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1.
Rev Bras Parasitol Vet ; 30(1): e025220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33605390

RESUMO

Southern cattle tick resistance to pour-on and injectable acaricides has yet to be evaluated on a broader scope, and the paucity of information on the subject may hinder efforts to control this parasite. The objective of this study was to evaluate the resistance profile of ten populations of Rhipicephalus microplus to the acaricides fluazuron, fipronil and ivermectin in cattle herds in Mato Grosso do Sul, Brazil. The larval immersion test (LIT) was used to evaluate susceptibility to ivermectin and fipronil and the adult immersion test (AIT) was performed to evaluate fluazuron. Samples were randomly obtained in ten farms, and in general, we found resistance in five samples to fluazuron and in four samples to ivermectin and fipronil. Six samples showed incipient resistance to ivermectin and fipronil. Five of the ten evaluated samples showed resistance and/or incipient resistance to all the active ingredients, and the other five to two active ingredients. Among the samples classified as resistant, the average resistance ratio for ivermectin was 2.75 and 3.26 for fipronil. These results demonstrate the advanced status of resistance to the most modern chemical groups for the control of R. microplus in the state of Mato Grosso do Sul.


Assuntos
Acaricidas , Doenças dos Bovinos , Resistência a Medicamentos , Rhipicephalus , Infestações por Carrapato , Acaricidas/farmacologia , Animais , Brasil , Bovinos , Doenças dos Bovinos/parasitologia , Ivermectina/farmacologia , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Rhipicephalus/efeitos dos fármacos , Infestações por Carrapato/parasitologia , Infestações por Carrapato/veterinária
2.
Anticancer Res ; 41(1): 123-130, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419805

RESUMO

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is a serious disease and the leading cause of death globally. Overexpression of protein kinase B/nuclear factor-kappa B (NF-κB) signaling transduction of NSCLC cells was recognized as a potential therapeutic target. Lenvatinib is a multiple kinase inhibitor against vascular endothelial growth factor receptor family. However, whether lenvatinib may affect AKT/NF-κB in NSCLC remains unknown. MATERIALS AND METHODS: MTT assay, NF-κB reporter gene assay, flow cytometry, tranwell migration/invasion analysis and western blotting were used to identify the alteration of cell viability, NF-κB activation, apoptosis effect, migration/invasion potential and AKT/NF-κB related protein expression, respectively, in CL-1-5-F4 cells after lenvatinib treatment. RESULTS: The cell viability and NF-κB activity were suppressed by lenvatinib. Extrinsic and intrinsic apoptosis were activated by lenvatinib. Additionally, the metastatic potential of CL-1-5-F4 cells was also suppressed by lenvatinib. CONCLUSION: Altogether, lenvatinib induced extrinsic/intrinsic apoptosis and suppressed migration/invasion ability of NSCLC cells that was associated with AKT/NF-κB signaling inactivation.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Inibidores de Proteínas Quinases/farmacologia
3.
Anticancer Res ; 41(2): 783-794, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517283

RESUMO

BACKGROUND/AIM: The inflammatory cytokine IL-8 and its receptor CXCR2 are key signalling pathway molecules in cancer development. We hypothesized that IL-8/CXCR2 signalling promotes tumour progression in oesophageal squamous cell carcinoma (ESCC) patients. MATERIALS AND METHODS: We examined the relationship between IL-8/CXCR2 expression and clinicopathological factors by immunohistochemistry in samples from 63 patients with resectable ESCC. The effects of IL-8/CXCR2 signalling on cell proliferation and gene expression were examined in vitro and in vivo using ESCC cell lines. RESULTS: Increased IL-8/CXCR2 signalling was associated with shorter overall survival (p<0.05) and recurrence-free survival (p<0.05) in ESCC patients. Multivariate analysis identified IL-8/CXCR2 expression as a prognostic factor for surgically treated ESCC (p<0.05). In vitro, IL-8 exposure or over-expression significantly enhanced ESCC cell proliferation. SB225002, a CXCR2-specific antagonist, and IL-8 siRNA significantly suppressed cell proliferation. CONCLUSION: IL-8/CXCR2 expression is an independent prognostic factor for surgically treated ESCC, and IL-8/CXCR2 signalling contributes to ESCC cell proliferation.


