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1.
Talanta ; 237: 122898, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34736714

RESUMO

A nucleolus as a prominent sub-nuclear, membraneless organelle plays a crucial role in ribosome biogenesis, which is in the major metabolic demand in a proliferating cell, especially in aggressive malignancies. We develop a γ-glutamyltranspeptidase (GGT)-activatable indole-quinolinium (QI) based cyanine consisting of a novel tripeptide fragment (Pro-Gly-Glu), namely QI-PG-Glu as a turn-on red fluorescent probe for the rapid detection of GGT-overexpressed A549 cancer cells in vivo. QI-PG-Glu can be triggered by GGT to rapidly release an activated fluorophore, namely HQI, in two steps including the cleavage of the γ-glutamyl group recognized by GGT and the rapid self-driven cyclization of the Pro-Gly linker. HQI exhibits dramatically red fluorescence upon binding to rRNA for imaging of nucleolus in live A549 cells. HQI also intervenes in rRNA biogenesis by declining the RNA Polymerase I transcription, thus resulting in cell apoptosis via a p53 dependent signaling pathway. Our findings may provide an alternative avenue to develop multifunctional cancer cell-specific nucleolus-targeting fluorescent probes with potential anti-cancer effects.


Assuntos
Neoplasias , Quinolinas , Fluorescência , Corantes Fluorescentes , Indóis , Neoplasias/diagnóstico por imagem , Quinolinas/farmacologia , gama-Glutamiltransferase
2.
Expert Opin Investig Drugs ; 30(10): 1017-1023, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34595995

RESUMO

INTRODUCTION: Resistant hypertension (RH) is more prevalent in the advanced stages of chronic kidney disease (CKD) and contributes to a greater likelihood of poor cardiovascular and renal outcomes. However, RH often goes untreated in this population as the currently available recommended add-on therapy, steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone, may lead to unacceptable side effects, mainly hyperkalemia in a cohort with reduced kidney function. KBP-5074 is a novel non-steroidal MRA that addresses the unmet need of treating RH in the CKD population without hyperkalemia. AREAS COVERED: We provide an overview of the current state of RH treatment in stage 3B/4 CKD as it relates to available steroidal MRAs and the current limitations of this treatment. We then explore the emerging data on nonsteroidal MRAs, particularly the novel agent KBP-5074 and its applicability to treatment in this context. EXPERT OPINION: In a randomized, double-blind, placebo-controlled phase 2b trial, the novel nonsteroidal MRA KBP-5074 demonstrated clinical efficacy and safety in treating RH in stage 3B/4 CKD and offers a potential new treatment option in this population at high risk for cardiovascular disease (CVD) and CKD progression.


Assuntos
Hipertensão/tratamento farmacológico , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Progressão da Doença , Resistência a Medicamentos , Humanos , Hipertensão/etiologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações
3.
J Pharm Biomed Anal ; 206: 114360, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34508926

RESUMO

Lenvatinib (LEN) is a multitargeted tyrosine kinase inhibitor registered for the first-line treatment of unresectable advanced hepatocellular carcinoma. Wuzhi capsule (WZC) is a traditional Chinese medicine preparation; it is used to decrease the aminotransferase level of the liver and protect liver function. Thus, patients with hepatocellular carcinoma (HCC) are potentially treated with a combination of LEN and WZC, but there is no information about the interaction between the two drugs. We developed a simple, rapid, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitative determination of lenvatinib in rat plasma. Liquid-liquid extraction of plasma samples was carried out with ethyl acetate. Chromatographic separation of analyte was performed using gradient elution with acetonitrile and 0.1% formic acid water. The positive ion multi-response monitoring mode was used, and the target of the parent and daughter ions of LEN and IS were m/z 427.1→370 and m/z 432.1→370, respectively. All the validation projects were in accordance with the guidelines. Good linearity of 0.2-1000 ng/mL (r > 0.999) was achieved. The lower limit of quantification was 0.2 ng/mL. The precision and accuracy are acceptable. The method was successfully applied to pharmacokinetics and drug interaction analysis. The results show that WZC can significantly increase the Cmax (maximum plasma concentration) and AUC (area under the concentration-time curve) of LEN. An UPLC -MS/MS method that can be used for studying drug-drug interaction as a valuable tool was developed in this study. Drug-drug interactions were observed between the WZC and LEN.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Compostos de Fenilureia/farmacologia , Quinolinas/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Interações Medicamentosas , Neoplasias Hepáticas/tratamento farmacológico , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
4.
Int J Cancer ; 149(11): 1961-1972, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469585

