RESUMEN
Group 2 innate lymphoid cells (ILC2s), characterized by secretion of type 2 cytokines, regulate multiple immune responses. ILC2s are found in different tumor tissues, and ILC2-derived interleukin (IL)-4, IL-5, and IL-13 act on the cells in tumor microenvironment to participate in tumor progression. ILC2s are abundant in colorectal cancer (CRC) tissue, but the role of ILC2s in CRC remains unclear. In this study, we found that the percentage of ILC2s was higher in CRC tissue than in the adjacent normal tissue and that these ILC2s were the dominant IL-9-secreting cell-subsets in CRC tissue, as shown by flow cytometry analysis. ILC2s-derived IL-9 could activate CD8+ T cells to inhibit tumor growth, while anti-IL-9 reversed this effect. In vivo experiments showed that neutralizing ILC2s promoted tumor growth, while tumor inhibition occurred by intravenous injection of IL-9. In conclusion, our results demonstrated that ILC2-derived IL-9 could activate CD8+ T cells to promote anti-tumor effects in CRC.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/patología , Interleucina-9/metabolismo , Linfocitos/inmunología , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunidad Innata , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Microambiente TumoralRESUMEN
Among the major bacterial secretions, outer membrane vesicles (OMVs) are significant and highly functional. The proteins and other biomolecules identified within OMVs provide new insights into the possible functions of OMVs in bacteria. OMVs are rich in proteins, nucleic acids, toxins and virulence factors that play a critical role in bacteria-host interactions. In this review, we discuss some proteins with multifunctional features from bacterial OMVs and their role involving the mechanisms of bacterial survival and defence. Proteins with moonlighting activities in OMVs are discussed based on their functions in bacteria. OMVs harbour many other proteins that are important, such as proteins involved in virulence, defence, and competition. Overall, OMVs are a power-packed aid for bacteria, harbouring many defensive and moonlighting proteins and acting as a survival kit in case of an emergency or as a defence weapon. In summary, OMVs can be defined as bug-out bags for bacterial defence and, therefore, survival.
Asunto(s)
Bacterias/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Vesículas Extracelulares/metabolismo , Aminoácidos/biosíntesis , Humanos , Metabolismo de los Lípidos/fisiología , Ácidos Nucleicos/biosíntesis , Factores de VirulenciaRESUMEN
Asthma is a disease of the respiratory system that is commonly considered a T-helper 2 (Th2) cell-associated inflammatory disease. Group 2 innate lymphoid cells (ILC2s) promote the inflammatory responses in asthma by secreting type 2 cytokines. Interleukin (IL)-9 also serves as a promoting factor in asthma and it is well known that ILC2s have an autocrine effect of IL-9 to sustain their survival and proliferation. However, the specific role of ILC2-derived IL-9 in asthma remains unclear. HMGB1 (High-Mobility Group Box-1) is a nuclear protein, and Previous studies have shown that HMGB1 can regulate the differentiation of T-helper cells and participate in the development of asthma. But whether HMGB1 can regulate the innate lymphocytes in the pathological process of asthma is unknown. In this study we have shown increased presence of HMGB1 protein in the lung of mice with asthma, which was associated with increased secretion of IL-9 by ILC2s. This led to the activation of dendritic cells (DCs) that can accelerate the differentiation of Th2 cells and worsen the severity of asthma. Taken together, our study provides a complementary understanding of the asthma development and highlights a novel inflammatory pathway in the pathogenesis of asthma.
Asunto(s)
Asma/metabolismo , Proteína HMGB1/metabolismo , Linfocitos/inmunología , Animales , Asma/fisiopatología , Diferenciación Celular/efectos de los fármacos , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteínas HMGB/metabolismo , Proteínas HMGB/fisiología , Proteína HMGB1/fisiología , Inmunidad Innata/efectos de los fármacos , Interleucina-9/inmunología , Interleucina-9/metabolismo , Pulmón/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Células Th2/inmunologíaRESUMEN
AIM AND OBJECTIVE: Actinomycetes produce structurally unique secondary metabolites with pharmaceutically essential bioactivities. Salinispora, an obligate marine actinomycete, produces structurally varied and unique secondary metabolites. There is plenty of scope for development of drugs from the novel compounds isolated from Salinispora. Anticancer, antibacterial and anti-protozoa activities have been shown for Salinosporamides A, B and C, the secondary metabolites identified from Salinispora, which make them interesting subjects for further extended biological activity prediction. MATERIAL AND METHODS: An in silico ligand based-pharmacophore approach was used for the prediction of extended biological targets for salinosporamide A, B and C. Pharmacophore models of salinosporamide A, B and C were generated individually and screened against known drug databases. The drugs with best fitness score were shortlisted, and their respective targets pertaining to their bioactivity were retrieved. The predicted biological drug targets were docked with salinosporamide A, B and C for validation. RESULTS: The glucocorticoid receptor and methionine aminopeptidase 2 showed good docking score and binding energy with salinosporamide A, B and C. Molecular dynamics studies of the protein-ligand complexes showed stable interactions suggesting that the predicted new targets for salinosporamides might be promising. CONCLUSIONS: The glucocorticoid receptor and methionine aminopeptidase 2 could be possible new drug targets of bioactivity of salinosporamides. These proteins could be the druggable targets for antiinflammatory and anticancer activity of salinosporamides.
