Bicuculline Ameliorated Chronic, but not Acute, Stress-Induced Feeding Suppression

This study was conducted to examine if γ-amino Butyric Acid (GABA)-ergic neurotransmission is implicated in the regulation of stress-induced feeding. Rats received GABA<inf>A</inf>receptor antagonist bicuculline before each stress session during 10 days of daily restraint stress. The hypothalamic mRNA expressions of corticotropin-releasing hormone and neuropeptide Y were analyzed by in situ hybridization and the plasma corticosterone with radioimmunoassay. Bicuculline ameliorated the decrease in food intake by repeated restraints but not by a single restraint. Corticosterone increase responding to acute stress but not to repeated restraints was attenuated by bicuculline. Stress-induced expression of corticotropin-releasing hormone was blunted by bicuculline pre-treatm ent. Restraint stress did not affect neuropeptide Y expression, regardless of bicuculline pre-treatment. It is concluded that GABA<inf>A</inf>receptors may mediate chronic but not acute, stress-induced suppression in food intake, possibly in relation with anorectic action of the hypothalamic corticotropin-releasing hormone and the hypothalamic neuropeptide Y may not be implicated in its regulatory mechanism. © Asian Network for Scientific Information.

Carborane-containing urea-based inhibitors of glutamate carboxypeptidase II: Synthesis and structural characterization

Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79 Å resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors. © 2015 Elsevier Ltd. All rights reserved.

X-ray diffraction and VT-NMR studies of (E)-3-(piperidinyl)-1-(2 '-hydroxyphenyl)-prop-2-en-1-one

A series of 1-aryl-3-(cyclicamino)-prop-2-en-1-one analogs was synthesized from commercial acetophenones in 2 or 3 steps. Compound 6, (E)-3-(piperidinyl)-1-(2′-hydroxyphenyl)-prop-2-en-1-one, exhibited the unique shape and intensity of the Csp2NCH2peaks in the 1H and 13C NMR spectra. Variable temperature (VT) nuclear magnetic resonance (NMR) and X-ray diffraction (XRD) studies of 6 revealed that the piperidine ring has a lower energy barrier to rotation than the 5-membered pyrrolidine 9 due to the less effective π electron delocalization along the Csp2N bond. © 2014 Elsevier B.V. All rights reserved.

Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues

Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium. In vivo chemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance arose from failed epigenetic control of the nuclear protein-1 (NUPR1)/histone deacetylase 11 (HDAC11) axis, and high NUPR1 expression correlated with poor clinical outcomes. These results suggest that the chip can rapidly induce resistant cells that increase tumor heterogeneity and chemoresistance, highlighting the need for further studies on the epigenetic control of the NUPR1/HDAC11 axis in TNBC

Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation

Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant patients. Taken together, we propose that upregulation of SCRN1 is an additional mechanism associated with acquired resistance to EGFR-TKIs and that its suppression serves as a novel therapeutic strategy to overcome drug resistance in these patients.