RESUMO

Adipocyte-rich omentum offers "good soil" for disseminating ovarian cancer (OvCa), contributing to therapeutic difficulty. However, little is understood about the association between adipocytes and tumor growth at peritoneal dissemination site. Herein, we report the induction of adipocyte dedifferentiation by OvCa cells and pro-tumorigenic effects of resulted adipocyte-derived fibroblasts. We confirmed that malignant ascites promoted the dedifferentiation of the primary human adipocytes obtained from surgical omental specimen into omental adipocyte-derived fibroblast (O-ADF) that possess both mesenchymal stem cell and myofibroblast-like features. This promotion of dedifferentiation by malignant ascites was blocked by addition of Wnt signaling inhibitor. The effects of dedifferentiated adipocytes in proliferation and migration of OvCa cells were analyzed with in vitro coculturing experimental models and in vivo mice model, and we demonstrated that OvCa cell lines showed enhanced proliferative characteristics, as well as increased migratory abilities upon coculturing with O-ADF. Additionally, exogenous transforming growth factor-ß1 augmented desmoplastic morphological change of O-ADF, leading to higher proliferative ability. Our results suggest that OvCa cells promote dedifferentiation of peritoneal adipocytes by activating Wnt/ß-catenin signaling, and generated O-ADFs exhibit pro-tumoral hallmarks.


Assuntos
Adipócitos/patologia , Fibroblastos Associados a Câncer/patologia , Omento/patologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral , Células 3T3-L1 , Actinas/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Ascite/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Desdiferenciação Celular/efeitos dos fármacos , Movimento Celular , Proliferação de Células , Feminino , Humanos , Imidas/farmacologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Omento/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Quinolinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt3A/metabolismo
5.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575827

RESUMO

The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy.


Assuntos
Antineoplásicos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Sinergismo Farmacológico , Glioblastoma , Humanos , Pirazóis/farmacologia , Quinolinas/farmacologia
6.
Molecules ; 26(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34577001

RESUMO

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its N-(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the tert-butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against Plasmodium falciparum NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.


Assuntos
Aminoquinolinas/química , Antimaláricos/química , Antimaláricos/farmacologia , Quinolinas/química , Tetrazóis/química , Aminoquinolinas/farmacologia , Animais , Antimaláricos/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Concentração Inibidora 50 , Plasmodium falciparum/efeitos dos fármacos , Primaquina/química , Quinolinas/farmacologia , Ratos , Tetrazóis/farmacologia
7.
Life Sci ; 285: 119955, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34520767

RESUMO

AIMS: G protein-coupled estrogen receptor 30 (GPR30) activation by its agonist, G1, exhibits beneficial actions in female with heart failure (HF). Recent evidence indicates its cardiovascular benefits may also include male as well. However, whether and how GPR30 activation may limit HF progression and have a salutary role in males is unknown. We hypothesized that chronic G1 treatment improves LV and cardiomyocyte function, [Ca2+]i regulation and ß-adrenergic reserve, thus limiting HF progression in male. MAIN METHODS: We compared left ventricle (LV) and myocyte function, [Ca2+]i transient ([Ca2+]iT) and ß-AR modulation in control male mice (12/group) and isoproterenol-induced HF (150 mg/kg s.c. for 2 days). Two weeks after isoproterenol injection, HF mice received placebo, or G1 (150 µg/kg/day s.c. mini-pump) for 2 weeks. KEY FINDINGS: Isoproterenol-treated mice exhibited HF with preserved ejection fraction (HFpEF) at 2-weeks and progressed to HF with reduced EF (HFrEF) at 4-weeks, manifested by significantly increased LV time constant of relaxation (τ), decreased EF and mitral flow (dV/dtmax), which were accompanied by reduced myocyte contraction (dL/dtmax), relaxation (dR/dtmax) and [Ca2+]iT. Acute isoproterenol-superfusion caused significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. G1 treatment in HF increased basal and isoproterenol-stimulated increases in EF and LV contractility of EES. Importantly, G1 improved basal and isoproterenol-stimulated dL/dtmax, dR/dtmax and [Ca2+]iT to control levels and restored normal cardiac ß-AR subtypes modulation. SIGNIFICANCE: Chronic G1 treatment restores normal myocyte basal and ß-AR-stimulated contraction, relaxation, and [Ca2+]iT, thereby reversing LV dysfunction and playing a rescue role in a male mouse model of HF.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Quinolinas/uso terapêutico , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Isoproterenol , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Quinolinas/farmacologia
8.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443487

