RESUMEN
Thyroid cancer is increasing globally, with anaplastic thyroid carcinoma (ATC) being the most aggressive type and having a poor prognosis. Current clinical treatments for thyroid cancer present numerous challenges, including invasiveness and the necessity of lifelong medication. Furthermore, a significant portion of patients with ATC experience cancer recurrence and metastasis. To overcome this dilemma, we developed a pH-responsive biomimetic nanocarrier (CLP@HP-A) through the incorporation of Chlorin e6 (Ce6) and Lenvatinib (Len) within hollow polydopamine nanoparticles (HP) that were further modified with platinum nanoparticles (Pt), enabling synergistic chemotherapy and sonodynamic therapy. The CLP@HP-A nanocarriers exhibited specific binding with galectin-3 receptors, facilitating their internalization through receptor-mediated endocytosis for targeted drug delivery. Upon exposure to ultrasound (US) irradiation, Ce6 rapidly generated reactive oxygen species (ROS) to induce significant oxidative stress and trigger apoptosis in tumor cells. Additionally, Pt not only alleviated tumor hypoxia by catalyzing the conversion of H2O2 to oxygen (O2) but also augmented intracellular ROS levels through the production of hydroxyl radicals (â¢OH), thereby enhancing the efficacy of sonodynamic therapy. Moreover, Len demonstrated a potent cytotoxic effect on thyroid cancer cells through the induction of apoptosis. Transcriptomics analysis findings additionally corroborated that CLP@HP-A effectively triggered cancer cell apoptosis, thereby serving as a crucial mechanism for its cytotoxic effects. In conclusion, the integration of sonodynamic/chemo combination therapy with targeted drug delivery systems offers a novel approach to the management of malignant tumors.
Asunto(s)
Clorofilidas , Indoles , Platino (Metal) , Polímeros , Porfirinas , Neoplasias de la Tiroides , Microambiente Tumoral , Terapia por Ultrasonido , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/terapia , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/metabolismo , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Indoles/química , Terapia por Ultrasonido/métodos , Porfirinas/química , Porfirinas/farmacología , Polímeros/química , Animales , Platino (Metal)/química , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Ratones , Quinolinas/farmacología , Quinolinas/química , Ratones Desnudos , Portadores de Fármacos/químicaRESUMEN
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients' survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients' poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-ß signaling pathway. TGF-ß signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-ß signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention.
Asunto(s)
Carcinogénesis , Proliferación Celular , Neoplasias Colorrectales , Transducción de Señal , Factor de Crecimiento Transformador beta , Animales , Femenino , Humanos , Masculino , Ratones , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Pronóstico , Pirazoles/farmacología , Quinolinas/farmacología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Predictions based on patient-derived materials of CFTR modulators efficacy have been performed lately in patient-derived cells, extending FDA-approved drugs for CF patients harboring rare variants. Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids. RESULTS: Our functional analysis (Ussing chamber) confirmed that S737F-CFTR is a mild variant with residual function as investigated in colonoids of patients with S737F/Dele22-24 and S737F/W1282X genotypes. An increase of current upon Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment was recorded for the former genotype. T465N is a poorly characterized missense variant that strongly impacts CFTR function, as almost no CFTR-mediated anion secretion was registered for T465N/Q39X colonoids. ETI treatment substantially improved CFTR-mediated anion secretion and increased the rescue of mature CFTR expression compared to either untreated colonoids or to dual CFTR modulator therapies. CONCLUSIONS: Our study confirms the presence of a residual function of the S737F variant and its limited response to CFTR modulators while predicting for the first time the potential clinical benefit of Trikafta® for patients carrying the rare T465N variant.
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Aminofenoles , Benzodioxoles , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Organoides , Quinolonas , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Organoides/metabolismo , Organoides/efectos de los fármacos , Benzodioxoles/farmacología , Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Quinolonas/farmacología , Aminofenoles/farmacología , Indoles/farmacología , Combinación de Medicamentos , Pirazoles/farmacología , Masculino , Femenino , Quinolinas/farmacología , Piridinas , PirrolidinasRESUMEN
Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in SupersomesTM in vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs.
