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Frontiers in Microbiology 2021Recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen is the hallmark of an acute immunopathologic inflammatory response during vulvovaginal...
Recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen is the hallmark of an acute immunopathologic inflammatory response during vulvovaginal candidiasis (VVC) caused by Recurrent VVC (RVVC) remains a chronic health burden in affected women worldwide despite the use of antifungal therapy. Based on the role leukotrienes (LTs) play in promoting inflammation, leukotriene receptor antagonists (LTRAs) targeted for LTB (etalocib) or LTC, LTD and LTE (zafirlukast or montelukast) have been shown to reduce inflammation of epithelial tissues. An open-label pilot study using long-term regimens of zafirlukast in women with RVVC indicated the potential for some relief from recurrent episodes. To investigate this clinical observation further, we evaluated the effects of LT antagonistic agents and LT deficiency on the immunopathogenic response in a mouse model of VVC. Results showed that mice given daily intraperitoneal injections of individual LTRAs, starting 2days prior to vaginal inoculation with and continuing through 14days post-inoculation, had no measurable reduction in PMN migration. The LTRAs were also ineffective in reducing levels of the hallmark vaginal inflammatory markers (S100A8, IL-1β) and tissue damage (LDH) associated with the immunopathogenic response. Finally, LT-deficient 5-lipoxygenase knockout mice showed comparable levels of vaginal fungal burden and PMN infiltration to wild-type mice following inoculation with a vaginal (ATCC 96113) or laboratory (SC5314) isolate. These results indicate that despite some clinical evidence suggestive of off-target efficacy of LTRAs in RVVC, LTs and associated signaling pathways appear to be dispensable in the immunopathogenesis of VVC.
PubMed: 34867856
DOI: 10.3389/fmicb.2021.739385 -
Bioengineered Dec 2021Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical...
Docetaxel-associated liver injury has become a serious public health problem, resulting in therapy discontinuation, liver failure, and death. Zafirlukast is a typical leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma. In this study, we investigate whether treatment with Zafirlukast could alleviate Docetaxel-induced cytotoxicity in hepatocytes. Our results indicate that Zafirlukast mitigated Docetaxel-induced toxicity in LO-2 hepatocytes. Firstly, Zafirlukast reduced the production of 8-hydroxy-2p-deoxyguanosine (8-OHdG) and increased the levels of reduced glutathione (GSH) against Docetaxel. Secondly, Zafirlukast elevated the levels of mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP). Thirdly, Zafirlukast prevented Docetaxel-induced release of lactate dehydrogenase (LDH) and increased cell viability of LO-2 hepatocytes against Docetaxel. We also found that Zafirlukast ameliorated Docetaxel-induced apoptosis by reducing Caspase-3 and Caspase-9 activity. Mechanistically, our results demonstrate that Zafirlukast inhibited the activation of NOD-like receptor protein 3 (NLRP3), mediated by SIRT1. Based on these findings, we conclude that the administration of Zafirlukast might have a protective effect against Docetaxel-induced cytotoxicity in hepatocytes.
Topics: Animals; Cell Death; Cell Line; Docetaxel; Gene Silencing; Hepatocytes; Humans; Indoles; Inflammasomes; Membrane Potential, Mitochondrial; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Phenylcarbamates; Sirtuin 1; Sulfonamides
PubMed: 34787067
DOI: 10.1080/21655979.2021.2005895 -
Alzheimer's Research & Therapy Sep 2021Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This... (Observational Study)
Observational Study
BACKGROUND
Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time.
METHODS
This longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models.
RESULTS
In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes.
CONCLUSIONS
The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.
Topics: Alzheimer Disease; Cognition; Cognitive Dysfunction; Disease Progression; Humans; Leukotriene Antagonists; Longitudinal Studies; Neuropsychological Tests
PubMed: 34479635
DOI: 10.1186/s13195-021-00892-7 -
European Journal of Pharmaceutics and... Nov 2021Drug solubility is a key parameter controlling oral absorption, but intestinal solubility is difficult to assess in vitro. Human intestinal fluid (HIF) aspirates can be...
