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1.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: mdl-35177474

ABSTRACT

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antiviral Agents/therapeutic use , Cidofovir/therapeutic use , Etanercept/administration & dosage , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/pharmacology , Cell Line , Chlorocebus aethiops , Cidofovir/pharmacology , Cytokines/metabolism , Drug Evaluation, Preclinical , Drug Therapy, Combination , Ectromelia virus/drug effects , Female , Lung/drug effects , Lung/metabolism , Mice, Inbred C57BL , NF-kappa B/metabolism , Pneumonia, Viral/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Viral Load/drug effects
2.
Article in English | MEDLINE | ID: mdl-33031994

ABSTRACT

As the infected cases of COVID-19 reach more than 20 million with more than 778,000 deaths globally, an increase in psychiatric disorders including anxiety and depression has been reported. Scientists globally have been searching for novel therapies and vaccines to fight against COVID-19. Improving innate immunity has been suggested to block progression of COVID-19 at early stages, while omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to have immunomodulation effects. Moreover, n-3 PUFAs have also been shown to improve mood disorders, thus, future research is warranted to test if n-3 PUFAs may have the potential to improve our immunity to counteract both physical and mental impact of COVID-19.


Subject(s)
Anxiety/prevention & control , Coronavirus Infections/prevention & control , Depression/prevention & control , Dietary Supplements , Fatty Acids, Omega-3/administration & dosage , Immunologic Factors/administration & dosage , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Anxiety/immunology , Anxiety/metabolism , Anxiety/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/biosynthesis , Cytokines/immunology , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/virology , Depression/immunology , Depression/metabolism , Depression/virology , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Fatty Acids, Omega-3/immunology , Fatty Acids, Omega-3/metabolism , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/drug effects , Immunologic Factors/immunology , Immunologic Factors/metabolism , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Macrophages/drug effects , Macrophages/immunology , Macrophages/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2
3.
Article in English | MEDLINE | ID: mdl-33038834

ABSTRACT

COVID-19 symptoms vary from silence to rapid death, the latter mediated by both a cytokine storm and a thrombotic storm. SARS-CoV (2003) induces Cox-2, catalyzing the synthesis, from highly unsaturated fatty acids (HUFA), of eicosanoids and docosanoids that mediate both inflammation and thrombosis. HUFA balance between arachidonic acid (AA) and other HUFA is a likely determinant of net signaling to induce a healthy or runaway physiological response. AA levels are determined by a non-protein coding regulatory polymorphisms that mostly affect the expression of FADS1, located in the FADS gene cluster on chromosome 11. Major and minor haplotypes in Europeans, and a specific functional insertion-deletion (Indel), rs66698963, consistently show major differences in circulating AA (>50%) and in the balance between AA and other HUFA (47-84%) in free living humans; the indel is evolutionarily selective, probably based on diet. The pattern of fatty acid responses is fully consistent with specific genetic modulation of desaturation at the FADS1-mediated 20:3→20:4 step. Well established principles of net tissue HUFA levels indicate that the high linoleic acid and low alpha-linoleic acid in populations drive the net balance of HUFA for any individual. We predict that fast desaturators (insertion allele at rs66698963; major haplotype in Europeans) are predisposed to higher risk and pathological responses to SARS-CoV-2 could be reduced with high dose omega-3 HUFA.


Subject(s)
Coronavirus Infections/complications , Fatty Acids, Unsaturated/biosynthesis , Inflammation/etiology , Lipid Metabolism/genetics , Pneumonia, Viral/complications , Thrombosis/etiology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Delta-5 Fatty Acid Desaturase , Fatty Acids, Unsaturated/genetics , Genetic Predisposition to Disease , Haplotypes , Humans , Individuality , Inflammation/epidemiology , Inflammation/genetics , Inflammation/metabolism , Lipogenesis/genetics , Metabolic Networks and Pathways/genetics , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Polymorphism, Single Nucleotide , Risk Factors , SARS-CoV-2 , Thrombosis/epidemiology , Thrombosis/genetics , Thrombosis/metabolism
4.
Phytomedicine ; 79: 153350, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33002827