Asunto(s)
Sistema Enzimático del Citocromo P-450 , Hígado , Oxidación-Reducción , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas , Quinolinas , Animales , Quinolinas/farmacología , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Oxidación-Reducción/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Ratas Sprague-Dawley , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
Echinochloa crus-galli (L.) P. Beauv is a monocotyledonous weed that seriously infests rice fields. Florpyrauxifen-benzyl, a novel synthetic auxin herbicide commercialized in China in 2018, is an herbicide for controlling E. crus-galli. However, a suspected resistant population (R) collected in 2012 showed resistance to the previously unused florpyrauxifen-benzyl. Whole-plant dose-response bioassay indicated that the R population evolved high resistance to quinclorac and florpyrauxifen-benzyl. Pretreatment with P450 inhibitors did not influence the GR50 of E. crus-galli to florpyrauxifen-benzyl. The expression of target receptor EcAFB4 was down-regulated in the R population, leading to the reduced response to florpyrauxifen-benzyl (suppresses over-production of ethylene and ABA). We verified this resistance mechanism in the knockout OsAFB4 in Oryza sativa L. The Osafb4 mutants exhibited high resistance to florpyrauxifen-benzyl and moderate resistance to quinclorac. Furthermore, DNA methylation in the EcAFB4 promoter regulated its low expression in the R population after florpyrauxifen-benzyl treatment. In summary, the low expression of the auxin receptor EcAFB4 confers target resistance to the synthetic auxin herbicide florpyrauxifen-benzyl in the R- E. crus-galli.
Asunto(s)
Echinochloa , Resistencia a los Herbicidas , Herbicidas , Proteínas de Plantas , Echinochloa/efectos de los fármacos , Echinochloa/genética , Echinochloa/metabolismo , Herbicidas/farmacología , Resistencia a los Herbicidas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Oryza/genética , Oryza/metabolismo , Oryza/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacología , Quinolinas/farmacología , Malezas/efectos de los fármacos , Malezas/genética , Malezas/metabolismoRESUMEN
The prevalence of obesity-induced asthma increases in women after menopause. We hypothesized that the increase in obese asthma in middle-aged women results from estrogen loss. In particular, we focused on the acute action of estrogen through the G protein-coupled estrogen receptor 1 (GPER), previously known as GPR30. We investigated whether GPER activation ameliorates obesity-induced asthma with a high-fat diet (HFD) using G-1, the GPER agonist, and G-36, the GPER antagonist. Administration of G-1 (0.5 mg/kg) suppressed HFD-induced airway hypersensitivity (AHR), and increased immune cell infiltration, whereas G-36 co-treatment blocked it. Histological analysis showed that G-1 treatment inhibited HFD-induced inflammation, fibrosis, and mucus hypersecretion in a GPER-dependent manner. G-1 inhibited the HFD-induced rise in the mRNA levels of pro-inflammatory cytokines in the gonadal white adipose tissue and lungs, whereas G-36 co-treatment reversed this effect. G-1 increased anti-inflammatory M2 macrophages and inhibited the HFD-induced rise in pro-inflammatory M1 macrophages in the lungs. In addition, G-1 treatment reversed the HFD-induced increase in leptin expression and decrease in adiponectin expression in the lungs and gonadal white adipose tissue. The results suggest that activation of GPER could be a therapeutic option for obesity-induced asthma.
Asunto(s)
Asma , Dieta Alta en Grasa , Macrófagos , Obesidad , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Animales , Receptores Acoplados a Proteínas G/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Asma/metabolismo , Asma/tratamiento farmacológico , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Receptores de Estrógenos/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Femenino , Quinolinas/farmacología , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Citocinas/metabolismoRESUMEN
The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 µM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 µM. Additionally, all compounds with IC50 < 10 µM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 µM, and the other thirteen behaving as double inhibitors.
Asunto(s)
Inhibidores Enzimáticos , L-Lactato Deshidrogenasa , Simulación del Acoplamiento Molecular , Pirimidinas , Humanos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/química , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a-f and 6a-f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a-h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a-d with organic azides. The structures of the obtained compounds were confirmed by 1H and 13C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a-f and 6a-f and 1,2,3-triazole derivatives 7a-h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a-f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC50 of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity.
