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1.
PLoS Biol ; 18(8): e3000805, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32810152

RESUMO

Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.


Assuntos
Antibacterianos/farmacologia , Ciprofloxacino/farmacologia , Colistina/farmacologia , Furanos/farmacologia , Gálio/farmacologia , Meropeném/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Tobramicina/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana , Biossíntese de Proteínas/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/metabolismo , Percepção de Quorum/efeitos dos fármacos , Virulência
2.
Anticancer Res ; 40(6): 3345-3354, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487630

RESUMO

BACKGROUND/AIM: In addition to its cytocidal effects as a microtubule dynamics inhibitor, eribulin mesylate (eribulin) regulates the tumour microenvironment. We examined the clinical significance of tumour infiltrating lymphocytes (TILs) and transforming growth factor-ß (TGF-ß), which are local markers of host immunity, and of the neutrophil-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC), which are systemic markers. PATIENTS AND METHODS: We administered eribulin chemotherapy to 106 patients with locally advanced or metastatic breast cancer. Of these, 21 had their lesions resected. RESULTS: The response to eribulin was significantly associated with ALC (p=0.007). The expression of pSmad2 (an indicator of activation of TGF-ß downstream signaling) was significantly decreased before and after eribulin chemotherapy (p<0.001). Moreover, a baseline ALC ≥ 1,500 /µl was observed in a significantly high number of patients with pSmad2 negative conversion (p<0.001). CONCLUSION: Eribulin improved the tumour immune microenvironment by decreasing TGF-ß expression. This demonstrated that local change can be evaluated based on ALC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Furanos/farmacologia , Humanos , Cetonas/farmacologia , Reprodutibilidade dos Testes , Microambiente Tumoral
3.
Leukemia ; 34(7): 1726-1729, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483300

RESUMO

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Células-Tronco Hematopoéticas/virologia , Inflamassomos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/prevenção & controle , Lesão Renal Aguda/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Furanos/farmacologia , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Inflamassomos/antagonistas & inibidores , Inflamassomos/genética , Miocardite/epidemiologia , Miocardite/imunologia , Miocardite/prevenção & controle , Miocardite/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Piroptose/efeitos dos fármacos , Piroptose/genética , Piroptose/imunologia , Fatores de Risco , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
4.
Life Sci ; 256: 117983, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565252

RESUMO

Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. AIMS: To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. MAIN METHODS: Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. KEY FINDINGS: The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3ß-mediated degradation. SIGNIFICANCE: These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Furanos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lignanas/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Feminino , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Proteólise/efeitos dos fármacos
5.
Anticancer Res ; 40(5): 2475-2479, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366391

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In the present report, we determined the drug sensitivity for a triple-negative MPBC using a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX model was established in the left 2nd mammary by surgical orthotopic implantation (SOI). MPBC PDOX models were randomized into 4 groups (6 mice per group) when the tumor volume became 80 mm3: G1, control group; G2, cisplatinum group [intraperitoneal (i.p.) injection, weekly, for 2 weeks]; G3, paclitaxel group (i.p., weekly, for 2 weeks); G4, eribulin group [intravenous (i.v.) injection, weekly, for 2 weeks]. All mice were sacrificed on day 15. Tumor volume and body weight were measured one time per week. RESULTS: The MPBC PDOX model was resistant to cisplatinum (p=0.800). Paclitaxel suppressed tumor growth compared to the control group (p=0.009). However, only eribulin regressed the tumor (p=0.001). CONCLUSION: Eribulin has clinical potential for triple-negative MPBC patients.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Feminino , Furanos/uso terapêutico , Humanos , Cetonas/uso terapêutico , Camundongos , Paclitaxel/farmacologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 40(5): 2509-2514, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366395

