-
Journal of Molecular Medicine (Berlin,... Jul 2024Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital...
Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (HR) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of HR in atherosclerosis have not been fully elucidated. Here, we explored the effect of HR on atherosclerosis using Apolipoprotein E-knockout (ApoE) mice with astemizole (AST, a long-acting HR antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b myeloid cells derived from HDC-knockout (HDC) mice compared to WT mice. Blocking HR promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking HR signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway. KEY MESSAGES: Blocking HR signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE mice. Blocking HR signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.
Topics: Animals; Foam Cells; Atherosclerosis; Mice; Mice, Knockout; Inflammation; Signal Transduction; Receptors, Histamine H1; Male; Apolipoproteins E; Mice, Inbred C57BL; Lipid Metabolism; p38 Mitogen-Activated Protein Kinases; Disease Models, Animal; Plaque, Atherosclerotic; Diet, High-Fat
PubMed: 38733386
DOI: 10.1007/s00109-024-02453-5 -
ACS Medicinal Chemistry Letters Apr 2024Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC = 0.0042 μM) and its derivatives, we designed and...
Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC = 0.0042 μM) and its derivatives, we designed and synthesized analogues based on compound ( NF54 IC = 0.012 μM; hERG IC = 0.63 μM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound retained multistage antiplasmodium activity (ABS NF54 IC = 0.017 μM; gametocytes iGc/LGc IC = 1.24/1.39 μM, and liver-stage HepG2 IC = 2.30 μM), good microsomal metabolic stability (MLM CL < 11 μL·min·mg, < 0.33), and solubility (150 μM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to and AST, respectively. Despite the excellent antiplasmodium activity profile, efficacy in the mouse infection model was diminished, attributable to suboptimal oral bioavailability ( = 14.9%) at 10 mg·kg resulting from poor permeability (log = -0.82). No cross-resistance was observed against 44 common mutant lines, suggesting activity via a novel mechanism of action.
PubMed: 38628794
DOI: 10.1021/acsmedchemlett.3c00496 -
Biomedicines Mar 2024The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an...
The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer's disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrP. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.
PubMed: 38540224
DOI: 10.3390/biomedicines12030611 -
BMC Public Health Feb 2024Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory... (Review)
Review
Recently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form "platforms" that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = - 12.58 kcal/mol), emetine (S = - 11.65 kcal/mol), pimozide (S = - 11.29 kcal/mol), carvedilol (S = - 11.28 kcal/mol), mebeverine (S = - 11.14 kcal/mol), cepharanthine (S = - 11.06 kcal/mol), hydroxyzin (S = - 10.96 kcal/mol), astemizole (S = - 10.81 kcal/mol), sertindole (S = - 10.55 kcal/mol), and bepridil (S = - 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = - 10.43 kcal/mol), making them better options for inhibition.
Topics: Humans; COVID-19; Molecular Docking Simulation; SARS-CoV-2; Sphingomyelin Phosphodiesterase; Ceramides; Sphingolipids
PubMed: 38321448
DOI: 10.1186/s12889-024-17747-z -
Scientific Reports Oct 2023Drug designing is high-priced and time taking process with low success rate. To overcome this obligation, computational drug repositioning technique is being promptly...
Drug designing is high-priced and time taking process with low success rate. To overcome this obligation, computational drug repositioning technique is being promptly used to predict the possible therapeutic effects of FDA approved drugs against multiple diseases. In this computational study, protein modeling, shape-based screening, molecular docking, pharmacogenomics, and molecular dynamic simulation approaches have been utilized to retrieve the FDA approved drugs against AD. The predicted MADD protein structure was designed by homology modeling and characterized through different computational resources. Donepezil and galantamine were implanted as standard drugs and drugs were screened out based on structural similarities. Furthermore, these drugs were evaluated and based on binding energy (Kcal/mol) profiles against MADD through PyRx tool. Moreover, pharmacogenomics analysis showed good possible associations with AD mediated genes and confirmed through detail literature survey. The best 6 drug (darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar) further docked and analyzed their interaction behavior through hydrogen binding. Finally, MD simulation study were carried out on these drugs and evaluated their stability behavior by generating root mean square deviation and fluctuations (RMSD/F), radius of gyration (Rg) and soluble accessible surface area (SASA) graphs. Taken together, darifenacin, astemizole, tubocurarine, elacridar, sertindole and tariquidar displayed good lead like profile as compared with standard and can be used as possible therapeutic agent in the treatment of AD after in-vitro and in-vivo assessment.
Topics: Humans; Drug Repositioning; Molecular Docking Simulation; Alzheimer Disease; Prognosis; Astemizole; Tubocurarine; Molecular Dynamics Simulation
PubMed: 37865690
DOI: 10.1038/s41598-023-45347-1 -
Molecular Psychiatry Sep 2023Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of... (Meta-Analysis)
Meta-Analysis
Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.
Topics: Adult; Humans; Antipsychotic Agents; Clozapine; Sulpiride; Amisulpride; Sialorrhea; Doxepin; Amitriptyline; Network Meta-Analysis; Propantheline; Trihexyphenidyl; Metoclopramide; Chlorpheniramine; Astemizole; Randomized Controlled Trials as Topic; Cyproheptadine; Diphenhydramine; Ipratropium; Atropine Derivatives
PubMed: 37821573
DOI: 10.1038/s41380-023-02266-x -
Journal of Thoracic Disease Aug 2023Long QT syndrome type 2 (LQT2) is caused by mutations in the /human ether-à-go-go-related gene (hERG). Some hERG genetic mutation-associated diseases are alleviated by...
4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene.
