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2.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1758461

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
4.
PLoS Pathog ; 18(2): e1010343, 2022 02.
Article in English | MEDLINE | ID: covidwho-1690680

ABSTRACT

The continuous emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2) variants and the increasing number of breakthrough infection cases among vaccinated people support the urgent need for research and development of antiviral drugs. Viral entry is an intriguing target for antiviral drug development. We found that diltiazem, a blocker of the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2 α1c) and an FDA-approved drug, inhibits the binding and internalization of SARS-CoV-2, and decreases SARS-CoV-2 infection in cells and mouse lung. Cav1.2 α1c interacts with SARS-CoV-2 spike protein and ACE2, and affects the attachment and internalization of SARS-CoV-2. Our finding suggests that diltiazem has potential as a drug against SARS-CoV-2 infection and that Cav1.2 α1c is a promising target for antiviral drug development for COVID-19.


Subject(s)
COVID-19 , Diltiazem/pharmacology , Lung/drug effects , SARS-CoV-2/drug effects , A549 Cells , Animals , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Cells, Cultured , Chlorocebus aethiops , Diltiazem/therapeutic use , Disease Models, Animal , Female , HEK293 Cells , HeLa Cells , Humans , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , SARS-CoV-2/physiology , Vero Cells , Virus Attachment/drug effects , Virus Internalization/drug effects
7.
Life Sci ; 293: 120324, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1616648

ABSTRACT

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Renin-Angiotensin System/physiology , Serine Endopeptidases/metabolism , Adult , Age Factors , Aged , Alveolar Epithelial Cells/chemistry , Alveolar Epithelial Cells/drug effects , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Female , Humans , Lung/chemistry , Lung/drug effects , Lung/metabolism , Male , Middle Aged , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Retrospective Studies , Serine Endopeptidases/analysis , Smoking/metabolism , Smoking/pathology
8.
Bull Exp Biol Med ; 172(3): 364-367, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1616180

ABSTRACT

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.


Subject(s)
COVID-19/complications , Oxygen/administration & dosage , Respiratory Insufficiency/therapy , Respiratory Therapy/methods , Xenon/administration & dosage , Administration, Inhalation , Anesthetics, Inhalation/administration & dosage , COVID-19/etiology , COVID-19/rehabilitation , COVID-19/therapy , Drug Combinations , Humans , Lung/drug effects , Lung/physiopathology , Male , Middle Aged , Respiration/drug effects , Respiratory Insufficiency/etiology , Russia , SARS-CoV-2
9.
Int J Mol Sci ; 23(1)2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1580702

ABSTRACT

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients.


Subject(s)
Cardiotonic Agents/pharmacology , Methylhydrazines/pharmacology , Animals , COVID-19/complications , COVID-19/drug therapy , Cardiotonic Agents/therapeutic use , Cardiotoxicity/drug therapy , Disease Models, Animal , Endothelium/drug effects , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Ventricles/drug effects , Hydrogen Peroxide/metabolism , Lung/drug effects , Male , Methylhydrazines/therapeutic use , Mice, Inbred C57BL , Mitochondria/drug effects , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Reperfusion Injury/drug therapy , Stroke Volume/drug effects , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Right/drug therapy
10.
Viruses ; 14(1)2021 12 21.
Article in English | MEDLINE | ID: covidwho-1580416

ABSTRACT

Coronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.


Subject(s)
Adenine/analogs & derivatives , Adenosine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Pyrrolidines/therapeutic use , SARS-CoV-2/drug effects , Adenine/pharmacology , Adenine/therapeutic use , Adenosine/pharmacology , Adenosine/therapeutic use , Animals , Antiviral Agents/pharmacology , COVID-19/pathology , COVID-19/virology , Cell Line , Cricetinae , Disease Models, Animal , Humans , Lung/drug effects , Lung/pathology , Lung/virology , Mesocricetus , Pyrrolidines/pharmacology , Viral Load/drug effects
12.
Viruses ; 13(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572663

ABSTRACT

BACKGROUND: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. METHODS: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. RESULTS: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. CONCLUSIONS: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.


