacology , Autophagy/drug effects , COVID-19/complications , COVID-19/mortality , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/mortality , Gastrointestinal Microbiome/drug effects , Humans , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Intracellular Signaling Peptides and Proteins/drug effects , Intracellular Signaling Peptides and Proteins/metabolism
7.
Eur J Public Health ; 31(3): 619-624, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1123256

ABSTRACT

BACKGROUND: In responding to Covid-19, governments have tried to balance protecting health while minimizing gross domestic product (GDP) losses. We compare health-related net benefit (HRNB) and GDP losses associated with government responses of the UK, Ireland, Germany, Spain and Sweden from UK healthcare payer perspective. METHODS: We compared observed cases, hospitalizations and deaths under 'mitigation' to modelled events under 'no mitigation' to 20 July 2020. We thus calculated healthcare costs, quality adjusted life years (QALYs), and HRNB at £20,000/QALY saved by each country. On per population (i.e. per capita) basis, we compared HRNB with forecast reductions in 2020 GDP growth (overall or compared with Sweden as minimal mitigation country) and qualitatively and quantitatively described government responses. RESULTS: The UK saved 3.17 (0.32-3.65) million QALYs, £33 (8-38) billion healthcare costs and £1416 (220-1637) HRNB per capita at £20,000/QALY. Per capita, this is comparable to £1455 GDP loss using Sweden as comparator and offsets 46.1 (7.1-53.2)% of total £3075 GDP loss. Germany, Spain, and Sweden had greater HRNB per capita. These also offset a greater percentage of total GDP losses per capita. Ireland fared worst on both measures. Countries with more mask wearing, testing, and population susceptibility had better outcomes. Highest stringency responses did not appear to have best outcomes. CONCLUSIONS: Our exploratory analysis indicates the benefit of government Covid-19 responses may outweigh their economic costs. The extent that HRNB offset economic losses appears to relate to population characteristics, testing levels, and mask wearing, rather than response stringency.


Subject(s)
COVID-19 , Cost-Benefit Analysis , Europe , Germany , Health Care Costs , Humans , Ireland , SARS-CoV-2 , Spain , Sweden , United Kingdom
8.
Cancers (Basel) ; 13(4)2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1090373

ABSTRACT

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml-1 causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold). Importantly, the BLM-caused effects on cell growth and DNA integrity are substantially suppressed by polyP. In parallel, the enlargement of the nuclei/chromatin in BLM-treated cells (diameter, 20-25 µm) is normalized to ~12 µm after co-incubation of the cells with BLM and polyP. A sequential application of the drugs (BLM for 3 days, followed by an exposure to polyP) does not cause this normalization. During co-incubation of BLM with polyP the gene for the BLM hydrolase is upregulated. It is concluded that by upregulating this enzyme polyP prevents the toxic side effects of BLM. These data might also contribute to an application of BLM in COVID-19 patients, since polyP inhibits binding of SARS-CoV-2 to cellular ACE2.

9.
EPMA J ; 11(2): 289-309, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1086691

ABSTRACT

RELEVANCE: Ivermectin, as an old anti-parasite drug, can suppress almost completely the growth of various human cancers, including ovarian cancer (OC). However, its anticancer mechanism remained to be further studied at the molecular levels. Ivermectin-related molecule-panel changes will serve a useful tool for its personalized drug therapy and prognostic assessment in OCs. PURPOSE: To explore the functional significance of ivermectin-mediated lncRNA-EIF4A3-mRNA axes in OCs and ivermectin-related molecule-panel for its personalized drug therapy monitoring. METHODS: Based on our previous study, a total of 16 lncRNA expression patterns were analyzed using qRT-PCR before and after ivermectin-treated different OC cell lines (TOV-21G and A2780). Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics was used to analyze the protein expressions of EIF4A3 and EIF4A3-binding mRNAs in ovarian cancer cells treated with and without ivermectin. A total of 411 OC patients from the Cancer Genome Atlas (TCGA) database with the selected lncRNA expressions and the corresponding clinical data were included. Lasso regression was constructed to examine the relationship between lncRNA signature and OC survival risk. The overall survival analysis between high-risk and low-risk groups used the Kaplan-Meier method. Heatmap showed the correlation between risk groups and clinical characteristics. The univariate and multivariate models were established with Cox regression. RESULTS: SILAC-based quantitative proteomics found the protein expression levels of EIF4A3 and 116 EIF4A3-binding mRNAs were inhibited by ivermectin in OC cells. Among the analyzed 16 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3), only 7 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, and LINC00565) were obtained for further lasso regression when combined with the results of drug testing and overall survival analysis. Lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565). The high-risk and low-risk groups based on the prognostic model were significantly related to overall survival and clinicopathologic characteristics (survival status, lymphatic invasion, cancer status, and clinical stage) in OC patients and remained independent risk factors according to multivariate COX analysis (p < 0.05). CONCLUSION: Those findings provided the potential targeted lncRNA-EIF4A3-mRNA pathways of ivermectin in OC, and constructed the effective prognostic model, which benefits discovery of novel mechanism of ivermectin to suppress ovarian cancer cells, and the ivermectin-related molecule-panel changes benefit for its personalized drug therapy and prognostic assessment towards its predictive, preventive, and personalized medicine (PPPM) in OCs.

