Previous cross-sectional studies have established that circulating osteoprotegerin (OPG) levels are associated with nonalcoholic fatty liver disease (NAFLD). However, the role of OPG in metabolic diseases, such as diabetes and NAFLD, is still unclear. In the current study, we demonstrated that hepatic OPG expression was downregulated in NAFLD individuals and in obese mice. OPG deficiency decreased lipid accumulation and expression of CD36 and peroxisome proliferator–activated receptor-γ (PPAR-γ) in the livers of OPG^−/− mice and cultured cells, respectively, whereas OPG overexpression elicited the opposite effects. The stimulatory role of OPG in lipid accumulation was blocked by CD36 inactivation in hepatocytes isolated from CD36^−/− mice. The overexpression of OPG led to a decrease in extracellular signal–regulated kinase (ERK) phosphorylation in the livers of OPG^−/− mice and in cultured cells, while OPG deficiency resulted in the opposite effect. The inhibition of PPAR-γ or the activation of ERK blocked the induction of CD36 expression by OPG in cultured cells. Mechanistically, OPG facilitated CD36 expression by acting on PPAR response element (PPRE) present on the CD36 promoter. Taken together, our study revealed that OPG signaling promotes liver steatosis through the ERK–PPAR-γ–CD36 pathway. The downregulation of OPG in NAFLD might be a compensatory response of the body to dampen excess hepatic fat accumulation in obesity.

Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when developing personalized treatment strategies. Herein, we report that dipeptidyl peptidase-4 inhibitors (DPP-4i), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4i promoted the migration and epithelial-mesenchymal transition (EMT) of keratinocytes both directly, and indirectly by inducing SDF-1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4i attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating diabetic patients with ulcers.

Fibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

Context Myonectin has been identified as a novel myokine expressed predominantly in skeletal muscle. However, its clinical implications are largely unknown. Objective The aim of this study is to investigate the relationship between myonectin (CTRP15) and T2DM in cross-sectional and interventional studies. Patients and Design 104 newly diagnosed T2DM patients (nT2DM), 109 IGT and 128 healthy individuals were recruited for this study. In a separate study, OGTT, a 45-min bout of exercise, lipid infusions and EHC were performed to investigate the association of myonectin with IR and T2DM. Circulating myonectin was measured by ELISA. Results nT2DM and IGT subjects had higher circulating myonectin concentrations than normal subjects (82.3 ± 47.6 and 68.9 ± 46.6 vs. 45.2 ± 23.5 µg/L, P<0.05 or P<0.01). It was also found that in nT2DM individuals, circulating myonectin was higher than in IGT subjects. Plasma myonectin correlated positively with WHR, FAT%, TG, FBG, 2h-BG, FIns, HbA1c and HOMA-IR and negatively with ISI in all study population. Multivariate logistic regression analysis revealed that circulating myonectin levels were significantly correlated with IGT and T2DM. A 45-min bout of exercise did not change circulating myonectin levels in healthy young individuals. Circulating myonectin levels were not significantly altered in response to an oral glucose challenge or EHC. In addition, acute elevated FFA levels induced by lipid infusion had no effects on circulating myonectin. Conclusions These data suggest that myonectin may be a useful marker in predicting the development of prediabetes and diabetes.

PRP-Exos are nanoscale cup-shaped vesicles that carry a variety of proteins, mRNAs, microRNAs, and other bioactive substances. PRP-Exos can be formed through several induction pathways, which determine their molecular profiles and facilitate their tailormade participation in intercellular communication. Currently, little is known on how the PRP-Exos activation method influences the quality and quantity of PRP-Exos. The present study aims to observe and analyze the number, profile, and growth factors of PRP-Exos through TEM, Nanoflow, and WB after PRP activation and compare the difference in function of PRP-Exos on HUVECs, with different stimuli (calcium gluconate, thrombin, or both). We found that PRP activated with both thrombin and calcium gluconate harvested the highest concentration of exosomes [(7.16 ± 0.46) × 10¹⁰ particles/ml], compared to thrombin group [(4.87 ± 0.15) × 10¹⁰ particles/ml], calcium gluconate group [(5.85 ± 0.43) × 10¹⁰ particles/ml], or saline group [(7.52 ± 0.19) × 10⁹ particles/ml], respectively ( P < 0.05) via Nanoflow analysis. The WB analysis showed that cytokines (VEGF, PDGFBB, bFGF, TGF-β) are differentially encapsulated in PRP-Exos, depending on the PRP stimulus, in which the mixture-PRP-Exos yielded the highest concentration of cytokines. In the function assay of PRP-Exos on HUVECs, the mixture-PRP-Exos promoted HUVECs proliferation, increased HUVECs migration, promoted the formation of vessel-like by HUVECs via the AKT ERK signal pathway more dramatically, compared with other groups. In summary, our studies showed that PRP activated by the mixture of calcium gluconate and thrombin harvested the best quality of exosomes which had the top biological functions. This study provides a protocol for selecting appropriate PRP activators to obtain high-quality exosomes for future applications.