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Antibacterianos , Antineoplásicos , Pruebas de Sensibilidad Microbiana , Quinolinas , Sulfonamidas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Línea Celular Tumoral , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Diseño de Fármacos , Relación Estructura-Actividad , Staphylococcus aureus/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Estructura MolecularRESUMEN
Phenol, quinoline, and pyridine, commonly found in industrial wastewater, disrupt the nitrification process, leading to nitrite accumulation. This study explores the potential mechanisms through which these biotoxic organic compounds affect nitrite accumulation, using metagenomic and molecular docking analyses. Despite increasing concentrations of these compounds from 40 to 160 mg/L, ammonia nitrogen removal was not hindered, and stable nitrite accumulation rates exceeding 90 % were maintained. Additionally, these compounds inhibited nitrite-oxidizing bacteria (NOB) and enriched ammonia-oxidizing bacteria (AOB) in situ. As the concentration of these compounds rose, protein (PN) and polysaccharide (PS) concentrations also increased, along with a higher PN/PS ratio. Metagenomic analysis further revealed an increase in hao relative abundance, while microbial community analysis showed increased Nitrosomonas abundance, which contributed to nitrite accumulation stability. Molecular docking indicated that these compounds have lower binding energy with hydroxylamine oxidoreductase (HAO) and nitrate reductase (NAR), theoretically supporting the observed sustained nitrite accumulation.
Asunto(s)
Metagenómica , Simulación del Acoplamiento Molecular , Nitrificación , Nitritos , Piridinas , Quinolinas , Nitritos/metabolismo , Quinolinas/farmacología , Metagenómica/métodos , Piridinas/farmacología , Piridinas/metabolismo , Fenol , Bacterias/metabolismo , Bacterias/efectos de los fármacos , Microbiota/efectos de los fármacos , Aguas Residuales , Oxidorreductasas/metabolismo , Amoníaco/metabolismoRESUMEN
Southern root-knot nematodes are among the most pernicious phytoparasites; they are responsible for substantial yield losses in agricultural crops worldwide. The limited availability of nematicides for the prevention and control of plant-parasitic nematodes necessitates the urgent development of novel nematicides. Natural products have always been a key source for the discovery of pesticides. Waltherione A, an alkaloid, exhibits potent nematocidal activity. In this study, we designed and synthesized a series of quinoline and quinolone derivatives from Waltherione A, leveraging a strategy of structural simplification. Bioassays have revealed that the quinoline derivatives exhibit better activity than quinolone derivatives in terms of both nematocidal and fungicidal activities. Notably, compound D1 demonstrated strong nematocidal activity, with a 72 h LC50 of 23.06 µg/mL, and it effectively controlled the infection of root-knot nematodes on cucumbers. The structure-activity relationship suggests that the quinoline moiety is essential for the nematocidal efficacy of Waltherione A. Additionally, compound D1 exhibited broad-spectrum fungicidal activity, with an EC50 of 2.98 µg/mL against Botrytis cinerea. At a concentration of 200 µg/mL, it significantly inhibited the occurrence of B. cinerea on tomato fruits, with an inhibitory effect of 96.65%, which is slightly better than the positive control (90.30%).
Asunto(s)
Antinematodos , Antinematodos/farmacología , Antinematodos/síntesis química , Antinematodos/química , Relación Estructura-Actividad , Animales , Diseño de Fármacos , Enfermedades de las Plantas/parasitología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Cucumis sativus/parasitología , Cucumis sativus/microbiología , Fungicidas Industriales/farmacología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Nematodos/efectos de los fármacos , Tylenchoidea/efectos de los fármacos , Botrytis/efectos de los fármacos , Quinolonas/farmacología , Quinolonas/química , Quinolonas/síntesis química , Estructura MolecularRESUMEN
Tetrahydroquinolines are key structures in a variety of natural products with diverse pharmacological utilities and other applications. A series of 3,4-diaryl-5,7-dimethoxy-1,2,3,4-tetrahydroquinolines were synthesized in good yield by reacting 3-aryl-5,7-dimethoxy-2,3-dihydroquinolin-4-ones with different Grignard reagents followed by the dehydration of the intermediate phenolic compounds. Subsequent reduction and deprotection were carried out to achieve the desired tetrahydroquinolone moiety. The lead compound 3c showed low micromolar inhibition of various cancer cell lines. Demethylation under different reaction conditions was also investigated to afford the corresponding monohydroxy analogues.