10.
Molecules ; 26(4)2021 Feb 13.
Article in English | MEDLINE | ID: covidwho-1085052

ABSTRACT

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Drug Repositioning , Nucleosides , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/drug therapy , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/metabolism , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/metabolism
11.
Oncol Lett ; 21(3): 233, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1076705

ABSTRACT

Liver cancer ranks as the second leading cause of cancer-associated mortality worldwide. To date, neither current ablation therapy nor chemotherapy are considered ideal in improving the outcome of liver cancer. Therefore, more effective therapies for treating this devastating disease are urgently required. Interventional therapy has been used for numerous years in the treatment of different types of cancer, and is characterized by the direct delivery of anticancer drugs into the tumor. It has been reported that antimalarial chloroquine diphosphate (CQ) exerts effective anticancer activity against several types of cancer. However, its effect on liver cancer remains unclear. Therefore, in the present study, 2D monolayer cell culture and 3D spheroid in vitro models, and a rat model, were utilized to investigate the effect of CQ on liver cancer. CQ demonstrated an effective anticancer effect on HepG2 cells and 3D liver spheroids. Furthermore, the drug significantly inhibited cell growth and viability in the 2D and 3D in vitro models. The CQ-based intervention treatment effectively attenuated tumor size and weight, increased food intake and consumption of drinking water, and improved body weight and survival rate of rats in the in vivo model. In addition, treatment with CQ potently increased the expression levels of the apoptosis-related genes. Taken together, the findings of the present study may provide a novel insight into the development of safe and effective treatments for liver cancer.

12.
Int J Mol Sci ; 22(3)2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1055069

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Viral Matrix Proteins/metabolism , Animals , Betacoronavirus/genetics , Betacoronavirus/immunology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Genome, Viral , Host-Pathogen Interactions , Humans , Immune Evasion , Protein Interaction Maps , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Viral Matrix Proteins/genetics , Viral Matrix Proteins/immunology , Virus Internalization , Virus Replication
13.
Drug Deliv ; 27(1): 1741-1749, 2020 Nov 26.
Article in English | MEDLINE | ID: covidwho-1045942

ABSTRACT

A novel ß-cyclodextrin pendant polymer (ε-PL-CD), composed of poly(ε-lysine) (ε-PL) main chain and glycine-ß-cyclodextrin (Gly-CD) side chains, was prepared by a simple two-step procedure. The ε-PL-CD was investigated as a drug carrier of hydrophobic drug scutellarin (SCU). The characterization and complexation mode of the SCU:ε-PL-CD were researched in both solution and solid state by means of photoluminescence spectroscopy, 1H and 2D NMR, X-Ray powder diffraction (XRPD), thermal gravimetric analysis, Particle size and Zeta potential. The solubility test indicated that the solubilizing ability of SCU:ε-PL-CD was significantly improved compared with SCU:ß-CD and free SCU. Besides, in vitro cell experiment, it was found that SCU:ε-PL-CD has a strong inhibitory effect on the growth and invasion of tumor cells. The present study provides useful information for ε-PL-CD as a drug carrier material.


