Efficient macrocyclization facilitated by skeleton preorganization.

Reported here is the efficient macrocyclization facilitated by skeleton preorganization. A pyridylcarbazole macrocycle and a phenylpyridylcarbazole macrocycle was synthesized in yield up to 75%. Single-crystal structures and theoretic computation uncovered that the skeleton preorganization promoted the formation of cyclization-favorable conformation of noncyclic precursors via π⋯π interactions. This result provided a new approach for the efficient syntheses of macrocycles.

Extracellular vesicles in neurodegenerative diseases: Insights and new perspectives.

Extracellular vesicles (EVs) are vesicle-like substances released by eukaryotic cells. Based on their origin and size, EVs are mainly divided into exosomes, microvesicles and apoptotic bodies, and they are secreted by eukaryotic cells under physiological and pathological conditions. EVs are enriched with nucleic acids, proteins and other factors. EVs can regulate the function of adjacent and distant cells, and they are even involved in the pathogenesis of diseases. They contain proteins associated with the pathogenesis of neurodegenerative diseases (NDs), such as the α-synuclein (α-syn) and tau proteins, which suggest potential roles for EVs as biomarkers and carriers of drugs and other therapeutic molecules that can cross the blood-brain barrier to treat NDs. In this review, we summarized the function of EVs in the pathogenesis of different NDs and related advances in EVs as diagnostic biomarkers and treatments for diseases.

A Multipronged Screening Approach Targeting Inhibition of ETV6 PNT Domain Polymerization.

ETV6 is an ETS family transcriptional repressor for which head-to-tail polymerization of its PNT domain facilitates cooperative binding to DNA by its ETS domain. Chromosomal translocations frequently fuse the ETV6 PNT domain to one of several protein tyrosine kinases. The resulting chimeric oncoproteins undergo ligand-independent self-association, autophosphorylation, and aberrant stimulation of downstream signaling pathways, leading to a variety of cancers. Currently, no small-molecule inhibitors of ETV6 PNT domain polymerization are known and no assays targeting PNT domain polymerization have been described. In this study, we developed complementary experimental and computational approaches for identifying such inhibitory compounds. One mammalian cellular approach utilized a mutant PNT domain heterodimer system covalently attached to split Gaussia luciferase fragments. In this protein-fragment complementation assay, inhibition of PNT domain heterodimerization reduces luminescence. A yeast assay took advantage of activation of the reporter HIS3 gene upon heterodimerization of mutant PNT domains fused to DNA-binding and transactivation domains. In this two-hybrid screen, inhibition of PNT domain heterodimerization prevents cell growth in medium lacking histidine. The Bristol University Docking Engine (BUDE) was used to identify virtual ligands from the ZINC8 library predicted to bind the PNT domain polymerization interfaces. More than 75 hits from these three assays were tested by nuclear magnetic resonance spectroscopy for binding to the purified ETV6 PNT domain. Although none were found to bind, the lessons learned from this study may facilitate future approaches for developing therapeutics that act against ETV6 oncoproteins by disrupting PNT domain polymerization.

Curcumin-Activated Mesenchymal Stem Cells Derived from Human Umbilical Cord and Their Effects on MPTP-Mouse Model of Parkinson's Disease: A New Biological Therapy for Parkinson's Disease.

BACKGROUND: The aim of this study was to investigate the effects of human umbilical cord mesenchymal stem cell activated by curcumin (hUC-MSCs-CUR) on Parkinson's disease (PD). hUC-MSCs can differentiate into many types of adult tissue cells including dopaminergic (DA) neurons. CUR could protect DA neurons from apoptosis induced by 6-hydroxydopamine (6-OHDA). Therefore, we used the hUC-MSCs activated by CUR for the treatment of PD in an animal model. METHODS: The hUC-MSCs-CUR was transplanted into the MPTP-induced PD mouse models via the tail vein. We found that hUC-MSCs-CUR significantly improved the motor ability, increased the tyrosine hydroxylase (TH), dopamine (DA), and Bcl-2 levels, and reduced nitric oxide synthase, Bax, and cleaved caspase 3 expression in PD mice. The supernatant of hUC-MSCs-CUR (CM-CUR) was used to stimulate the SH-SY5Y cellular model of PD; cell proliferation, differentiation, TH, and neuronal-specific marker microtubular-associated protein 2 (MAP2) expressions were examined. RESULTS: Our data showed that CM-CUR significantly promoted cell proliferation and gradually increased TH and MAP2 expression in SH-SY5Y PD cells. The beneficial effects could be associated with significant increase of rough endoplasmic reticulum in the hUC-MSCs-CUR, which secretes many cytokines and growth factors beneficial for PD treatment. CONCLUSIONS: Transplantation of hUC-MSCs-CUR could show promise for improving the motor recovery of PD.