RESUMO

BACKGROUND/AIM: Matrix-producing breast carcinoma (MPBC) is a rare and usually aggressive triple-negative breast cancer (TNBC). In this study, we determined drug sensitivity for a triple-negative MPBC, without BRCA mutations, in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The MPBC PDOX model was established in the left 2nd mammary gland of nude mouse by implantation of the patient tumor using surgical orthotopic implantation (SOI). We randomized MPBC PDOX mice into 5 groups (n=5 mice/per treatment group) when the tumor volume reached 80 mm3: G1, control-no treatment; G2, bevacizumab [intra-peritoneal (i.p.), weekly, for 2 weeks]; G3, vinorelbine (i.p., weekly, for 2 weeks); G4, olaparib (oral., daily, for 2 weeks); G5, eribulin [intravenous (i.v.), weekly, for 2 weeks]. The mice in each treatment group were sacrificed on day 15. Tumor volume and body weight were measured once/week. RESULTS: The MPBC PDOX model was resistant to olaparib (p=0.22). The MPBC PDOX model treated with bevacizumab and vinorelbine showed significantly suppressed tumor growth compared to the untreated group (p=0.005 and 0.002, respectively). However, only eribulin regressed the tumor (p=0.0001). Eribulin was more effective than olaparib (p=0.0001), bevacizumab (p=0.0025) and vinorelbine (p=0.0061). CONCLUSION: Eribulin has clinical potential as treatment for triple-negative MPBC patients that are resistant to a PARP inhibitor such as olaparib.


Assuntos
Bevacizumab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Vinorelbina/farmacologia , Adulto , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Life Sci ; 253: 117747, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376270

RESUMO

AIMS: Multiple sclerosis (MS) whose pathogenesis is still unclear is a chronic progressive disease in the central nervous system. Gut microbiota can directly or indirectly affect the immune system through the brain gut axis to engage in the occurrence and development of the disease. MATERIALS AND METHODS: C57BL/6 mice which were immunized by MOG35-55 to prepare experimental autoimmune encephalomyelitis (EAE) animal models were treated with rapamycin and MCC950 (CP-456773) in combination or separately. After sequencing the 16S rRNA V4 region of gut microbiota, the species, abundance and composition of gut microbiota were analyzed by Alpha diversity, Bata diversity and LEfSe analysis. The pathological changes and the expression of CD4 and CD8 of brain, large intestine and spleen were detected. KEY FINDINGS: The results showed that rapamycin and MCC950 could alleviate the progression of the disease by inducing autophagy and inhibiting the immune response. The Alpha diversity of EAE model group was no significant difference compering to control group while the number of OTUs was decreased. After the treatment by rapamycin and MCC950, the abundance and composition of gut microbiota was relatively recovered, which was close to that of normal mice. SIGNIFICANCE: Inhibiting immune cell-mediated inflammation and restoring the composition of gut microbiota may help to alleviate the clinical symptoms of multiple sclerosis. Furthermore, to research the regulatory effect between immune response and gut microbiota may be a new strategy for the prevention and treatment of multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/farmacologia , Microbioma Gastrointestinal/imunologia , Esclerose Múltipla/tratamento farmacológico , Sirolimo/farmacologia , Sulfonamidas/farmacologia , Animais , Encéfalo/imunologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Furanos/administração & dosagem , Inflamação/imunologia , Inflamação/patologia , Intestino Grosso/imunologia , Intestino Grosso/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , RNA Ribossômico 16S , Sirolimo/administração & dosagem , Baço/imunologia , Baço/patologia , Sulfonamidas/administração & dosagem
8.
PLoS One ; 15(5): e0223344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365104

RESUMO

Stilbenes are a group of chemicals characterized with the presence of 1,2-diphenylethylene. Previously, our group has demonstrated that synthesized (E)-N-(2-(3, 5-dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) possesses potential chemopreventive activity specifically inducing NAD(P)H:quinone oxidoreductase 1 (NQO1) protein expression and activity. In this study, the cytoprotective effects of BK3C231 on cellular DNA and mitochondria were investigated in normal human colon fibroblast, CCD-18Co cells. The cells were pretreated with BK3C231 prior to exposure to the carcinogen 4-nitroquinoline 1-oxide (4NQO). BK3C231 was able to inhibit 4NQO-induced cytotoxicity. Cells treated with 4NQO alone caused high level of DNA and mitochondrial damages. However, pretreatment with BK3C231 protected against these damages by reducing DNA strand breaks and micronucleus formation as well as decreasing losses of mitochondrial membrane potential (ΔΨm) and cardiolipin. Interestingly, our study has demonstrated that nitrosative stress instead of oxidative stress was involved in 4NQO-induced DNA and mitochondrial damages. Inhibition of 4NQO-induced nitrosative stress by BK3C231 was observed through a decrease in nitric oxide (NO) level and an increase in glutathione (GSH) level. These new findings elucidate the cytoprotective potential of BK3C231 in human colon fibroblast CCD-18Co cell model which warrants further investigation into its chemopreventive role.


Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Colo/efeitos dos fármacos , Citoproteção , Dano ao DNA/efeitos dos fármacos , Furanos/farmacologia , Mutagênicos/toxicidade , Estilbenos/farmacologia , Linhagem Celular , Colo/citologia , Reparo do DNA/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Furanos/química , Humanos , Mitocôndrias/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estilbenos/química
9.
Life Sci ; 251: 117638, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251636

RESUMO

AIMS: Brain edema is a common threat to life in ischaemic brain injury. The NLRP3 inflammasome promotes the inflammatory injury after ischaemic stroke. Previous studies have shown that aquaporin-4 (AQP4) modulates brain water transport and endothelin-1 (ET-1) induces cerebral edema. However, the contribution of the NLRP3 inflammasome to regulation of brain edema and blood-brain barrier (BBB) disruption in cerebral ischaemia-reperfusion is elusive. The aim of this study is to investigate the effect of inhibition of the NLRP3 inflammasome by MCC950 on regulation of cerebral edema, BBB disruption and the expression of AQP4 and ET-1 in cerebral ischaemia-reperfusion. MAIN METHODS: The male C57BL/6 mice were used to establish the experimental transient middle cerebral artery occlusion (tMCAO) model. The mice were intraperitoneally injected with MCC950. Changes in NLRP3, IL-1ß, IL-18, the pyroptosis protein gasdermin D (GSDMD), brain water content, AQP4 and ET-1 in brain tissue were detected. KEY FINDINGS: MCC950 inhibited NLRP3 and GSDMD after tMCAO. MCC950 improved cerebral edema and alleviated the damage of BBB after tMCAO. The levels of AQP4 and ET-1 were decreased by MCC950. In addition, MCC950 regulated the distribution of AQP4 after tMCAO in mice. SIGNIFICANCE: The NLRP3 inflammasome facilitated brain edema and BBB disruption after cerebral ischaemia-reperfusion in mice, and NLRP3 inflammasome inhibition with MCC950 regulated the expression and distribution of AQP4 in the infarct area. Hence, the NLRP3 inflammasome is considered to be an important target for the treatment of brain edema in cerebral ischaemia-reperfusion, and MCC950 has potential value for ischaemic stroke treatment.


Assuntos
Edema Encefálico/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Furanos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Sulfonamidas/farmacologia , Animais , Aquaporina 4/metabolismo , Barreira Hematoencefálica/metabolismo , Edema Encefálico/patologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Furanos/administração & dosagem , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/patologia , Sulfonamidas/administração & dosagem
10.
J Food Sci ; 85(4): 1338-1343, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32232993

RESUMO

Inhalation of odors can affect physiological parameter and change gene expression-related specific function. 2,5-Dimethyl-4-hydroxy-3(2H)-furanone (DMHF) is one of the major odor compounds generated by the Maillard reaction. We previously reported that the inhalation of DMHF decreased systolic blood pressure via the autonomic nervous system in rats. The autonomic nervous system is also closely related to appetite regulation. The present study investigated the effects of DMHF on dietary intake and gene expression. The inhalation of DMHF increased the dietary intake of rats during the feeding period. However, body weight did not change after 6 weeks feeding. A DNA microarray analysis showed that DMHF altered gene expression associated with feeding behavior and neurotransmission in the rat brain. DMHF inhalation promotes appetite and changes gene expression in rats. Furthermore, phenotypic changes may regulate neurotransmission and appetite at the mRNA level in addition to controlling the autonomic nervous system. PRACTICAL APPLICATION: DMHF is an important flavor component in the food industry. In this study, we first observed that the inhalation of DMHF promotes appetite. This finding is directly connected with the industrial application.


Assuntos
Encéfalo/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Reação de Maillard , Administração por Inalação , Animais , Apetite , Aromatizantes/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Odorantes/análise , Ratos , Ratos Wistar , Paladar
11.
Nat Commun ; 11(1): 1264, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152287

RESUMO

Wildfires can encourage the establishment of invasive plants by releasing potent germination stimulants, such as karrikins. Seed germination of Brassica tournefortii, a noxious weed of Mediterranean climates, is strongly stimulated by KAR1, the archetypal karrikin produced from burning vegetation. In contrast, the closely-related yet non-fire-associated ephemeral Arabidopsis thaliana is unusual because it responds preferentially to KAR2. The α/ß-hydrolase KARRIKIN INSENSITIVE 2 (KAI2) is the putative karrikin receptor identified in Arabidopsis. Here we show that B. tournefortii expresses three KAI2 homologues, and the most highly-expressed homologue is sufficient to confer enhanced responses to KAR1 relative to KAR2 when expressed in Arabidopsis. We identify two amino acid residues near the KAI2 active site that explain the ligand selectivity, and show that this combination has arisen independently multiple times within dicots. Our results suggest that duplication and diversification of KAI2 proteins could confer differential responses to chemical cues produced by environmental disturbance, including fire.


