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International Journal of Molecular... Dec 2023Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal...
Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available carboxylic acids, the parallel synthesis of a variety of disubstituted 4-(piperazin-1-ylmethyl)thiazol-2-amine derivatives is described. the screening of the compounds led to the identification of antiplasmodial compounds that exhibited interesting antimalarial activity, primarily against the chloroquine-resistant Dd2 strain. The hit compound demonstrated an antiplasmodial EC of 102 nM in the chloroquine-resistant Dd2 strain and a selectivity of over 140.
Topics: Antimalarials; Piperazine; Thiazoles; Chloroquine; Plasmodium falciparum
PubMed: 38139243
DOI: 10.3390/ijms242417414 -
International Journal of Pharmaceutics Aug 2023Feasibility of electrospinning in the manufacturing of sildenafil-containing orodispersible films (ODFs) intended to enhance oxygenation and to reduce pulmonary arterial...
Feasibility of electrospinning in the manufacturing of sildenafil-containing orodispersible films (ODFs) intended to enhance oxygenation and to reduce pulmonary arterial pressure in pediatric patients was evaluated. Given the targeted subjects, the simplest and safest formulation was chosen, using water as the only solvent and pullulan, a natural polymer, as the sole fiber-forming agent. A systematic characterization in terms of shear and extensional viscosity as well as surface tension of solutions containing different amounts of pullulan and sildenafil was carried out. Accordingly, electrospinning parameters enabling the continuous production, at the highest possible rate, of defect-free fibers with uniform diameter in the nanometer range were assessed. Morphology, microstructure, drug content and relevant solid state as well as ability of the resulting non-woven films to interact with aqueous fluids were evaluated. To better define the role of the fibrous nanostructure on the performance of ODFs, analogous films were produced by spin- and blade-coating and tested. Interestingly, the disintegration process of electrospun products turned out to be the fastest (i.e. occurring within few s) and compliant with Ph. Eur. and USP limits, making relevant ODFs particularly promising for increasing sildenafil bioavailability, thus lowering its dosages.
Topics: Humans; Child; Drug Delivery Systems; Sildenafil Citrate; Solubility; Glucans; Water
PubMed: 37479102
DOI: 10.1016/j.ijpharm.2023.123258 -
Cell Communication and Signaling : CCS Feb 2024Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both... (Review)
Review
Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance. Video Abstract.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Epigenesis, Genetic; Pyrimidines; Proto-Oncogene Proteins c-kit; Mutation; Biological Products; Drug Resistance, Neoplasm; Protein Kinase Inhibitors
PubMed: 38414063
DOI: 10.1186/s12964-023-01411-x -
Advanced Science (Weinheim,... Jun 2024The recent discovery of copper-mediated and mitochondrion-dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer...
The recent discovery of copper-mediated and mitochondrion-dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer therapy. Here the design of a core-shell nanoparticle, CuP/Er, for the co-delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis is reported. The anti-Warburg effect of Er sensitizes tumor cells to Cu-mediated cuproptosis, leading to irreparable mitochondrial damage by depleting glutathione and enhancing lipid peroxidation. CuP/Er induces strong immunogenic cell death, enhances antigen presentation, and upregulates programmed death-ligand 1 expression. Consequently, CuP/Er promotes proliferation and infiltration of T cells, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple-negative breast cancer and prevent tumor metastasis. This study suggests a unique opportunity to synergize cuproptosis and ferroptosis with combination therapy nanoparticles to elicit strong antitumor effects and potentiate current cancer immunotherapies.
Topics: Ferroptosis; Animals; Mice; Immunotherapy; Copper; Nanoparticles; Disease Models, Animal; Humans; Cell Line, Tumor; Female; Triple Negative Breast Neoplasms; Piperazines
PubMed: 38477411
DOI: 10.1002/advs.202310309 -
Free Radical Biology & Medicine Jun 2024Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation...
Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation by its phospholipase A (aiPLA) and lysophosphatidylcholine acyltransferase activities. Prdx6 is highly expressed in the lung, and intact lungs and cells null for Prdx6 or with single-point mutations that inactivate either Prdx6-peroxidase or aiPLA activity alone exhibit decreased viability, increased lipid peroxidation, and incomplete repair when exposed to paraquat, hyperoxia, or organic peroxides. Ferroptosis is form of cell death driven by the accumulation of phospholipid hydroperoxides. We studied the role of Prdx6 as a ferroptosis suppressor in the lung. We first compared the expression Prdx6 and glutathione peroxidase 4 (GPx4) and visualized Prdx6 and GPx4 within the lung. Lung Prdx6 mRNA levels were five times higher than GPx4 levels. Both Prdx6 and GPx4 localized to epithelial and endothelial cells. Prdx6 knockout or knockdown sensitized lung endothelial cells to erastin-induced ferroptosis. Cells with genetic inactivation of either aiPLA or Prdx6-peroxidase were more sensitive to ferroptosis than WT cells, but less sensitive than KO cells. We then conducted RNA-seq analyses in Prdx6-depleted cells to further explore how the loss of Prdx6 sensitizes lung endothelial cells to ferroptosis. Prdx6 KD upregulated transcriptional signatures associated with selenoamino acid metabolism and mitochondrial function. Accordingly, Prdx6 deficiency blunted mitochondrial function and increased GPx4 abundance whereas GPx4 KD had the opposite effect on Prdx6. Moreover, we detected Prdx6 and GPx4 interactions in intact cells, suggesting that both enzymes cooperate to suppress lipid peroxidation. Notably, Prdx6-depleted cells remained sensitive to erastin-induced ferroptosis despite the compensatory increase in GPx4. These results show that Prdx6 suppresses ferroptosis in lung endothelial cells and that both aiPLA and Prdx6-peroxidase contribute to this effect. These results also show that Prdx6 supports mitochondrial function and modulates several coordinated cytoprotective pathways in the pulmonary endothelium.
Topics: Ferroptosis; Peroxiredoxin VI; Phospholipid Hydroperoxide Glutathione Peroxidase; Lung; Animals; Endothelial Cells; Mice; Lipid Peroxidation; Humans; Phospholipases A2; Mice, Knockout; Piperazines; Group VI Phospholipases A2
PubMed: 38579937
DOI: 10.1016/j.freeradbiomed.2024.04.208 -
International Journal of Molecular... May 2024Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations... (Review)
Review
Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.
Topics: Humans; Antipsychotic Agents; Piperazines; Receptors, Dopamine D3; Schizophrenia; Animals; Bipolar Disorder; Drug Development
PubMed: 38891871
DOI: 10.3390/ijms25115682 -
Arteriosclerosis, Thrombosis, and... Oct 2023ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation...
BACKGROUND
ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y and P2Y receptors in ADP-induced TF exposure; (2) modulation of TF-platelets in anti-P2Y-treated patients with coronary artery disease. Based on the obtained results, we revisited the intracellular localization of TF in platelets.
METHODS
The effects of P2Y or P2Y antagonists on ADP-induced TF expression and activity were analyzed in vitro by flow cytometry and thrombin generation assay in blood from healthy subjects, P2Y, and patients with gray platelet syndrome. Ex vivo, P2Y inhibition of TF expression by clopidogrel/prasugrel/ticagrelor, assessed by VASP (vasodilator-stimulated phosphoprotein) platelet reactivity index, was investigated in coronary artery disease (n=238). Inhibition of open canalicular system externalization and electron microscopy (TEM) were used for TF localization.
RESULTS
In blood from healthy subjects, stimulated in vitro by ADP, the percentage of TF-platelets (17.3±5.5%) was significantly reduced in a concentration-dependent manner by P2Y inhibition only (-81.7±9.5% with 100 nM AR-C69931MX). In coronary artery disease, inhibition of P2Y is paralleled by reduction of ADP-induced platelet TF expression (VASP platelet reactivity index: 17.9±11%, 20.9±11.3%, 40.3±13%; TF-platelets: 10.5±4.8%, 9.8±5.9%, 13.6±6.3%, in prasugrel/ticagrelor/clopidogrel-treated patients, respectively). Despite this, 15% of clopidogrel good responders had a level of TF-platelets similar to the poor-responder group. Indeed, a stronger P2Y inhibition (130-fold) is required to inhibit TF than VASP. Thus, a VASP platelet reactivity index <20% (as in prasugrel/ticagrelor-treated patients) identifies patients with TF-platelets <20% (92% sensitivity). Finally, colchicine impaired in vitro ADP-induced TF expression but not α-granule release, suggesting that TF is open canalicular system stored as confirmed by TEM and platelet analysis of patients with gray platelet syndrome.
