The Na⁺/glucose cotransporter 1 (SGLT1) is responsible for glucose uptake in intestinal epithelial cells. It has been shown that the intestinal SGLT1 level is significantly increased in diabetic individuals and positively correlated with the pathogenesis of diabetes. The development of targeted therapeutics that can reduce the intestinal SGLT1 expression level is, therefore, important. In this study, we showed that ginsenoside Rg1 effectively decreased intestinal glucose uptake through inhibition of SGLT1 gene expression in vivo and in vitro. Transient transfection analysis of the SGLT1 promoter revealed an essential cAMP response element (CRE) that confers the Rg1-mediated inhibition of SGLT1 gene expression. Chromatin immunoprecipitation assay and targeted CRE-binding protein (CREB) silencing demonstrated that Rg1 reduced the promoter binding of CREB and CREB binding protein associated with an inactivated chromatin status. In addition, further studies showed that the epidermal growth factor receptor (EGFR) signaling pathway also plays an essential role in the inhibitory effect of Rg1; taken together, our study demonstrates the involvement of the EGFR-CREB signaling pathway in the Rg1-mediated downregulation of SGLT1 expression, which offers a potential strategy in the development of antihyperglycemic and antidiabetic treatments.

Background: For thousands of years, it remains unclear why Chinese prefer complex herbal remedy and seldom try to purify it. One of the reasons is that they believe Chinese herbs compared to Western drugs are relatively less toxic and better tolerated. The so called “Junn-Chenn-Zuou-SS” theory illustrates a concept of coordinated effects from a combination of different Chinese herbs. PG27, a refined extract from a well-known Chinese antirheumatic herb Tripterygium wilfordii Hook f (TwHf), is effective in attenuating transplantation rejection and extending survival of cardiac xenografts. Methods: Experiments were conducted in human primary T lymphocytes isolated from buffy coat. The activities of the inhibitor of kappaB alpha kinase-inhibitor of kappaB alpha-nuclear factor kappaB (IKK-IκBα-NF-κB) and mitogen activated protein kinase-activator protein-1 (MAPK-AP-1) signaling pathways were determined via electrophoretic mobility shift assays, immunoprecipitation kinase assays, Western blots, and transfection assays. Results: We showed that PG27 inhibited IKKα-IκBα-NF-κB and MAPK-AP-1 signaling pathways; however, IKKβ activity was less susceptible to inhibition by PG27. In contrast, the purified component of TwHf, PG490 (triptolide), reduced both MAPK-AP-1 and IKK-IκBα-NF-κB signaling pathways, including both IKKα and IKKβ, with similar potency. By means of high performance liquid chromatography analysis, it was estimated that PG490 constituted 1.27 ± 0.06% of the total PG27 content. Further analysis demonstrated that compared to PG490 alone, PG27 that contained an equal amount of PG490 was less toxic and less immunosuppressive, suggesting the presence of cytoprotective ingredient(s) in the non-PG490 components of PG27. Conclusions: In addition to demonstrating the immunomodulatory capacity of PG27 as the potential therapeutics for arthritis and prevention of transplantation rejection, the differential regulatory effects and mechanisms by PG27 and PG490 further support in part a possibly-existing Chinese herbal theory “Junn-Chenn-Zuou-SS”.