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1.
Mol Cell Neurosci ; 68: 24-35, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25823690

RESUMO

Gut microbiota-innate immunity axis is emerging as a key player to guarantee the structural and functional integrity of the enteric nervous system (ENS). Alterations in the composition of the gut microbiota, derangement in signaling of innate immune receptors such as Toll-like receptors (TLRs), and modifications in the neurochemical coding of the ENS have been associated with a variety of gastrointestinal disorders. Indeed, TLR2 activation by microbial products controls the ENS structure and regulates intestinal neuromuscular function. However, the cellular populations and the molecular mechanisms shaping the plasticity of enteric neurons in response to gut microbes are largely unexplored. In this study, smooth muscle cells (SMCs), enteric glial cells (EGCs) and macrophages/dendritic cells (MΦ/DCs) were isolated and cultured from the ileal longitudinal muscle layer of wild-type (WT) and Toll-like receptor-2 deficient (TLR2(-/-)) mice. Quantification of mRNA levels of neurotrophins at baseline and following stimulation with TLR ligands was performed by RT-PCR. To determine the role of neurotrophins in supporting the neuronal phenotype, we performed co-culture experiments of enteric neurons with the conditioned media of cells isolated from the longitudinal muscle layer of WT or TLR2(-/-) mice. The neuronal phenotype was investigated evaluating the expression of ßIII-tubulin, HuC/D, and nNOS by immunocytochemistry. As detected by semi-quantitative RT-PCR, SMCs expressed mRNA coding TLR1-9. Among the tested cell populations, un-stimulated SMCs were the most prominent sources of neurotrophins. Stimulation with TLR2, TLR4, TLR5 and TLR9 ligands further increased Gdnf, Ngf, Bdnf and Lif mRNA levels in SMCs. Enteric neurons isolated from TLR2(-/-) mice exhibited smaller ganglia, fewer HuC/D(+ve) and nNOS(+ve) neurons and shorter ßIII-tubulin axonal networks as compared to neurons cultured from WT mice. The co-culture with the conditioned media from WT-SMCs but not with those from WT-EGCs or WT-MΦ/DCs corrected the altered neuronal phenotype of TLR2(-/-) mice. Supplementation of TLR2(-/-) neuronal cultures with GDNF recapitulated the WT-SMC co-culture effect whereas the knockdown of GDNF expression in WT-SMCs using shRNA interference abolished the effect on TLR2(-/-) neurons. These data revealed that by exploiting the repertoire of TLRs to decode gut-microbial signals, intestinal SMCs elaborate a cocktail of neurotrophic factors that in turn supports neuronal phenotype. In this view, the SMCs represent an attractive target for novel therapeutic strategies.


Assuntos
Regulação da Expressão Gênica/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Intestino Delgado/citologia , Miócitos de Músculo Liso/metabolismo , Receptor 2 Toll-Like/metabolismo , Actinas/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Proteína Semelhante a ELAV 3/metabolismo , Proteína Semelhante a ELAV 4/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos de Músculo Liso/efeitos dos fármacos , Neuroglia/fisiologia , Neurônios/fisiologia , Quinolinas/metabolismo , Tiazóis/metabolismo , Receptor 2 Toll-Like/genética , Tubulina (Proteína)/metabolismo
2.
Eur J Med Chem ; 115: 416-25, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27035798

RESUMO

Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fibrose/tratamento farmacológico , Quinazolinonas/uso terapêutico , Simulação de Acoplamento Molecular
3.
Nat Prod Res ; 29(10): 939-46, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25280163

RESUMO

The essential oils (EOs) from the Brazilian species Croton zehntneri, Pterodon emarginatus and Schinopsis brasiliensis were examined for their chemical constituents, and antioxidant and antimicrobial activities. The composition of EOs was determined by using gas chromatography coupled with mass spectrometry analysis, while the antioxidant activity was evaluated through the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) assays. Furthermore, the antimicrobial activity was investigated against Escherichia coli and Pseudomonas aeruginosa (both Gram-negative), Staphylococcus aureus (Gram-positive) and Candida parapsilosis (fungus). The main components of C. zehntneri, P. emarginatus and S. brasiliensis were identified as estragole, trans-anethole, ß-caryophyllene and myrcene. Among the EOs, P. emarginatus showed the highest antioxidant activity, with an IC50 of 7.36 mg/mL and a Trolox equivalent antioxidant capacity of 3748 µmol/g determined by DPPH and ORAC assays, respectively. All EOs showed low activities against the bacterial strains tested, whereas the C. zehntneri oil and its main constituent estragole exhibited an appreciable antifungal activity against C. parapsilosis.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Croton/química , Fabaceae/química , Sequestradores de Radicais Livres/farmacologia , Óleos Voláteis/química , Monoterpenos Acíclicos , Alcenos/farmacologia , Derivados de Alilbenzenos , Anacardiaceae/química , Anisóis/farmacologia , Candida/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia , Sesquiterpenos Policíclicos , Pseudomonas aeruginosa/efeitos dos fármacos , Sesquiterpenos/farmacologia , Staphylococcus aureus/efeitos dos fármacos
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