RESUMO
Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg·kg-1 , i.g.) was shown to ameliorate collagen-induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti-arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells.
Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Berberina/farmacologia , Imunossupressores/farmacologia , Neuropeptídeos/genética , Células Th17/efeitos dos fármacos , Administração Oral , Animais , Antirreumáticos/uso terapêutico , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Comunicação Autócrina , Berberina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/metabolismo , Células Enteroendócrinas/efeitos dos fármacos , Células Enteroendócrinas/metabolismo , Feminino , Imunossupressores/uso terapêutico , Intestino Delgado/efeitos dos fármacos , Neuropeptídeos/metabolismo , Células PC12 , Ratos , Ratos Wistar , Células Th17/metabolismo , Ativação Transcricional/efeitos dos fármacosRESUMO
Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.
Assuntos
Alcaloides/farmacologia , Alcaloides/uso terapêutico , Artrite/metabolismo , Lindera/química , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Artrite/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ligante RANK/farmacologia , Ratos , Ratos Wistar , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.