Subject(s)
Antiviral Agents/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Cell Line , Drug Synergism , Humans , Lung/drug effects , Lung/metabolism , Lung/virology , Metabolome/drug effects , Organoids , RNA, Viral/biosynthesis , RNA, Viral/drug effects , Signal Transduction/drug effects , Transcriptome/drug effects , Virus Replication/drug effects , Viruses/classification , Viruses/drug effects
13.
Int J Mol Sci ; 22(23)2021 Nov 27.
Article in English | MEDLINE | ID: covidwho-1560687

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Subject(s)
Acute Lung Injury/metabolism , Lung/drug effects , Pneumonia/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Female , Hydrochloric Acid/toxicity , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Prostaglandins F/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
14.
Front Immunol ; 12: 761250, 2021.
Article in English | MEDLINE | ID: covidwho-1556220

ABSTRACT

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.


Subject(s)
Antibodies, Heterophile/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Heterophile/therapeutic use , Antibodies, Viral/therapeutic use , Antigenic Variation , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/therapy , COVID-19/virology , Disease Models, Animal , Epitopes , Humans , Immunization, Passive , Lung/drug effects , Lung/virology , Mice , Protein Interaction Domains and Motifs , Spike Glycoprotein, Coronavirus/genetics , Swine , Viral Load/drug effects
15.
Indian J Pharmacol ; 53(5): 394-402, 2021.
Article in English | MEDLINE | ID: covidwho-1547558

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 is spreading like wildfire with no specific recommended treatment in sight. While some risk factors such as the presence of comorbidities, old age, and ethnicity have been recognized, not a lot is known about who the virus will strike first or impact more. In this hopeless scenario, exploration of time-tested facts about viral infections, in general, seems to be a sound basis to prop further research upon. The fact that immunity and its various determinants (e.g., micronutrients, sleep, and hygiene) have a crucial role to play in the defense against invading organisms, may be a good starting point for commencing research into these as yet undisclosed territories. Herein, the excellent immunomodulatory, antiviral, and anti-inflammatory roles of Vitamin D necessitate thorough investigation, particularly in COVID-19 perspective. This article reviews mechanisms and evidence suggesting the role Vitamin D plays in people infected by the newly identified COVID-19 virus. For this review, we searched the databases of Medline, PubMed, and Embase. We studied several meta-analyses and randomized controlled trials evaluating the role of Vitamin D in influenza and other contagious viral infections. We also reviewed the circumstantial and anecdotal evidence connecting Vitamin D with COVID-19 emerging recently. Consequently, it seems logical to conclude that the immune-enhancing, antiviral, anti-inflammatory, and lung-protective role of Vitamin D can be potentially lifesaving. Hence, Vitamin D deserves exhaustive exploration through rigorously designed and controlled scientific trials. Using Vitamin D as prophylaxis and/or chemotherapeutic treatment of COVID-19 infection is an approach worth considering. In this regard, mass assessment and subsequent supplementation can be tried, especially considering the mechanistic evidence in respiratory infections, low potential for toxicity, and widespread prevalence of the deficiency of Vitamin D affecting many people worldwide.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Immunity/drug effects , Lung/drug effects , SARS-CoV-2/drug effects , Vitamin D Deficiency/drug therapy , Vitamin D/therapeutic use , Vitamins/therapeutic use , Animals , Antiviral Agents/adverse effects , COVID-19/immunology , COVID-19/physiopathology , COVID-19/virology , Host-Pathogen Interactions , Humans , Lung/immunology , Lung/physiopathology , Lung/virology , Risk Assessment , Risk Factors , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Treatment Outcome , Vitamin D/adverse effects , Vitamin D/blood , Vitamin D Deficiency/immunology , Vitamin D Deficiency/physiopathology , Vitamins/adverse effects
16.
Platelets ; 33(1): 48-53, 2022 Jan 02.
Article in English | MEDLINE | ID: covidwho-1541393

