Abstract
There is a major unmet need for the development of effective therapies for diabetes induced inflammation. Increased adenosine-uridine rich elements (AREs) containing mRNAs of inflammatory molecules are reported in inflamed monocytes. Destabilizing these inflammatory mRNAs by the miR-16 could reduce inflammation. DNA microarrays andin vitrocell studies showed that exogenous miR16 and its mimic treatment, in LPS/PMA induced monocytes, significantly downregulated several ARE containing inflammatory cytokine mRNAs similar to those seen in the normal monocytes. Ingenuity pathway analyses showed exogenous miR-16 or its synthetic mimic treatment alleviates inflammatory responses. To selectively target uptake, especially to inflamed cells, one of the CD36 substrate cholesterol was tagged tomiR16/siRNA. Cholesterol tagged miR-16/ARE-siRNA showed enhanced uptake in CD36 expressing inflamed cells. In LPS or PMA, treated monocytes, candidate genes expressions levels such as IL-6, IL-8, IL-12β, IP-10, and TNF-α mRNA were increased, as measured by RT-qPCR as seen in primary monocytes of diabetes patients. Exogenous miR16 or ARE-siRNA transfection reduced mRNAs of pro-inflammatory cytokines levels in monocyte, and its adhesion. Increased uptake of cholesterol tagged miR-16 through the CD36 receptor was observed. This destabilizes numerous inflammatory ARE containing mRNAs and alleviates inflammatory responses. Cholesterol-tagged miR-16 and its mimic are novel anti-inflammatory molecules that can be specifically targeted to, via through CD36 expressing, "inflamed" cells and thus serve as therapeutic candidates to alleviate inflammatory diseases.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call