ABSTRACT

BACKGROUND: Vascular endothelial activation is pivotal for the pathological development of various infectious and inflammatory diseases. Therapeutic interventions to prevent endothelial activation are of great clinical significance to achieve anti-inflammatory strategy. Previous studies indicate that the total flavonoids from the endemic herbal medicine Nervilia fordii (Hance) Schltr exerts potent anti-inflammatory effect and protective effect against endotoxin lipopolysaccharide (LPS)-induced acute lung injury, and shows clinical benefit in severe acute respiratory syndromes (SARS). However, the exact effective component of Nervilia fordii and its potential mechanism remain unknown. PURPOSE: The aim of this study was to investigate the effect and mechanism of rhamnocitrin (RH), a flavonoid extracted from Nervilia fordii, on LPS-induced endothelial activation. METHODS: The in vitro endothelial cell activation model was induced by LPS in human umbilical vein endothelial cells (HUVECs). Cell viability was measured to determine the cytotoxicity of RH. RT-PCR, Western blot, fluorescent probe and immunofluorescence were conducted to evaluate the effect and mechanism of RH against endothelial activation. RESULTS: RH was extracted and isolated from Nervilia fordii. RH at the concentration from 10-7 M-10-5 M inhibited the expressions of interlukin-6 (IL-6) and -8 (IL-8), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) in response to LPS challenge. Mechanistically, RH repressed calcium store-operated Ca2+ entry (SOCE) induced by LPS, which is due to downregulation of stromal interaction molecule-1 (STIM-1) following upregulating microRNA-185 (miR-185). Ultimately, RH abrogated LPS-induced activation of SOCE-mediated calcineurin/NFATc3 (nuclear factor of activated T cells, cytoplasmic 3) signaling pathway. CONCLUSION: The present study identifies RH as a potent inhibitor of endothelial activation. Since vascular endothelial activation is a pivotal cause of excessive cytokine production, leading to cytokine storm and severe pathology in infectious diseases such as SARS and the ongoing COVID-19 pneumonia disease, RH might suggest promising therapeutic potential in the management of cytokine storm in these diseases.


Subject(s)
Endothelium, Vascular/drug effects , Intracellular Calcium-Sensing Proteins/metabolism , Kaempferols/pharmacology , Membrane Proteins/metabolism , NFATC Transcription Factors/metabolism , Neoplasm Proteins/metabolism , Orchidaceae/chemistry , Stromal Interaction Molecule 1/metabolism , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Endothelium, Vascular/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Kaempferols/isolation & purification , Lipopolysaccharides/pharmacology , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Vascular Cell Adhesion Molecule-1/metabolism
5.
Molecules ; 25(19)2020 Sep 25.
Article in English | MEDLINE | ID: mdl-32992875

ABSTRACT

Fighting infectious diseases, particularly viral infections, is a demanding task for human health. Targeting the pathogens or targeting the host are different strategies, but with an identical purpose, i.e., to curb the pathogen's spreading and cure the illness. It appears that targeting a host to increase tolerance against pathogens can be of substantial advantage and is a strategy used in evolution. Practically, it has a broader protective spectrum than that of only targeting the specific pathogens, which differ in terms of susceptibility. Methods for host targeting applied in one pandemic can even be effective for upcoming pandemics with different pathogens. This is even more urgent if we consider the possible concomitance of two respiratory diseases with potential multi-organ afflictions such as Coronavirus disease 2019 (COVID-19) and seasonal flu. Melatonin is a molecule that can enhance the host's tolerance against pathogen invasions. Due to its antioxidant, anti-inflammatory, and immunoregulatory activities, melatonin has the capacity to reduce the severity and mortality of deadly virus infections including COVID-19. Melatonin is synthesized and functions in mitochondria, which play a critical role in viral infections. Not surprisingly, melatonin synthesis can become a target of viral strategies that manipulate the mitochondrial status. For example, a viral infection can switch energy metabolism from respiration to widely anaerobic glycolysis even if plenty of oxygen is available (the Warburg effect) when the host cell cannot generate acetyl-coenzyme A, a metabolite required for melatonin biosynthesis. Under some conditions, including aging, gender, predisposed health conditions, already compromised mitochondria, when exposed to further viral challenges, lose their capacity for producing sufficient amounts of melatonin. This leads to a reduced support of mitochondrial functions and makes these individuals more vulnerable to infectious diseases. Thus, the maintenance of mitochondrial function by melatonin supplementation can be expected to generate beneficial effects on the outcome of viral infectious diseases, particularly COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Mitochondria/drug effects , Pneumonia, Viral/drug therapy , Virus Diseases/drug therapy , Virus Diseases/immunology , COVID-19 , Coronavirus Infections/metabolism , Drug Delivery Systems , Humans , Melatonin/metabolism , Mitochondria/metabolism , Pandemics , Pneumonia, Viral/metabolism , Virus Diseases/metabolism
6.
Mol Biol Rep ; 47(10): 8229-8233, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32920757