Assuntos
Arabidopsis/metabolismo , Brassica/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Furanos/farmacologia , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/metabolismo , Piranos/farmacologia , Arabidopsis/efeitos dos fármacos , Arabidopsis/genética , Proteínas de Arabidopsis , Brassica/efeitos dos fármacos , Brassica/genética , Domínio Catalítico , Fogo , Regulação da Expressão Gênica de Plantas , Germinação/efeitos dos fármacos , Germinação/fisiologia , Hidrolases/genética , Hidrolases/metabolismo , Magnoliopsida , Proteínas de Plantas/efeitos dos fármacos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plântula , Sementes/efeitos dos fármacos , Sementes/fisiologia , Análise de Sequência de Proteína , Transcriptoma , Incêndios Florestais
12.
Artigo em Inglês | MEDLINE | ID: mdl-32159972

RESUMO

The incidence of asthma has increased from 5.5% to near 8% of the population, which is a major health concern. The hallmarks of asthma include eosinophilic airway inflammation that is associated with chronic airway remodeling. Allergic airway inflammation is characterized by a complex interplay of resident and inflammatory cells. MicroRNAs (miRNAs) are small noncoding RNAs that function as posttranscriptional modulators of gene expression. However, the role of miRNAs, specifically miR-451, in the regulation of allergic airway inflammation is unexplored. Our previous findings showed that oxidant stress regulates miR-451 gene expression in macrophages during an inflammatory process. In this paper, we examined the role of miR-451 in regulating macrophage phenotype using an experimental poly-allergenic murine model of allergic airway inflammation. We found that miR-451 contributes to the allergic induction of CCL17 in the lung and plays a key role in proasthmatic macrophage activation. Remarkably, administration of a Sirtuin 2 (Sirt2) inhibitor diminished alternate macrophage activation and markedly abrogated triple-allergen [dust mite, ragweed, Aspergillus fumigatus (DRA)]-induced lung inflammation. These data demonstrate a role for miR-451 in modulating allergic inflammation by influencing allergen-mediated macrophages phenotype.


Assuntos
Asma/genética , Macrófagos Alveolares/imunologia , MicroRNAs/genética , Pneumonia/genética , Sirtuína 2/genética , Alérgenos/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Antígenos de Plantas/administração & dosagem , Aspergillus/química , Aspergillus/imunologia , Asma/induzido quimicamente , Asma/patologia , Asma/terapia , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Modelos Animais de Doenças , Fungos/química , Fungos/imunologia , Furanos/farmacologia , Regulação da Expressão Gênica , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/imunologia , Extratos Vegetais/administração & dosagem , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia/terapia , Pyroglyphidae/química , Pyroglyphidae/imunologia , Quinolinas/farmacologia , Transdução de Sinais , Sirtuína 2/antagonistas & inibidores , Sirtuína 2/imunologia
13.
J Nat Med ; 74(3): 525-532, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207025

RESUMO

Autophagy is a catabolic process that degrades dysfunctional proteins and organelles and plays critical roles in cancer development. Our preliminary screening identified that extracts of the fruits of Arctium lappa and the fruits of Forsythia suspensa notably suppressed the proliferation of hepatocellular carcinoma HepG2 cells and downregulated the autophagy. In this study, we explored the effect of arctigenin (ARG), a bioactive lignan in both extracts, on cell proliferation and autophagy-related proteins in HepG2 cells. ARG inhibited the proliferation of HepG2 cells. Analysis of autophagy-related proteins demonstrated that ARG might block the autophagy that leads to sequestosome 1/p62 (p62) accumulation. The stage of inhibition in autophagy by ARG differed from those by the autophagy inhibitors 3-methyladenine (3-MA) or chloroquine (CQ). ARG could also inhibit starvation-induced autophagy. Further analysis of apoptosis-related proteins indicated that ARG did not affect caspase-3 activation and PARP cleavage, suggesting that the antiproliferative effect of ARG can occur independently of apoptosis. In summary, our study showed that ARG suppresses cell proliferation and inhibits autophagy, and might lead to the development of agents for autophagy research and cancer chemoprevention.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Lignanas/farmacologia , Neoplasias Hepáticas/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Arctium/química , Linhagem Celular Tumoral , Cloroquina/farmacologia , Forsythia/química , Células Hep G2 , Humanos , Proteína Sequestossoma-1
14.
Yakugaku Zasshi ; 140(2): 129-137, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32009033

