The reticulon family has been found to induce apoptosis, inhibit axon regeneration and regulate protein trafficking. However, little is known about the mechanisms of how reticulon proteins are involved in neuronal death-promoting processes during ischemia. Here, we report that the expression of Reticulon Protein 1-C (RTN1-C) was associated with the progression of cerebral ischemia/reperfusion (I/R) injury. Using a combination of rat middle cerebral artery occlusion (MCAO) stroke and oxygen-glucose deprivation followed by reoxygenation (OGD/R) models, we determined that the expression of RTN1-C was significantly increased during cerebral ischemic/reperfusion. RTN1-C overexpression induced apoptosis and increased the cell vulnerability to ischemic injury, whereas RTN1-C knockdown reversed ischemia-induced apoptosis and attenuated the vulnerability of OGD/R-treated neural cells. Mechanistically, we demonstrated that RTN1-C mediated OGD/R-induced apoptosis through ER stress and mitochondria-associated pathways. RTN1-C interacted with Bcl-xL and increased its localization in the ER, thus reducing the anti-apoptotic activity of Bcl-xL. Most importantly, knockdown of Rtn1-c expression in vivo attenuated apoptosis in MCAO rats and reduced the extent of I/R-induced brain injury, as assessed by infarct volume and neurological score. Collectively, these data support for the first time that RTN1-C may represent a novel candidate for therapies against cerebral ischemia/reperfusion injury.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage‐based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii , a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor‐transgenic macrophage (Mφ ^tgmif ) shows stable fibrinolysis and strong chemotactic capacity. Mφ ^tgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6C ^hi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6C ^lo macrophage through the secretion of CX3CL1. Remarkably, Mφ ^tgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN‐γ‐treated macrophages, making macrophage‐based immune therapy more efficient and safer. Mechanistically, Tg MIF promotes CCL2 expression by activating the ERK/HMGB1/NF‐κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.

Alcohol-associated liver disease (ALD) is a widely prevalent chronic liver disease caused by alcohol overconsumption. However, the pathogenesis of ALD is complex and has not been fully elucidated. Ring finger protein 2 (RNF2) is associated with the occurrence and development of hepatocellular carcinoma (HCC), but its function in ALD has not been explored. In this study, we investigated the role of RNF2 in ALD and its underlying mechanisms. In vivo, an ALD model was established and adeno-associated virus (AAV8-shRNA-RNF2) was used to knock down RNF2. Liver injury, hepatic steatosis, and inflammation were assessed and functional studies were conducted in AML-12 cells and macrophages. The study found that hepatic-specific RNF2 knockdown attenuated EtOH-induced liver steatosis and inflammation. Furthermore, RNF2 knockdown significantly alleviated EtOH-mediated lipid accumulation and inflammation. Additionally, RNF2 interacted with ubiquitin-specific peptidase 7 (USP7) and regulated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway. Importantly, inhibition of USP7 or PI3K/AKT signaling pathway suppressed lipid accumulation and inflammation in the ALD model. Our research demonstrated that RNF2 had a novel function of regulating lipid metabolism and inflammation in ALD through its interaction with USP7 and modulation of the PI3K/AKT signaling pathway.