ABSTRACT

COVID-19 caused by the SARS-CoV-2 outbreak quickly has turned into a pandemic. However, no specific antiviral agent is yet available. In this communication, we aimed to evaluate the significance of CD147 protein and the potential protective effect of melatonin that is mediated by this protein in COVID-19. CD147 is a glycoprotein that is responsible for the cytokine storm in the lungs through the mediation of viral invasion. Melatonin use previously was shown to reduce cardiac damage by blocking the CD147 activity. Hence, melatonin, a safe drug, may prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients. In conclusion, the use of melatonin, which is reduced in the elderly and immune-compromised patients, should be considered as an adjuvant through its CD147 suppressor and immunomodulatory effect.


Subject(s)
Adjuvants, Pharmaceutic/therapeutic use , Antiviral Agents/therapeutic use , Basigin/metabolism , Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Pneumonia, Viral/drug therapy , Animals , Antioxidants/metabolism , Antiviral Agents/pharmacology , Basigin/antagonists & inhibitors , COVID-19 , Coronavirus Infections/metabolism , Humans , Immune System/drug effects , Melatonin/pharmacology , Pandemics , Pneumonia, Viral/metabolism , Signal Transduction/drug effects
7.
Pharmacol Res Perspect ; 8(5): e00653, 2020 10.
Article in English | MEDLINE | ID: mdl-32930523

ABSTRACT

More than ten million patients worldwide have been diagnosed with coronavirus disease 19 (COVID-19) to date (WHO situation report, 1st July 2020). There is no vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing compounds is a key route of action. In this hypothesis paper, we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilized in traditional Chinese medicine, may have potential in the treatment of COVID-19 and should be further investigated. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two-pore channel 2 (TPC2). While tetrandrine's particular history of use provides a very limited pharmacological dataset, there is a suggestion from the available evidence that it could be effective at doses used in clinical practice. We suggest that further research to investigate this possibility should be conducted.


Subject(s)
Antiviral Agents/administration & dosage , Benzylisoquinolines/administration & dosage , Betacoronavirus/drug effects , Calcium Channel Blockers/administration & dosage , Calcium Channels/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Antiviral Agents/adverse effects , Benzylisoquinolines/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Calcium Channel Blockers/adverse effects , Calcium Channels/metabolism , Coronavirus Infections/diagnosis , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Drug Interactions , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , COVID-19 Drug Treatment
8.
Circ J ; 84(11): 2027-2031, 2020 10 23.
Article in English | MEDLINE | ID: mdl-32981925

ABSTRACT

BACKGROUND: SARS-CoV-2 infection is associated with myocardial injury, but there is a paucity of experimental platforms for the condition.Methods and Results:Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected by SARS-CoV-2 for 3 days ceased beating and exhibited cytopathogenic changes with reduced viability. Active viral replication was evidenced by an increase in supernatant SARS-CoV-2 and the presence of SARS-CoV-2 nucleocaspid protein within hiPSC-CMs. Expressions of BNP, CXCL1, CXCL2, IL-6, IL-8 and TNF-α were upregulated, while ACE2 was downregulated. CONCLUSIONS: Our hiPSC-CM-based in-vitro SARS-CoV-2 myocarditis model recapitulated the cytopathogenic effects and cytokine/chemokine response. It could be exploited as a drug screening platform.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/complications , Induced Pluripotent Stem Cells/virology , Myocarditis/complications , Myocytes, Cardiac/virology , Pneumonia, Viral/complications , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , COVID-19 , Cell Survival , Cells, Cultured , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Coronavirus Nucleocapsid Proteins , Cytokines/metabolism , Cytopathogenic Effect, Viral , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/metabolism , Myocarditis/metabolism , Myocarditis/virology , Myocytes, Cardiac/metabolism , Nucleocapsid Proteins/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Phosphoproteins , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Virus Replication
9.
J Pharm Biomed Anal ; 191: 113604, 2020 Nov 30.
Article in English | MEDLINE | ID: mdl-32957066