CONCLUSIONS
Data show that TF expression is regulated by P2Y and not P2Y; P2Y antagonists downregulate the percentage of TF-platelets. In clopidogrel good-responder patients, assessment of TF-platelets highlights those with residual platelet reactivity. TF is stored in open canalicular system, and its membrane exposure upon activation is prevented by colchicine.
Topics: Humans; Blood Platelets; Clopidogrel; Coronary Artery Disease; Gray Platelet Syndrome; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thromboplastin; Ticagrelor
PubMed: 37589138
DOI: 10.1161/ATVBAHA.123.319099 -
Drug Metabolism and Disposition: the... Nov 2023Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin C and area under the blood concentration...
Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin C and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (-)--hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC: 4.9, 13.1, and 5.8 M for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (-)--hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin C by 31% and 25%, respectively, and had no effect on half-life. Berberine and (-)--hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal-metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT: Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.
Topics: Humans; Animals; Mice; Metformin; Berberine; Hydrastis; Imatinib Mesylate; Alkaloids; Membrane Transport Proteins; Organic Cation Transport Proteins
PubMed: 37562957
DOI: 10.1124/dmd.123.001360 -
Hepatology International Apr 2024Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the...
BACKGROUND & AIMS
Combination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME).
METHODS
We established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database.
RESULTS
The number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells.
CONCLUSIONS
In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.
Topics: Animals; Mice; Humans; Carcinoma, Hepatocellular; B7-H1 Antigen; Granzymes; Liver Neoplasms; Fibroblast Growth Factors; Antineoplastic Agents; Immunosuppressive Agents; Protein Kinase Inhibitors; Forkhead Transcription Factors; Tumor Microenvironment; Quinolines; Pyrazoles; Benzamides; Phenylurea Compounds; Anilides; Piperazines; Pyridines
PubMed: 37864726
DOI: 10.1007/s12072-023-10603-z -
Scientific Reports Nov 2023Microglia chronic activation is a hallmark of several neurodegenerative diseases, including the retinal ones, possibly contributing to their etiopathogenesis. However,...
Microglia chronic activation is a hallmark of several neurodegenerative diseases, including the retinal ones, possibly contributing to their etiopathogenesis. However, some microglia sub-populations have anti-inflammatory and neuroprotective functions, thus making arduous deciphering the role of these cells in neurodegeneration. Since it has been proposed that functionally different microglia subsets also rely on different metabolic routes, we hypothesized that modulating microglia metabolism might be a tool to enhance their anti-inflammatory features. This would have a preventive and therapeutic potential in counteracting neurodegenerative diseases. For this purpose, we tested various molecules known to act on cell metabolism, and we revealed the anti-inflammatory effect of the FDA-approved piperazine derivative Ranolazine on microglia cells, while confirming the one of the flavonoids Quercetin and Naringenin, both in vitro and in vivo. We also demonstrated the synergistic anti-inflammatory effect of Quercetin and Idebenone, and the ability of Ranolazine, Quercetin and Naringenin to counteract the neurotoxic effect of LPS-activated microglia on 661W neuronal cells. Overall, these data suggest that using the selected molecules -also in combination therapies- might represent a valuable approach to reduce inflammation and neurodegeneration while avoiding long term side effects of corticosteroids.
Topics: Humans; Microglia; Ranolazine; Quercetin; Anti-Inflammatory Agents; Inflammation; Neurodegenerative Diseases; Lipopolysaccharides; Neuroprotective Agents
PubMed: 37978212
DOI: 10.1038/s41598-023-47540-8