Subject(s)
Apigenin/administration & dosage , Cellulose/chemistry , Cyclodextrins/chemistry , Drug Carriers/chemistry , Glucuronates/administration & dosage , Apigenin/chemistry , Apigenin/pharmacology , Crystallography, X-Ray , Drug Delivery Systems , Glucuronates/chemistry , Glucuronates/pharmacology , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Nanoparticles , Particle Size , Polylysine/chemistry , Solubility
14.
Expert Rev Mol Diagn ; 21(1): 119-129, 2021 01.
Article in English | MEDLINE | ID: covidwho-1003446

ABSTRACT

Introduction: With the ongoing SARS-CoV-2 pandemic, different articles have been published highlighting the superiority of droplet digital PCR (ddPCR) over the gold-standard reverse transcription PCR (RT-PCR) in SARS-CoV-2 detection. However, few studies have been reported on developing multiplex ddPCR assays for SARS-CoV-2 detection and their performance. This study shows steps on how to develop different ddPCR SAR-CoV-2 assays including higher order multiplex assays for SARS-CoV-2 detection and antiviral screening.Methods: Using multiple primer/probe sets, we developed, optimized, and analyzed the performance of simplex (1 target), duplex (2 targets), triplex probe mix (3 targets), and quadruplex (4 targets) SARS-CoV-2 ddPCR assays based on a two-color ddPCR detection system.Results: Results showed that the quadruplex assay had similar limits of detection and accuracy to the lower multiplex assays. Analyzing 94 clinical samples demonstrated that the ddPCR triplex probe mix assay had better sensitivity than the RT-qPCR assay. Additionally, the ddPCR multiplex assay showed that remdesivir could inhibit the growth of SARS-CoV-2 in vitro while another testing drug could not.Conclusion: Our research shows that developing multiplex ddPCR assays is possible by combing probe mix and amplitude-based multiplexing, which will help in developing multiplexed ddPCR assays for different SARS-CoV-2 applications.


Subject(s)
COVID-19 Nucleic Acid Testing , COVID-19/diagnosis , Multiplex Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification , Antiviral Agents/pharmacology , DNA Primers/genetics , False Positive Reactions , Humans , Limit of Detection , Pandemics , RNA, Viral/isolation & purification , Real-Time Polymerase Chain Reaction/methods , Reproducibility of Results , Sensitivity and Specificity , Temperature , Viral Load/methods
15.
PLoS One ; 15(12): e0244177, 2020.
Article in English | MEDLINE | ID: covidwho-999834

ABSTRACT

This paper reports the results of a Bayesian analysis on large-scale empirical data to assess the effectiveness of eleven types of COVID-control policies that have been implemented at various levels of intensity in 40 countries and U.S. states since the onset of the pandemic. The analysis estimates the marginal impact of each type and level of policy as implemented in concert with other policies. The purpose is to provide policymakers and the general public with an estimate of the relative effectiveness of various COVID-control strategies. We find that a set of widely implemented core policies reduces the spread of virus but not by enough to contain the pandemic except in a few highly compliant jurisdictions. The core policies include the cancellation of public events, restriction of gatherings to fewer than 100 people, recommendation to stay at home, recommended restrictions on internal movement, implementation of a partial international travel ban, and coordination of information campaigns. For the median jurisdiction, these policies reduce growth rate in new infections from an estimated 270% per week to approximately 49% per week, but this impact is insufficient to prevent eventual transmission throughout the population because containment occurs only when a jurisdiction reduces growth in COVID infection to below zero. Most jurisdictions must also implement additional policies, each of which has the potential to reduce weekly COVID growth rate by 10 percentage points or more. The slate of these additional high-impact policies includes targeted or full workplace closings for all but essential workers, stay-at-home requirements, and targeted school closures.


Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , Infection Control/legislation & jurisprudence , Bayes Theorem , Europe/epidemiology , Health Policy , Humans , Mexico/epidemiology , Pandemics/prevention & control , South America/epidemiology , United States/epidemiology
16.
J Antibiot (Tokyo) ; 74(4): 260-265, 2021 04.
Article in English | MEDLINE | ID: covidwho-997818

ABSTRACT

The emergence of SARS-CoV-2, the causative agent of COVID-19, highlights the increasing need for new and effective antiviral and antimicrobial agents. The FDA has recently banned several active ingredients used in hand sanitizers, including triclosan and benzethonium chloride. Nitric oxide (NO) is involved in the innate immune response and is a major component of macrophage-mediated attack on foreign viruses and bacteria. The specific aim of this study was to assess the antibacterial effects of 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NONOate) against Escherichia coli (E. coli). A bacterial growth assay was compared to an adenosine triphosphate (ATP) activity assay at various time points to assess effects of DEA-NONOate on E. coli growth. A UV/Vis spectrophotometer was used to determine concentration of E. coli by measuring optical density (OD) at 630 nm. A luminescent assay was used to measure ATP activity correlating to viable cells. DEA-NONOate at a concentration of 65 mM was able to inhibit the growth of E. coli with the same efficacy as 1 µg ml-1 concentration of ciprofloxacin. Both the OD and ATP assays demonstrated a 99.9% reduction in E. coli. Both a 1 µg ml-1 concentration of ciprofloxacin and a 65 mM concentration of DEA-NONOate achieved 99.9% inhibition of E. coli, verified using both optical density measurement of bacterial cultures in 96 well plates and a luminescent ATP activity assay. The bactericidal effects of DEA-NONOate against E. coli is proof-of-concept to pursue evaluation of nitric oxide-based formulations as antimicrobial and antiviral agents as hand sanitizers.