RESUMO

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure-activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Chalconas/síntese química , Chalconas/farmacologia , Desenho de Fármacos , Quinolinas/síntese química , Quinolinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Humanos , Quinolinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
9.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361688

RESUMO

Trans-(-)-kusunokinin, an anticancer compound, binds CSF1R with low affinity in breast cancer cells. Therefore, finding an additional possible target of trans-(-)-kusunokinin remains of importance for further development. Here, a computational study was completed followed by indirect proof of specific target proteins using small interfering RNA (siRNA). Ten proteins in breast cancer were selected for molecular docking and molecular dynamics simulation. A preferred active form in racemic trans-(±)-kusunokinin was trans-(-)-kusunokinin, which had stronger binding energy on HER2 trans-(+)-kusunokinin; however, it was weaker than the designed HER inhibitors (03Q and neratinib). Predictively, trans-(-)-kusunokinin bound HER2 similarly to a reversible HER2 inhibitor. We then verified the action of (±)-kusunokinin compared with neratinibon breast cancer cells (MCF-7). (±)-Kusunokinin exhibited less cytotoxicity on normal L-929 and MCF-7 than neratinib. (±)-Kusunokinin and neratinib had stronger inhibited cell proliferation than siRNA-HER2. Moreover, (±)-kusunokinin decreased Ras, ERK, CyclinB1, CyclinD and CDK1. Meanwhile, neratinib downregulated HER, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1. Knocking down HER2 downregulated only HER2. siRNA-HER2 combination with (±)-kusunokinin suppressed HER2, c-Myc, CyclinB1, CyclinD and CDK1. On the other hand, siRNA-HER2 combination with neratinib increased HER2, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1 to normal levels. We conclude that trans-(±)-kusunokinin may bind HER2 with low affinity and had a different action from neratinib.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Lignanas/metabolismo , Lignanas/farmacologia , Piper nigrum/química , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Quinolinas/farmacologia , RNA Interferente Pequeno/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transfecção
10.
Expert Opin Investig Drugs ; 30(9): 913-921, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34428101

RESUMO

INTRODUCTION: Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain. AREAS COVERED: We provide an overview from the literature of in vitro, in vivo and real-life studies regarding lenvatinib as an investigational agent for the treatment of aggressive TC. EXPERT OPINION: According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.


Assuntos
Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Terapia Combinada , Progressão da Doença , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Humanos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia
11.
Pharmacology ; 106(9-10): 469-476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34350893

RESUMO

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host. SUMMARY: This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.


Assuntos
Acetatos/farmacologia , COVID-19/tratamento farmacológico , Ciclopropanos/farmacologia , Antagonistas de Leucotrienos/farmacologia , Quinolinas/farmacologia , Sulfetos/farmacologia , Acetatos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/metabolismo , COVID-19/fisiopatologia , Ciclopropanos/uso terapêutico , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Quinolinas/uso terapêutico , Receptores de Leucotrienos/metabolismo , Sulfetos/uso terapêutico
12.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452503

RESUMO

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (-1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro -1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential -1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting.