Assuntos
Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Interleucina-8/metabolismo , Receptores de Interleucina-8B/metabolismo , Regulação para Cima , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Compostos de Fenilureia/farmacologia , Prognóstico , RNA Interferente Pequeno/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida
4.
Int J Nanomedicine ; 16: 1-14, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33442247

RESUMO

Introduction: The present study reports on examination of the effects of encapsulating the tyrosine kinase inhibitors (TKIs) vandetanib and lenvatinib into a biomacromolecular ferritin-based delivery system. Methods: The encapsulation of TKIs was performed via two strategies: i) using an active reversible pH-dependent reassembly of ferritin´s quaternary structure and ii) passive loading of hydrophobic TKIs through the hydrophobic channels at the junctions of ferritin subunits. After encapsulation, ferritins were surface-functionalized with folic acid promoting active-targeting capabilities. Results: The physico-chemical and nanomechanical analyses revealed that despite the comparable encapsulation efficiencies of both protocols, the active loading affects stability and rigidity of ferritins, plausibly due to their imperfect reassembly. Biological experiments with hormone-responsive breast cancer cells (T47-D and MCF-7) confirmed the cytotoxicity of encapsulated and folate-targeted TKIs to folate-receptor positive cancer cells, but only limited cytotoxic effects to healthy breast epithelium. Importantly, the long-term cytotoxic experiments revealed that compared to the pH-dependent encapsulation, the passively-loaded TKIs exert markedly higher anticancer activity, most likely due to undesired influence of harsh acidic environment used for the pH-dependent encapsulation on the TKIs' structural and functional properties. Conclusion: Since the passive loading does not require a reassembly step for which acids are needed, the presented investigation serves as a solid basis for future studies focused on encapsulation of small hydrophobic molecules.


Assuntos
Sistemas de Liberação de Medicamentos , Ferritinas/química , Ácido Fólico/química , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Quinolinas/farmacologia , Animais , Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Clonais , Difusão , Portadores de Fármacos/química , Cavalos , Humanos , Concentração de Íons de Hidrogênio , Compostos de Fenilureia/química , Piperidinas/química , Quinazolinas/química , Quinolinas/química , Propriedades de Superfície
5.
Mol Cell ; 81(2): 355-369.e10, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33321093

RESUMO

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.


Assuntos
Membrana Celular/química , Sistema Enzimático do Citocromo P-450/genética , Citocromo-B(5) Redutase/genética , Ácidos Graxos Insaturados/metabolismo , Ferroptose/genética , NADP/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Concanavalina A/farmacologia , Sistema Enzimático do Citocromo P-450/deficiência , Citocromo-B(5) Redutase/deficiência , Transporte de Elétrons/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Oxigênio/metabolismo , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Sorafenibe/farmacologia
6.
PLoS One ; 15(9): e0239094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915912

RESUMO

The G protein-gated inwardly rectifying K+ (GIRK) channels play important signaling roles in the central and peripheral nervous systems. However, the role of GIRK channel activation in pain signaling remains unknown mainly due to the lack of potent and selective GIRK channel activators until recently. The present study was designed to determine the effects and mechanisms of ML297, a selective GIRK1/2 activator, on nociception in the spinal cord by using behavioral studies and whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons. Rats were prepared for chronic lumber catheterization and intrathecal administration of ML297. The nociceptive flexion reflex was tested using an analgesy-meter, and the influence on motor performance was assessed using an accelerating rotarod. We also investigated pre- and post-synaptic actions of ML297 in spinal cord preparations by whole-cell patch-clamp recordings. Intrathecal administration of ML297 increased the mechanical nociceptive threshold without impairing motor function. In voltage-clamp mode of patch-clamp recordings, bath application of ML297 induced outward currents in a dose-dependent manner. The ML297-induced currents demonstrated specific equilibrium potential like other families of potassium channels. At high concentration, ML297 depressed miniature excitatory postsynaptic currents (mEPSCs) but not their amplitude. The ML297-induced outward currents and suppression of mEPSCs were not inhibited by naloxone, a µ-opioid receptor antagonist. These results demonstrated that intrathecal ML297 showed the antinociceptive effect, which was mediated through direct activation of pre- and post-synaptic GIRK channels. Selective GIRK channel activation is a promising strategy for the development of new agents against chronic pain and opioid tolerance.


