RESUMEN
Objective:To investigate the effects of the taurochenodeoxycholic acid(TCDCA)on cartilage degeneration in tem-poromandibular joint osteoarthritis(TMJ OA).Methods:36 female SD rats aged 6 weeks were randomly divided into 3 groups:con-trol group(CON),unilateral anterior crossbite group(UAC),UAC plus TCDCA injection group(UAC+TCDCA).UAC model was es-tablished in all rats in UAC and UAC+TCDCA groups.Samples were collected at 8 and 12 weeks(control group,UAC group,UAC+TCDCA group)after set up of the experiment(n=6),and TMJ morphological examination was performed.The expression of CYP7A1,BAAT and TGR5 in the tissue and cells was examined by immunohistochimical staining.Results:(1)Compared with the CON group of the same age,the cells in the condylar cartilage were disordered,the cartilage matrix was reduced and thinner in UAC group.Compared with UAC group of the same age,cell arrangement,cell number,cartilage matrix and cartilage thickness were im-proved in UAC+TCDCA group(P＜0.05).(2)Compared with the CON group of the same age,the positive cells for TCDCA-specific receptor TGR5 and the key enzymes CYP7A1 and BAAT were mainly distributed in the anterior hypertrophic layer and hypertrophic layer at each time point.The number of positive cells in the UAC group was significantly reduced compared with the CON group.Conclusion:TCDCA has obvious therapeutic effects on the degeneration in TMJ OA.
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Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.
Asunto(s)
Animales , Humanos , Ratas , Línea Celular , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Citocinas/metabolismo , Inflamación , Macrófagos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
To investigate the anti-inflammatory mechanisms of taurochenodeoxycholic acid (TCDCA), the molecule structure file of TCDCA was downloaded from PubChem database, PharmMapper and GeneCards were used to predict and screen the targets of TCDCA. STRING database and Cytoscape software were used to construct protein interactions network. GO and KEGG analysis was preformed through STRING database. The key targets were validated by molecular docking and the targets type was attributed by DisGeNET database. The network showed that 89 targets were involved in 68 biological processes including response to stimulus, multicellular organismal process, single-multicellular organism process, response to chemical, response to organic substance, by adjusting 51 signaling pathways, such as pathways in cancer, progesterone-mediated oocyte maturation, MAPK signaling pathway, proteoglycans in cancer. These findings provide an overview of anti-inflammation of TCDCA, which reflects the characteristic of multi-targets and multi-pathways of TCDCA. It pointed out the direction for further research on anti-inflammatory mechanism of TCDCA.
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Aim To study the effect of Taurochenodeoxycholic Acid (TCDCA) on immunologic cell in vitro and in vivo in mice. Methods Five doses were used , including 0.043, 0.065, 0.1, 0.153, 0.189 g?kg-1 in vivo and 0.01, 0.05, 0.1, 1, 10 mg?L-1 in vitro. Effects of TCDCA on peritoneal macrophage in mouse in vitro,splenic lymphocyte, normal organism, immunologic functional inhibiting model and nerve-endocrine-immunoregulation system were investigated. Results TCDCA had the obvious immunoregulation effect on normal organisms in mouse. 0.1 g?kg-1 TCDCA had the obvious anastated effects on the immunological inhibiting model made up by the cyclosporine A and cyclophosphamide. TCDCA may affect the peritoneal macrophage and splenic lymphocyte in vitro directly, meanwhile two kinds of immunological cells showed the obvious immunoregulation effects on the whole. 0.1 g?kg-1 TCDCA can increase the hydrocortisone contents of the nerve-endocrine-immunoregulation system in mouse most remarkably. Conclusion TCDCA had the adjustment effect on the immunoregulation function in mouse.