Asunto(s)
Antineoplásicos , Quinolinas , Humanos , Quinolinas/química , Quinolinas/síntesis química , Quinolinas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Estructura Molecular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Solanum torvum Sw. (ST) is used to clear heat toxins, promote blood circulation, and alleviate blood stasis. Therefore, this plant has traditionally been used as an ethnomedicine for common cold, chronic gastritis, and tumors. AIM OF THE STUDY: This study aimed to elucidate the mechanism by which ST induces ferroptosis in hepatocellular carcinoma (HCC), the combination effect with lenvatinib, and the impact on lenvatinib-resistant cells. MATERIALS AND METHODS: Cell viability assays were performed using different hepatoma cell lines treated with ST. Lipid peroxidation and iron assays were performed using flow cytometry. Molecules involved in the ferroptosis pathway were detected by Western blotting. Finally, a lenvatinib-resistant cell line was established to evaluate the antiproliferative effects of ST. RESULTS: ST ethanol extract inhibited the growth of various hepatoma cell lines. A significant reduction in glutathione peroxidase 4 (GPX4) expression was observed following ST treatment, which was accompanied by increased lipid peroxidation and Fe2+ accumulation. ST induced ferroptosis mainly through heme oxygenase-1 (HO-1) expression. HO-1 knockdown reduced ST-induced lipid peroxidation and reversed GPX4 suppression. Acyl-CoA synthetase long-chain family member 4 (ACSL4) also participated in ST-induced ferroptosis. ST and lenvatinib combination showed an additive effect, and ST retained its potential anti-HCC efficacy in a lenvatinib-resistant cell line. CONCLUSION: This study demonstrated that the ethanol extract of ST inhibits hepatoma cell growth by inducing ferroptosis. ST displayed an additive effect with lenvatinib in Hep 3B cells and showed remarkable anti-HCC activity in lenvatinib-resistant Hep 3B cells. Collectively, the study shows that ST might have the potential to reduce lenvatinib use in clinical practice and salvage cases of lenvatinib resistance.
Asunto(s)
Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Extractos Vegetales , Quinolinas , Solanum , Ferroptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Solanum/química , Extractos Vegetales/farmacología , Línea Celular Tumoral , Quinolinas/farmacología , Compuestos de Fenilurea/farmacología , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on human health. As a first-line drug for HCC, despite its excellent efficacy, lenvatinib (Len) is prone to developing drug resistance in HCC patients. The N6-methyladenosine (m6A) modification is not only related to the development of HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, our group first screened a small molecule m6A regulator, lobeline (Lob), from a library of 390 compounds (mostly natural products). In vitro experiments demonstrated that Lob could significantly enhance the sensitivity to Len of Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In Len-resistant cell-derived and patient-derived xenograft models, Lob could reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, respectively. Furthermore, MeRIP-m6A sequencing results indicated that the underlying molecular mechanism of Lob reversal of HCC drug resistance was related to UBE3B. Taken together, this study highlighted that Lob, a plant derived natural product, could reverse the resistance of HCC to Len by regulating the m6A levels. It is hoped that this will provide a pharmacological research basis for the clinical treatment of HCC patients.
Asunto(s)
Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Animales , Humanos , Ratones , Adenosina/análogos & derivados , Adenosina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Productos Biológicos/farmacología , Productos Biológicos/química , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Estructura Molecular , Compuestos de Fenilurea/farmacología , Quinolinas/farmacología , Quinolinas/química , LobelinaRESUMEN
BACKGROUND: When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment. METHODS: As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine. RESULTS: In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations. CONCLUSIONS: The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates.