Assuntos
Analgésicos/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Nociceptividade/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Substância Gelatinosa/efeitos dos fármacos , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Injeções Espinhais , Masculino , Modelos Animais , Naloxona/administração & dosagem , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/fisiologia , Técnicas de Patch-Clamp , Compostos de Fenilureia/uso terapêutico , Pirazóis/uso terapêutico , Ratos , Substância Gelatinosa/citologia , Substância Gelatinosa/fisiologia
7.
Cell Prolif ; 53(10): e12895, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32914523

RESUMO

OBJECTIVES: DNA damage and errors of accurate chromosome segregation lead to aneuploidy and foetal defects. DNA repair and the spindle assembly checkpoint (SAC) are the mechanisms developed to protect from these defects. Checkpoint kinase 1 (CHK1) is reported to be an important DNA damage response protein in multiple models, but its functions remain unclear in early mouse embryos. MATERIALS AND METHODS: Immunofluorescence staining, immunoblotting and real-time reverse transcription polymerase chain reaction were used to perform the analyses. Reactive oxygen species levels and Annexin-V were also detected. RESULTS: Loss of CHK1 activity accelerated progress of the cell cycle at the first cleavage; however, it disturbed the development of early embryos to the morula/blastocyst stages. Further analysis indicated that CHK1 participated in spindle assembly and chromosome alignment, possibly due to its regulation of kinetochore-microtubule attachment and recruitment of BubR1 and p-Aurora B to the kinetochores, indicating its role in SAC activity. Loss of CHK1 activity led to embryonic DNA damage and oxidative stress, which further induced early apoptosis and autophagy, indicating that CHK1 is responsible for interphase DNA damage repair. CONCLUSIONS: Our results indicate that CHK1 is a key regulator of the SAC and DNA damage repair during early embryonic development in mice.


Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Reparo do DNA , Pontos de Checagem da Fase M do Ciclo Celular , Animais , Apoptose/efeitos dos fármacos , Aurora Quinase B/metabolismo , Proteínas de Ciclo Celular/metabolismo , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Segregação de Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Cinetocoros/metabolismo , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Camundongos , Microtúbulos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
8.
Am J Physiol Renal Physiol ; 319(4): F563-F570, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799675

RESUMO

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glomerulonefrite/prevenção & controle , Hipertensão/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Enalapril/farmacologia , Inibidores Enzimáticos/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , Fibrose , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Compostos de Fenilureia/toxicidade , Piperidinas/toxicidade , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia
9.
Nat Commun ; 11(1): 4153, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32814769

RESUMO

The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptores Androgênicos/genética , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Linhagem Celular Tumoral , Intervalo Livre de Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Compostos de Fenilureia/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Terapêutica com RNAi/métodos , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Chemosphere ; 259: 127499, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32629314

