Chao Lei

Abstract High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.

Plant exosomes protect plants against infection; however, whether edible plant exosomes can protect mammalian hosts against infection is not known. In this study, we show that ginger exosome-like nanoparticles (GELNs) are selectively taken up by the periodontal pathogen Porphyromonas gingivalis in a GELN phosphatidic acid (PA) dependent manner via interactions with hemin-binding protein 35 (HBP35) on the surface of P. gingivalis. Compared with PA (34:2), PA (34:1) did not interact with HBP35, indicating that the degree of unsaturation of PA plays a critical role in GELN-mediated interaction with HBP35. On binding to HBP35, pathogenic mechanisms of P. gingivalis were significantly reduced following interaction with GELN cargo molecules, including PA and miRs. These cargo molecules interacted with multiple pathogenic factors in the recipient bacteria simultaneously. Using edible plant exosome-like nanoparticles as a potential therapeutic agent to prevent/treat chronic periodontitis was further demonstrated in a mouse model.

Metastasis is a major clinical obstacle responsible for the high mortality and poor prognosis of gastric cancer (GC). MicroRNAs (miRNAs) are critical mediators of metastasis that act by modulating their target genes. In this study, we found that miR-143 and miR-145 act via a common target gene, MYO6, to regulate the epithelial-mesenchymal transition (EMT) and inhibit metastasis. We determined that miR-143 and miR-145 were downregulated in GC, and the ectopic expression of miR-143 and/or miR-145 inhibited GC cell migration and metastasis. Furthermore, MYO6 was identified as a direct common target of miR-143 and miR-145 and was elevated in GC. Silencing of MYO6 resulted in a metastasis-suppressive activity similar to that of miR-143 and miR-145, while restoring MYO6 attenuated the anti-metastatic or anti-EMT effects caused by miR-143 and miR-145. Clinically, an inverse correlation was observed between miR-143/145 levels and MYO6 levels in GC tissues, and either miR-143/145 downregulation or MYO6 upregulation was associated with more malignant phenotypes in patients with GC. In conclusion, miR-143 and miR-145 suppress GC cell migration and metastasis by inhibiting MYO6 expression and the EMT, which provides a novel mechanism and promising therapeutic target for the treatment of GC metastasis.