ABSTRACT

Coagulopathy is an evident complication of COVID-19 with predominance of a prothrombotic state. Platelet activation plays a key role. The terms "hyper-reactivity" and "hyperactivity" used in recent literature may not be clear or sufficient to explain the pathological events involved in COVID-related thrombosis (CRT). Inflammation may play a bigger role compared to thrombosis in COVID-related mortality because a smaller percentage of patients with COVID-19 die due to direct effects of thrombosis. Not all COVID-19 patients have thrombocytopenia and a few show thrombocytosis. We believe the platelet pathology is more complex than just activation or hyper-activation, particularly due to the platelets' role in inflammation. Understanding the pathology and consequences of platelets' role may help optimize management strategies and diminish CRT-associated morbidity and mortality. In this viewpoint report, we examine the published evidence of platelet hyper-reactivity in COVID-19 with a focused analysis of the key pathologies, diverse alterations, disease outcomes, and therapeutic targets. We believe that COVID-19 is a disease of inflammation and pathologic platelets, and based on the complexity and diverse pathologies, we propose the term "thrombocytopathy" as a more reflective term of the platelets' involvement in COVID-19. In our opinion, thrombocytopathy is the unpredictable pathologic alterations of platelets in function, morphology and number, caused by different factors with a variety of presentations.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Pulmonary Embolism/complications , SARS-CoV-2/pathogenicity , Abciximab/therapeutic use , Acute Disease , Anticoagulants/therapeutic use , Aspirin/therapeutic use , Blood Platelets/drug effects , Blood Platelets/virology , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Clopidogrel/therapeutic use , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/virology , Fibrinolytic Agents/therapeutic use , Humans , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Platelet Activation/drug effects , Pulmonary Embolism/diagnosis , Pulmonary Embolism/drug therapy , Pulmonary Embolism/virology , Treatment Outcome
17.
BMC Pulm Med ; 21(1): 371, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1526622

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a kind of chronic lung diseases with the characteristics of airway remodeling and airflow obstruction. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating hepatitis. However, whether MgIG can treat other diseases and its action mechanism is still obscure. In this study, we evaluated the anti-inflammatory effect of MgIG in rats with COPD and investigated the underlying mechanisms. METHODS: Rat model of COPD was constructed by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction. Rats were randomly divided into 5 groups: control group, COPD model group, salmeterol fluticasone comparator group, low dose of MgIG group, and high dose of MgIG group. Except for normal control group, the other four groups received sensitization treatment by cigarette smoking and endotracheal-atomization of endotoxin lipopolysaccharide to construct COPD rats model. After model established successfully, the COPD rats in each group received corresponding dose of endotracheal-atomized normal saline, salmeterol fluticasone, and MgIG every day prior to exposure of cigarette smoke from days 30 to 45. Normal control group were treated with normal saline. Finally, All rats were euthanatized. Pulmonary function was measured. Cells in bronchoalveolar lavage fluid were classified, inflammatory factors IL-6 and TNF-α were determined, histopathological analysis was performed by HE staining, and expression of NLRP3 and cleaved caspase-1 in the lung tissue was also determined by Western blotting. RESULTS: It showed that MgIG treatment (0.40 or 0.80 mg/kg/day) could recover the weight and the clinical symptoms of rats with COPD, accompanied with lung inflammation infiltration reduction, airway wall attenuation, bronchial mucus secretion reduction. Additionally, MgIG administration reduced inflammatory cells (white blood cells, neutrophils, lymphocytes and monocytes) accumulation in bronchoalveolar lavage fluid and decreased IL-6 and TNF-α production in the serum of COPD rats. Furthermore, MgIG treatment also reduced the expression level of NLRP3 and cleaved caspase-1. CONCLUSION: It indicate that MgIG might be an alternative for COPD treatment, and its mechanism of action might be related to the suppression of NLRP3 inflammasome.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Pulmonary Disease, Chronic Obstructive/drug therapy , Saponins/pharmacology , Triterpenes/pharmacology , Animals , China , Inflammation/prevention & control , Lung/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein , Pulmonary Disease, Chronic Obstructive/pathology , Rats , Rats, Wistar , Smoking
18.
Sci Rep ; 11(1): 22195, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1514424

ABSTRACT

To initiate SARS-CoV-2 infection, the Receptor Binding Domain (RBD) on the viral spike protein must first bind to the host receptor ACE2 protein on pulmonary and other ACE2-expressing cells. We hypothesized that cardiac glycoside drugs might block the binding reaction between ACE2 and the Spike (S) protein, and thus block viral penetration into target cells. To test this hypothesis we developed a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding. Here we report that ouabain, digitoxin, and digoxin, as well as sugar-free derivatives digitoxigenin and digoxigenin, are high-affinity competitive inhibitors of ACE2 binding to the Original [D614] S1 and the α/ß/γ [D614G] S1 proteins. These drugs also inhibit ACE2 binding to the Original RBD, as well as to RBD proteins containing the ß [E484K], Mink [Y453F] and α/ß/γ [N501Y] mutations. As hypothesized, we also found that ouabain, digitoxin and digoxin blocked penetration by SARS-CoV-2 Spike-pseudotyped virus into human lung cells, and infectivity by native SARS-CoV-2. These data indicate that cardiac glycosides may block viral penetration into the target cell by first inhibiting ACE2:RBD binding. Clinical concentrations of ouabain and digitoxin are relatively safe for short term use for subjects with normal hearts. It has therefore not escaped our attention that these common cardiac medications could be deployed worldwide as inexpensive repurposed drugs for anti-COVID-19 therapy.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Cardiotonic Agents/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , A549 Cells , Animals , COVID-19/metabolism , Chlorocebus aethiops , Digitoxin/pharmacology , Digoxin/pharmacology , Humans , Lung/drug effects , Lung/metabolism , Ouabain/pharmacology , Protein Binding/drug effects , SARS-CoV-2/physiology , Vero Cells
19.
J Ethnopharmacol ; 285: 114838, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1509996