RESUMO

Soybean looper (SBL), Chrysodeixis includens (Walker), is an economically important soybean and cotton pest in Brazil. Here, we selected an SBL strain resistant to teflubenzuron using F2 screening, estimated the resistance allele frequency, characterized the inheritance of resistance, investigated fitness costs, evaluated patterns of cross-resistance, and determined the magnitude of resistance. The teflubenzuron-resistant strain (Teflu-R) was selected from field-collected populations with an estimated allele frequency of 0.1700. Estimated LC50 values were 0.010 and 363.61 µg a.i. cm-2 for the susceptible (Sus) and Teflu-R strains, respectively, representing a 36,361-fold resistance ratio (RR). The LC50 values of reciprocal crosses were 1.02 and 0.59 µg a.i. cm-2, suggesting that resistance is autosomally inherited. The low survival of reciprocal crosses (16 and 20%) on teflubenzuron-sprayed leaves indicates incomplete recessive resistance. The number of segregations influencing resistance was 2.72, suggesting a polygenic effect. The Teflu-R strain showed longer development periods as well as lower survival and population growth than the Sus strain, revealing fitness costs. The Teflu-R strain also showed high cross-resistancesto other chitin inhibitor insecticides, such as novaluron (RR = 6147-fold) and lufenuron (RR = 953-fold), but low cross-resistance to methoxyfenozide, flubendiamide, and indoxacarb (RR < 3.45-fold). On discriminatory concentrations of teflubenzuron and novaluron, populations of SBL showed survival rates from 15 to 52%, indicating field resistance to these insecticides. Our findings indicated that resistance to teflubenzuron in SBL is autosomal, recessive, polygenic, and associated with fitness cost. We also found a high cross-resistance to other benzoylphenylureas and a high frequency of resistance to this mode-of-action in SBL in Brazil.


Assuntos
Quitina/antagonistas & inibidores , Resistência a Inseticidas , Inseticidas , Mariposas/efeitos dos fármacos , Soja/parasitologia , Animais , Benzamidas/farmacologia , Brasil , Quitina/biossíntese , Quitina/farmacologia , Hidrazinas/farmacologia , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Larva/efeitos dos fármacos , Lepidópteros/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Doenças das Plantas/parasitologia , Soja/efeitos dos fármacos , Sulfonas/farmacologia
11.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188391, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32659252

RESUMO

Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma (HCC). Its application has changed the status of sorafenib as the only first-line TKI treatment for HCC for more than a decade. Evidence has shown that lenvatinib possesses antitumor proliferation and immunomodulatory activity in preclinical studies. In comparison, lenvatinib was non-inferior to sorafenib in overall survival (OS), and even shows superiority with regard to all the secondary efficacy endpoints. Immune-checkpoint inhibitors(ICIs)are now being incorporated into HCC treatment. Positive outcomes have been achieved in the combination of lenvatinib plus ICIs, bringing broader prospects for HCC. This review presents an overview on the therapeutic mechanisms and clinical efficacy of lenvatinib in HCC, and we discuss the future perspectives of lenvatinib in HCC management with focus on biomarker-guided precision medicine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/metabolismo , Humanos , Imunomodulação , Imunoterapia , Neoplasias Hepáticas/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
12.
Arch Biochem Biophys ; 689: 108415, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32562663

RESUMO

Regorafenib, a multiple kinase inhibitor, is recently approved for treatment of patients with advanced hepatocellular carcinoma (HCC). Previous studies demonstrated that regorafenib was a mitochondrial toxicant, which associated with the impairment of mitochondria. Sirt3 is involved in the regulation of mitochondrial function in cancers. This study aimed to investigate the mechanism of Sirt3 involved in the mitochondrial dysfunction which associated with regorafenib treatment in liver cancer cells. We found regorafenib inhibited Sirt3 and p-ERK expression in HCC cells in a dose-dependent manner. Bioinformatics analysis showed that Sirt3 expression was down-regulated in liver cancer tissues and its low expression was correlated with worse overall survival (OS) in liver cancer patients. After transfected with Sirt3 overexpression plasmid, we found that Sirt3 sensitized liver cancer cells to regorafenib and resulted in much more apoptosis with a significant increase of ROS level. However, exogenous antioxidant could not weaken the apoptosis. Mitochondrial membrane potential assay indicated that Sirt3 overexpression accelerated the mitochondrial depolarization process induced by regorafenib and aggravated mitochondrial injury. Cellular oxygen consumption assay showed that mitochondrial dysfunction was caused by the damage of the electron transport chain. The results demonstrated that Sirt3 overexpression promoted the increase of ROS and apoptosis induced by regorafenib through the acceleration of mitochondrial dysfunction by impairing function of the electron transport chain in liver cancer cells. Our studies verified the functional role of Sirt3 in regorafenib treatment and suggested that regorafenib accompanied with Sirt3 activator as a novel treatment strategy for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Sirtuína 3/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
Leukemia ; 34(11): 2981-2991, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32409689

RESUMO

FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.