Drug solubility is a key parameter controlling oral absorption, but intestinal solubility is difficult to assess in vitro. Human intestinal fluid (HIF) aspirates can be applied but they are variable, difficult to obtain and expensive. Simulated intestinal fluids (SIF) are a useful surrogate but multiple recipes are available and the optimum is unknown. A recent study characterised fasted HIF aspirates using a multi-dimensional approach and determined nine bioequivalent SIF media recipes that represented over ninety percent of HIF compositional variability. In this study these recipes have been applied to determine the equilibrium solubility of twelve drugs (naproxen, indomethacin, phenytoin, piroxicam, aprepitant, carvedilol, zafirlukast, tadalafil, fenofibrate, griseofulvin, felodipine, probucol) previously investigated using a statistical design of experiment (DoE) approach. The bioequivalent solubility measurements are statistically equivalent to the previous DoE, enclose literature solubility values in both fasted HIF and SIF, and the solubility range is less than the previous DoE. These results indicate that the system is measuring the same solubility space as literature systems with the lower overall range suggesting improved equivalence to in vivo solubility, when compared to DoEs. Three drugs (phenytoin, tadalafil and griseofulvin) display a comparatively narrow solubility range, a behaviour that is consistent with previous studies and related to the drugs' molecular structure and properties. This solubility behaviour would not be evident with single point solubility measurements. The solubility results can be analysed using a custom DoE to determine the most statistically significant factor within the media influencing solubility. This approach has a lower statistical resolution than a formal DoE and is not appropriate if determination of media factor significance for solubilisation is required. This study demonstrates that it is possible to assess the fasted intestinal equilibrium solubility envelope using a small number of bioequivalent media recipes obtained from a multi-dimensional analysis of fasted HIF. The derivation of the nine bioequivalent SIF media coupled with the lower measured solubility range indicate that the solubility results are more likely to reflect the fasted intestinal solubility envelope than previous DoE studies and highlight that intestinal solubility is a range and not a single value.
Topics: Administration, Oral; Fasting; Humans; In Vitro Techniques; Intestinal Absorption; Intestinal Secretions; Pharmaceutical Preparations; Solubility; Therapeutic Equivalency
PubMed: 34419602
DOI: 10.1016/j.ejpb.2021.08.002 -
Drug Design, Development and Therapy 2021[This corrects the article DOI: 10.2147/DDDT.S154814.].
[This corrects the article DOI: 10.2147/DDDT.S154814.].
PubMed: 33603335
DOI: 10.2147/DDDT.S304214 -
Journal of Biomolecular Structure &... Sep 2022The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International...
The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International concern. As part of the efforts to discover lead compounds for clinical use, 53 molecules were screened using molecular docking and dynamic simulations (MDS) techniques to identify potential inhibitors of SARS-CoV-2 spike protein (COVID-19 S) and main protease (COVID-19 M) or both. Lopinavir (LPV), nelfinavir (NEF), hydroxychloroquine (HCQ), remdesivir (RDV) and an irreversible inhibitor of SARS-CoV (N3) were used as standard drugs for COVID-19 M, while zafirlukast (ZFK) and cefoperazone (CSP)) as standard drugs for COVID-19 S. After 100ns of MDS, with reference to standard drugs (N3, -52.463 Kcal/mol, NEF, -51.618 Kcal/mol, RDV, -48.780 Kcal/mol, LPV, -46.788 Kcal/mol, DRV, -33.655 Kcal/mol and HCQ, -21.065 Kcal/mol), five molecules, HCR, GRN, C3G, EGCG, and K7G were predicted to be promising inhibitors of COVID-19 M with binding energies of -53.877kcal/mol, -50.653 Kcal/mol, -48.600kcal/mol, -47.798kcal/mol and -46.902kcal/mol, respectively. These lead molecules were then docked at receptor-binding domain (RBD) of COVID-19 S to examine their inhibitory effects. C3G, GRN and K7G exhibited higher binding energies of -42.310kcal/mol, -32.210kcal/mol, -26.922kcal/mol than the recorded values for the reference drugs (CSP, -35.509kcal/mol, ZFK, -24.242kcal/mol), respectively. The results of the binding energy and structural analyses from this study revealed that C3G, GRN and K7G could serve as potential dual inhibitors of COVID-19 S and COVID-19 M, while HCR and EGCG would be inhibitors of COVID-19 Mpro.Communicated by Ramaswamy H. Sarma.
Topics: Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Peptide Hydrolases; Protease Inhibitors; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 33590806
DOI: 10.1080/07391102.2021.1886993 -
Medicine in Drug Discovery Mar 2021Over the past few years, AI has been considered as potential important area for improving drug development and in the current urgent need to fight the global COVID-19...
AIMS
Over the past few years, AI has been considered as potential important area for improving drug development and in the current urgent need to fight the global COVID-19 pandemic new technologies are even more in focus with the hope to speed up this process. The purpose of our study was to identify the best repurposing candidates among FDA-approved drugs, based on their predicted antiviral activity against SARS-CoV-2.
MATERIALS AND METHODS
This article describes a drug discovery screening based on a supervised machine learning model, trained on data encoded in chemical fingerprints, representing particular molecular substructures. Predictive performance of our model has been evaluated using so-called scaffold splits offering a state-of-the-art setup for assessing model's ability to generalize to new chemical spaces, critical for drug repurposing applications.
