-
Annals of Nuclear Medicine Feb 2024The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different...
BACKGROUND
The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HTR is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, glioblastoma multiform (GBM) overexpresses 5-HTR; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HTR imaging agents. METHODS: Compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[Tc(CO)(HO)] and Tc(CO)-[6] and Tc(CO)-[7] were obtained with high radiochemical purity (RCP > 94%). The stability of the radiotracers was evaluated in both saline and mouse serum. Specific binding on different cell lines including U-87 MG, MCF-7, SKBR3, and HT-29 was performed. The biodistribution of these radiotracers was evaluated in normal and U-87 MG Xenografted models. Finally, Tc(CO)-[6] and Tc(CO)-[7] were applied for in vivo imaging in U-87 MG Xenografted models.
RESULTS
Specific binding study indicates that Tc(CO)-[6] and Tc(CO)-[7] can recognize 5-HTR of U87-MG cell line. The biodistribution study in normal mice indicates that the brain uptake of Tc(CO)-[6] and Tc(CO)-[7] is the highest at 30 min post-injection (0.8 ± 0.25 and 0.64 ± 0.18%ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38 ± 0.65 and 3.27 ± 0.5%ID/g, respectively). The injection of pimozide can block the tumor's radiotracer uptake, indicating the binding of these radiotracers to the 5-HTR. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for Tc(CO)-[6] and Tc(CO)-[7] at 60 min was 3.33 and 3.88, respectively. CONCLUSIONS: Tc(CO)-[6] and Tc(CO)-[7] can visualize tumor in the U87-MG xenograft model due to their affinity toward 5-HTR.
Topics: Mice; Humans; Animals; Serotonin; Tissue Distribution; Neoplasms; Radiopharmaceuticals; Piperazines; Technetium; Cell Line, Tumor
PubMed: 38032496
DOI: 10.1007/s12149-023-01885-2 -
Journal of Hepatology May 2024The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We...
BACKGROUND & AIMS
The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear.
METHODS
To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMOXCT1 (OXCT1 conditional knockout in macrophages) mice.
RESULTS
Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8 T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8 T-cell exhaustion and increasing CD8 T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8 T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC.
CONCLUSIONS
In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
IMPACT AND IMPLICATIONS
The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
PubMed: 38759889
DOI: 10.1016/j.jhep.2024.05.007 -
Biotechnology and Applied Biochemistry Oct 2023In spite of the higher nosocomial and community-acquired infections caused by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality...
In spite of the higher nosocomial and community-acquired infections caused by Staphylococcus aureus, emerging drug resistance is a leading cause of increased mortality and morbidity associated with the overuse of antimicrobials. It is an emergent need to find out new molecules to combat such infections. In the present study, we analyzed the antibacterial effect of pimozide (PMZ) against gram-positive and gram-negative bacterial strains, including methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) S. aureus. The growth of MSSA and MRSA was completely inhibited at concentrations of 12.5 and 100 μg/mL, respectively, which is referred to as 1× minimum inhibitory concentration (MIC). The cell viability was completely eliminated within 90 min of PMZ treatment (2× MIC) through reactive oxygen species (ROS)-mediated killing without affecting cell membrane permeability. It suppressed α-hemolysin production and biofilm formation of different S. aureus strains by almost 50% at 1× MIC concentration, and was found to detach matured biofilm. PMZ treatment effectively eliminates S. aureus infection in Caenorhabditis elegans and improves its survival by 90% and is found safe to use with no hemolytic effect on human and chicken blood tissues. Taken together, it is concluded that PMZ may turn out to be an effective antibacterial for treating bacterial infections including MSSA and MRSA.
Topics: Humans; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Pimozide; Reactive Oxygen Species; Anti-Bacterial Agents; Staphylococcal Infections; Methicillin; Anti-Infective Agents; Microbial Sensitivity Tests
PubMed: 37000616
DOI: 10.1002/bab.2465 -
Frontiers in Pharmacology 2023analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor...
analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission. In order to assess the patient's medication profile, real-time PCR was performed to analyze the main genes responsible for its metabolization, namely, and . The pharmacogenetic study revealed that the patient is a poor metabolizer for , presenting deletion of both copies of the gene (diplotype *5/*5). Fortunately, the symptomatology disappeared after the withdrawal of the responsible drug. In conclusion, abiding by the pharmacogenetic clinical practice guidelines and the pharmacogenetic analysis of when prescribing pimozide would have probably saved the patient from the consequences of severe side effects and the health system expenditure. There is an important need for more training in the pharmacogenetic field for specialists in psychiatry.