Assuntos
Benzotiazóis/farmacologia , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético , Duplicação Gênica , Técnicas de Silenciamento de Genes , Glicólise , Humanos , Fosforilação , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética
14.
Anticancer Res ; 40(5): 2667-2673, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366411

RESUMO

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pulmonares/genética , Mutação/genética , Oncogenes , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Pirimidinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Pharmacol Exp Ther ; 374(1): 223-232, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32238455

RESUMO

1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) and 1-(4-trifluoro-methoxy-phenyl)-3-(1-cyclopropanecarbonyl-piperidin-4-yl)-urea (TCPU) are potent inhibitors of soluble epoxide hydrolase (sEH) that have much better efficacy in relieving nociceptive response than the Food and Drug Administration-approved drug gabapentin in a rodent model of diabetic neuropathy. Experiments conducted in sEH knockout mice or with coadministration of a potent sEH displacer demonstrated that the pharmacokinetics of TPPU and TCPU were influenced by the specific binding to their pharmacologic target sEH, a phenomenon known as target-mediated drug disposition (TMDD). To quantitatively characterize the complex pharmacokinetics of TPPU and TCPU and gain better understanding on their target occupancy, population pharmacokinetics analysis using a nonlinear mixed-effect modeling approach was performed in the current study. The final model was a novel simultaneous TMDD interaction model, in which TPPU and TCPU compete for sEH, with TCPU binding to an additional unknown target pool with larger capacity that we refer to as a refractory pool. The total amount of sEH enzyme in mice was predicted to be 16.2 nmol, which is consistent with the experimental value of 10 nmol. The dissociate rate constants of TPPU and TCPU were predicted to be 2.24 and 2.67 hours-1, respectively, which is close to the values obtained from in vitro experiments. Our simulation result predicted that 90% of the sEH will be occupied shortly after a low dose of 0.3 mg/kg TPPU administration, with ≥40% of sEH remaining to be bound with TPPU for at least 7 days. Further efficacy experiments are warranted to confirm the predicted target occupancy. SIGNIFICANCE STATEMENT: Although target-mediated drug disposition (TMDD) models have been well documented, most of them were established in a single compound scenario. Our novel model represents the first TMDD interaction model for two small-molecule compounds competing for the same pharmacological target.


Assuntos
Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Modelos Biológicos , Terapia de Alvo Molecular , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/química , Compostos de Fenilureia/farmacocinética , Piperidinas/farmacocinética , Solubilidade
16.
Ecotoxicol Environ Saf ; 197: 110591, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283411

RESUMO

Benzoylphenylureas as an important type of insect growth regulators, acting on the moulting stage in immature insects, are highly effective and low toxic. The new benzoylphenylurea TXH09 [N-((2,6-dimethyl-4-(heptafluoropropyl-2-yl)phenyl)carbamoyl)-2,6-difluorobenzamide] has high efficacy against chewing insect pests harming vegetables and rice. In this paper, the efficacy of TXH09 against two intractable borers Ostrinia furnacalis and Grapholitha molesta were evaluated in field, and safety assessment by exploring the characteristics of photodegradation, cytotoxicity, micronucleus generation and chromosome aberration was performed. The results showed that TXH09 had good capability in preventing infested corn and reducing the population of O. furnacalis larvae, and maintained high efficacy on shoot protection and peach conservation against G. molesta larvae. There were no significant differences between the control effects of TXH09 and that of hexaflumuron or diflubenzuron at the same active dose. TXH09 photolysis in solvents N,N-dimethylformamide, toluene and methanol yielded two major products, and the photodegradation of TXH09 was more prone to occur in N,N-dimethylformamide. TXH09 and the mixture of its photoproducts showed higher cytotoxicity on insect Sf-9 cells than on human Hek293 cells. Moreover, TXH09 didn't show significant effects in inducing micronucleated cells in both male and female mice and chromosomal aberrations in mouse spermatocytes by its own. In conclusion, TXH09, as an effective insecticide, has good environmental safety performance against O. furnacalis and G. molesta in field.


