Rhogef17: A novel target for endothelial barrier function.

ARHGEF17 encodes the protein RhoGEF17, which is highly expressed in vascular endothelial cells. It is a guanine nucleotide exchange factor (GEF) that accelerates the exchange of GDP with GTP on many small GTPases through its Dbl homology (DH) domain, enabling the activation of Rho-GTPases such as RhoA, RhoB, and RhoC. Rho GTPase-regulated changes in the actin cytoskeleton and cell adhesion kinetics are the main mechanisms mediating many endothelial cell (EC) alterations, including cell morphology, migration, and division changes, which profoundly affect EC barrier function. This review focuses on ARHGEF17 expression, activation and biological functions in ECs, linking its regulation of cellular morphology, migration, mitosis and other cellular behaviors to disease onset and progression. Understanding ARHGEF17 mechanisms of action will contribute to the design of therapeutic approaches targeting RhoGEF17, a potential drug target for the treatment of various endothelium-related diseases, Such as vascular inflammation, carcinogenesis and transendothelial metastasis of tumors.

Koumine alleviates rheumatoid arthritis by regulating macrophage polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: The imbalance between M1-and M2-polarized macrophages is one of the major pathophysiological changes in RA. Therefore, targeted macrophage polarization may be an effective therapy for RA. Koumine, an alkaloid monomer with the highest content and low toxicity in Gelsemium elegans Benth., has the effect of treating RA by playing an immunomodulatory role by influencing various immune cells. However, whether koumine affects macrophage polarization in RA and the associated molecular mechanisms remain unknown. AIM OF THE STUDY: To investigate the mechanism of the anti-RA effect of koumine on macrophage polarization. MATERIALS AND METHODS: The effect of koumine on macrophage polarization was investigated in vivo and in vitro. We first explored the effects of koumine on AIA rats and detected the levels of M1/M2 macrophage polarization markers in the spleen by western blotting. Then, we explored the regulatory effect of koumine on M1/M2 macrophage polarization and the effect on the PI3K/AKT signaling pathway in vitro. Finally, we verified the effects of koumine on macrophage polarization in CIA mice. RESULTS: We found that koumine alleviated symptoms, including relieving pain, reducing joint redness and swelling in AIA rats and restoring the M1/M2 macrophage balance in vivo. Interestingly, koumine had an inhibitory effect on both M1 and M2 macrophage polarization in vitro, but it had a stronger inhibitory effect on M1 macrophage. In a mixed polarization experiment, koumine mainly inhibited M1 macrophage polarization and had an inhibitory effect on the PI3K/AKT signaling pathway. Finally, we found that koumine had therapeutic effects on CIA mice, regulated macrophage polarization and inhibited the PI3K/AKT signaling pathway. CONCLUSIONS: Our results reveal that koumine regulates macrophage polarization through the PI3K/AKT signaling pathway. This may be one of the important mechanisms of its anti-RA effect, which provides a theoretical and scientific basis for the possible clinical application of koumine.