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Antimaláricos , Desarrollo Embrionario , Reproducción , Pez Cebra , Animales , Antimaláricos/toxicidad , Antimaláricos/farmacología , Conejos , Femenino , Ratas , Embarazo , Desarrollo Embrionario/efectos de los fármacos , Reproducción/efectos de los fármacos , Quinolinas/toxicidad , Quinolinas/farmacología , Embrión no Mamífero/efectos de los fármacos , Masculino , Exposición Materna/efectos adversos , Desarrollo Fetal/efectos de los fármacos , Malaria/tratamiento farmacológicoRESUMEN
Human P-glycoprotein (P-gp) utilizes energy from ATP hydrolysis for the efflux of chemically dissimilar amphipathic small molecules and plays an important role in the development of resistance to chemotherapeutic agents in most cancers. Efforts to overcome drug resistance have focused on inhibiting P-gp-mediated drug efflux. Understanding the features distinguishing P-gp inhibitors from substrates is critical. Cryo-electron microscopy has revealed distinct binding patterns, emphasizing the role of the L-site or access tunnel in inhibition. We substituted 5-9 residues of the L-site with alanine to investigate whether the binding of a second inhibitor molecule to the L-site is required for inhibiting drug efflux. We reveal, for the first time, that mutations in the L-site affect the drug efflux activity of P-gp, despite their distance from the substrate-binding pocket (SBP). Surprisingly, after the mutations were introduced, inhibitors such as tariquidar and zosuquidar still inhibited drug efflux by mutant P-gps. Communication between the transmembrane helices (TMHs) and nucleotide-binding domains (NBDs) was evaluated using the ATPase assay, revealing distinct modulation patterns by inhibitors for the mutants, with zosuquidar exhibiting substrate-like stimulation of ATPase. Furthermore, L-site mutations abolished ATP-dependent thermal stabilization. In silico molecular docking studies corroborated the altered inhibitor binding due to mutations in the L-site residues, shedding light on their critical role in substrate transport and inhibitor interactions with P-gp. These findings suggest that inhibitors bind either to the SBP alone, and/or to alternate site(s) when the L-site is disabled by mutagenesis.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Humanos , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Sitios de Unión , Quinolinas/química , Quinolinas/farmacología , Quinolinas/metabolismo , Mutación , Modelos MolecularesRESUMEN
The irreversible pan-HER tyrosine kinase inhibitor neratinib is approved for patients with HER2-positive, early-stage and metastatic breast cancer (BC). Neratinib-associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib-induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2-positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2-positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib- versus control-treated animals were not seen. Two of four endpoint-evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib-induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.
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Neoplasias de la Mama , Colonoscopía , Diarrea , Quinolinas , Ratas Wistar , Receptor ErbB-2 , Animales , Femenino , Diarrea/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Quinolinas/farmacología , Quinolinas/uso terapéutico , Ratas , Proyectos Piloto , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Humanos , Persona de Mediana Edad , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidadRESUMEN
New iridium(III) compounds (C1-C3) bearing 2-(1H-benzimidazol-2-yl)quinoline ligands with different side groups (benzyl, 2,3,4,5,6-pentamethylbenzyl and 2,3,4,5,6-pentafluorobenzyl) were synthesized and characterized by using spectroscopic analyses. The effects of different side groups of iridium compounds on the photophysical and electrochemical properties have been investigated. The cytotoxicity and apoptosis of the compounds have been evaluated on breast cancer cell lines using various methods including MTT assay, flow cytometry, qRT-PCR, and colony formation. The cytotoxicity of C1, expressed as IC50 values, was found to be 11.76 µM for MDA-MB-231 and 5.35 µM for MCF-7 cells. For C3, the IC50 value was 16.22 µM for MDA-MB-231 and 8.85 µM for MCF-7 cells. In both cell lines, increased levels of Bax and caspase 3, along with downregulation of BCL-2 and positive annexin V staining, were observed, confirming apoptosis. Moreover, the colony-forming abilities in both cell lines decreased after C1 and C3 complex treatment. All these results suggest that the compounds C1 and C3 may have potential in the treatment of breast cancer, though further research is needed to confirm their efficacy.