Assuntos
Antivirais/farmacologia , Mudança da Fase de Leitura do Gene Ribossômico/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Quinolinas/farmacologia , Vírus da SARS/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Células A549 , Animais , Linhagem Celular , Mudança da Fase de Leitura do Gene Ribossômico/fisiologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Vírus da SARS/genética , Vírus da SARS/fisiologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Bibliotecas de Moléculas Pequenas , Zoonoses Virais/virologia , Replicação Viral/efeitos dos fármacos
13.
Biochem Pharmacol ; 192: 114721, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363795

RESUMO

G protein-coupled estrogen receptor (GPER) is important for maintaining normal blood vessel function by preventing endothelial cell dysfunction. It has been reported that G-1, an agonist of GPER, increases nitric oxide (NO) production through the phosphorylation of endothelial nitric oxide synthase (eNOS). However, the effect of GPER activation on eNOS expression has not been studied. Our results show that G-1 significantly increased the expression of eNOS and Kruppel-like factor 2 (KLF2) in human endothelial EA.hy926 cells. The individual silences of KLF2 and GPER attenuated G-1-induced eNOS expression. In addition, inhibition of the Gαq and Gßγ suppressed G-1-induced the expression of eNOS and KLF2 in EA.hy926 cells. Interestingly, these effects were similar in HUVECs. Furthermore, we found that GPER-mediated Ca2+ signaling increased the phosphorylation of CaMKKß, AMPK, and CaMKIIα in the cells. The phosphorylation of histone deacetylase 5 (HDAC5) by activation of AMPK and CaMKIIα increased the expression of eNOS via transcriptional activity of KLF2. We further demonstrate that GPER activation increased the phosphorylation of Src, EGFR, ERK5, and MEF2C and consequently induced the expression of eNOS and KLF2. Meanwhile, inhibition of ERK5 and HDAC5 suppressed the expression of eNOS and KLF2 induced by G-1 in the cells. These findings suggest that GPER provides a novel mechanism for understanding the regulation of eNOS expression and is an essential therapeutic target in preventing cardiovascular-related endothelial dysfunction.


Assuntos
Sinalização do Cálcio/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Óxido Nítrico Sintase Tipo III/biossíntese , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Ciclopentanos/farmacologia , Receptores ErbB/metabolismo , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Óxido Nítrico Sintase Tipo III/genética , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas
14.
Cells ; 10(8)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34440856

RESUMO

The primary cause of colorectal cancer (CRC) recurrence is increased distant metastasis after radiotherapy, so there is a need for targeted therapeutic approaches to reduce the metastatic-relapse risk. Dysregulation of the cell-surface glycoprotein podocalyxin-like protein (PODXL) plays an important role in promoting cancer-cell motility and is associated with poor prognoses for many malignancy types. We found that CRC cells exposed to radiation demonstrated increased TGFß and PODXL expressions, resulting in increased migration and invasiveness due to increased extracellular matrix deposition. In addition, both TGFß and PODXL were highly expressed in tissue samples from radiotherapy-treated CRC patients compared to those from patients without this treatment. However, it is unclear whether TGFß and PODXL interactions are involved in cancer-progression resistance after radiation exposure in CRC. Here, using CRC cells, we showed that silencing PODXL blocked radiation-induced cell migration and invasiveness. Cell treatment with galunisertib (a TGFß-pathway inhibitor) also led to reduced viability and migration, suggesting that its clinical use may enhance the cytotoxic effects of radiation and lead to the effective inhibition of CRC progression. Overall, the results demonstrate that downregulation of TGFß and its-mediated PODXL may provide potential therapeutic targets for patients with radiotherapy-resistant CRC.


Assuntos
Neoplasias Colorretais/patologia , Radiação Ionizante , Sialoglicoproteínas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/efeitos da radiação , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/efeitos da radiação , Humanos , Metástase Neoplásica , Prognóstico , Pirazóis/farmacologia , Quinolinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sialoglicoproteínas/antagonistas & inibidores , Sialoglicoproteínas/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Vimentina/genética , Vimentina/metabolismo
15.
Aging (Albany NY) ; 13(13): 17097-17117, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34252884

