Inducing
immune tolerance through repeated administration of self-antigens
is a promising strategy for treating rheumatoid arthritis (RA), and
current research indicates that coadministration of immunomodulators
can further orchestrate the tolerogenic response. However, most of
the clinical trials based on tolerance induction have negligible therapeutic
effects. Peripheral lymphoid organs play critical roles in immunotherapy.
Here, we design an engineered nanoemulsion for targeted codelivery
of self-antigens and an immunomodulator to ectopic lymphoid structures
(ELSs) in inflamed joints of RA. Namely, a citrullinated multiepitope
self-antigen (CitP) and rapamycin are incorporated into the nanoemulsions
(NEs@CitP/Rapa), which are fabricated by a facial method using commercialized
pharmaceutical excipients. After intravenous administration, the nanoemulsion
shows satisfactory accumulation in the inflamed paws and provides
enhanced anti-inflammatory effect in various experimental murine models
of RA. Our study provides a promising targeting strategy to induce
immune tolerance for the treatment of RA.
Aim: Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. Methods: Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 μmol/L) or its analogue berberine (1 μmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting. Results: In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation. In the serum-starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serumstarved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells. Conclusion: Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b.
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