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https://www.readbyqxmd.com/read/27914038/serotonin-5-ht6-receptor-antagonists-in-alzheimer-s-disease-therapeutic-rationale-and-current-development-status
#1
Hilda Ferrero, Maite Solas, Paul T Francis, Maria J Ramirez
Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Because of the lack of effective treatments for this illness, research focused on identifying compounds that restore cognition and functional impairments in patients with AD is a very active field. Since its discovery in 1993, the serotonin 5-HT6 receptor has received increasing attention, and a growing number of studies supported 5-HT6 receptor antagonism as a target for improving cognitive dysfunction in AD. This article reviews the rationale behind investigations into the targeting of 5-HT6 receptors as a symptomatic treatment for cognitive and/or behavioral symptoms of AD...
December 3, 2016: CNS Drugs
https://www.readbyqxmd.com/read/27913993/antifreeze-glycopeptides-from-structure-and-activity-studies-to-current-approaches-in-chemical-synthesis
#2
REVIEW
Małgorzata Urbańczyk, Jerzy Góra, Rafał Latajka, Norbert Sewald
Antifreeze glycopeptides (AFGPs) are a class of biological antifreeze agents found predominantly in Arctic and Antarctic species of fish. They possess the ability to regulate ice nucleation and ice crystal growth, thus creating viable life conditions at temperatures below the freezing point of body fluids. AFGPs usually consist of 4-55 repetitions of the tripeptide unit Ala-Ala-Thr that is O-glycosylated at the threonine side chains with β-D-galactosyl-(1 → 3)-α-N-acetyl-D-galactosamine. Due to their interesting properties and high antifreeze activity, they have many potential applications, e...
December 2, 2016: Amino Acids
https://www.readbyqxmd.com/read/27913592/complexin-mutants-reveal-partial-segregation-between-recycling-pathways-that-drive-evoked-and-spontaneous-neurotransmission
#3
Nadezhda Sabeva, Richard W Cho, Alexander Vasin, Agustin Gonzalez, J Troy Littleton, Maria Bykhovskaia
: Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27913581/a-proteomic-approach-to-analyse-the-aspirin-mediated-lysine-acetylome
#4
Michael H Tatham, Christian Cole, Paul Scullion, Ross Wilkie, Nicholas J Westwood, Lesley A Stark, Ronald T Hay
Aspirin, or acetylsalicylic acid is widely used to control pain, inflammation and fever. Important to this function is its ability to irreversibly acetylate cyclooxygenases at active site serines. Aspirin has the potential to acetylate other amino-acid side-chains, leading to the possibility that aspirin-mediated lysine acetylation could explain some of its as-yet unexplained drug actions or side-effects. Using isotopically labeled aspirin-d3, in combination with acetylated lysine purification and LC-MS/MS, we identified over 12000 sites of lysine acetylation from cultured human cells...
December 2, 2016: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/27913536/reversal-of-direct-oral-anticoagulants-a-practical-approach
#5
Andrew W Shih, Mark A Crowther
Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913313/the-role-of-vitamin-d-and-vdr-in-carcinogenesis-through-epidemiology-and-basic-sciences
#6
REVIEW
Borja Bandera Merchan, Sonsoles Morcillo, Gracias Martin-Nuñez, Francisco José Tinahones, Manuel Macías-González
In the last two decades vitamin D (VD) research has demonstrated new extraskeletal actions of this pre-hormone, suggesting a protective role of this secosteroid in the onset, progression and prognosis of several chronic noncommunicable diseases, such as cardiovascular disease, diabetes mellitus or cancer. Regarding carcinogenesis, both preclinical and epidemiological evidence available show oncoprotective actions of VD and its receptor, the VDR. However, in late neoplastic stages the VD system (VDS) seems to be less functional, which appears to be due to an epigenetic silencing of the system...
November 29, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27913286/cytotoxic-activity-of-soy-phytoestrogen-coumestrol-against-human-breast-cancer-mcf-7%C3%A2-cells-insights-into-the-molecular-mechanism
#7
Atif Zafar, Swarnendra Singh, Imrana Naseem
Coumestrol is a phytoestrogen present in soybean products and recognized as potential cancer therapeutic agent against breast cancer. However, the clear molecular mechanism of anticancer-activity of coumestrol in breast carcinoma has not been reported. It is well established that copper levels are elevated in different malignancies. Therefore, the objective of this study was to investigate the copper-dependent cytotoxic action of coumestrol in human breast cancer MCF-7 cells. Results showed that coumestrol inhibited proliferation and induced apoptosis in MCF-7 cells, which was prevented by copper chelator neocuproine and ROS scavengers...
