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1.
Molecules ; 27(9)2022 Apr 24.
Article in English | MEDLINE | ID: covidwho-1810048

ABSTRACT

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Animals , Benzylisoquinolines , Biological Availability , Bleomycin/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chromatography, Liquid , Humans , Lung , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Rats , Tandem Mass Spectrometry , Transforming Growth Factor beta1/metabolism
2.
Nanomedicine ; 34: 102388, 2021 06.
Article in English | MEDLINE | ID: covidwho-1142161

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a devastating pulmonary disease with significant in-hospital mortality and is the leading cause of death in COVID-19 patients. Excessive leukocyte recruitment, unregulated inflammation, and resultant fibrosis contribute to poor ARDS outcomes. Nanoparticle technology with cerium oxide nanoparticles (CNP) offers a mechanism by which unstable therapeutics such as the anti-inflammatory microRNA-146a can be locally delivered to the injured lung without systemic uptake. In this study, we evaluated the potential of the radical scavenging CNP conjugated to microRNA-146a (termed CNP-miR146a) in preventing acute lung injury (ALI) following exposure to bleomycin. We have found that intratracheal delivery of CNP-miR146a increases pulmonary levels of miR146a without systemic increases, and prevents ALI by altering leukocyte recruitment, reducing inflammation and oxidative stress, and decreasing collagen deposition, ultimately improving pulmonary biomechanics.


Subject(s)
Bleomycin/adverse effects , Cerium , Drug Delivery Systems , MicroRNAs , Respiratory Distress Syndrome/drug therapy , Animals , Bleomycin/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/metabolism , Cerium/chemistry , Cerium/pharmacology , Disease Models, Animal , Male , Mice , MicroRNAs/chemistry , MicroRNAs/pharmacology , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/metabolism , SARS-CoV-2/metabolism
3.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1066781

ABSTRACT

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.


Subject(s)
COVID-19/metabolism , DNA-Binding Proteins/metabolism , Macrophages/metabolism , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Fibrosis , Gene Expression Profiling , Gene Expression Regulation , Humans , Liposomes/chemistry , Lung Diseases, Interstitial/metabolism , Lung Neoplasms/metabolism , Macrophages/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/virology , RNA, Small Interfering/metabolism , Scleroderma, Systemic/metabolism , Signal Transduction , Transforming Growth Factor beta1/metabolism
4.
SLAS Discov ; 25(10): 1152-1161, 2020 12.
Article in English | MEDLINE | ID: covidwho-846185

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has triggered an ongoing global pandemic whereby infection may result in a lethal severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, millions of confirmed cases and hundreds of thousands of deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. The purported development of a vaccine could require at least 1-4 years, while the typical timeline from hit finding to drug registration of an antiviral is >10 years. Thus, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we developed and initiated a high-throughput cell-based screen that incorporates the essential viral papain-like protease (PLpro) and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or US Food and Drug Administration (FDA)-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Here, we report the identification of four clinically relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral PLpro.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , High-Throughput Screening Assays/methods , Protease Inhibitors/pharmacology , Bleomycin/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , HEK293 Cells , Humans , Papain/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
5.
Mol Syst Biol ; 16(7): e9628, 2020 07.
Article in English | MEDLINE | ID: covidwho-707164

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , A549 Cells , Angiotensin-Converting Enzyme 2 , Betacoronavirus , Bleomycin/pharmacology , COVID-19 , Dexamethasone/pharmacology , Drug Design , Drug Evaluation, Preclinical , Erlotinib Hydrochloride/pharmacology , Fluphenazine/pharmacology , HEK293 Cells , Humans , Kidney/drug effects , Lung/drug effects , MCF-7 Cells , Pandemics , Peptidyl-Dipeptidase A , SARS-CoV-2 , Systems Biology , Up-Regulation , Vemurafenib/pharmacology
6.
Med Hypotheses ; 144: 110167, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-696940

ABSTRACT

Adult respiratory distress syndrome (ARDS) is the leading cause of death associated with SARS-CoV-2 infection and COVID-19. IGF-1 has been implicated in ARDS, yet its role in relation to COVID-19-related lung injury has not been investigated. We hypothesize that blockage of the IGF-1 receptor (IGF-1R) mitigates lung injury and decreases the risk of death in patients COVID-19-related ARDS. Patients with fibroproliferative ARDS have been shown to have increased IGF-1 and IGF-1R staining in lung tissue specimens. Rising levels of IGF-1 in bronchioalveolar fluid (BAL) and increased IGF-1 mRNA expression in lung tissues (but declining serum IGF-1 levels) have been found in late stage ARDS compared with early lung injury. Blockage of IGF-1R decreases lung tissue damage and increases survival in bleomycin-induced as well as H1N1 influenza-related lung injury in animal models. Teprotumumab is a monoclonal antibody directed against the IGF-1R that was FDA-approved in 2020 for the treatment of Graves' orbitopathy. In order to determine if teprotumumab may reduce lung injury and death related to ARDS in the setting of COVID-19, preliminary clinical data is needed. IGF-1 levels in serum and BAL fluid must be measured in patients with COVID-19-related ARDS. Histopathology from lung samples from patients with COVID-19-related ARDS must be examined for increased expression of the IGF-1R. Once these are ascertained, and if the data support IGF-1 involvement, a randomized, placebo-controlled phase 2A trial of teprotumumab therapy in the setting of COVID-19-related ARDS and non-COVID-19-related ARDS designed to generate initial data on short-term efficacy, safety, dosing and administration should be performed.


Subject(s)
COVID-19/drug therapy , Respiratory Distress Syndrome/drug therapy , Somatomedins/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Bleomycin/pharmacology , Bronchoalveolar Lavage Fluid , Humans , Influenza A Virus, H1N1 Subtype , Insulin-Like Growth Factor I/metabolism , Mice , Models, Theoretical , Receptor, IGF Type 1/metabolism , Respiratory Distress Syndrome/virology , Risk , Treatment Outcome
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