Asunto(s)
Actinobacteria/química , Descubrimiento de Drogas , Lactamas/farmacología , Lactonas/farmacología , Pirroles/farmacología , Actinobacteria/metabolismo , Aminopeptidasas/metabolismo , Humanos , Lactamas/química , Lactamas/metabolismo , Lactonas/química , Lactonas/metabolismo , Ligandos , Metaloendopeptidasas/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Pirroles/química , Pirroles/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMEN
The discovery of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors has become a promising strategy to develop novel lead molecules against variety of stress. Hence, Keap1-Nrf2 system plays an important role in oxidative/electrophilic stress associated disorders. Our earlier studies identified pterostilbene (PTS), a natural analogue of resveratrol, as a potent Nrf2 activator and Keap1-Nrf2 PPI inhibitor as assessed by luciferase complementation assay. In this study, we further identified the potential of PTS in Nrf2 activation and ARE-driven downstream target genes expression by nuclear translocation experiments and ARE-luciferase reporter assay, respectively. Further, the luciferase complementation assay identified that PTS inhibits Keap1-Nrf2 PPI in both dose and time-dependent manner. Computational studies using molecular docking and dynamic simulation revealed that PTS directly interacts with the basic amino acids of kelch domain of Keap1 and perturb Keap1-Nrf2 interaction pattern. This manuscript not only shows the binding determinants of Keap1-Nrf2 proteins but also provides mechanistic insights on Nrf2 activation potential of PTS.
Asunto(s)
Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estilbenos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Unión ProteicaRESUMEN
Pseudomonas aeruginosa and Escherichia coli are resistant to wide range of antibiotics rendering the treatment of infections very difficult. A main mechanism attributed to the resistance is the function of efflux pumps. MexAB-OprM and AcrAB-TolC are the tripartite efflux pump assemblies, responsible for multidrug resistance in P. aeruginosa and E. coli respectively. Substrates that are more susceptible for efflux are predicted to have a common pharmacophore feature map. In this study, a new criterion of excluding compounds with efflux substrate-like features was used, thereby refining the selection process and enriching the inhibitor identification process. An in-house database of phytochemicals was created and screened using high-throughput virtual screening against AcrB and MexB proteins and filtered by matching with the common pharmacophore models (AADHR, ADHNR, AAHNR, AADHN, AADNR, AAADN, AAADR, AAANR, AAAHN, AAADD and AAADH) generated using known efflux substrates. Phytochemical hits that matched with any one or more of the efflux substrate models were excluded from the study. Hits that do not have features similar to the efflux substrate models were docked using XP docking against the AcrB and MexB proteins. The best hits of the XP docking were validated by checkerboard synergy assay and ethidium bromide accumulation assay for their efflux inhibition potency. Lanatoside C and diadzein were filtered based on the synergistic potential and validated for their efflux inhibition potency using ethidium bromide accumulation study. These compounds exhibited the ability to increase the accumulation of ethidium bromide inside the bacterial cell as evidenced by these increase in fluorescence in the presence of the compounds. With this good correlation between in silico screening and positive efflux inhibitory activity in vitro, the two compounds, lanatoside C and diadzein could be promising efflux pump inhibitors and effective to use in combination therapy against drug resistant strains of P. aeruginosa and E. coli.
Asunto(s)
Antibacterianos/farmacología , Productos Biológicos/farmacología , Farmacorresistencia Bacteriana Múltiple , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Secuencia de Aminoácidos , Antibacterianos/química , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/metabolismo , Productos Biológicos/química , Simulación por Computador , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Etidio/química , Etidio/metabolismo , Ensayos Analíticos de Alto Rendimiento , Técnicas In Vitro , Ligandos , Proteínas de Transporte de Membrana/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Datos de Secuencia Molecular , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/química , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Fitoquímicos/química , Fitoquímicos/farmacología , Unión Proteica , Reproducibilidad de los Resultados , Alineación de SecuenciaRESUMEN
Sporolides A and B are novel polycyclic macrolides from the obligate marine actinomycetes, Salinispora tropica. The unique and novel structure of sporolides makes them interesting candidates for targeting diverse biological activities. Biological target prediction of sporolides was carried out using ligand-based pharmacophore screening against known inhibitors and drugs. Validation of pharmacophore screening was carried out for the identified hits. New biological targets predicted for sporolides using this method were HIV-1 reverse transcriptase, adenosine A3 receptor, endothelin receptor ET-A, oxytocin receptor, voltage-gated L-type calcium channel α-1C subunit/calcium channel α/Δ subunit 1. Drug-likeness properties were predicted for the selected compounds using QikProp module. Sporolides A and B showed maximum docking score with HIV-1 reverse transcriptase. Structural interaction fingerprints analysis indicated similar binding pattern of the sporolides with the HIV-1 reverse transcriptase. Sporolide B exhibited good inhibitory activity against HIV-1 reverse transcriptase in in vitro fluorescent assay.