YY1/miR-140-5p/Jagged1/Notch axis mediates cartilage progenitor/stem cells fate reprogramming in knee osteoarthritis.

Osteoarthritis is a multifactorial disease characterized by cartilage degeneration, while cartilage progenitor/stem cells (CPCs) are responsible for endogenous cartilage repair. However, the relevant regulatory mechanisms of CPCs fate reprogramming in OA are rarely reported. Recently, we observed fate disorders in OA CPCs and found that microRNA-140-5p (miR-140-5p) protects CPCs from fate changes in OA. This study further mechanistically investigated the upstream regulator and downstream effectors of miR-140-5p in OA CPCs fate reprogramming. As a result, luciferase reporter assay and validation assays revealed that miR-140-5p targets Jagged1 and inhibits Notch signaling in human CPCs, and the loss-/gain-of-function experiments and rescue assays discovered that miR-140-5p improves OA CPCs fate, but this effect can be counteracted by Jagged1. Moreover, increased transcription factor Ying Yang 1 (YY1) was associated with OA progression, and YY1 could disturb CPCs fate via transcriptionally repressing miR-140-5p and enhancing the Jagged1/Notch signaling. Finally, the relevant changes and mechanisms of YY1, miR-140-5p, and Jagged1/Notch signaling in OA CPCs fate reprogramming were validated in rats. Conclusively, this study identified a novel YY1/miR-140-5p/Jagged1/Notch signaling axis that mediates OA CPCs fate reprogramming, wherein YY1 and Jagged1/Notch signaling exhibits an OA-stimulative role, and miR-140-5p plays an OA-protective effect, providing attractive targets for OA therapeutics.

Improving the circulation time and renal therapeutic potency of extracellular vesicles using an endogenous ligand binding strategy.

Kidney diseases are a serious health issue worldwide, and novel therapeutics are urgently needed. Extracellular vesicles (EVs) have emerged as potent drug delivery systems (DDSs), but their therapeutic potential is limited by short circulation times and insufficient renal retention. Here, we report that endogenous ligand (albumin, ALB) binding is an efficient modification strategy to improve the therapeutic potency of EV-based DDSs for kidney diseases. Surface albumin-binding peptide (ABP)-displayed EVs (ABP-EVs) were produced by transfecting parent cells with the ABP-Lamp2b fusion plasmid. Compared with unmodified EVs (NC-EVs), ABP-EVs showed increased binding to ALB in vitro and elevated circulation time and multiple organ retention in vivo after systemic (iv) injection. Moreover, ABP-EVs had higher renal retention than NC-EVs in mice with acute kidney injury through a complex mechanism involving microvascular injury and megalin-mediated endocytosis. As a result, delivery of small molecule drugs (e.g., curcumin) or proteins (e.g., hepatocyte growth factor) by ABP-EVs had superior therapeutic (e.g., anti-apoptotic, antioxidant, anti-inflammatory) effects in vitro and in vivo. This study highlights that ABP-EVs are versatile DDSs for kidney diseases and provides insights into the new strategies of engineering EVs for drug delivery.

Oleic acid protects saturated fatty acid mediated lipotoxicity in hepatocytes and rat of non-alcoholic steatohepatitis.

Aim This study aims to demonstrate the protective effects of monounsaturated oleic acid (OA) against saturated palmitic acid (PA) induced cellular lipotoxicity in hepatocytes and rats with non-alcoholic steatohepatitis (NASH). MAIN METHODS: Human hepatoma cell line HepG2 cells and neonatal rat primary hepatocytes were treated with PA or/and OA for 24 h. SD rats were fed with high fat diet (HFD) to induce NASH. From the 16th w, the HFD was full or half replaced by olive oil to observe the protective effects. KEY FINDINGS: In vitro, OA substantially alleviated PA induced cellular apoptosis, oxidative stress, ER stress, mitochondrial dysfunction, as well as inflammation in hepatocytes. In vivo, only olive oil supplementation had no detrimental effects, while HFD developed NASH in normal rats. Full replacement of HFD with olive oil had profoundly reversed NASH. Noteworthily, half replacement of HFD with olive oil (a mixed diet) has ameliorated NASH injury as well. It strikingly changed the hepatic histology from macrovesicular-steatosis into entire microvesicular-steatosis, and significantly reduced inflammation, ballooning and fibrosis. SIGNIFICANCE: Our study has demonstrated in both hepatocytes and NASH rats that oleic acids had great potential to combat the saturated fatty acids induced hepatic lipotoxicity. Only half replacement of HFD by monounsaturated fatty acids rich diet still had significant therapeutic outcome in NASH rats. Redirecting the toxic saturated fatty acids into triglyceride storage and reduction of cholesterol accumulation might be the possible explanation of OA driven protection in this scenario.