ABSTRACT

Stress and stress-related diseases are leading to drastic consequences in private and professional life. Therefore, the need for stress prevention strategies is of personal and economic interest. Especially during the recent period related to covid-19 outbreak and lock-down, an ongoing discussion of increasing stress etiology is reported. Biomarker analysis may help to assist diagnosis and classification of stress-related diseases and therefore support therapeutical decisions. Due to its non-invasive sampling, the analysis of saliva has become highly attractive compared to the detection methods in other specimen. This review article summarizes the status of research, innovative approaches, and trends. Scientific literature published since 2011 was excerpted with concentration on the detection of up to seven promising marker substances. Most often reported cortisol represents the currently best evaluated stress marker, while norepinephrine (noradrenaline) or its metabolite 3-methoxy-4-hydroxyphenylglycol is also a quite commonly considered stress marker. Other complementary stress marker candidates are testosterone, dehydroepiandrosterone (DHEA) and its sulfonated analogue DHEA-S, alpha-amylase, secretory immunoglobulin A, and chromogranin A. Several working groups are researching in the field of stress marker detection to develop reliable, fast, and affordable methods. Analytical methods reported mainly focused on immunological and electrochemical as well as chromatographic methods hyphenated to mass spectrometric detection to yield the required detection limits.


Subject(s)
Biomarkers/analysis , Coronavirus Infections/metabolism , Pandemics , Pneumonia, Viral/metabolism , Saliva/chemistry , Stress, Psychological/diagnosis , Stress, Psychological/metabolism , COVID-19 , Humans , Specimen Handling
10.
Phytomedicine ; 78: 153296, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32890913

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extensively and rapidly spread in the world, causing an outbreak of acute infectious pneumonia. However, no specific antiviral drugs or vaccines can be used. Phillyrin (KD-1), a representative ingredient of Forsythia suspensa, possesses anti-inflammatory, anti-oxidant, and antiviral activities. However, little is known about the antiviral abilities and mechanism of KD-1 against SARS-CoV-2 and human coronavirus 229E (HCoV-229E). PURPOSE: The study was designed to investigate the antiviral and anti-inflammatory activities of KD-1 against the novel SARS-CoV-2 and HCoV-229E and its potential effect in regulating host immune response in vitro. METHODS: The antiviral activities of KD-1 against SARS-CoV-2 and HCoV-229E were assessed in Vero E6 cells using cytopathic effect and plaque-reduction assay. Proinflammatory cytokine expression levels upon infection with SARS-CoV-2 and HCoV-229E infection in Huh-7 cells were measured by real-time quantitative PCR assays. Western blot assay was used to determine the protein expression of nuclear factor kappa B (NF-κB) p65, p-NF-κB p65, IκBα, and p-IκBα in Huh-7 cells, which are the key targets of the NF-κB pathway. RESULTS: KD-1 could significantly inhibit SARS-CoV-2 and HCoV-229E replication in vitro. KD-1 could also markedly reduce the production of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1, and IP-10) at the mRNA levels. Moreover, KD-1 could significantly reduce the protein expression of p-NF-κB p65, NF-κB p65, and p-IκBα, while increasing the expression of IκBα in Huh-7 cells. CONCLUSIONS: KD-1 could significantly inhibit virus proliferation in vitro, the up-regulated expression of proinflammatory cytokines induced by SARS-CoV-2 and HCoV-229E by regulating the activity of the NF-кB signaling pathway. Our findings indicated that KD-1 protected against virus attack and can thus be used as a novel strategy for controlling the coronavirus disease 2019.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus 229E, Human/drug effects , Coronavirus Infections , Glucosides/pharmacology , NF-kappa B/metabolism , Pandemics , Pneumonia, Viral , Animals , COVID-19 , Chlorocebus aethiops , Coronavirus/drug effects , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/metabolism , Forsythia/chemistry , Humans , Phytotherapy , Plant Extracts/pharmacology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
11.
Biologicals ; 68: 122-124, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32891497

