Activated
fibroblast-like synovial (FLS) cells are regarded as
an important target for rheumatoid arthritis (RA) treatment via starvation
therapy mediated by glucose oxidase (GOx). However, the hypoxic RA-FLS
environment greatly reduces the oxidation process of glucose and leads
to a poor therapeutic effect of the GOx-based starvation therapy.
In this work, we designed a hollow mesoporous copper sulfide nanoparticles
(CuS NPs)-based smart GOx/atovaquone (ATO) codelivery system (named
as V-HAGC) targeting RA-FLS cells to realize a O2-economized
dual energy inhibition strategy to solve the limitation of GOx-based
starvation therapy. V-HAGC armed with dual multi-stimuli-responsive
“doorkeepers” can guard drugs intelligently. Once under
the stimulation of photothermal and acidic conditions at the targeted
area, the dual intelligent responsive “doors” would
orderly open to realize the controllable release of drugs. Besides,
the efficacy of V-HAGC would be much improved by the additional chemodynamic
therapy (CDT) and photothermal therapy (PTT) stimulated by CuS NPs.
Meanwhile, the upregulated H2O2 and acid levels
by starvation therapy would promote the Fenton-like reaction of CuS
NPs under O2-economized dual energy inhibition, which could
enhance the PTT and CDT efficacy as well. In vitro and in vivo evaluations revealed V-HAGC with much
improved efficacy of this combination therapy for RA. In general,
the smart V-HAGC based on the O2-economized dual energy
inhibition strategy combined with enhanced CDT and PTT has the potential
to be an alternative methodology in the treatment of RA.
The type-2 cannabinoid receptor (CB2) is expressed in osteoblasts and plays a role in bone metabolism through regulation on bone mass and bone turnover, but the functional importance of CB2 in osteoblasts under Titanium (Ti) stimulation is incompletely understood. This study aimed to investigate the CB2 expression in osteoblasts under Ti stimulation and the effects of CB2 activation on proliferation, apoptosis, differentiation, mineralization, OPG, and RANKL expression of MC3T3-E1 cells exposed to Ti particles. MC3T3-E1 cells were incubated in the presence of Ti particles with or without CB2-specific agonist HU-308 and antagonist SR144528. Ti particles treatment obviously induced the CB2 expression in MC3T3-E1 cells, and reduced the cell survival in a dose- and time-dependent manner (p < 0.05). Addition of HU-308 could dose-dependently alleviate the Ti-induced decrease of cell survival (p < 0.05). The flow cytometry assay showed that comparing with the control group, the apoptosis rate and caspase-3 activity in the Ti group were significantly elevated (p < 0.05), which could be alleviated by HU-308. Moreover, HU-308 effectively attenuated the decrease of cell mineralization capability, alkaline phosphates (ALP) and osteocalcin activity, and increase of OPG/RANKL ratio induced by Ti particles treatment (p < 0.05). These effects were partially counteracted by combined treatment of CB2 antagonist SR144528 (p < 0.05). In conclusion, CB2 activation has a favorable inhibitory effect on Ti-induced reactions in MC3T3-E1 cell through modulating proliferation, apoptosis, differentiation, and RANKL expression. These findings suggest that activation of CB2 might be an effective therapeutic strategy to promote bone formation and reduce bone dissolution.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.