Anti-ARRB1 monoclonal antibody, clone 2I5-G6-D22

LAM is a rare low-grade metastasizing lung neoplasm. Inhibitors of mTOR improve clinical outcome of LAM patients by preventing loss of lung function. Nevertheless, other cell targets may be of interest for drug development. Therefore, we explored the potential role of EDN1(endothelin) in LAM. We report an increased endothelin blood level in LAM patients as well as EDN1 overexpression and EDN1 receptor downregulation in LAM-derived primary cells and in TSC2(NEG) cells mutated in TSC2. We evidenced EDN pathway dysregulation based on EDN1, EDNRA, EDNRB and ARRB1 mRNA expression in LAM-derived primary cells. We showed overexpression of EDN1 and ARRB1 mRNAs in TSC2(NEG) cells; these cells lost their ability to respond to stimulation by endothelin. We analyzed the effects of endothelin receptor antagonists alone or in combination with rapamycin, an mTOR inhibitor, on proliferation and migration of LAM cells. Rapamycin treatment ofTSC2(NEG) cells significantly reduced cell proliferation or migration, while none of the tested inhibitors of EDN receptors impaired these functions. We showed that TSC2(NEG) cells have acquired a transformed phenotype as showed by their ability to grow as spheroids in semi-solid medium and that unlike endothelin receptors antagonists, rapamycin reduced anchorage-independent cell growth and prevented expansion of TSC2(NEG) spheroids.

Alzheimer's disease (AD) is characterized by the loss of neurogenesis and excessive induction of apoptosis. The induction of neurogenesis and inhibition of apoptosis may be a promising therapeutic approach to combating the disease. Celecoxib (CB), a cyclooxygenase-2 specific inhibitor, could offer neuroprotection. Specifically, the CB-encapsulated erythrocyte membranes (CB-RBCMs) sustained the release of CB over a period of 72 h in vitro and exhibited high brain biodistribution efficiency following intranasal administration, which resulted in the clearance of aggregated beta-amyloid proteins (A beta) in neurons. The high accumulation of the CB-RBCMs in neurons resulted in a decrease in the neurotoxicity of CB and an increase in the migratory activity of neurons, and alleviated cognitive decline in APP/PS1 transgenic (Tg) mice. Indeed, COX-2 metabolic products including prostaglandin E2 (PGE(2)) and PGD(2), PGE2 induced neurogenesis by enhancing the expression of SOD2 and 14-3-zeta, and PGD2 stimulated apoptosis by increasing the expression of BIK and decreasing the expression of ARRB1. To this end, the CB-RBCMs achieved better effects on concurrently increasing neurogenesis and decreasing apoptosis than the phospholipid membrane-encapsulated CB liposomes (CB-PSPD-LPs), which are critical for the development and progression of AD. Therefore, CB-RBCMs provide a rational design to treat AD by promoting the self-repairing capacity of the brain. (C) 2017 Elsevier Ltd. All rights reserved.