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1.
FASEB J ; 34(1): 1497-1515, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914638

RESUMO

The NLRP3 inflammasome regulates innate immune and inflammatory responses by promoting caspase1-dependent induction of pro-inflammatory cytokines. However, aberrant inflammasome activation causes diverse diseases, and thus inflammasome activity must be tightly controlled. Here, we reveal a molecular mechanism underlying the regulation of NLRP3 inflammasome. NLRP3 interacts with SUMO-conjugating enzyme (UBC9), which subsequently promotes small ubiquitin-like modifier 1 (SUMO1) to catalyze NLRP3 SUMOylation at residue Lys204. SUMO1-catalyzed SUMOylation of NLRP3 facilitates ASC oligomerization, inflammasome activation, and interleukin-1ß secretion. Moreover, this study also reveals that SUMO-specific protease 3 (SENP3) is required for the deSUMOylation of NLRP3. Interestingly, SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment and speck formation, the NLRP3 inflammasome activation, as well as IL-1ß cleavage and secretion. In conclusion, we reveal that SUMO1-catalyzed SUMOylation and SENP3-mediated deSUMOylation of NLRP3 orchestrate the inflammasome activation.

2.
Vet Microbiol ; 232: 146-150, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31030839

RESUMO

Newcastle disease virus (NDV) is a major threat to poultry worldwide. Virulent Newcastle disease virus infection can cause 100% morbidity and mortality in chickens. Vaccination is the most effective way to prevent and control NDV outbreaks in poultry. Previously, we demonstrated that a duck enteritis virus (DEV) vaccine strain is a promising vector to generate recombinant vaccines in chickens. Here, we constructed two recombinant DEVs expressing the F protein (rDEV-F) or HN protein (rDEV-HN) of NDV. We then evaluated the protective efficacy of these recombinant DEVs in specific-pathogen-free chickens. rDEV-F induced 100% protection of chickens from lethal NDV challenge after a single dose of 104 TCID50, whereas rDEV-HN did not induce effective protection. rDEV-F may therefore serve as a promising vaccine candidate for chickens. This is the first report of a DEV-vectored vaccine providing robust protection against lethal NDV infection in chickens.


Assuntos
Mardivirus/genética , Doença de Newcastle/prevenção & controle , Doenças das Aves Domésticas/prevenção & controle , Proteínas Virais de Fusão/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais , Galinhas/imunologia , Galinhas/virologia , Patos/virologia , Proteína HN/genética , Proteína HN/imunologia , Doença de Newcastle/imunologia , Vírus da Doença de Newcastle/genética , Vírus da Doença de Newcastle/imunologia , Doenças das Aves Domésticas/virologia , Organismos Livres de Patógenos Específicos , Vacinação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Proteínas Virais de Fusão/genética , Vacinas Virais/administração & dosagem
3.
J Neurovirol ; 25(2): 141-149, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30478797

RESUMO

Simian immunodeficiency virus (SIV)-infected macaque is a widely used model to study human immunodeficiency virus. The purpose of the study is to discover the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) changes in SIV-infected macaques. Seven rhesus macaques were involved in the longitudinal MRI scans: (1) baseline (healthy state); (2) SIV infection stage (12 weeks after SIV inoculation). ALFF and fALFF were subsequently computed and compared to ascertain the changes caused by SIV infection. Whole-brain correlation analysis was further used to explore the possible associations between ALFF/fALFF values and immune status parameters (CD4+ T cell counts, CD4/CD8 ratio and virus load). Compared with the baseline, macaques in SIV infection stage displayed strengthened ALFF values in left precuneus, postcentral gyrus, and temporal gyrus, and weakened ALFF values in orbital gyrus and inferior temporal gyrus. Meanwhile, increased fALFF values were found in left superior frontal gyrus, right precentral gyrus, and superior temporal gyrus, while decreased fALFF values existed in left hippocampus, left caudate, and right inferior frontal gyrus. Furthermore, ALFF and fALFF values in several brain regions showed significant relationships with CD4+ T cell counts, CD4/CD8 ratio, and plasma virus load. Our findings could promote the understanding of neuroAIDS caused by HIV infection, which may provide supplementary evidences for the future therapy study in SIV model.

