RESUMEN
The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factorα (TNFα) increased the level of vascular cell adhesion molecule1 (VCAM1) expression in a dosedependent manner. The nuclear factor-κB (NF-κB), extracellular signalregulated kinase (ERK) and cJun Nterminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM1 expression induced by TNFα at the mRNA and protein levels (P<0.05). TNFα augmented the activation of NFκB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NFκB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NFκB, ERK and JNK signaling pathways.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Células Madre Mesenquimatosas/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Antracenos/farmacología , Biomarcadores , Butadienos/farmacología , Adhesión Celular , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunofenotipificación , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Nitrilos/farmacología , Fosforilación , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Molécula 1 de Adhesión Celular Vascular/genéticaRESUMEN
Depression is highly prevalent in individuals with diabetes, and depressive symptoms are less responsive to current antidepressant therapies. Oxidative stress plays a major role both in the pathogenesis of diabetes and in major depression and anxiety disorders. Hydrogen sulfide (H2S), the third gaseous mediator, is a novel signaling molecule in the brain that has both antioxidative activity and antidepressant-like and anxiolytic-like effects. We hypothesized that H2S could produce antidepressant-like and anxiolytic-like effects in diabetic patients through its antioxidative effect. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic rats. We found that H2S alleviated depressive-like behaviors of STZ-induced diabetic rats in the forced swimming and tail suspension tests and reduced their anxiety-like behaviors in the elevated plus maze test. We also found that H2S significantly reduced levels of malondialdehyde and 4-hydroxynonenal and elevated levels of superoxide dismutase and reduced glutathione in the hippocampus of STZ-induced diabetic rats. The results provide evidence for antidepressant-like and anxiolytic-like effects of H2S in STZ-induced diabetic rats and suggest that the therapeutic effects may result from inhibition of hippocampal oxidative stress. These findings suggest that elevating H2S signaling is a potential target for treatment of depressive and anxiety disorders related to diabetes.