Cheng-Juan Chen

Triptolide has demonstrated potent immunosuppressive properties in multiple autoimmune disorders, but its severe toxicity has greatly hampered clinical application. Here, we synthesized a triptolide derivative STP1, which exhibits remarkably reduced toxicity compared with triptolide. Immune dysfunction plays a critical role in systemic lupus erythematosus (SLE), an archetypical and refractory autoimmune disorder with limited therapeutic options and suboptimal outcomes. To elucidate the drugability and effect, we investigated the therapeutic potential, safety, regulatory mechanism and target of STP1 on SLE. Our data indicated that STP1 significantly ameliorates imiquimod-induced murine SLE by reducing anti-IgG, anti-dsDNA IgG, proteinuria, and renal pathological injury. Mechanistically, STP1 exerts markedly immunosuppressive roles by modulating the differentiation of B cell into plasma cells and T cell into Tfh cells. Further investigation showed that STP1 regulates B-cell receptor and T-cell receptor signaling by directly targeting Fyn kinase responsible for its immunosuppressive activity. For safety of STP1, our findings indicated that the STP1 did not show any toxicity in biochemical parameters and organ pathological analysis in subacute toxicity experiment. The findings suggested that STP1 is an attractive novel candidate for SLE and other autoimmune diseases for thorough evaluation. STP1, a structurally modified derivative of triptolide with improved safety, alleviates murine systemic lupus erythematosus by targeting and inhibiting Fyn, a Src kinase family member that regulates B- and T- cell responses.

The JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2V617F inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN. HTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2V617F mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2V617F mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay. We found that ZT55 showed a selective inhibition of a 0.031 μM IC50 value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2V617F and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2V617F-expressing HEL cell line, leading to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2V617F mutation. These results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling.

Shenqi is a traditional Chinese polyherbal medicine has been widely used for the treatment of allergic rhinitis (AR). The aim of this study was to investigate the anti-allergic rhinitis activity of Shenqi and explore its underlying molecular mechanism. Ovalbumin (OVA)-induced allergic rhinitis rat model was used to evaluate the anti-allergic rhinitis effect of Shenqi. The effect of Shenqi on IgE-mediated degranulation was measured using rat basophilic leukemia (RBL-2H3) cells. Primary spleen lymphocytes were isolated to investigate the anti-allergic mechanism of Shenqi by detecting the expression of transcription factors via Western blot and the level of cytokines (IL-4 and IFN-γ) via ELISA. In OVA-induced AR rat models, Shenqi relieved the allergic rhinitis symptoms, inhibited the histopathological changes of nasal mucosa, and reduced the levels of IL-4 and IgE. The results from the in vitro study certified that Shenqi inhibited mast cell degranulation. Furthermore, the results of GATA3, T-bet, p-STAT6, and SOCS1 expression and production of IFN-γ and IL-4 demonstrated that Shenqi balanced the ratio of Th1/Th2 (IFN-γ/IL-4) in OVA-stimulated spleen lymphocytes. In conclusion, these results suggest that Shenqi exhibits an obvious anti-allergic effect by suppressing the mast cell-mediated allergic response and by improving the imbalance of Th1/Th2 ratio in allergic rhinitis.