Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

Pancreatic β-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing β-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of β-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in β-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis

Targeting Epithelial–Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer

Epithelial–mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance

Cholesterol Trafficking: An Emerging Therapeutic Target for Angiogenesis and Cancer

Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol trafficking in endothelial cell signaling. Small molecule inhibitors of cholesterol trafficking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed

TRIM family proteins: roles in proteostasis and neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs

Fetal plasma cortisol and dehydroepiandrosterone sulfate concentrations in pregnancy and term parturition

OBJECTIVE: To examine if changes in fetal plasma concentrations of cortisol or dehydroepiandrosterone sulfate (DHEAS) levels are associated with human term parturition. METHODS: Umbilical cord plasma cortisol and DHEAS concentrations were measured in 374 singleton pregnancies that delivered at term in the following six groups: group 1, cordocentesis for clinical indications before 36 weeks of gestation (n = 93); group 2, cordocentesis for clinical indications after 36 weeks of gestation (n = 9); group 3, cord blood sampling after elective cesarean section (CS) at term without labor (n = 140); group 4, cord blood sampling after CS at term with early labor (cervical dilatation 36 weeks) but did not increase during active labor; (4) the cortisol/DHEAS ratio (stress index) increased with advancing gestation and with active labor at term. CONCLUSIONS. Human parturition at term is associated with an increase in fetal plasma cortisol and in the cortisol/DHEAS ratio, but not in DHEAS