November 29, 2016: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/27912879/how-do-the-alkaloids-emetine-and-homoharringtonine-kill-trypanosomes-an-insight-into-their-molecular-modes-of-action
#8
Sonja Krstin, Tamer Mohamed, Xiaojuan Wang, Michael Wink
BACKGROUND: Although Trypanosoma brucei causes deadly sleeping sickness, the number of the registered medications is rather limited. Some plant alkaloids are potent trypanocidal agents. PURPOSE: In this study, we wanted to elucidate the molecular modes of trypanocidal activity of the alkaloids emetine and homoharringtonine against Trypanosoma brucei brucei. METHODS: We investigated the activity of both alkaloids regarding growth recovery from alkaloid-induced stress...
December 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/27912151/euclidean-distances-as-measures-of-speaker-similarity-including-identical-twin-pairs-a-forensic-investigation-using-source-and-filter-voice-characteristics
#9
Eugenia San Segundo, Athanasios Tsanas, Pedro Gómez-Vilda
There is a growing consensus that hybrid approaches are necessary for successful speaker characterization in Forensic Speaker Comparison (FSC); hence this study explores the forensic potential of voice features combining source and filter characteristics. The former relate to the action of the vocal folds while the latter reflect the geometry of the speaker's vocal tract. This set of features have been extracted from pause fillers, which are long enough for robust feature estimation while spontaneous enough to be extracted from voice samples in real forensic casework...
November 17, 2016: Forensic Science International
https://www.readbyqxmd.com/read/27912148/anti-cancer-effect-of-lactic-acid-bacteria-expressing-antioxidant-enzymes-or-il-10-in-a-colorectal-cancer-mouse-model
#10
Silvina Del Carmen, Alejandra de Moreno de LeBlanc, Romina Levit, Vasco Azevedo, Philippe Langella, Luis G Bermúdez-Humarán, Jean Guy LeBlanc
The association between inflammatory bowel diseases and colorectal cancer is well documented. The genetic modification of lactic acid bacteria as a tool to increase the anti-inflammatory potential of these microorganisms has also been demonstrated. Thus the aim of the present work was to evaluate the anti-cancer potential of different genetically modified lactic acid bacteria (GM-LAB) producing antioxidant enzymes (catalase or superoxide dismutase) or the anti-inflammatory cytokine IL-10 (protein or DNA delivery) using a chemical induced colon cancer murine model...
November 29, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27912145/chloroquine-cq-exerts-anti-breast-cancer-through-modulating-microenvironment-and-inducing-apoptosis
#11
Yanjun Zhang, Yu Cao, Xiaodan Sun, Yonghui Feng, Yunting Du, Fei Liu, Chunyun Yu, Feng Jin
CQ is an anti-malaria drug, which has been used for years. However, there are published articles about its activity in anti-cancers. The aim of this approach was to look at possibility and related mechanisms of anti-breast cancer (mouse breast cancer cell line 4T1) by CQ alone. The studies of anti 4T1 in vitro and in vivo by CQ were performed. The growth of 4T1 in vitro and in vivo, survival of mice post treatment with CQ, changes of immune parameters and microenvironment in mice were evaluated. Our results demonstrate that CQ could markedly inhibit growth of 4T1 in vitro through inducing apoptosis of cells, inhibiting secretion of TGF-β and prolong the mice survival in vivo through boosting immune system by upregulating CD8+ T cell, and through down-regulating tumor associated macrophages (TAM), myeloid derived suppressing cells (MDSC) and Tregs, in microenvironment of mice bearing tumor...
November 29, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27911898/bilaterian-giant-ankyrins-have-a-common-evolutionary-origin-and-play-a-conserved-role-in-patterning-the-axon-initial-segment
#12
Timothy Jegla, Michelle M Nguyen, Chengye Feng, Daniel J Goetschius, Esteban Luna, Damian B van Rossum, Bishoy Kamel, Aditya Pisupati, Elliott S Milner, Melissa M Rolls
In vertebrate neurons, the axon initial segment (AIS) is specialized for action potential initiation. It is organized by a giant 480 Kd variant of ankyrin G (AnkG) that serves as an anchor for ion channels and is required for a plasma membrane diffusion barrier that excludes somatodendritic proteins from the axon. An unusually long exon required to encode this 480Kd variant is thought to have been inserted only recently during vertebrate evolution, so the giant ankyrin-based AIS scaffold has been viewed as a vertebrate adaptation for fast, precise signaling...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27911877/icariside-ii-activates-egfr-akt-nrf2-signaling-and-protects-osteoblasts-from-dexamethasone
#13
Weidong Liu, Li Mao, Feng Ji, Fengli Chen, Shouguo Wang, Yue Xie
The potential effect of icariside II on dexamethasone-induced osteoblast cell damages was evaluated here. In MC3T3-E1 osteoblastic cells and the primary murine osteoblasts, co-treatment with icariside II dramatically attenuated dexamethasone- induced cell death and apoptosis. Icariside II activated Akt signaling, which is required for its actions in osteoblasts. Akt inhibitors (LY294002, perifosine and MK-2206) almost abolished icariside II-induced osteoblast cytoprotection against dexamethasone. Further studies showed that icariside II activated Nrf2 signaling, downstream of Akt, to inhibit dexamethasone-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary osteoblasts...