RESUMO

(-)-2S,3S,4S,5S-Talaumidin (1) exhibits potent neurotrophic activities such as neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in nerve growth factor (NGF)-differentiated PC12 cells. To examine the stereochemistry-activity relationship of 1, systematic syntheses of seven stereoisomers of 1 were accomplished via Evans aldol reaction, diastereoselective hydroboration, and Mitsunobu reaction. All stereoisomers showed moderate-to-potent neurite-outgrowth promotion in NGF-differentiated PC12 cells. In particular, (-)-2S,3R,4S,5R-1e having all-cis-substituted configuration exhibited the most significant neurite-outgrowth promotion. Subsequently, we developed a short-step synthetic route for talaumidin derivatives so as to explore new neurotrophic compounds that could be obtained on a large scale. First, we synthesized derivative 2a, which is a racemic compound of (-)-1e, and compared its neurotrophic activity with (-)-1e. It was found that the neurotrophic activity of racemic 2a was similar to that of (-)-1e. Using the same synthetic route, several talaumidin derivatives were synthesized to optimize the oxy-functionality on aromatic rings. Thereby, bis(methylenedioxybenzene) derivative 2b was found to exhibit the highest neurotrophic activity. In addition, examination of the structure-activity relationship of 2b indicated that the 2,5-diphenyl structure was crucial moiety, and the two methyl groups on the tetrahydrofuran (THF) ring could enhance the neurotrophic activity. Furthermore, 2a and 2b were found to induce mouse optic nerve regeneration in vivo.


Assuntos
Desenvolvimento de Medicamentos , Furanos , Animais , Furanos/farmacologia , Humanos , Regeneração Nervosa/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Nervo Óptico/fisiologia , Ratos , Relação Estrutura-Atividade
15.
BMC Complement Med Ther ; 20(1): 49, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046692

RESUMO

BACKGROUND: Inflammation is one of the key components in the initiation and progression of hepatic diseases. If not treated, inflammation may cause cell dysplasia, and ultimately cancer. In the current study, we investigated the anti-inflammatory and anti-cancer activities of plant isolated compound Lirioresinol B Dimethyl Ether (LBDE) extracted from the seeds of Magnolia fargesii CHENG (Magnoliaceae) against HepG2 cells as well as in BALB/C male mice. METHODS: We assessed the antioxidant and anti-proliferative effects of plant compounds using DPPH assay and HepG2 cell lines. Carbon tetrachloride (CCl4) and Diethylnitrosamine (DEN) were used to induce liver cell dysplasia followed by hepatocellular carcinoma (HCC) in BALB/C male mice for 12 weeks. We investigated the underlying mechanism by using histopathology and immunoblot experiments. RESULTS: Intraperitoneal injection of LBDE (50 mg/kg body weight/day) inhibited CCl4-induced HCC. Free radical scavenging assay shows the strong anti-oxidant activity of LBDE. Western blot results show that LBDE down-regulated nuclear factor kappa B (NFκB) and cyclooxygenase (COX-2) by preventing the phosphorylation of I kappa B alpha (IκBα) in CCl4 treated group. LBDE also improved liver function by decreasing Alkaline Phosphatase (ALP), aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) levels. Histopathology results revealed that LBDE decreased granulomas and express normal morphology of hepatocytes. CONCLUSIONS: These preliminary results show that LBDE has the potential to inhibit CCl4-induced liver cell dysplasia and prevents cancer development by regulating NFκB/COX-2 activation.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Furanos/farmacologia , Cirrose Hepática/tratamento farmacológico , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Ciclo-Oxigenase 2 , Modelos Animais de Doenças , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Sementes
16.
Mol Pharmacol ; 97(4): 237-249, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32063580