PubMed: 37637419
DOI: 10.3389/fphar.2023.1237446 -
Journal of Biomolecular Structure &... 2023In the present study, we screened eighty seven novel phytochemical compounds from four popular herbs, such as, and identified the best three for targeting the main...
In the present study, we screened eighty seven novel phytochemical compounds from four popular herbs, such as, and identified the best three for targeting the main protease (M) receptor of SARS-CoV-2. After categorizing all the phytochemicals based upon LibDock scores and hydrogen bonding interactions, the top ranked 26 compounds were further subjected for detailed Molecular dynamics (MD) study. From these screening we identified that Aegelinosides B leads the list with a high LibDock value of 142.50 (binding energy: -8.54 kcal/mol), which is better than several popular reference compounds namely, Tipranavir (LibDock score, 141.50), Saquinavir (125.34), Zopicole (122.9), Pirenepine (122.70), (115.37), Metixene (109.18), Oxiconazole Pimozide (138.00) and Rimonabant (91.88). Detailed analysis for structural stability (RMSD), Cα fluctuations (RMSF), intermolecular hydrogen bond interactions, effect of solvent accessibility (SASA) and compactness (Rg) factors were performed for the best six compounds and it is found that they are very stable and exhibit folding behavior. Apart from the docking and MD tests, through further drug-likeness and toxicity tests, three compounds, such as, Aegelinosides B, Epicatechin, and Feruloyltyramine (LibDock scores, respectively, 142.50, 124.33 and 129.06) can be suggested for fighting SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
PubMed: 35930306
DOI: 10.1080/07391102.2022.2107573 -
Journal of Interferon & Cytokine... Apr 2024Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1)...
Ponatinib and STAT5 Inhibitor Pimozide Combined Synergistic Treatment Applications Potentially Overcome Drug Resistance via Regulating the Cytokine Expressional Network in Chronic Myeloid Leukemia Cells.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance. The unsuccessful therapeutic approaches targeting BCR::ABL1, in particular third-line therapy with ponatinib, still need to be further developed with alternative combination strategies to overcome drug resistance. As treatment with the STAT5 inhibitor pimozide in combination with ponatinib resulted in an efficient and synergistic therapeutic approach in TKI-resistant CML cells, this study focused on identifying the underlying amplification of ponatinib response mechanisms by determining different cytokine expression profiles in parental and ponatinib-resistant CML cells, . The results showed that expression of interleukin , , and was increased by 2-fold, while was downregulated by 2-fold in the ponatinib-resistant cells compared to sensitive ones. Importantly, ponatinib treatment upregulated the expression of 21 of the 23 interferon and genes in the ponatinib-resistant cells, while treatment with pimozide or a combination dose resulted in a reduction in the expression of 19 different cytokine genes, such as for example, inflammatory cytokines, and or cytokine genes associated with supporting tumor progression, leukemia stem cell growth or poor survival, such as , , , , , or . Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results showed that the genes were mainly enriched in the regulation of receptor signaling through the Janus kinase/signal transducer and activator of transcription pathway, cytokine-cytokine receptor interaction, and hematopoietic cell lineage. Protein-protein interaction analysis showed that , , , , and others appeared in the top lists of pathways, indicating their high centrality and importance in the network. Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.
Topics: Humans; Pimozide; Cytokines; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; STAT5 Transcription Factor; Interleukin-15; Interleukin-6; Interleukin-9; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imidazoles; Pyridazines
PubMed: 38579140
DOI: 10.1089/jir.2023.0170 -
ACS Infectious Diseases Dec 2023The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using...
The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in . From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in . Seven compounds, including ivacaftor (), butenafine (), naftifine (), pimozide (), thioridazine (), trifluoperazine (), and meloxicam (), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor () inhibited efflux dose dependently, had no effect on an strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.