KEY FINDINGS
Our study identified zafirlukast as the best repurposing candidate for COVID-19.
SIGNIFICANCE
Zafirlukast could be potent against COVID-19 both due to its predicted antiviral properties and its ability to attenuate the so called . Thus, these two critical mechanisms of action may be combined in one drug as a novel and promising pharmacotherapy in the current pandemic.
PubMed: 33521623
DOI: 10.1016/j.medidd.2020.100077 -
British Journal of Pharmacology Feb 2021Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet...
BACKGROUND AND PURPOSE
Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet responses, aggregation, adhesion and thrombus formation. Recently, the therapeutic potential of TI inhibition has been recognised and drug-development technologies were used to identify selective small molecule inhibitors. To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin, is known to be nephrotoxic, which prohibits its systemic therapeutic usage.
EXPERIMENTAL APPROACH
We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. A total of 3,641 compounds were screened for inhibitory effects on the redox activity of ERp5, protein disulphide isomerase (PDI), ERp57, ERp72 and thioredoxin in an insulin turbidity assay. Of the lead compounds identified, zafirlukast was selected for further investigation.
KEY RESULTS
When applied to platelets, zafirlukast diminished platelet responses in vitro. Zafirlukast was antithrombotic in murine models of thrombosis but did not impair responses in a model of haemostasis. Since TIs are known to modulate adhesion receptor function, we explored the effects of zafirlukast on cell migration. This was inhibited independently of cysteinyl LT receptor expression and was associated with modulation of cell-surface free thiol levels consistent with alterations in redox activity on the cell surface.
CONCLUSION AND IMPLICATIONS
We identify zafirlukast to be a novel, potent, broad-spectrum TI inhibitor, with wide-ranging effects on platelet function, thrombosis and integrin-mediated cell migration. Zafirlukast is antithrombotic but does not cause bleeding.
Topics: Animals; Bleeding Time; Blood Platelets; Indoles; Mice; Phenylcarbamates; Sulfhydryl Compounds; Sulfonamides; Thrombosis
PubMed: 33080041
DOI: 10.1111/bph.15291 -
Scientific Reports Oct 2020The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on...
The retinal pigment epithelium (RPE), which is among the tissues in the body that are exposed to the highest levels of phagocytosis and oxidative stress, is dependent on autophagy function. Impaired autophagy and continuous cellular stress are associated with various disorders, such as dry age-related macular degeneration (AMD), a disease for which effective therapies are lacking. Cysteinyl leukotriene receptor (CysLTR) 1 is a potential modulator of autophagy; thus, the aim of this study was to investigate the role of CysLTR1 in autophagy regulation in the RPE cell line ARPE-19. The polarized ARPE-19 monolayer exhibited expression of CysLTR1, which was colocalized with β-tubulin III. In ARPE-19 cells, autophagic activity was rhythmically regulated and was increased upon CysLTR1 inhibition by Zafirlukast (ZK) treatment. HO affected the proautophagic regulatory effect of ZK treatment depending on whether it was applied simultaneously with or prior to ZK treatment. Furthermore, mRNA levels of genes related to the leukotriene system, autophagy and the unfolded protein response were positively correlated. As CysLTR1 is involved in autophagy regulation under basal and oxidative stress conditions, a dysfunctional leukotriene system could negatively affect RPE functions. Therefore, CysLTR1 is a potential target for new treatment approaches for neurodegenerative disorders, such as AMD.
Topics: Autophagy; Cell Line; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Hydrogen Peroxide; Indoles; Leukotriene Antagonists; Oxidative Stress; Phenylcarbamates; Polymerase Chain Reaction; Receptors, Leukotriene; Retinal Pigment Epithelium; Sulfonamides; Tosyl Compounds; Transcription Factors
PubMed: 33077798
DOI: 10.1038/s41598-020-74755-w -
ACS Medicinal Chemistry Letters Oct 2020is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast...
is a Gram-negative anaerobic pathogen that can trigger oral dysbiosis as an early event in the pathogenesis of periodontal disease. The FDA-approved drug zafirlukast (ZAF) was recently shown to display antibacterial activity against . Here, 15 novel ZAF derivatives were synthesized and evaluated for their antibacterial activity against and for their cytotoxic effects. Most derivatives displayed superior antibacterial activity against compared to ZAF and its first generation derivatives along with little to no growth inhibition of other oral bacterial species. The most active compounds displayed bactericidal activity against and less cytotoxicity than ZAF. The superior and selective antibacterial activity of ZAF derivatives against along with an increased safety profile compared to ZAF suggest these new compounds, especially and , show promise as antibacterials for future studies aimed to test their potential for preventing/treating -induced periodontal disease.
PubMed: 33062172
DOI: 10.1021/acsmedchemlett.9b00614