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1.
Proc Natl Acad Sci U S A ; 117(41): 25679-25689, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32973091

RESUMO

Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Vesículas Extracelulares/metabolismo , Inflamação/metabolismo , Fosfolipases A2/metabolismo , Receptor 4 Toll-Like/agonistas , Animais , Artrite Reumatoide/metabolismo , Feminino , Gota/metabolismo , Células HEK293 , Humanos , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Estresse Oxidativo , Líquido Sinovial/química
2.
Int J Mol Sci ; 21(20)2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081396

RESUMO

Cardioprotection against ischemia/reperfusion injury is still an unmet clinical need. The transient activation of Toll-like receptors (TLRs) has been implicated in cardioprotection, which may be achieved by treatment with blood-derived extracellular vesicles (EVs). However, since the isolation of EVs from blood takes considerable effort, the aim of our study was to establish a cellular model from which cardioprotective EVs can be isolated in a well-reproducible manner. EV release was induced in HEK293 cells with calcium ionophore A23187. EVs were characterized and cytoprotection was assessed in H9c2 and AC16 cell lines. Cardioprotection afforded by EVs and its mechanism were investigated after 16 h simulated ischemia and 2 h reperfusion. The induction of HEK293 cells by calcium ionophore resulted in the release of heterogenous populations of EVs. In H9c2 and AC16 cells, stressEVs induced the downstream signaling of TLR4 and heme oxygenase 1 (HO-1) expression in H9c2 cells. StressEVs decreased necrosis due to simulated ischemia/reperfusion injury in H9c2 and AC16 cells, which was independent of TLR4 induction, but not that of HO-1. Calcium ionophore-induced EVs exert cytoprotection by inducing HO-1 in a TLR4-independent manner.


Assuntos
Exossomos/metabolismo , Heme Oxigenase-1/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Calcimicina/farmacologia , Ionóforos de Cálcio/farmacologia , Morte Celular , Exossomos/efeitos dos fármacos , Células HEK293 , Heme Oxigenase-1/genética , Humanos , Camundongos , Ratos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
3.
Phytother Res ; 29(3): 381-92, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25414115

RESUMO

Gouania leptostachya DC. var. tonkinensis Pitard. Rhamnaceae is a traditional medicinal plant used in Thailand for treating various inflammatory symptoms. However, no systematic studies have been performed concerning the anti-inflammatory effects or molecular mechanisms of this plant. The immunopharmacological activities of a methanol extract from the leaves and twigs of G. leptostachya (Gl-ME) were elucidated based on the gastritis symptoms of mice treated with HCl/EtOH and the inflammatory responses, such as nitric oxide (NO) release and prostaglandin E2 (PGE2) production, from RAW264.7 cells and peritoneal macrophages. Moreover, inhibitory target molecules were also assessed. Gl-ME dose-dependently diminished the secretion of NO and PGE2 from LPS-stimulated RAW264.7 cells and peritoneal macrophages. The gastritis lesions of HCl/EtOH-treated mice were also attenuated after Gl-ME treatment. The extract (50 and 300 µg/mL) clearly reduced mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, nuclear translocation of p65/nuclear factor (NF)-κB, phosphorylation of p65-activating upstream enzymes, such as protein kinase B (AKT), inhibitor of κBα kinase (IKK), and inhibitor of κB (IκBα), and the enzymatic activity of Src. By HPLC analysis, one of the major components in the extract was revealed as resveratrol with NO and Src inhibitory activities. Moreover, this compound suppressed NO production and HCl/EtOH-induced gastric symptoms. Therefore, these results suggest that Gl-ME might be useful as an herbal anti-inflammatory medicine through the inhibition of Src and NF-κB activation pathways. The efficacy data of G. leptostachya also implies that this plant could be further tested to see whether it can be developed as potential anti-inflammatory preparation.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Rhamnaceae/química , Estilbenos/farmacologia , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Gastrite/tratamento farmacológico , Proteínas I-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol , Tailândia
4.
Mediators Inflamm ; 2014: 354843, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25386046

RESUMO

AP736 was identified as an antimelanogenic drug that can be used for the prevention of melasma, freckles, and dark spots in skin by acting as a suppressor of melanin synthesis and tyrosinase expression. Since macrophage-mediated inflammatory responses are critical for skin health, here we investigated the potential anti-inflammatory activity of AP736. The effects of AP736 on various inflammatory events such as nitric oxide (NO)/prostaglandin (PG) E2 production, inflammatory gene expression, phagocytic uptake, and morphological changes were examined in RAW264.7 cells. AP736 was found to strongly inhibit the production of both NO and PGE2 in lipopolysaccharide- (LPS-) treated RAW264.7 cells. In addition, AP736 strongly inhibited both LPS-induced morphological changes and FITC-dextran-induced phagocytic uptake. Furthermore, AP736 also downregulated the expression of multiple inflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase- (COX-) 2, and interleukin- (IL-) 1ß in LPS-treated RAW264.7 cells. Transcription factor analysis, including upstream signalling events, revealed that both NF-κB and AP-1 were targeted by AP736 via inhibition of the IKK/IκBα and IRAK1/TAK1 pathways. Therefore, our results strongly suggest that AP736 is a potential anti-inflammatory drug due to its suppression of NF-κB-IKK/IκBα and AP-1-IRAK1/TAK1 signalling, which may make AP736 useful for the treatment of macrophage-mediated skin inflammation.


Assuntos
Adamantano/análogos & derivados , Anti-Inflamatórios não Esteroides/farmacologia , Benzamidas/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , NF-kappa B/antagonistas & inibidores , Fator de Transcrição AP-1/antagonistas & inibidores , Adamantano/química , Adamantano/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Benzamidas/química , Linhagem Celular , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Interleucina-1beta/genética , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Melaninas/biossíntese , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pigmentação da Pele/efeitos dos fármacos
5.
Mol Nutr Food Res ; 59(7): 1400-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25917334

RESUMO

Kaempferol (KF) is the most abundant polyphenol in tea, fruits, vegetables, and beans. However, little is known about its in vivo anti-inflammatory efficacy and mechanisms of action. To study these, several acute mouse inflammatory and nociceptive models, including gastritis, pancreatitis, and abdominal pain were employed. Kaempferol was shown to attenuate the expansion of inflammatory lesions seen in ethanol (EtOH)/HCl- and aspirin-induced gastritis, LPS/caerulein (CA) triggered pancreatitis, and acetic acid-induced writhing.


Assuntos
Dor Abdominal/tratamento farmacológico , Gastrite/tratamento farmacológico , Quempferóis/farmacologia , Nociceptividade/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/efeitos adversos , Ceruletídeo/efeitos adversos , Modelos Animais de Doenças , Gastrite/induzido quimicamente , Gastrite/patologia , Camundongos , Pancreatite/induzido quimicamente
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