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Keguan-1, a new traditional Chinese medicine (TCM) prescription contained seven Chinese herbs, is developed to treat coronavirus disease 19 (COVID-19). The first internationally registered COVID-19 randomised clinical trial on integrated therapy demonstrated that Keguan-1 significantly reduced the incidence of ARDS and inhibited the severe progression of COVID-19. AIM OF THE STUDY: To investigate the protective mechanism of Keguan-1 on ARDS, a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model was used to simulate the pathological state of ARDS in patients with COVID-19, focusing on its effect and mechanism on ALI. MATERIALS AND METHODS: Mice were challenged with LPS (2 mg/kg) by intratracheal instillation (i.t.) and were orally administered Keguan-1 (low dose, 1.25 g/kg; medium dose, 2.5 g/kg; high dose, 5 g/kg) after 2 h. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected 6 h and 24 h after i.t. administration of LPS. The levels of inflammatory factors tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß, keratinocyte-derived chemokine (KC or mCXCL1), macrophage inflammatory protein 2 (MIP2 or mCXCL2), angiotensin II (Ang II), and endothelial cell junction-associated proteins were analysed using ELISA or western blotting. RESULTS: Keguan-1 improved the survival rate, respiratory condition, and pathological lung injury; decreased the production of proinflammatory factors (TNF-α, IL-6, IL-1ß, KC, and MIP2) in BALF and the number of neutrophils in the lung tissues; and ameliorated inflammatory injury in the lung tissues of the mice with LPS-induced ALI. Keguan-1 also reduced the expression of Ang II and the adhesion molecule ICAM-1; increased tight junction proteins (JAM-1 and claudin-5) and VE-cadherin expression; and alleviated pulmonary vascular endothelial injury in LPS-induced ALI. CONCLUSION: These results demonstrate that Keguan-1 can improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, providing scientific support for the clinical treatment of patients with COVID-19. Moreover, it also provides a theoretical basis and technical support for the scientific use of TCMs in emerging infectious diseases.


Subject(s)
Acute Lung Injury , Antiviral Agents/pharmacology , Bronchoalveolar Lavage Fluid , COVID-19 , Drugs, Chinese Herbal/pharmacology , Lung , Acute Lung Injury/drug therapy , Acute Lung Injury/immunology , Acute Lung Injury/pathology , Animals , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/virology , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Capsules , Chemokine CXCL2/analysis , Coix , Forsythia , Interleukin-1beta/analysis , Interleukin-6/analysis , Lonicera , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Mice , Mortality , Morus , Peptide Fragments/analysis , Prunus armeniaca , Respiration/drug effects , SARS-CoV-2 , Treatment Outcome , Tumor Necrosis Factor-alpha/analysis
20.
Front Immunol ; 12: 656419, 2021.
Article in English | MEDLINE | ID: covidwho-1506563

ABSTRACT

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.


Subject(s)
Antitubercular Agents/therapeutic use , Berberine/therapeutic use , Immunologic Factors/therapeutic use , Isoniazid/therapeutic use , Rifampin/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Animals , Antitubercular Agents/pharmacology , Berberine/pharmacology , Cytokines/immunology , Dendritic Cells/drug effects , Drug Therapy, Combination , Female , Humans , Immunologic Factors/pharmacology , Isoniazid/pharmacology , Lung/drug effects , Lung/immunology , Lung/microbiology , Lung/pathology , Macrophages/drug effects , Macrophages/immunology , Male , Mice, Inbred C3H , Mice, Inbred C57BL , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/growth & development , Neutrophils/drug effects , Neutrophils/immunology , Rifampin/pharmacology , Spleen/drug effects , Spleen/immunology , Spleen/microbiology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/pathology
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