Subject(s)
Escherichia coli/drug effects , Hydrazines/pharmacology , Adenosine Triphosphate/metabolism , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Hand Sanitizers/chemistry , Humans , Luminescent Measurements , Pilot Projects , Spectrophotometry, Ultraviolet
17.
J Med Virol ; 93(4): 1843-1846, 2021 04.
Article in English | MEDLINE | ID: covidwho-971501

ABSTRACT

In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We discuss the current literature on mTOR in SARS-CoV-2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019.


Subject(s)
COVID-19/drug therapy , RNA Viruses/physiology , SARS-CoV-2/physiology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Middle East Respiratory Syndrome Coronavirus/physiology , RNA Viruses/genetics , RNA Viruses/pathogenicity , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Virus Replication
18.
Steroids ; 165: 108759, 2021 01.
Article in English | MEDLINE | ID: covidwho-917434

ABSTRACT

Gastric ulcers are a very common public health problem affecting up to 10% worldwide. Russelioside B is a steroidal glycoside isolated from several Caralluma species. No study tested the ulcer healing potential of the compound. The current study aimed to assess the protective effect of russelioside B against ethanol-induced gastric mucosal injury in rats. Ulcer was induced on rats by a single intragastric dose of absolute ethanol (5 mL/kg). Rats were randomly assorted into four groups (n = 8) and given treatments (Antodine, 20 mg/kg or russelioside B, 50 mg/kg) by oral gavage 1 h before ulcer induction. Pretreatment with russelioside B (50 mg/kg) attenuated the gastric mucosal injury as proved by a decrease of ulcer index, and histological scores. It suppressed the gastric inflammation by a significant lowering the tumor necrosis factor-α and interleukin-6 levels with myeloperoxidase activity (which are also aggravating factors in the case of Covid-19 infection). In addition, administration of russelioside B halted the gastric oxidative stress via inhibition of lipid peroxides by maintaining reduced glutathione and by decreasing malondialdehyde. It was able also to restore the sharp drop in the levels of heat shock protein-70, vascular endothelial growth factor and prostaglandin E2 induced by ethanol. Additionally, it showed carbonic anhydrase inhibition activity. The gastroprotective action of russelioside B was umpired through multi mechanistic actions; suppression of gastric oxidative stress, inflammation, anti-apoptotic activities and enhanced gastric mucosal protection by up-regulation of endothelial growth factor, normalization of heat shock protein-70 and prostaglandin E2. These actions were comparable in part to some classical antiulcer drugs such as Antodine.


Subject(s)
Dinoprostone/genetics , Glycosides/pharmacology , HSP70 Heat-Shock Proteins/genetics , Pregnanes/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Ulcer Agents/pharmacology , Apocynaceae/chemistry , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Disease Models, Animal , Ethanol/toxicity , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gene Expression Regulation/drug effects , Glycosides/chemistry , Humans , Interleukin-6/genetics , Oxidative Stress/drug effects , Peroxidase/genetics , Pregnanes/chemistry , Rats , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Stomach Ulcer/chemically induced , Stomach Ulcer/genetics , Stomach Ulcer/pathology , Tumor Necrosis Factor-alpha/genetics
19.
Pharmaceutics ; 12(10)2020 Sep 25.
Article in English | MEDLINE | ID: covidwho-906532

ABSTRACT

(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (CYP3A4, ABCB1) and aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1A2). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine's interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine.

20.
Pharm Res ; 37(11): 212, 2020 Oct 06.
Article in English | MEDLINE | ID: covidwho-834023

ABSTRACT

PURPOSE: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette-Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. METHODS: We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. RESULTS: Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. CONCLUSIONS: Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2.


Subject(s)
BCG Vaccine/administration & dosage , Biomimetic Materials/administration & dosage , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Drug Repositioning/methods , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Small Molecule Libraries/administration & dosage , Viral Vaccines/administration & dosage , BCG Vaccine/immunology , Betacoronavirus/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Humans , Immunity, Innate , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , SARS-CoV-2 , Systems Biology/methods , Viral Vaccines/immunology , Workflow
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