BACKGROUND
Long QT syndrome type 2 (LQT2) is caused by mutations in the /human ether-à-go-go-related gene (hERG). Some hERG genetic mutation-associated diseases are alleviated by hERG-specific drug chaperones (glycerol, dimethyl sulfoxide, trimethylamine N-oxide, thapsigargin), delayed rectifier K current (IKr) blockers methanesulfonanilide E4031, the antihistamine astemizole, or the prokinetic drug cisapride, and the anti-arrhythmic drug quinidine. Meanwhile, many and studies have reported the efficacy of 4-phenylbutyric acid (4-PBA) in diseases with inherited genetic mutations. This study aims to explore potential therapeutic agents for hERG/G572R mutated ion channel.
METHODS
pcDNA3/hERG [wild type (WT)]-FLAG and pcDNA3/hERG (G572R)-FLAG plasmids were transfected into HEK293 cells. A western blot (WB) experiment was conducted to analyze protein expression. Quantitative real-time polymerase chain reaction (qPCR) was used to analyze the messenger RNA (mRNA) expression levels in the WT/G572R heterozygous HEK293 cell model treated with or without 4-PBA. The interaction between WT/G572R and BIP (GRP78), GRP94, and 3-hydroxy-3-methylglutaryl coenzyme A reductase degradation protein 1 (HRD1) was tested by co-immunoprecipitation (co-IP). To investigate the effect of 4-PBA on the WT/G572R channel current, we used electrophysiological assays (patch-clamp electrophysiological recordings).
RESULTS
The results showed that WT/G572R activated the ATF6 pathway in the endoplasmic reticulum stress (ERS), the ERS response markers GRP78, GRP94, and calreticulin (CRT)/calnexin (CNX), and HRD1, which decreased after application of the ERS inhibitor 4-PBA. The results of co-IP confirmed that the ability of hERG interacted with GRP78, GRP94, and HRD1. Moreover, 4-PBA increased the current of WT/G572R and reversed the gating kinetics of the WT/G572R channel.
CONCLUSIONS
4-PBA corrects hERG channel transport defects by inhibiting excessive ERS and the endoplasmic reticulum-associated degradation (ERAD)-related gene E3 ubiquitin ligase HRD1. Additionally, 4-PBA improved WT/G572R channel current. 4-PBA is expected to be developed as a new treatment method for LQT2.
PubMed: 37691654
DOI: 10.21037/jtd-23-1252 -
Journal For Immunotherapy of Cancer Jul 2023Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics...
BACKGROUND
Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations.
METHOD
For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2).
RESULTS
The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4 and CD8 T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8/Foxp3 ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8 T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4 or CD8 T cells, as well as on neutralization of IFN-γ.
CONCLUSIONS
These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.
Topics: United States; Mice; Animals; CD8-Positive T-Lymphocytes; Interleukin-2; Astemizole; Oxaliplatin; Immunity, Cellular; Histocompatibility Antigens Class I; Interferon-gamma
PubMed: 37419511
DOI: 10.1136/jitc-2023-006785 -
Frontiers in Pharmacology 2022Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of...
Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of novel drugs. A concept of the Connectivity Map (CMap) was previously proposed to connect genes, drugs, and disease states based on the common gene-expression signatures. For a new query compound, the CMap-based method can infer its potential targets by searching similar drugs with known targets (reference drugs) and measuring the similarities into their specific transcriptional responses between the query compound and those reference drugs. However, the available methods are often inefficient due to the requirement of the reference drugs as a medium to link the query agent and targets. Here, we developed a general procedure to extract target-induced consensus gene modules from the transcriptional profiles induced by the treatment of perturbagens of a target. A specific transcriptional gene module pair (GMP) was automatically identified for each target and could be used as a direct target signature. Based on the GMPs, we built the target network and identified some target gene clusters with similar biological mechanisms. Moreover, a gene module pair-based target identification (GMPTI) approach was proposed to predict novel compound-target interactions. Using this method, we have discovered novel inhibitors for three PI3K pathway proteins PI3Kα/β/δ, including PU-H71, alvespimycin, reversine, astemizole, raloxifene HCl, and tamoxifen.
PubMed: 36726786
DOI: 10.3389/fphar.2022.1089217 -
Cancers Dec 2022Since the multifunctionality of transglutaminase 2 (TG2) includes extra- and intracellular functions, we investigated the effects of intracellular administration of TG2...
Since the multifunctionality of transglutaminase 2 (TG2) includes extra- and intracellular functions, we investigated the effects of intracellular administration of TG2 inhibitors in three breast cancer cell lines, MDA-MB-231, MDA-MB-436 and MDA-MB-468, which are representative of different triple-negative phenotypes, using a patch-clamp technique. The first cell line has a highly voltage-dependent a membrane current, which is low in the second and almost absent in the third one. While applying a voltage protocol to responsive single cells, injection of TG2 inhibitors triggered a significant decrease of the current in MDA-MB-231 that we attributed to voltage-dependent K channels using the specific inhibitors 4-aminopyridine and astemizole. Since the Kv10.1 channel plays a dominant role as a marker of cell migration and survival in breast cancer, we investigated its relationship with TG2 by immunoprecipitation. Our data reveal their physical interaction affects membrane currents in MDA-MB-231 but not in the less sensitive MDA-MB-436 cells. We further correlated the efficacy of TG2 inhibition with metabolic changes in the supernatants of treated cells, resulting in increased concentration of methyl- and dimethylamines, representing possible response markers. In conclusion, our findings highlight the interference of TG2 inhibitors with the Kv10.1 channel as a potential therapeutic tool depending on the specific features of cancer cells.
PubMed: 36612174
DOI: 10.3390/cancers15010178