RESUMO

Dysfunction of p53 and resistance to cancer drugs can arise through mutually exclusive overexpression of MDM2 or MDM4. Cisplatin-resistant cells, however, can demonstrate increased binding of both MDM2 and MDM4 to p53 but in absence of cellular overexpression. Whether MDM2 inhibitors alone can activate p53 in these resistant cells was investigated with the goal to establish the mechanism for potential synergy with cisplatin. Thus, growth inhibition by individual drugs and combinations was assessed by a colorimetric assay. Drug-treated parental A2780 and resistant tumor cells were also examined for protein expression using immunoblot and reverse phase protein array (RPPA) and then subjected to Ingenuity Pathway Analysis (IPA). Gene expression was assessed by real-time polymerase chain reaction, DNA damage by confocal microscopy, cell cycle by flow cytometry, and homologous recombination (HR) by a GFP reporter assay. Our results demonstrate that Nutlin-3 but not RITA (reactivation of p53 and induction of tumor cell apoptosis) effectively disrupted the p53-MDM2-MDM4 complex to activate p53, which increased robustly with cisplatin/Nutlin-3 combination and enhanced antitumor effects more than either agent alone. RPPA, IPA, and confocal microscopy provided evidence for an "apparent" increase in DNA damage resulting from HR inhibition by cisplatin/Nutlin-3. Molecularly, the specific HR protein Rad51 was severely downregulated by the combination via two mechanisms: p53-dependent transrepression and p53/MDM2-mediated proteasomal degradation. In conclusion, Nutlin-3 fully destabilizes the p53-MDM2-MDM4 complex and synergizes with cisplatin to intensify p53 function, which then downregulates Rad51 through a bimodal mechanism. As a result, HR is inhibited and antitumor activity enhanced in otherwise HR-proficient sensitive and resistant tumor cells. SIGNIFICANCE STATEMENT: Rad51 downregulation by the combination of cisplatin and Nutlin-3 inhibits homologous recombination (HR), which leads to persistence in DNA damage but not an increase. Thus, inhibition of HR enhances antitumor activity in otherwise HR-proficient sensitive and resistant tumor cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Rad51 Recombinase/genética , Proteína Supressora de Tumor p53/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Furanos/farmacologia , Furanos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Recombinação Homóloga/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias/genética , Neoplasias/patologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética
17.
Mol Med Rep ; 21(3): 1374-1382, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016480

RESUMO

Arctigenin is a natural lignan that is found in burdock with anti­viral, ­oxidative, ­inflammatory and anti­tumor activities. In the current study, the effect of arctigenin on metastatic potential was examined in 4T­1 mouse triple­negative breast cancer cells. The results indicated that arctigenin inhibited cell motility and invasiveness, which was determined using wound healing and transwell invasion assays. Arctigenin suppressed matrix metalloprotease­9 (MMP­9) activity via gelatin zymography, and protein expression of cyclooxygenase­2 (COX­2) and MMP­3. Furthermore, arctigenin attenuated the mRNA expression of metastatic factors, including MMP­9, MMP­3 and COX­2. Based on these results, the effect of arctigenin on the mitogen­activated protein kinase (MAPK)/activating protein­1 (AP­1) signaling pathway was assessed in an attempt to identify the regulatory mechanism responsible for its anti­metastatic effects. Arctigenin was demonstrated to inhibit the phosphorylation of extracellular signal­regulated protein kinase (ERK) and c­Jun N­terminal kinase (JNK), and the nuclear translocations of the AP­1 subunits, c­Jun and c­Fos. In summary, the present study demonstrated that in 4T­1 mouse triple­negative breast cancer cells the anti­metastatic effect of arctigenin is mediated by the inhibition of MMP­9 activity and by the inhibition of the metastasis­enhancing factors MMP­9, MMP­3 and COX­2, due to the suppression of the MAPK/AP­1 signaling pathway. The results of the current study demonstrated that arctigenin exhibits a potential for preventing cell migration and invasion in triple negative breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Arctium/química , Furanos/farmacologia , Lignanas/farmacologia , Sistema de Sinalização das MAP Quinases , Inibidores de Metaloproteinases de Matriz/farmacologia , Fator de Transcrição AP-1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
Mol Cell Biochem ; 467(1-2): 45-56, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32065351