RESUMO

Aberrant expression and denaturation of Tau, amyloid-beta and TDP-43 can lead to cell death and is a major component of pathologies such as Alzheimer's Disease (AD). AD neurons exhibit a reduced ability to form autophagosomes and degrade proteins via autophagy. Using genetically manipulated colon cancer cells we determined whether drugs that directly inhibit the chaperone ATPase activity or cause chaperone degradation and endoplasmic reticulum stress signaling leading to macroautophagy could reduce the levels of these proteins. The antiviral chaperone ATPase inhibitor AR12 reduced the ATPase activities and total expression of GRP78, HSP90, and HSP70, and of Tau, Tau 301L, APP, APP692, APP715, SOD1 G93A and TDP-43. In parallel, it increased the phosphorylation of ATG13 S318 and eIF2A S51 and caused eIF2A-dependent autophagosome formation and autophagic flux. Knock down of Beclin1 or ATG5 prevented chaperone, APP and Tau degradation. Neratinib, used to treat HER2+ breast cancer, reduced chaperone levels and expression of Tau and APP via macroautophagy, and neratinib interacted with AR12 to cause further reductions in protein levels. The autophagy-regulatory protein ATG16L1 is expressed as two isoforms, T300 or A300: Africans trend to express T300 and Europeans A300. We observed higher basal expression of Tau in T300 cells when compared to isogenic A300 cells. ATG16L1 isoform expression did not alter basal levels of HSP90, HSP70 or HSP27, however, basal levels of GRP78 were reduced in A300 cells. The abilities of both AR12 and neratinib to stimulate ATG13 S318 and eIF2A S51 phosphorylation and autophagic flux was also reduced in A300 cells. Our data support further evaluation of AR12 and neratinib in neuronal cells as repurposed treatments for AD.


Assuntos
Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas de Choque Térmico/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Adenosina Trifosfatases/antagonistas & inibidores , Grupo com Ancestrais do Continente Africano , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Proteína 5 Relacionada à Autofagia/genética , Proteína Beclina-1/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu , Técnicas de Silenciamento de Genes , Humanos , Quinolinas/farmacologia , Superóxido Dismutase-1/biossíntese , Superóxido Dismutase-1/genética , Proteínas tau/biossíntese , Proteínas tau/genética
16.
Biomed Pharmacother ; 139: 111697, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243614

RESUMO

Excessive osteoclast activity, along with relatively weak osteoblast function, is strongly associated with bone disease. Therefore, studies to identify novel anti-osteoporosis candidates with dual actions of inhibiting osteoclastogenesis and increasing osteoblastogenesis may provide an ideal approach for treating osteoporosis. Pitavastatin, an inhibitor of 3-hydroxy-3 methyl-glutaryl coenzyme A reductase, has demonstrated various pharmacological activities, including anti-inflammation, bone anabolic effects, vasodilation, and inhibition of revascularization; however, the precise effects and mechanisms of pitavastatin on the regulation of osteoblast and osteoclast activity need to be comprehensively elucidated. Herein, we demonstrated that pitavastatin is a potential candidate for treating osteoporosis by enhancing osteoblast differentiation and bone growth and inhibiting osteoclast differentiation and bone resorption. Pitavastatin exerted dose-dependent inhibitory effects on receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation, bone resorption, and osteoclast-specific marker gene expression. These inhibitory effects were achieved by inhibiting the Akt, NF-κB, and mitogen-activated protein kinase (p38, ERK, and JNK) signaling pathways, resulting in the downregulation of major transcription factors c-Fos and NFATc1. Furthermore, pitavastatin potentially stimulated osteoblast differentiation by activating alkaline phosphatase (ALP), enhancing mineralization by Alizarin Red S, and increasing the expression of osteoblastogenic marker genes such as runt-related transcription factor 2, ALP, osteocalcin, and collagen type 1 alpha. Furthermore, we evaluated the therapeutic potential of pitavastatin in ovariectomy-induced systematic bone loss based on micro-computed tomography and histological analysis of femurs. Our findings demonstrated a new function and mechanism for pitavastatin in bone remodeling, indicating its potential as a therapeutic candidate in treating osteoporosis by inhibiting osteoclastic resorption and promoting osteoblastic formation.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ovariectomia/efeitos adversos , Quinolinas/farmacologia , Animais , Biomarcadores/metabolismo , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
ACS Appl Mater Interfaces ; 13(30): 35431-35443, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34304556