ABSTRACT

With the pandemic emergence of SARS-CoV-2, the exposure of cell substrates used for manufacturing of medicines has become a possibility. Cell lines used in biomanufacturing were thus evaluated for their SARS-CoV-2 susceptibility, and the detection of SARS-CoV-2 in culture supernatants by routine adventitious virus testing of fermenter harvest tested.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Pneumonia, Viral/metabolism , Virus Replication , Animals , Antiviral Agents/pharmacology , Biological Factors/pharmacology , CHO Cells , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Cricetulus , Drug Evaluation, Preclinical , HEK293 Cells , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Vero Cells
12.
Int J Infect Dis ; 100: 390-393, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32795605

ABSTRACT

The relationship between immunity and nutrition is well known and its role in coronavirus disease 2019 (COVID-19) is also being paid great attention. However, the nutritional status of COVID-19 patients is unknown. Vitamin B1, B6, B12, vitamin D (25-hydroxyvitamin D), folate, selenium, and zinc levels were measured in 50 hospitalized patients with COVID-19. Overall, 76% of the patients were vitamin D deficient and 42% were selenium deficient. No significant increase in the incidence of deficiency was found for vitamins B1, B6, and B12, folate, and zinc in patients with COVID-19. The COVID-19 group showed significantly lower vitamin D values than the healthy control group (150 people, matched by age/sex). Severe vitamin D deficiency (based on a cut-off of ≤10 ng/dl) was found in 24.0% of the patients in the COVID-19 group and 7.3% in the control group. Among 12 patients with respiratory distress, 11 (91.7%) were deficient in at least one nutrient. However, patients without respiratory distress showed a deficiency in 30/38 cases (78.9%; p = 0.425). These results suggest that a deficiency of vitamin D or selenium may decrease the immune defenses against COVID-19 and cause progression to severe disease. However, more precise and large-scale studies are needed.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Nutritional Status , Pneumonia, Viral/metabolism , Adult , Aged , COVID-19 , Coronavirus Infections/immunology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , Selenium/deficiency , Vitamin D Deficiency/epidemiology , Vitamins/blood , Zinc/blood
13.
Biochem Biophys Res Commun ; 530(1): 4-9, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32828312

ABSTRACT

COVID-19 has become one of the worst epidemic in the world, currently already more than four million people have been infected, which probably co-exist with human beings, and has a significant impact on the global economy and political order. In the process of fighting against the epidemic in China, the clinical value of a variety of herbal medicines has been recognized and written into the clinical application guide. However, their effective molecular mechanism and potential targets are still not clear. Pathology and pharmacology research will gradually attract attention in the post-epidemic outbreak term. Here, we constructed a COVID-19 protein microarray of potential therapy targets, which contains the main drug targets to the SARS-CoV-2 virus and the anti-virus, anti-inflammatory cellar targets of the host. Series of quality controls test has been carried out, which showed that it could be applied for drug target screening of bio-active natural products. The establishment of this microarray will provide a useful tool for the study of the molecular pharmacology of natural products.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Pneumonia, Viral/drug therapy , Proteins/metabolism , Viral Proteins/metabolism , Betacoronavirus/metabolism , Biological Products/pharmacology , COVID-19 , Chlorogenic Acid/pharmacology , Coronavirus Infections/metabolism , Diterpenes/pharmacology , Drug Discovery , Glucosides/pharmacology , HEK293 Cells , Humans , Molecular Docking Simulation , Molecular Targeted Therapy , Pandemics , Pneumonia, Viral/metabolism , Protein Array Analysis , SARS-CoV-2 , Stilbenes/pharmacology
14.
Medicina (Kaunas) ; 56(8)2020 Jul 31.
Article in English | MEDLINE | ID: mdl-32752010

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the corona virus disease-19 which is accompanied by severe pneumonia, pulmonary alveolar collapses and which stops oxygen exchange. Viral transmissibility and pathogenesis depend on recognition by a receptor in the host, protease cleavage of the host membrane and fusion. SARS-CoV-2 binds to the angiotensin converting enzyme 2 receptor. Here, we discuss the general characteristics of the virus, its mechanism of action and the way in which the mechanism correlates with the comorbidities that increase the death rate. We also discuss the currently proposed therapeutic measures and propose the use of antioxidant drugs to help patients infected with the SARS-CoV-2. Oxidizing agents come from phagocytic leukocytes such as neutrophils, monocytes, macrophages and eosinophils that invade tissue. Free radicals promote cytotoxicity thus injuring cells. They also trigger the mechanism of inflammation by mediating the activation of NFkB and inducing the transcription of cytokine production genes. Release of cytokines enhances the inflammatory response. Oxidative stress is elevated during critical illnesses and contributes to organ failure. In corona virus disease-19 there is an intense inflammatory response known as a cytokine storm that could be mediated by oxidative stress. Although antioxidant therapy has not been tested in corona virus disease-19, the consequences of antioxidant therapy in sepsis, acute respiratory distress syndrome and acute lung injury are known. It improves oxygenation rates, glutathione levels and strengthens the immune response. It reduces mechanical ventilation time, the length of stay in the intensive care unit, multiple organ dysfunctions and the length of stay in the hospital and mortality rates in acute lung injury/acute respiratory distress syndrome and could thus help patients with corona virus disease-19.