Topics: Escherichia coli; Escherichia coli Proteins; Ligands; Membrane Transport Proteins; Bacterial Outer Membrane Proteins; Multidrug Resistance-Associated Proteins; Anti-Bacterial Agents; Carrier Proteins
PubMed: 37888944
DOI: 10.1021/acsinfecdis.3c00350 -
Cureus Sep 2023Tics are sudden, repetitive, non-rhythmic movements and/or vocalizations. Generally, tics begin during childhood as a part of Tourette syndrome (TS) and rarely have an...
Tics are sudden, repetitive, non-rhythmic movements and/or vocalizations. Generally, tics begin during childhood as a part of Tourette syndrome (TS) and rarely have an onset during adulthood. We describe a 30-year-old male who presented with multiple motor and vocal tics two weeks following a closed head injury with alteration of consciousness as a result of being crushed against the wall by a 4,100-pound air-conditioning unit. He started having motor tics that developed in a rostrocaudal distribution, followed by simple and complex vocal tics. His tics increased in severity over several months following the injury until presentation. He was started on pimozide and received hyperbaric oxygen treatment which improved both motor and vocal tics.
PubMed: 37876411
DOI: 10.7759/cureus.45741 -
Neuropharmacology Sep 2023Conditioned stimuli (CS) paired with foot-shock can enhance memory consolidation. Because the dopamine D3 receptor (D3R) has been implicated in mediating various...
Conditioned stimuli (CS) paired with foot-shock can enhance memory consolidation. Because the dopamine D3 receptor (D3R) has been implicated in mediating various responses to CSs, the current study explored its potential role in modulation of memory consolidation by an avoidance CS. Male Sprague-Dawley rats trained to avoid foot-shocks in a two-way signalled active avoidance task (8 sessions, 30 trials per session, 0.8 mA foot-shock) were pre-treated with the D3R antagonist NGB-2904 (Vehicle, 0.1 or 5 mg/kg) and exposed to the CS immediately after the sample phase of an object recognition memory task. Discrimination ratios were assessed 72 h later. Immediate, but not delayed (6 h), post-sample exposure to the CS enhanced object recognition memory and this effect was blocked by NGB-2904. Control experiments with the beta-noradrenergic receptor antagonist propranolol (10 or 20 mg/kg) and D2R antagonist pimozide (0.2 or 0.6 mg/kg) indicated that NGB-2904 targeted post-training memory consolidation. Exploring the pharmacological selectivity of the NGB-2904 effect, it was found that: 1) 5 mg/kg NGB-2904 blocked conditioned memory modulation produced by post-sample exposure to a "weak" CS (one day of avoidance training) and concurrent stimulation of catecholamine activity by 10 mg/kg bupropion; and 2) post-sample exposure to a "weak" CS and concurrent administration of the D3R agonist 7-OH-DPAT (1 mg/kg) enhanced consolidation of object memory. Finally, because 5 mg/kg NGB-2904 had no effect on modulation by avoidance training in the presence of foot-shocks, the findings herein support the hypothesis that the D3R plays an important role in modulation of memory consolidation by CSs.
Topics: Rats; Animals; Male; Rats, Sprague-Dawley; Memory Consolidation; Conditioning, Operant; Conditioning, Classical; Receptors, Dopamine D3; Propranolol; Avoidance Learning
PubMed: 37149214
DOI: 10.1016/j.neuropharm.2023.109572 -
IScience Feb 2024Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We...
Human iPSC-derived cardiomyocytes (hiPSC-CMs) exhibit functional immaturity, potentially impacting their suitability for assessing drug proarrhythmic potential. We previously devised a traveling wave (TW) system to promote maturation in 3D cardiac tissue. To align with current drug assessment paradigms (CiPA and JiCSA), necessitating a 2D monolayer cardiac tissue, we integrated the TW system with a multi-electrode array. This gave rise to a hiPSC-derived closed-loop cardiac tissue (iCT), enabling spontaneous TW initiation and swift pacing of cardiomyocytes from various cell lines. The TW-paced cardiomyocytes demonstrated heightened sarcomeric and functional maturation, exhibiting enhanced response to isoproterenol. Moreover, these cells showcased diminished sensitivity to verapamil and maintained low arrhythmia rates with ranolazine-two drugs associated with a low risk of torsades de pointes (TdP). Notably, the TW group displayed increased arrhythmia rates with high and intermediate risk TdP drugs (quinidine and pimozide), underscoring the potential utility of this system in drug assessment applications.
PubMed: 38333703
DOI: 10.1016/j.isci.2024.108992