RESUMO

Stent implantation is the primary method used to treat coronary heart disease. However, it is associated with complications such as restenosis and late thrombosis. Despite surface modification being an effective way to improve the biocompatibility of stents, the current research studies are not focused on changes in the vascular microenvironment at the implantation site. In the present study, an adaptive drug-loaded coating was constructed on the surface of vascular stent materials that can respond to oxidative stress at the site of vascular lesions. Two functional molecules, epigallocatechin gallate (EGCG) and cysteine hydrochloride, were employed to fabricate a coating on the surface of 316L stainless steel. In addition, the coating was used as a drug carrier to load pitavastatin calcium. EGCG has antioxidant activity, and pitavastatin calcium can inhibit smooth muscle cell proliferation. Therefore, EGCG and pitavastatin calcium provided a synergistic anti-inflammatory effect. Moreover, the coating was cross-linked using disulfide bonds, which accelerated the release of the drug in response to reactive oxygen species. A positive correlation was observed between the rate of drug release and the degree of oxidative stress. Collectively, this drug-loaded oxidative stress-responsive coating has been demonstrated to significantly inhibit inflammation, accelerate endothelialization, and reduce the risk of restenosis of vascular stents in vivo.


Assuntos
Stents Farmacológicos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Catequina/administração & dosagem , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Reestenose Coronária/prevenção & controle , Cistamina/administração & dosagem , Cistamina/química , Liberação Controlada de Fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacologia , Coelhos , Ratos Sprague-Dawley , Aço Inoxidável/química
18.
Antiviral Res ; 193: 105127, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34217752

RESUMO

In this study, a series of 10 quinoline analogues was evaluated for their in vitro antiviral activity against a panel of alpha- and beta-coronaviruses, including the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2), as well as the human coronaviruses (HCoV) 229E and OC43. Chloroquine and hydroxychloroquine were the most potent with antiviral EC50 values in the range of 0.12-12 µM. Chloroquine displayed the most favorable selectivity index (i.e. ratio cytotoxic versus antiviral concentration), being 165 for HCoV-OC43 in HEL cells. Potent anti-coronavirus activity was also observed with amodiaquine, ferroquine and mefloquine, although this was associated with substantial cytotoxicity for mefloquine. Primaquine, quinidine, quinine and tafenoquine only blocked coronavirus replication at higher concentrations, while piperaquine completely lacked antiviral and cytotoxic effects. A time-of-addition experiment in HCoV-229E-infected HEL cells revealed that chloroquine interferes with viral entry at a post-attachment stage. Using confocal microscopy, no viral RNA synthesis could be detected upon treatment of SARS-CoV-2-infected cells with chloroquine. The inhibition of SARS-CoV-2 replication by chloroquine and hydroxychloroquine coincided with an inhibitory effect on the autophagy pathway as visualized by a dose-dependent increase in LC3-positive puncta. The latter effect was less pronounced or even absent with the other quinolines. In summary, we showed that several quinoline analogues, including chloroquine, hydroxychloroquine, amodiaquine, ferroquine and mefloquine, exhibit broad anti-coronavirus activity in vitro.


Assuntos
Antimaláricos/farmacologia , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Coronavirus/efeitos dos fármacos , Quinolinas/farmacologia , Animais , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Cloroquina/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Humanos , Hidroxicloroquina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Células Vero , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
19.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299067

RESUMO

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.


Assuntos
Acetatos/farmacologia , Antiasmáticos/farmacologia , Proliferação de Células , Ciclopropanos/farmacologia , Leucotrieno D4/metabolismo , Nitrosaminas/toxicidade , Neoplasias Pancreáticas/tratamento farmacológico , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , Animais , Carcinógenos/toxicidade , Cricetinae , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
20.
Nat Commun ; 12(1): 4351, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272380

RESUMO

Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107's unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs.


Assuntos
Imidazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/antagonistas & inibidores , Calorimetria , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Inflamação , Simulação de Acoplamento Molecular , Quinolinas/química , Quinolinas/farmacologia , RNA/química , RNA/farmacologia , Proteínas Recombinantes , Transdução de Sinais/imunologia , Relação Estrutura-Atividade , Receptor 8 Toll-Like/química , Receptor 8 Toll-Like/metabolismo , Difração de Raios X
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