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Cholestatic liver disease is defined as the bile acids (BAs) accumulation in the liver caused by impaired synthesis, and secretion, together with excretion of BAs due to a variety of factors, which, if left untreated, can result in hepatic fibrosis, cholestatic cholangitis, cholestatic cirrhosis, eventually, end-stage liver disease. Currently, modulation of BA metabolism is still a prospective therapeutic strategy for treating the cholestatic diseases. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with far-reaching effects on the chronic liver disease. However, its role and mechanism in cholestatic liver damage is still unknown. Therefore, in this work, we explored the impact of AHR on the cholestatic liver injury using AHR overexpression mediated by adeno-associated viral (AAV) vectors. We found that AHR is differentially expressed in different stages of cholestatic liver disease, showing either down-regulation or an increase in protective effects. Overexpression of AHR increased body weight, decreased serum total bilirubin (TBil) and alkaline phosphatase (ALP), reduced porphyrin accumulation in liver tissue, and regulated the bile acid pool in the cholestatic mouse model induced by DDC diet. Overall, our data indicate that AHR attenuated cholestatic liver injury. AHR function indicates that it may have an action in the clinical management of cholestasis. • AHR attenuates initial weight loss by DDC intoxication. • AHR reduced the accumulation of porphyrin caused by the DDC diet. • AHR selectively reduces taurine-conjugated bile acid contents. [ABSTRACT FROM AUTHOR]

Previous studies showed that Nel-like molecule-1 (Nell-1) can positively regulate odontoblastic differentiation and dentin formation. Intriguingly, our group found that Nell-1 is co-expressed with neural markers. The purpose of this study was to investigate whether Nell-1 protein plays a regulatory role in the differentiation of dental pulp cells into neural-like cells by in vivo and in vitro studies. The expression patterns of Nell-1 and dental pulp neural markers were observed by double immunofluorescence staining in normal dental pulp tissue sections of Wistar rat. Collagen sponge containing Nell-1 protein was added into the pulp cavity of rat molars in order to observe the expression patterns of neural markers in rat dental pulp repair and regeneration model by immunohistochemical staining. Moreover, human dental pulp stem cells (hDPSCs) were cultured, and different concentrations of Nell-1 protein were added for 12 h, 24 h, and 72h. The expression of neural markers was detected by using quantitative real-time polymerase chain reaction and Western blot. Nell-1 was co-expressed with neural markers including substance P (SP) and Nestin in rat dental pulp tissue. The expression of neural markers including SP, neuron-specific enolase (NSE), and Nestin was increased obviously in rat dental pulp tissues stimulated with Nell-1 protein. In cultured hDPSCs induced by Nell-1 protein, the expression of neural markers including glial fibrillary acidic protein (GFAP), Nestin, and β-III tubulin was increased. Nell-1 plays a positive role in inducing the differentiation of DPSCs into neural-like cells. • Nell-1 is co-expressed with neural markers in pulp, which indicates that Nell-1 might be expressed in dental pulp nerve. • The expression levels of neural markers were increased in rat pulp and in cultured hDPSCs stimulated with Nell-1 protein. • This is the first study to demonstrate the effect of Nell-1 on dental pulp cells neural-like differentiation. [ABSTRACT FROM AUTHOR]

Nel-like molecule 1 (Nell-1) is an essential positive regulator of tooth development and odontoblast differentiation. However, its precise mechanism remains undetermined. This study aims to explore the possible receptor or binding protein of Nell-1. Results showed that Nell-1 and Apoptosis related protein 3(APR3) expression levels were high in odontoblasts and inversely correlated. Endogenous Nell-1 co-immunoprecipitated with APR3, and this co-IP was reciprocal. Double immunofluorescence staining revealed that Nell-1 and APR3 colocalized on the nuclear envelope of human dental pulp cells. Nell-1 inhibited the proliferation of these cells co-infected with APR3 through Cyclin D1 downregulation. The interaction of Nell-1 with APR3 stimulated alkaline phosphatase (ALP) activity and promoted the expression and mineralization of DSPP, ALP, OPN, and BSP. The shRNA of APR3 decreased cell differentiation and mineralization. Nell-1 could reciprocally interact with APR3 and stimulate the differentiation and mineralization of human dental pulp cells. Future studies should explore the potential functional connection and the molar mechanism of such interaction. • Nell-1 as a secreted protein stimulates human dental pulp cells proliferation and differentiation and induces teeth formation and regeneration. • Nell-1 and APR3, which were both expressed in the dental pulp stem cells, had similar spatiotemporal expression patterns. Nell-1 and APR3 proteins were primarily present in the cytosol. • Nell-1 could reciprocally interact with APR3 and stimulate the differentiation and mineralization of human dental pulp cells. [ABSTRACT FROM AUTHOR]

Although overexpression of eukaryotic translation initiation factor 4E (eIF4E) is associated with enhanced growth and poor prognosis in nasopharyngeal carcinoma (NPC), the function of eIF4E in NPC response to chemotherapy has not been revealed. In this work, we demonstrate that eIF4E inhibition using both ribavirin and siRNA targets NPC cells and enhances the efficacy of 5-fluorouracil (5-FU). Mechanism studies indicate that 5-FU treatment increases phosphorylation of eIF4E in NPC cells, and this is dependent on ERK activation. eIF4E inhibition thus significantly sensitizes NPC cell response to 5-FU. Of note, ribavirin is a clinically available anti-viral drug. We show that ribavirin exhibits preferential toxicity to NPC with normal nasopharyngeal epithelial cells largely unaffected. Ribavirin acts on NPC cells via inhibiting eIF4E/Akt signaling, and the suppression of eIF4E by ribavirin are not the consequence of inhibition of eIF4E upstream signaling: Mnk and mTOR. In two independent NPC xenograft mouse models, ribavirin at well-tolerated dose that significantly inhibited NPC growth as single drug alone and its combination with 5-FU completely arrests tumor growth throughout the whole duration of treatment, without causing toxicity in mice. Our findings provide the better understanding on the role of eIF4E in NPC in response to 5-FU and preclinical rationale to explore ribavirin as a sensitizing strategy to treat NPC, particularly in those who develop 5-FU resistance. • Ribavirin targets NPC in vitro and in vivo , and acts synergistically with 5-FU. • Ribavirin acts on NPC via inhibiting eIF4E/Akt. • Chemotherapy activates eIF4E in NPC cells in an Erk-dependent manner. • Ribavirin sensitizes NPC to 5-FU via inhibiting 5-FU-induced eIF4E activation. [ABSTRACT FROM AUTHOR]