4.
Nano Lett ; 19(4): 2215-2222, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30543300

RESUMO

Zika virus (ZIKV) has emerged as a global health threat due to its unexpected causal link to devastating neurological disorders such as fetal microcephaly; however, to date, no approved vaccine or specific treatment is available for ZIKV infection. Here we develop a biomimetic nanodecoy (ND) that can trap ZIKV, divert ZIKV away from its intended targets, and inhibit ZIKV infection. The ND, which is composed of a gelatin nanoparticle core camouflaged by mosquito medium host cell membranes, effectively adsorbs ZIKV and inhibits ZIKV replication in ZIKV-susceptible cells. Using a mouse model, we demonstrate that NDs significantly attenuate the ZIKV-induced inflammatory responses and degenerative changes and thus improve the survival rate of ZIKV-challenged mice. Moreover, by trapping ZIKV, NDs successfully prevent ZIKV from passing through physiologic barriers into the fetal brain and thereby mitigate ZIKV-induced fetal microcephaly in pregnant mice. We anticipate that this study will provide new insights into the development of safe and effective protection against ZIKV and various other viruses that threaten public health.


Assuntos
Microcefalia/prevenção & controle , Nanopartículas/administração & dosagem , Infecção por Zika virus/prevenção & controle , Zika virus/efeitos dos fármacos , Animais , Biomimética/métodos , Membrana Celular/efeitos dos fármacos , Membrana Celular/virologia , Culicidae/efeitos dos fármacos , Culicidae/virologia , Modelos Animais de Doenças , Feminino , Feto , Gelatina/administração & dosagem , Gelatina/química , Humanos , Camundongos , Microcefalia/patologia , Microcefalia/virologia , Nanopartículas/química , Gravidez , Zika virus/patogenicidade , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
5.
Biochem Biophys Res Commun ; 500(2): 398-404, 2018 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-29655789

RESUMO

The activation of the NLRP3 inflammasome is a key process of host immune response that establishes the first line of defense against pathogen infections and cellular stresses, whereas excessive inflammasome activation may damage the hosts, and thus it must be precisely controlled. However, the mechanism underlying the repression of the NLRP3 inflammasome activation remains largely unknown. In this study, by establishing and using a reconstructed NLRP3 inflammasome activation system, we reveal that the NLRP3 inflammasome activation, pro-caspase-1 cleavage, and pro-interleukin-1ß (pro-IL-1ß) activation are repressed by the interleukin-enhanced binding factor 2 (ILF2). Further studies demonstrate that ILF2 represses the activation of NLRP3 inflammasome through interacting with the NACHT-associated domain (NAD) of NLRP3 and co-localized with NLRP3 in the cytoplasm of HEK293T cells. Finally, by generating a THP-1 cell line stably expressing ILF2 protein using the lentivirus infection system, we demonstrate that ILF2 represses ATP-induced activation of endogenous NLRP3 inflammasome in macrophages. Therefore, this study identifies a new role of ILF2 in the regulation of the NLRP3 inflammasome, and reveals a unique mechanism underlying the repression of the NLRP3 inflammasome activation.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína do Fator Nuclear 45/metabolismo , Células HEK293 , Humanos , Interleucina-1beta/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos
6.
Nat Commun ; 9(1): 106, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29317641

