Vitamin A (all-trans retinol) plays critical roles in mammalian development and vision. Since vitamin A is food-derived, tissue-specific uptake and storage mechanism are needed. In the eye, uptake of RBP4-retinol is mediated by the receptor Stra6, whereas the receptor mediating RBP4 binding and retinol transport into the liver has just recently been discovered. Here we examined the role of zebrafish retinol binding protein receptor 2 (Rbpr2) for RBP4-retinol uptake in developing embryos, using eye development and vision as sensitive readouts. In cultured cells, Rbpr2 localized to membranes and promoted RBP4-retinol uptake. In larvae, Rbpr2 expression was detected in developing intestinal enterocytes and liver hepatocytes. Two rbpr2 mutant zebrafish lines, each resulting in Rbpr2 deficiency, exhibit a small eye defect, and systemic malformations including hydrocephaly and cardiac edema, phenotypes associated with vitamin A deficiency. In the retina, Rbpr2 loss resulted in shorter photoreceptor outer segments, mislocalization and decrease in visual pigments, decreased expression of retinoic acid-responsive genes and photoreceptor cell loss, overall leading to a reduction of visual function. Together, these results demonstrate that Rbpr2-mediated RBP4-retinol uptake in developing liver and intestine is necessary to provide sufficient substrate for ocular retinoid production required for photoreceptor cell maintenance and visual function.

Abstract. MicroRNAs (miRNA/miR) are short non-coding RNAs that function in the endogenous regulation of genes. miRNAs serve important roles in cellular events such as apoptosis, cell proliferation, migration, invasion, autophagy and the cell cycle. They also control the genesis and progression of tumors. Autophagy is a self-digestive process that occurs as a response to stress, and serves two opposite roles in tumor promotion or inhibition that may result in resistance to therapy. A number of studies have revealed that miRNAs control autophagic activity by targeting autophagy-associated genes, particularly in cancer. These previous studies demonstrated that miR-96-5p is upregulated in several types of malignant tumors. However, other functions of miR-96-5p in breast cancer, particularly those that are associated with autophagy, remain unknown. miR-96-5p expression was demonstrated to be upregulated in breast cancer cells compared with in normal breast epithelial cells. The overexpression of miR-96-5p inhibited autophagy, particularly starvation-induced autophagy, in MCF-7 and MDA-MB-231 cells. In addition, this inhibitory effect may have resulted in the suppression of Forkhead box O1. Additionally, the overexpression of miR-96-5p may promote cell proliferation, migration and invasion and inhibit apoptosis in MCF-7 and MDA-MB-231 cells. These data indicate that miR-96-5p is involved in the progression of breast cancer cells and may represent a potential therapeutic target for the treatment of breast cancer.

Background: To investigate the role of Programmed death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in tumor recurrence and metastasis of Chinese patients suffering from triple negative breast cancer (TNBC).Methods: PD-L1 immunohistochemistry was performed on 215 TNBCs. Also, the prevalence of TILs correlated the expression of PD-L1 and TILs with clinical outcomes. Kaplan-Meier and the model analyses of univariate Cox proportional hazards were utilized to compare the survival of patients with positive PD-L1 expression with those with negative PD-L1 expression.Results: The median follow-up time was 67.7 months (range: 7-159 months). PD-L1-positive breast cancer patients had significantly longer disease-free survival (DFS) and Overall survival (OS) compared with PD-L1-negative patients (P=0.046; P=0.019) in TNBC. The presence of increased stromal lymphocytic infiltrates (STILs) was significantly associated with overall survival (P=0.026). The model analysis of univariate Cox proportional hazards showed that PD-L1 and STILs were independent prognostic factors for tumor prognosis.Conclusions: Our study found that high levels of PD-L1 could be expressed in TNBC, which was correlated with the prevalence of TILs.

Ginsenoside Rg3 is one of the main constituents of Panax ginseng. Compelling evidence has demonstrated that ginsenoside Rg3 is capable of inhibiting inflammation.However, the mechanism mediating its anti-inflammatory effects remain unclear.Here we show that ginsenoside Rg3 blocks IL-1β secretion and caspase-1 activation through inhibiting LPS priming and the NLRP3 inflammasome activation in human and mouse macrophages. Rg3 specifically inhibits activation of NLRP3 but not the NLRC4 or AIM2 inflammasomes. In addition, Rg3 has no effect on upstream regulation of NLRP3 inflammasome, such as K + efflux, ROS production, or mitochondrial membrane potential. Mechanistically, Rg3 abrogates NEK7-NLRP3 interaction, and subsequently inhibits NLRP3-ASC interaction, ASC oligomerization, and speckle formation. More importantly, Rg3 can reduce IL-1β secretion induced by LPS in mice and protect mice from lethal endotoxic shock. Thus, our findings reveal an anti-inflammatory mechanism for Rg3 and suggest its potential use in NLRP3-driven diseases. K E Y W O R D Santi-inflammation, ginsenoside Rg3, inflammasome, NLRP3 inflammasome | 209 SHI et al. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.