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Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via LPC-induced “abnormal splicing” when the canonical splicing for generation of corresponding mRNAs is suppressed; (3) Upregulation of 47 circRNAs is temporally associated with mRNAs-mediated LPC-upregulated cholesterol synthesis-SREBP2 pathway and LPC-downregulated TGF-β pathway; (4) Increase in upstream chromatin long-range interaction sites to circRNA related genes is associated with preferred circRNA generation over canonical splicing for mRNAs, suggesting that shifting chromatin long-range interaction sites from downstream to upstream may promote induction of a list of circRNAs in lysoPC-activated HAECs; (5) Six significantly changed circRNAs may have sponge functions for miRNAs; and (6) 74% significantly changed circRNAs contain open reading frames, suggesting that putative short proteins may interfere with the protein interaction-based signaling. Our findings have demonstrated for the first time that a new set of LPC-induced circRNAs may contribute to homeostasis in LPC-induced HAEC activation. These novel insights may lead to identifications of new therapeutic targets for treating metabolic cardiovascular diseases, inflammations, and cancers.

We reported that microRNA-155 (miR-155) deficiency in ApoE-/- mice yields a novel metabolically healthy obese (MHO) model, which exhibits improved atherosclerosis but results in obesity, non-alcoholic fatty liver disease (NAFLD) without insulin resistance. Using experimental data mining approaches combined with experiments, we found that, among 109 miRNAs, miR-155, and miR-221 are significantly modulated in all four hyperlipidemia-related diseases (HRDs), namely atherosclerosis, NAFLD, obesity and type II diabetes (T2DM). MiR-155 is significantly upregulated in atherosclerosis and decreased in other HRDs. MiR-221 is increased in three HRDs but reduced in obesity. These findings led to our new classification of types I and II MHOs, which are regulated by miR-221 and miR-155, respectively. Western blots showed that the proinflammatory adipokine, resistin, is significantly increased in white adipose tissues (WAT) of the MHO mice, revealing our newly proposed, miR-155-suppressed “secondary wave inflammatory state (SWIS),” characteristic of MHO transition to classical obesity (CO). Taken together, we are first to show that MHO may have heterogeneity in comorbidities, and is therefore classified into type I, and type II MHOs; and that increased expression of resistin in miR-155-/- white adipose tissues may be a driver for SWIS in MHO transition to CO. Our findings provide novel insights into the pathogenesis of MHO, MHO transition to CO, hyperlipidemic pathways related to cancer, and new therapeutic targets.

Background: Low-intensity ultrasound (LIUS) was shown to be beneficial in mitigating inflammation and facilitating tissue repair in various pathologies. Determination of the molecular mechanisms underlying the anti-inflammatory effects of LIUS allows to optimize this technique as a therapy for the treatment of malignancies and aseptic inflammatory disorders.Methods: We conducted cutting-edge database mining approaches to determine the anti-inflammatory mechanisms exerted by LIUS.Results: Our data revealed following interesting findings: (1) LIUS anti-inflammatory effects are mediated by upregulating anti-inflammatory gene expression; (2) LIUS induces the upregulation of the markers and master regulators of immunosuppressor cells including MDSCs (myeloid-derived suppressor cells), MSCs (mesenchymal stem cells), B1-B cells and Treg (regulatory T cells); (3) LIUS not only can be used as a therapeutic approach to deliver drugs packed in various structures such as nanobeads, nanospheres, polymer microspheres, and lipidosomes, but also can make use of natural membrane vesicles as small as exosomes derived from immunosuppressor cells as a novel mechanism to fulfill its anti-inflammatory effects; (4) LIUS upregulates the expression of extracellular vesicle/exosome biogenesis mediators and docking mediators; (5) Exosome-carried anti-inflammatory cytokines and anti-inflammatory microRNAs inhibit inflammation of target cells via multiple shared and specific pathways, suggesting exosome-mediated anti-inflammatory effect of LIUS feasible; and (6) LIUS-mediated physical effects on tissues may activate specific cellular sensors that activate downstream transcription factors and signaling pathways.Conclusions: Our results have provided novel insights into the mechanisms underlying anti-inflammatory effects of LIUS, and have provided guidance for the development of future novel therapeutic LIUS for cancers, inflammatory disorders, tissue regeneration and tissue repair.