RESUMO

Zika virus (ZIKV) infection is a public health emergency and host innate immunity is essential for the control of virus infection. The NLRP3 inflammasome plays a key role in host innate immune responses by activating caspase-1 to facilitate interleukin-1ß (IL-1ß) secretion. Here we report that ZIKV stimulates IL-1ß secretion in infected patients, human PBMCs and macrophages, mice, and mice BMDCs. The knockdown of NLRP3 in cells and knockout of NLRP3 in mice inhibit ZIKV-mediated IL-1ß secretion, indicating an essential role for NLRP3 in ZIKV-induced IL-1ß activation. Moreover, ZIKV NS5 protein is required for NLRP3 activation and IL-1ß secretion by binding with NLRP3 to facilitate the inflammasome complex assembly. Finally, ZIKV infection in mice activates IL-1ß secretion, leading to inflammatory responses in the mice brain, spleen, liver, and kidney. Thus we reveal a mechanism by which ZIKV induces inflammatory responses by facilitating NLRP3 inflammasome complex assembly and IL-1ß activation.


Assuntos
Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Infecção por Zika virus/imunologia , Zika virus/imunologia , Aedes , Animais , Encéfalo/imunologia , Encéfalo/patologia , Caspase 1/genética , Caspase 1/imunologia , Linhagem Celular , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Células HEK293 , Humanos , Imunidade Inata/imunologia , Interleucina-1beta/sangue , Rim/imunologia , Rim/patologia , Fígado/imunologia , Fígado/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neutrófilos/imunologia , Baço/imunologia , Baço/patologia , Células THP-1 , Células Vero , Proteínas não Estruturais Virais/imunologia , Infecção por Zika virus/virologia
7.
Front Plant Sci ; 8: 1647, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28983312

RESUMO

C-repeat binding factors (CBF) are a subfamily of AP2 transcription factors that play critical roles in the regulation of plant cold tolerance and growth in low temperature. In the present work, we sought to perform a detailed investigation into global transcriptional regulation of plant hormone signaling associated genes in transgenic plants engineered with CBF genes. RNA samples from Arabidopsis thaliana plants overexpressing two CBF genes, CBF2 and CBF3, were subjected to Illumina HiSeq 2000 RNA sequencing (RNA-Seq). Our results showed that more than half of the hormone associated genes that were differentially expressed in CBF2 or CBF3 transgenic plants were related to auxin signal transduction and metabolism. Most of these alterations in gene expression could lead to repression of auxin signaling. Accordingly, the IAA content was significantly decreased in young tissues of plants overexpressing CBF2 and CBF3 compared with wild type. In addition, genes associated with the biosynthesis of Jasmonate (JA) and Salicylic acid (SA), as well as the signal sensing of Brassinolide (BR) and SA, were down-regulated, while genes associated with Gibberellin (GA) deactivation were up-regulated. In general, overexpression of CBF2 and CBF3 negatively affects multiple plant hormone signaling pathways in Arabidopsis. The transcriptome analysis using CBF2 and CBF3 transgenic plants provides novel and integrated insights into the interaction between CBFs and plant hormones, particularly the modulation of auxin signaling, which may contribute to the improvement of crop yields under abiotic stress via molecular engineering using CBF genes.

8.
Am J Case Rep ; 18: 1140-1144, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-29070785

RESUMO

BACKGROUND Cryptococcus neoformans (C. neoformans) infection is one of the most common opportunistic infections in AIDS patients. C. neoformans usually infects the central nervous system (CNS) and/or lungs with typical clinical manifestation. CASE REPORT Here, we report the case of a 52-year-old HIV-1-infected man with disseminated cryptococcosis, including subacute meningitis, pulmonary, and cutaneous cryptococcosis, but only skin lesion served as the chief complaint. Moreover, the results of cerebrospinal fluid (CSF) tests and lung computed tomography (CT) scan were atypical. CONCLUSIONS We present the clinical characteristics of this case and discuss the diagnostic procedure, which will likely help clinicians in making a timely definitive diagnosis of this disease.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Criptococose/diagnóstico , Dermatomicoses/microbiologia , Pneumopatias Fúngicas/microbiologia , Meningite/diagnóstico , Doenças Assintomáticas , Cryptococcus neoformans/isolamento & purificação , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade
9.
Sci Rep ; 7(1): 12417, 2017 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963470