December 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27911816/rapid-emergence-and-mechanisms-of-resistance-by-u87-glioblastoma-cells-to-doxorubicin-in-an-in-vitro-tumor-microfluidic-ecology
#14
Jeonghun Han, Yukyung Jun, So Hyun Kim, Hong-Hoa Hoang, Yeonjoo Jung, Suyeon Kim, Jaesang Kim, Robert H Austin, Sanghyuk Lee, Sungsu Park
In vitro prediction of the probable rapid emergence of resistance to a drug in tumors could act to winnow out potential candidates for further costly development. We have developed a microfluidic device consisting of ∼500 hexagonal microcompartments that provides a complex ecology with wide ranges of drug and nutrient gradients and local populations. This ecology of a fragmented metapopulation induced the drug resistance in stage IV U87 glioblastoma cells to doxorubicin in 7 d. Exome and transcriptome sequencing of the resistant cells identified mutations and differentially expressed genes...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27911814/distinct-cortical-and-striatal-actions-of-a-%C3%AE-arrestin-biased-dopamine-d2-receptor-ligand-reveal-unique-antipsychotic-like-properties
#15
Nikhil M Urs, Steven M Gee, Thomas F Pack, John D McCorvy, Tama Evron, Joshua C Snyder, Xiaobao Yang, Ramona M Rodriguiz, Emiliana Borrelli, William C Wetsel, Jian Jin, Bryan L Roth, Patricio O'Donnell, Marc G Caron
The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling...
December 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27911765/optical-magnetic-detection-of-single-neuron-action-potentials-using-quantum-defects-in-diamond
#16
John F Barry, Matthew J Turner, Jennifer M Schloss, David R Glenn, Yuyu Song, Mikhail D Lukin, Hongkun Park, Ronald L Walsworth
Magnetic fields from neuronal action potentials (APs) pass largely unperturbed through biological tissue, allowing magnetic measurements of AP dynamics to be performed extracellularly or even outside intact organisms. To date, however, magnetic techniques for sensing neuronal activity have either operated at the macroscale with coarse spatial and/or temporal resolution-e.g., magnetic resonance imaging methods and magnetoencephalography-or been restricted to biophysics studies of excised neurons probed with cryogenic or bulky detectors that do not provide single-neuron spatial resolution and are not scalable to functional networks or intact organisms...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27911759/neurotransmitter-release-can-be-stabilized-by-a-mechanism-that-prevents-voltage-changes-near-the-end-of-action-potentials-from-affecting-calcium-currents
#17
Stephen G Clarke, Matthew S Scarnati, Kenneth G Paradiso
: At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27911746/new-insight-in-cold-pain-role-of-ion-channels-modulation-and-clinical-perspectives
#18
Stéphane Lolignier, Dimitra Gkika, David Andersson, Enrico Leipold, Irina Vetter, Felix Viana, Jacques Noël, Jérôme Busserolles
Cold temperature detection involves the process of sensory transduction in cutaneous primary sensory nerve terminals, which converts thermal stimuli into depolarizations of the membrane. This transformation into electrical signals is followed by the subsequent propagation of action potentials in cold-sensitive afferent nerve fibers. A large array of ion channels shapes this process; however, the precise contribution of specific ion channel subtypes to cold perception and cold pain remains elusive. This review aims at giving an update on our current understanding of the role played by TRPs, leak K(+) and voltage-gated Na(+) and K(+) channels in the transduction of cold by nociceptors and in cold-induced pain...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27911605/gnrh-neuron-activity-and-pituitary-response-in-estradiol-induced-vs-proestrous-luteinizing-hormone-surges-in-female-mice
#19
Marina Silveira, Laura L Burger, R Anthony DeFazio, Elizabeth R Wagenmaker, Suzanne M Moenter
During the female reproductive cycle, estradiol exerts negative and positive feedback at both the central level to alter GnRH release and at the pituitary to affect response to GnRH. Many studies of the neurobiological mechanisms underlying estradiol feedback have been done on ovariectomized, estradiol-replaced (OVX+E) mice. In this model, GnRH neuron activity depends on estradiol and time of day, increasing in estradiol-treated mice in the late afternoon coincident with a daily LH surge. Amplitude of this surge appears lower than in proestrous mice, perhaps because other ovarian factors are not replaced...
December 2, 2016: Endocrinology
https://www.readbyqxmd.com/read/27911303/amylin-treatment-reduces-neuroinflammation-and-ameliorates-abnormal-patterns-of-gene-expression-in%C3%A2-the-cerebral-cortex-of-an-alzheimer-s-disease-mouse-model
#20
Erming Wang, Haihao Zhu, Xiaofan Wang, Adam Gower, Max Wallack, Jan Krzysztof Blusztajn, Neil Kowall, Wei Qiao Qiu
Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice...
November 28, 2016: Journal of Alzheimer's Disease: JAD
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