RESUMO

Arctigenin, a mitochondrial complex I inhibitor, has been identified as a potential anti-tumor agent, but the involved mechanism still remains elusive. Herein, we studied the underlying mechanism(s) of action of arctigenin on acidity-tolerant prostate cancer PC-3AcT cells in the lactic acid-containing medium. At concentration showing no toxicity on normal prostate epithelial RWPE-1 and HPrEC cells, arctigenin alone or in combination with docetaxel induced significant cytotoxicity in PC-3AcT cells compared to parental PC-3 cells. With arctigenin treatment, reactive oxygen species (ROS) levels, annexin V-PE positive fractions, sub-G0/G1 peak in cell cycle analysis, mitochondrial membrane depolarization, and cell communication network factor 1 (CCN1) levels were increased, while cellular ATP content and phospho (p)-Akt level were decreased. Pretreatment with ROS scavenger N-acetylcysteine effectively reversed the series of phenomena caused by arctigenin, suggesting that ROS served as upstream molecules of arctigenin-driven cytotoxicity. Meanwhile, arctigenin increased the levels of p-receptor-interacting serine/threonine-protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like pseudokinase (p-MLKL) as necroptosis mediators, and pretreatment with necroptosis inhibitor necrostatin-1 restored their levels and cell viability. Treatment of spheroids with arctigenin resulted in necroptotic cell death, which was prevented by N-acetylcysteine. The siRNA-based knockdown of CCN1 suppressed the levels of MLKL, B-cell lymphoma 2 (Bcl-2), and induced myeloid leukemia cell differentiation (Mcl-1) with increased cleavage of Bcl-2-associated X (Bax) and caspase-3. Collectively, these results provide new insights into the molecular mechanisms underlying arctigenin-induced cytotoxicity, and support arctigenin as a potential therapeutic agent for targeting non-Warburg phenotype through induction of necroptosis via ROS-mediated mitochondrial damage and CCN1 upregulation.


Assuntos
Furanos/farmacologia , Ácido Láctico/farmacologia , Lignanas/farmacologia , Mitocôndrias/metabolismo , Neoplasias da Próstata/metabolismo , Regulação para Cima , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/química , Ciclina D1 , Docetaxel/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Necroptose , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
19.
J Mycol Med ; 30(2): 100924, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32037102

RESUMO

Cryptococcus neoformans, an encapsulated fungal pathogen is evolving as a major threat to immune-compromised patients and rarely to healthy individuals also. The cell wall bound capsular polysaccharide, melanin pigment and biofilm formation are major virulence factors that are known to contribute to cryptococcal meningitis. In the present study, a furanone derivative, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6) was evaluated against biofilm of seven different strains of C. neoformans in melanized and non-melanized condition. In addition, the efficacy of compound-6 in activation of TLR-2, opsonophagocytosis, and modulation of cytokine expression during phagocytosis were studied. During the biofilm study, we found that moderate capsule size favored biofilm formation. Interestingly, the minimum biofilm eradication concentration (MBEC0.5) of melanized biofilm was found to be achieved at 1- to 1.7-fold higher MBEC0.5 of non-melanized cells. The maximum eradication of 77% and 69% of non-melanized and melanized biofilm were observed. The capsule size was reduced to half of its size with marked changes in morphology. Furthermore, expression of TLR2, iNOS and pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ were also facilitated by compound-6. The correlation analysis showed a positive correlation between phagocytosis and the expression of TLR-2, iNOS, IL-6, IL-12. Collectively, the significant effect of compound-6, anti-melanization activity, antibiofilmand effective immunomodulant could be an interesting dual strategy drug agonist against cryptococcal meningitis.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Proteínas Opsonizantes/fisiologia , Fagocitose/efeitos dos fármacos , Animais , Antifúngicos/síntese química , Antifúngicos/química , Cápsulas Bacterianas/efeitos dos fármacos , Cápsulas Bacterianas/fisiologia , Células Cultivadas , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus/fisiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/fisiologia , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Melaninas/metabolismo , Meningite Criptocócica/imunologia , Meningite Criptocócica/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Opsonizantes/metabolismo
20.
Cancer Res ; 80(7): 1538-1550, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32019870

RESUMO

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFß, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo These findings might pave a way for new synthetic lethal combination therapies.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Oncogenes/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transcrição Genética/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Feminino , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Furanos/farmacologia , Furanos/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteoma/genética , Proteômica/métodos , Reparo de DNA por Recombinação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Mutações Sintéticas Letais/efeitos dos fármacos
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