RESUMO

Toll-like receptors (TLRs) play a key role in innate and adaptive immunity, protecting the host from viral pathogens. We studied the effect of TLR7 polymorphisms on disease susceptibility and progression of chronic hepatitis B (CHB) infection in Chinese adults. Blood samples were taken from 612 patients with confirmed CHB, hepatitis B virus (HBV)-related liver cirrhosis (LC) or hepatocellular carcinoma (HCC) and 293 controls. TLR7 polymorphisms (rs179010-C > T, rs2074109-T > C, and rs179009-A > G) were analyzed by PCR-based sequencing. A significantly higher frequency of TLR7 rs179010 C allele was found in male CHB patients than in controls (74.8% vs 59.5%, P = 0.002). The frequency of rs179009 G allele was markedly increased with disease progression when male patients with CHB, LC and HCC were compared (P = 0.012). The haplotype CTA was significantly associated with an increased susceptibility to CHB among male patients (P = 0.000). Frequency of the haplotype CTG was higher in male patients with HCC than CHB (P = 0.005). No such differences in these allele frequencies were found between female patients and controls. Our results indicated that TLR7 polymorphisms play an important role in disease susceptibility and the progression of CHB infections in Chinese adults, and may partly explain the high incidence of HBV related diseases in Chinese men.


Assuntos
Predisposição Genética para Doença , Vírus da Hepatite B , Hepatite B Crônica/genética , Receptor 7 Toll-Like/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Criança , China/epidemiologia , Progressão da Doença , Feminino , Frequência do Gene , Haplótipos , Hepatite B Crônica/epidemiologia , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade
10.
Int J Genomics ; 2017: 9264034, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28831389

RESUMO

Drug-induced myopathy (DIM) is a rare side effect; however, the consequence could be fatal. There are few reports to systematically assess the underlying mechanism of DIM. In this study, we curated the comprehensive DIM drug list based on structured labeling products (SPLs) and carried out the analysis based on chemical structure space, drug protein interaction, side effect space, and transcriptomic profiling space. Some key features are enriched from each of analysis. Specifically, the similarity of DIM drugs is more significant than random chance, which shows that the chemical structure could distinguish the DIM-positive drugs from negatives. The cytochrome P450 (CYP) was identified to be shared by DIM drugs, which indicated the important role of metabolism in DIM. Three pathways including pathways in cancer, MAPK signaling pathway, and GnRH signaling pathway enriched based on transcriptomic analysis may explain the underlying mechanism of DIM. Although the DIM is the current focus of the study, the proposed approaches could be applied to other toxicity assessments and facilitate the safety evaluation.

11.
APMIS ; 125(8): 708-716, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28543911

RESUMO

Toll-like receptors (TLRs) play a crucial role in innate and adaptive immunity, protecting the host from viral pathogens. Studies have implicated that TLR5 is associated with various diseases such as autoimmune and inflammation related diseases. However, little is known about the relationship between TLR5 and hepatitis B virus (HBV) infection. We studied the effect of TLR5 gene polymorphisms on susceptibility to and disease progression of chronic hepatitis B (CHB) infection in Chinese. Blood samples were taken from 636 patients with CHB, HBV-related liver cirrhosis (LC) or hepatocellular carcinoma (HCC) and 273 controls. Polymorphisms of TLR5 (1775A>G rs2072493 and 1846T>C rs5744174) were analyzed by PCR-based sequencing. No difference in genotypic and allelic frequencies of TLR5 rs2072493 and rs5744174 was observed between patients and controls. Significant difference was found in frequency of TLR5 rs5744174 TT genotype between men with CHB and LC (p = 0.035). Frequency of TT genotype of TLR5 rs5744174 in patients positive for HBeAg was increased from 53.2% in patients with CHB to 74.1% in those with HCC (p = 0.024). Our results indicate that in Chinese genetic variation of TLR5 may be not a determinant of susceptibility to HBV-related diseases but may play a role in development of HBV-related severe liver diseases.