Subject(s)
Antioxidants/pharmacology , Betacoronavirus/physiology , Coronavirus Infections , Pandemics , Pneumonia, Viral , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Oxidative Stress/drug effects , Oxidative Stress/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2 , COVID-19 Drug Treatment
15.
Eur Rev Med Pharmacol Sci ; 24(15): 8219-8225, 2020 08.
Article in English | MEDLINE | ID: mdl-32767353

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 , COVID-19 , Coronavirus Infections/metabolism , Drug Therapy, Combination , Humans , Italy , Leukocyte Count , Middle Aged , Oxygen/metabolism , Pandemics , Partial Pressure , Pneumonia, Viral/metabolism , Retrospective Studies , SARS-CoV-2 , COVID-19 Drug Treatment
16.
Virus Res ; 287: 198108, 2020 10 02.
Article in English | MEDLINE | ID: mdl-32768490

ABSTRACT

Viral infections are dangerous diseases for human health worldwide, which lead to significant morbidity and mortality each year. Because of their importance and the lack of effective therapeutic approaches, further attempts should be made to discover appropriate alternative or complementary treatments. Melatonin, a multifunctional neurohormone mainly synthesized and secreted by the pineal gland, plays some roles in the treatment of viral infections. Regarding a deadly outbreak of COVID-19 across the world, we decided to discuss melatonin functions against various viral infections including COVID-19. Therefore, in this review, we summarize current evidence on melatonin therapy for viral infections with focus on possible underlying mechanisms of melatonin actions.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Melatonin/pharmacology , Pneumonia, Viral/virology , Antioxidants , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Host-Pathogen Interactions , Humans , Melatonin/therapeutic use , Oxidative Stress/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , SARS-CoV-2 , Signal Transduction/drug effects , Vaccination , Viral Vaccines/administration & dosage , Viral Vaccines/immunology , Virus Diseases/drug therapy , Virus Diseases/metabolism , Virus Diseases/virology
17.
Commun Biol ; 3(1): 466, 2020 08 18.
Article in English | MEDLINE | ID: mdl-32811894

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 , COVID-19 , 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 , SARS-CoV-2 , Viral Proteins/antagonists & inhibitors , COVID-19 Drug Treatment
18.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Article in English | MEDLINE | ID: mdl-32814759

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 , COVID-19 , 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 , SARS-CoV-2 , Vero Cells , Viral Load/drug effects
19.
Cell ; 182(3): 685-712.e19, 2020 08 06.
Article in English | MEDLINE | ID: mdl-32645325

ABSTRACT

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Drug Evaluation, Preclinical/methods , Pneumonia, Viral/metabolism , Proteomics/methods , A549 Cells , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/pharmacology , COVID-19 , Caco-2 Cells , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Chlorocebus aethiops , Coronavirus Infections/virology , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphorylation , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism , Axl Receptor Tyrosine Kinase
20.
Med Hypotheses ; 143: 110051, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32650197

ABSTRACT

Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline - might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals - yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium - might also improve therapeutic outcomes in COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Dipyridamole/therapeutic use , Pandemics , Pentoxifylline/therapeutic use , Pneumonia, Viral/drug therapy , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Agonists/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Dietary Supplements , Fibrinolytic Agents/therapeutic use , Humans , Models, Biological , Pneumonia/etiology , Pneumonia/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , SARS-CoV-2 , Signal Transduction/drug effects , Thrombosis/etiology , Thrombosis/prevention & control , Translational Research, Biomedical , Virus Replication/drug effects , COVID-19 Drug Treatment
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