| Background:Glucocorticoids(GCs) have main role in the performance of a variety of fundamental processes such as growth, development, metabolism, immune responses and homeostasis. GCs also play an important role in immunosuppression,anti-inflammation and anti-shock. Plenty of synthetic glucocorticoid hormones are used for treatment of autoimmune diseases, allergic diseases, dermatoses and tumors. GCs cause their effects by binding to the glucocorticoid receptor(GR). Long-term and big dosage usage of GCs may down-regulate the expression and affinity of GR, and decrease the human body’s sensitivity to GCs, which induces GCs resistance. GCs resistance is a most important hurdle in the treatment of numerous inflammatory diseases such as asthma,rheumatoid arthritis, inflammatory bowel disease and COPD.A lot of researches have been implemented to investigate their causative factors and molecular mechanisms of GCs resistance. Strategies for reversal of resistance and treatments of GCs resistance have been investigated, and a number of alternative anti-inflammatory drμgs are available for the treatment of GC-resistant diseases. However,these new drμgs have some kind of disadvantage, such as side effects and unaffordable price, so it is difficult for them to be widely used in clinical therapies.In recent years, Chinese herbs exert an increasingly effect in clinical treatment. An increasing number of researchers are focusing on reversal of GCs resistance with Chinese herbs. The general ginsenosides(GSS) are the main extract from ginseng, composed of panoxadiol and panaxatriol, which are available for the treatment of inflammations, tumors and fatigue. In our previous research, it showed that GSS could reverse the down-regulation of GCs sensitivity and GR expression induced by dexamethasone(DEX),and enhance the effects of GCs in vivo and vitro. In our previous study, it also shows that GSS could alleviate the side effects such as fever and abnormal liver function after transcatheter arterial chemoembolization(TACE) in hepatic tumors, and also GSS could reduce adverse effects such as hyperglycemia and osteoporosis induced by DEX, but the mechanism is unclear. In this study, we plan to explore the mechanism from a new point of view.Many researches reveal that GSS can antagonize the effects of oxidative stress response. In the previous studies, we find that Rh1 and Rg1 could reverse GCs resistence in HaCat cells induced by UVB, and also the exact mechanism is still unclear. It is reported3. Inspect the effect of alleviating inflammation in inflammatory mice models induced by UVB by the selected ginsenoside.Results:1. Ginsenoside Rb1, Rh1, Rg1 and Rb3 all could reduce ROS, and they could assist DEX to down-regulate the expression of IL-6 and IL-8 in GCs resistance cell models induced by oxidative stress, among which Rg1 is the most effective.2. DEX could inhibit the expression of IL-6 and IL-8 induced by TNF-α in mormal conditions, but in GCs resistance cell models induced by oxidative stress, DEX could not maintain the suppression of the expression of IL-6 and IL-8, it also could not inhibit the phosphorylation of P38, ERK, JNK in MAPKs signaling pathway and IκBα in NF-КB signaling pathways and P65 nuclear translocation, however, when DEX is assisted by Rg1,it is reverse.3. Rg1 could up-regulate the expression of HDAC2, inhibit GR acetylation and increase the expression of GR, then antagonist GCs resistance. Its possible mechanism is Rg1 stimulates Nrf2 nuclear translocation, maintain the expression of HDAC2 and down-regulate the acetylation of GR, which makes DEX could exert its actions even in GCs resistance cell models.4. In vivo investigations in the mice models, Rg1 still could antagonize oxidative stress and assist DEX maintain its anti-inflammation function.Conclusions: Rg1 could assist DEX resist GCs resistance induced by oxidative stress by stimulating Nrf2 nuclear translocation, maintaining the expression of HDAC2,down-regulating the acetylation of GR and increasing the expression of GR. |