Assuntos
Carcinoma Hepatocelular/patologia , Predisposição Genética para Doença , Hepatite B/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Polimorfismo de Nucleotídeo Único , Receptor 5 Toll-Like/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/genética , Criança , China , Progressão da Doença , Feminino , Hepatite B/complicações , Hepatite B/genética , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Inflammation ; 38(5): 1979-85, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25920808

RESUMO

The present study aimed to investigate the protective role of ergosterol, isolated from Scleroderma polyrhizum Pers., in lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced in mice by LPS (0.5 mg/kg), and ergosterol (25 and 50 mg/kg) was administrated orally 1 h prior to LPS administration. Ergosterol pretreatment at doses of 25 and 50 mg/kg decreased LPS-induced lung histopathological changes, lung wet-to-dry weight ratio. In addition, pretreatment with ergosterol inhibited inflammatory cells and proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Furthermore, we demonstrated that ergosterol blocked the activation of nuclear factor-kappaB (NF-κB), cyclooxygenase (COX)-2, and nitric oxide synthase (iNOS) pathways. The results presented here suggest that the protective mechanism of ergosterol may be attributed partly to the inhibition of NF-κB, COX-2, and iNOS pathways.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Ergosterol/isolamento & purificação , Ergosterol/uso terapêutico , Lipopolissacarídeos/toxicidade , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Feminino , Fungos , Camundongos , Camundongos Endogâmicos BALB C
13.
Foodborne Pathog Dis ; 8(6): 687-92, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21457048

RESUMO

One hundred two pathogenic Escherichia coli isolates from diseased pigs were analyzed for serotypes, virulence genes, antimicrobial susceptibility, and the molecular basis of phenicol resistance. Of these 102 E. coli isolates, 101 were typeable and belonged to 27 different O serogroups. However, 69% of these isolates belonged to one of the following eight serogroups: O8, O54, O64, O65, O92, O108, O119, and O120. Serogroups O8 (23%) and O64 (10%) were the most prevalent among typeable isolates. High-resistance phenotypes were observed in all the isolates, with the majority displaying resistance to chloramphenicol (89%), streptomycin (83%), enrofloxacin (78%), and doxycycline (60%). The chloramphenicol resistance genes cat1, cat2, and cmlA were detected in 58%, 49%, and 65%, respectively, of the chloramphenicol-resistant isolates. The floR gene was detected in 57% of the florfenicol-resistant isolates and in 52% of chloramphenicol-resistant isolates. Pulsed-field gel electrophoresis showed that the 32 floR-positive isolates with florfenicol minimum inhibitory concentration ≥ 8 µg mL⁻¹ belonged to 25 different pulsed-field gel electrophoresis profiles, indicating the spread of floR among swine pathogenic E. coli isolates.


Assuntos
Farmacorresistência Bacteriana , Infecções por Escherichia coli/veterinária , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Gastroenteropatias/veterinária , Variação Genética , Fatores de Virulência/genética , Animais , Antibacterianos/farmacologia , China , Diarreia/etiologia , Diarreia/veterinária , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana Múltipla/genética , Edema/etiologia , Edema/veterinária , Eletroforese em Gel de Campo Pulsado/veterinária , Escherichia coli/isolamento & purificação , Escherichia coli/patogenicidade , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/fisiopatologia , Proteínas de Escherichia coli/genética , Fezes/microbiologia , Gastroenteropatias/microbiologia , Gastroenteropatias/fisiopatologia , Genes Bacterianos , Testes de Sensibilidade Microbiana/veterinária , Sorotipagem/veterinária , Sus scrofa , Tianfenicol/análogos & derivados , Tianfenicol/farmacologia , Virulência/genética
14.
Zhonghua Yi Xue Za Zhi ; 90(29): 2071-3, 2010 Aug 03.
Artigo em Chinês | MEDLINE | ID: mdl-21029649