Assuntos
Inseticidas/farmacologia , Mariposas/fisiologia , Compostos de Fenilureia/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Inseticidas/química , Larva/fisiologia , Masculino , Camundongos , Testes de Mutagenicidade , Compostos de Fenilureia/química , Fotólise , Doenças das Plantas/parasitologia , Doenças das Plantas/prevenção & controle , Células Sf9
17.
Sci Rep ; 10(1): 4000, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132577

RESUMO

Fibroblast-like transformation of retinal pigment epithelial (RPE) cells is a pathological feature of proliferative vitreoretinopathy (PVR) that may cause blindness. The effect of oxidative stress alone or together with transforming growth factor-beta 2 (TGF-ß2) on epithelial-mesenchymal transformation (EMT) is not fully understood in RPE. TGF-ß2 induced the upregulation EMT markers including α-smooth muscle actin (α-SMA), Snail, and Slug and downregulation of E-cadherin (E-cad) in ARPE-19 cells. Hydrogen peroxide (H2O2) not only upregulated α-SMA but also enhanced the effect of TGF-ß2 on the expression of Snail and Slug. The CXCL family of cytokines could be the mediators of EMT induced by H2O2 and TGF-ß2. H2O2 induced CXCL1, that upregulated α-SMA and fibronectin. Both SB225002, an inhibitor of CXCR2, and antioxidant N-acetylcysteine suppressed the TGF-ß2-induced EMT in ARPE-19 cells. Taken together, the results suggest that oxidative stress enhanced TGF-ß2-induced EMT through the possible autocrine effect of CXCL1 on CXCR2 in ARPE-19 cells.


Assuntos
Comunicação Autócrina/efeitos dos fármacos , Quimiocina CCL1/biossíntese , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Crescimento Transformador beta2/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Vitreorretinopatia Proliferativa/metabolismo , Vitreorretinopatia Proliferativa/patologia
18.
Sci Rep ; 10(1): 4012, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132601

RESUMO

Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4CRBN. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/metabolismo , Talidomida/análogos & derivados , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Estudo de Associação Genômica Ampla , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/genética , Compostos de Fenilureia/farmacologia , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/genética
19.
Pediatr Blood Cancer ; 67(6): e28222, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32207565

RESUMO

BACKGROUND: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3. PROCEDURES: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model. RESULTS: Regorafenib induced modest inhibition of tumor growth in the models evaluated. CONCLUSION: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Proliferação de Células , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Am J Physiol Heart Circ Physiol ; 318(4): H985-H993, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167781

RESUMO

The roles of ACE-independent ANG II production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus we tested the hypothesis that a high-fructose diet (HFD) in young rats elicits chymase-dependent increases in ANG II production and oxidative stress, responses that are reversible by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD, and HFD with TPPU, respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia, and hypertension and associated with decreases in cardiac output and stroke volume and loss of nitric oxide (NO) modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac angiotensin-converting enzyme (ACE) expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent ANG II formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent ANG II production was paralleled with increases in ANG II type 1 receptor (AT1R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by a lower Ang-(1-7) level displayed in an TPPU-irreversible manner. In conclusion, HFD-driven adverse chymase/ANG II/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via, at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS.NEW & NOTEWORTHY As the highest fructose consumers, the adolescent population is highly susceptible to the metabolic syndrome, where increases in mast cell chymase-dependent formation of ANG II, ensued by cardiometabolic dysfunction, are reversible in response to inhibition of soluble epoxide hydrolase (sEH). This study highlights chymase and sEH as therapeutic targets and unravels novel avenues for the development of optimal strategies for young patients with fructose-induced metabolic syndrome.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Angiotensina II/metabolismo , Quimases/metabolismo , Frutose/efeitos adversos , Cardiopatias/metabolismo , Síndrome Metabólica/complicações , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Débito Cardíaco , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Síndrome Metabólica/etiologia , Miocárdio/metabolismo , Estresse Oxidativo , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley
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