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Antineoplásicos , Apoptosis , Complejos de Coordinación , Ensayos de Selección de Medicamentos Antitumorales , Iridio , Quinolinas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Relación Dosis-Respuesta a Droga , Técnicas Electroquímicas , Iridio/química , Iridio/farmacología , Estructura Molecular , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Relación Estructura-Actividad , Compuestos de Bencilo/síntesis química , Compuestos de Bencilo/química , Compuestos de Bencilo/farmacologíaRESUMEN
Sporadically and periodically, influenza outbreaks threaten global health and the economy. Antigen drift-induced influenza virus mutations hamper antiviral drug development. Thus, a novel antiviral agent is urgently needed to address medication inefficacy issues. Herein, sixteen new quinoline-triazole hybrids 6a-h and 9a-h were prepared and evaluated in vitro against the H1N1 virus. In particular, 6d, 6e, and 9b showed promising H1N1 antiviral activity with selective index (SI) CC50/IC50 values of 15.8, 37, and 29.15. After that, the inhibition rates for various mechanisms of action (virus replication, adsorption, and virucidal activity) were investigated for the most efficient candidates 6d, 6e, and 9b. Additionally, their ability to inhibit neuraminidase was evaluated. With an IC50 value of 0.30 µM, hybrid 6d demonstrated effective and comparable inhibitory activity to Oseltamivir. Ultimately, molecular modeling investigations, encompassing molecular docking and molecular dynamic simulations, were conducted to provide a scientific basis for the observed antiviral results.
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Antivirales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos , Subtipo H1N1 del Virus de la Influenza A , Neuraminidasa , Quinolinas , Triazoles , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/enzimología , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Quinolinas/química , Quinolinas/farmacología , Quinolinas/síntesis química , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Humanos , Pruebas de Sensibilidad Microbiana , Descubrimiento de Drogas , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: Pharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases. METHODS: We employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS. RESULTS: Complete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans. CONCLUSIONS: This work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Acridinas , Barrera Hematoencefálica , Encéfalo , Ratones Noqueados , Tetrahidroisoquinolinas , Animales , Tetrahidroisoquinolinas/farmacología , Tetrahidroisoquinolinas/administración & dosificación , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Ratones , Acridinas/farmacología , Acridinas/administración & dosificación , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/farmacocinética , Quinolinas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Masculino , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Hypercholesterolemia is associated with increased inflammation and impaired serotonin neurotransmission, potentially contributing to depressive symptoms. However, the role of statins, particularly pitavastatin, in modulating serotonin transporter (SERT) function within this context remains underexplored. This study aimed to investigate whether pitavastatin counteracts the neurobiological effects of hypercholesterolemia. METHODS: Low-density lipoprotein receptor knockout (LDLR-/-) mice on a C57BL/6 background were assigned to three groups: a control group fed a standard chow diet, a group fed a high-fat diet (HFD), and a third group fed a high-fat diet supplemented with pitavastatin (HFD + Pita). We evaluated the effects of HFD with or without pitavastatin on lipid profiles, inflammatory markers, and SERT availability using small-animal positron emission tomography (PET) scans with the radioligand 4-[18F]-ADAM over a 20-week period. RESULTS: Pitavastatin treatment in HFD-fed mice significantly reduced both total cholesterol and LDL cholesterol levels in HFD-fed mice compared to those on HFD alone. Elevated inflammatory markers such as IL-1α, MCP-1/CCL2, and TNF-α in HFD mice were notably decreased in the HFD + Pita group. PET scans showed reduced SERT availability in the brains of HFD mice; however, pitavastatin improved this in brain regions associated with mood regulation, suggesting enhanced serotonin neurotransmission. Additionally, the sucrose preference test showed a trend towards increased preference in the HFD + Pita group compared to the HFD group, indicating a potential reduction in depressive-like behavior. CONCLUSION: Our findings demonstrate that pitavastatin not only lowers cholesterol and reduces inflammation but also enhances SERT availability, suggesting a potential role in alleviating depressive symptoms associated with hypercholesterolemia. These results highlight the multifaceted benefits of pitavastatin, extending beyond its lipid-lowering effects to potentially improving mood regulation and neurotransmitter function.