RESUMO

OBJECTIVE: To analyze the epidemiology and clinical characteristics of influenza A (H1N1). METHODS: A retrospective analysis was performed on the clinical data of 137 cases of influenza A (H1N1) admitted into our hospital during May to August 2009. RESULTS: In the early stage, most cases were imported from the US, Australia, Canada and the UK. While in the later stage, most of them were secondary. The patients were mainly children and youngsters. And the most common clinical manifestations were fever (n = 108), cough (n = 93) and sore throat (n = 67) while the most common signs congestive throat (n = 99) and swelling tonsil (n = 46). The average fever period was 3.3 ± 1.5 days. The clinical symptoms vanished in 4.4 ± 1.9 days. And the average length of stay was 5.5 ± 2.1 days. Laboratory tests: the count of leukocytes declined while that of lymphocytes increased in 39 cases (39.5%). The test of influenza A (H1N1) nucleic acid was positive. The chest radiograph showed intensive pulmonary markings or patchy pneumonia-like signs. TREATMENTS: the groups of patients using Chinese herbs, western medicine plus Chinese herbs, symptomatic relief and placebo showed no significant difference in fever period, recovery time and the negative-converting period of influenza A (H1N1) nucleic acid tests became negative. CONCLUSION: Influenza A (H1N1) may be recessive or dominant. Despite a strong infectivity, the clinical symptoms are mild and the clinical course is self-limited, similar to the seasonal influenza.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Influenza Humana/virologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Adulto Jovem
15.
Bioorg Med Chem Lett ; 20(10): 3182-5, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20399649

RESUMO

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.


Assuntos
Benzimidazóis/química , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Camundongos , Camundongos Nus , Piperazinas/síntese química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Bioorg Med Chem Lett ; 20(5): 1744-8, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20153189
17.
Mol Cancer Ther ; 8(12): 3341-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19996272

RESUMO

BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.


Assuntos
Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Western Blotting , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administração & dosagem , Triazinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Med Chem ; 52(23): 7360-3, 2009 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-19778024
19.
Cancer Res ; 69(1): 161-70, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19117999

RESUMO

Overexpression and enhanced activity of insulin-like growth factor-I receptor (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. BMS-536924 is a potent small molecule inhibitor of IGF-IR, which shows antitumor activity in multiple tumor models, including sarcoma. To facilitate the development of IGF-IR inhibitors as cancer therapy, identification of biomarkers for selecting patients most likely to derive clinical benefit is needed. To do so, 28 sarcoma and neuroblastoma cell lines were screened for in vitro response to BMS-536924 to identify sensitive and resistant cell lines. Notably, Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma are more responsive to BMS-536924, suggesting these specific subtypes may represent potential targeted patient subpopulations for the IGF-IR inhibitor. Gene expression and protein profiling were performed on these cell lines, and candidate biomarkers correlating with intrinsic and/or acquired resistance to BMS-536924 were identified. IGF-I, IGF-II, and IGF-IR were highly expressed in sensitive cell lines, whereas IGFBP-3 and IGFBP-6 were highly expressed in resistant lines. Overexpression of epidermal growth factor receptor (EGFR) and its ligands in resistant cell lines may represent one possible resistance mechanism by the adaptation of IGF-IR-independent growth using alternative signaling pathways. Based on cross-talk between IGF-IR and EGFR pathways, combination studies to target both pathways were performed, and enhanced inhibitory activities were observed. These results provide a strategy for testing combinations of IGF-IR inhibitors with other targeted therapies in clinical studies to achieve improved patient outcomes. Further exploration of mechanisms for intrinsic and acquired drug resistance by these preclinical studies may lead to more rationally designed drugs that target multiple pathways for enhanced antitumor efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Receptores ErbB/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Piridonas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Receptor ErbB-2/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologia
20.
J Med Chem ; 51(19): 5897-900, 2008 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-18763755

RESUMO

We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Receptor de Pregnano X , Inibidores de Proteínas Quinases/química , Piridonas/química , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
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