Abstract:
:The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4.
journal_name
Front Pharmacoljournal_title
Frontiers in pharmacologyauthors
Laselva O,Marzaro G,Vaccarin C,Lampronti I,Tamanini A,Lippi G,Gambari R,Cabrini G,Bear CE,Chilin A,Dechecchi MCdoi
10.3389/fphar.2018.00719subject
Has Abstractpub_date
2018-07-04 00:00:00pages
719issn
1663-9812journal_volume
9pub_type
杂志文章abstract::Background: From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry. Objectives: The aim of this paper is to provide a European overview of (list) prices of origin...
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doi:10.3389/fphar.2020.591134
更新日期:2021-01-08 00:00:00
abstract::Blockchain systems are a fast emerging and a currently widely discussed novel strategy for a decentralized cryptographically enhanced digital ledger recording transactions among stakeholders. This perspective paper looks at its potential uses in the context of high value and mostly low volume botanical material traded...
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abstract::The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Ov...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2018.00030
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abstract::Product mislabeling and/or species fraud in Traditional Chinese Medicine (TCM) not only decrease TCM quality, but also pose a potential health issue to the end user. Up to now, methods to control TCM quality have been developed to detect specific metabolites or identify the original species. However, species quantific...
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abstract::The increasing use of antibiotics is being driven by factors such as the aging of the population, increased occurrence of infections, and greater prevalence of chronic diseases that require antimicrobial treatment. The excessive and unnecessary use of antibiotics in humans has led to the emergence of bacteria resistan...
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abstract::Organic anion transporter 2 (OAT2) is likely important for renal and hepatic drug elimination. Three variants of the OAT2 peptide sequence have been described - OAT2 transcript variant 1 (OAT2-tv1), OAT2 transcript variant 2 (OAT2-tv2), and OAT2 transcript variant 3 (OAT2-tv3). Early studies helping to define the liga...
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pub_type: 杂志文章
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abstract::Osteosarcoma (OS) is a malignant primary bone tumor with high metastatic rate. C-X-C motif chemokine ligand 6 (CXCL6) and its receptor C-X-C motif chemokine receptor 1/2 (CXCR1/2) have been found to participate in the process of carcinogenesis. In this study, we evaluated the role of CXCL6/CXCR1/2 axis in proliferatio...
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abstract::The Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) or novel coronavirus (COVID-19) infection has been declared world pandemic causing a worrisome number of deaths, especially among vulnerable citizens, in 209 countries around the world. Although several therapeutic molecules are being tested, no ...
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pub_type: 杂志文章,评审
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abstract::Flavonoids are the largest class of plant polyphenols, with common structure of diphenylpropanes, consisting of two aromatic rings linked through three carbons and are abundant in both daily diets and medicinal plants. Fueled by the recognition of consuming flavonoids to get better health, researchers became intereste...
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abstract:Background and Purpose:The exact mechanism of spontaneous pacemaking is not fully understood. Recent results suggest tight cooperation between intracellular Ca2+ handling and sarcolemmal ion channels. An important player of this crosstalk is the Na+/Ca2+ exchanger (NCX), however, direct pharmacological evidence was una...
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abstract::Background and Objectives: Limited research focuses on the risk of ischemic cerebrovascular disease associated with use of dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) in patients with type 2 diabetes mellitus in Taiwan. This study aimed to investigate the association between DPP-4 inhibitors use and the first...
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doi:10.3389/fphar.2017.00859
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abstract::[This corrects the article on p. 287 in vol. 7, PMID: 27630568.]. ...
journal_title:Frontiers in pharmacology
pub_type: 已发布勘误
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更新日期:2016-12-05 00:00:00
abstract::Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardio...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章,评审
doi:10.3389/fphar.2020.00891
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abstract::This study explores historical iatrosophia texts from Cyprus from a botanical and medico-pharmacological point of view focusing on remedies containing resins and gums. The iatrosophia are a genre of Greek medical literature of Byzantine origin and can be described as medicine handbooks which serve as therapeutic repos...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2011.00032
更新日期:2011-07-01 00:00:00
abstract::Background: HIV pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine is effective when taken daily. Previously, we developed a urine assay capable of detecting the prodrug tenofovir (TFV) in patients taking tenofovir disoproxil fumarate (TDF)-based PrEP. However, tenofovir alafenamide (TAF) has replaced TDF du...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2020.00286
更新日期:2020-03-19 00:00:00
abstract::The use of therapeutic peptides in various inflammatory diseases and autoimmune disorders has received considerable attention; however, the identification of anti-inflammatory peptides (AIPs) through wet-lab experimentation is expensive and often time consuming. Therefore, the development of novel computational method...
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doi:10.3389/fphar.2018.00276
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abstract::Lead is a multi-organ toxicant implicated in various cancers, diseases of the hepatic, renal, and reproductive systems etc. In search of cheap and readily available antidote this study has investigated the role of activated charcoal in chronic lead exposure in albino rats. Eighteen mature male albino rats were used, d...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2017.00107
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abstract::Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. In Parkinson's disease patients, CBD is able to attenuate the psychotic symptoms induced by L-DOPA and to improve quality of life. Repeated administration of...
journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2016.00343
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abstract::Flavonoids are some of the most important natural products with a variety of physiological activities. 8-Formylophiopogonanone B (8-FOB) is a naturally existing homoisoflavonoid in Ophiopogon japonicus. Paraquat (PQ) has been widely used as a potent herbicide and has high toxicity in humans. The goal of the present st...
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abstract::Cissus quadrangularis (C. quadrangularis) is a plant of the Vitaceae family known for its anticonvulsant effects in traditional medicine. The objective of this study was to elucidate the anxiolytic and antiepileptic effects of aqueous extract of C. quadrangularis. The mice were divided into different groups and treate...
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journal_title:Frontiers in pharmacology
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pub_type: 杂志文章
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abstract:BACKGROUND:The dried root of Paeonia lactiflora Pall. (PLP) is a classical Chinese herbal medicine that has been used to treat hepatic disease for 1000s of years. Our previous work suggested that PLP can be used to treat hepatitis with severe cholestasis. This study explored the mechanism by which PLP affects ANIT-indu...
journal_title:Frontiers in pharmacology
pub_type: 杂志文章
doi:10.3389/fphar.2016.00014
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journal_title:Frontiers in pharmacology
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doi:10.3389/fphar.2017.00822
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journal_title:Frontiers in pharmacology
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journal_title:Frontiers in pharmacology
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abstract::Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 comp...
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