CD47 decline in pancreatic islet cells promotes macrophage-mediated phagocytosis in type I diabetes.

BACKGROUND: Type I diabetes (T1D) is characterized by insulin loss caused by inflammatory cells that excessively infiltrate and destroy the pancreas, resulting in dysregulation of tissue homeostasis, mechanobiological properties, and the immune response. The streptozotocin (STZ)-induced mouse model exhibits multiple features of human T1D and enables mechanistic analysis of disease progression. However, the relationship between the mechanochemical signaling regulation of STZ-induced T1D and macrophage migration and phagocytosis is unclear. AIM: To study the mechanochemical regulation of STZ-induced macrophage response on pancreatic beta islet cells to gain a clearer understanding of T1D. METHODS: We performed experiments using different methods. We stimulated isolated pancreatic beta islet cells with STZ and then tested the macrophage migration and phagocytosis. RESULTS: In this study, we discovered that the integrin-associated surface factor CD47 played a critical role in immune defense in the STZ-induced T1D model by preventing pancreatic beta islet inflammation. In comparison with healthy mice, STZ-treated mice showed decreased levels of CD47 on islet cells and reduced interaction of CD47 with signal regulatory protein α (SIRPα), which negatively regulates macrophage-mediated phagocytosis. This resulted in weakened islet cell immune defense and promoted macrophage migration and phagocytosis of target inflammatory cells. Moreover, lipopolysaccharide-activated human acute monocytic leukemia THP-1 cells also exhibited enhanced phagocytosis in the STZ-treated islets, and the aggressive attack of the inflammatory islets correlated with impaired CD47-SIRPα interactions. In addition, CD47 overexpression rescued the pre-labeled targeted cells. CONCLUSION: This study indicates that CD47 deficiency promotes the migration and phagocytosis of macrophages and provides mechanistic insights into T1D by associating the interactions between membrane structures and inflammatory disease progression.

Small molecule inhibitor of myogenic microRNAs leads to a discovery of miR-221/222-myoD-myomiRs regulatory pathway.

Myogenic microRNAs (myomiRs) that are specifically expressed in cardiac and skeletal muscle are highly relevant to myogenic development and diseases. Discovery and elucidation of unknown myomiRs-involved regulatory pathways in muscle cells are important, but challenging due to the lack of proper molecular tools. We report here a miR-221/222-myoD-myomiRs regulatory pathway revealed by using a small-molecule probe that selectively inhibits myomiRs including miR-1, miR-133a, and miR-206. The small-molecule inhibitor screened from luciferase assay systems was found to inhibit myomiRs and differentiation of C2C12 cells. Using the small molecule as a probe, we found that the transcriptional factor myoD, which is upstream of myomiRs, was further regulated by miR-221/222. This miR-221/222-myoD-myomiRs regulatory pathway was confirmed by over-expressing or knockdown miR-221/222 in muscle cells, which respectively led to the inhibition or enhancement of myoD protein expression and subsequent downregulation or upregulation of myomiR expression.

Small molecular inhibitors of miR-1 identified from photocycloadducts of acetylenes with 2-methoxy-1,4-naphthalenequinone.

Small molecules which can modulate endogenous microRNAs are important chemical tools to study microRNA regulational network. In this Letter we screened the [2+2] photocycloadducts of 2-methoxy-1,4-naphthalenequinone with a series of aryl acetylenes on their activity to modulate endogenous microRNAs. A potent inhibitor of the muscle-specific miR-1 which is closely related with cardiac development and disease was identified. The small molecular inhibitor was the cyclobutene type product derived from the photocycloaddition of 2-methoxy-1,4-naphthalenequinone with tert-butyl (5-(phenylethynyl)quinolin-8-yl) carbonate. Analogues of the small molecular inhibitor were then prepared using similar photocycloaddition reactions for evaluation on inhibition activity on miR-1 to provide structure-activity relationship of the miR-1 inhibitor.

Microphotochemistry: a reactor comparison study using the photosensitized addition of isopropanol to furanones as a model reaction.

Three types of micro-photoreactor setups were investigated using DMBP-sensitized additions of isopropanol to furanones as model reactions. The results were compared to experiments using a conventional batch reactor. Based on conversion rates, reactor geometries and energy efficiency calculations the microsystems showed superior performances over the batch process. Of the three micro setups examined, the LED-driven microchip gave the best overall results.