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https://www.readbyqxmd.com/read/29156327/asiatic-acid-and-maslinic-acid-attenuated-kainic-acid-induced-seizure-through-decreasing-hippocampal-inflammatory-and-oxidative-stress
#1
Zhi-Hong Wang, Mei-Chin Mong, Ya-Chen Yang, Mei-Chin Yin
Seizure is a neurological disorder including hippocampal oxidative and inflammatory stress, and glutamate toxicity. Thus, any agent(s) that mitigate(s) these events in hippocampus might attenuate seizure severity. The effects of asiatic acid (AA) or maslinic acid (MA) pre-administration at 20 or 40mg/kg body weight/day upon inflammatory, oxidative and apoptotic injury in hippocampus of kainic acid (KA)-treated mice were examined. KA induced seizure-like behavioral patterns, which was attenuated by AA or MA pre-administration...
November 17, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/29155846/soluble-cd40-ligand-directly-alters-glomerular-permeability-and-may-act-as-a-circulating-permeability-factor-in-fsgs
#2
Sophie Doublier, Cristina Zennaro, Luca Musante, Tiziana Spatola, Giovanni Candiano, Maurizio Bruschi, Luca Besso, Massimo Cedrino, Michele Carraro, Gian Marco Ghiggeri, Giovanni Camussi, Enrico Lupia
CD40/CD40 ligand (CD40L) dyad, a co-stimulatory bi-molecular complex involved in the adaptive immune response, has also potent pro-inflammatory actions in haematopoietic and non-haematopoietic cells. We describe here a novel role for soluble CD40L (sCD40L) as modifier of glomerular permselectivity directly acting on glomerular epithelial cells (GECs). We found that stimulation of CD40, constitutively expressed on GEC cell membrane, by the sCD40L rapidly induced redistribution and loss of nephrin in GECs, and increased albumin permeability in isolated rat glomeruli...
2017: PloS One
https://www.readbyqxmd.com/read/29155590/semisynthesis-and-biological-evaluation-of-xanthone-amphiphilics-as-selective-highly-potent-antifungal-agents-to-combat-fungal-resistance
#3
Shuimu Lin, Wan Ling Wendy Sin, Jun-Jie Koh, Fanghui Lim, Lin Wang, Derong Cao, Roger W Beuerman, Li Ren, Shouping Liu
New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangostin resulted in interesting antifungal agents with a novel mode of action. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including drug-resistant C...
November 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29155147/selective-and-membrane-permeable-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase-reverse-high-fat-diet-induced-obesity-in-mice
#4
Harshini Neelakantan, Virginia Vance, Michael D Wetzel, Hua-Yu Leo Wang, Stanton F McHardy, Celeste C Finnerty, Jonathan D Hommel, Stanley J Watowich
There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29154090/proliferative-and-metastatic-roles-for-phospholipase-d-in-mouse-models-of-cancer
#5
REVIEW
Eric Roth, Michael A Frohman
Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer...
November 14, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/29153590/heterocyclic-periphery-in-the-design-of-carbonic-anhydrase-inhibitors-1-2-4-oxadiazol-5-yl-benzenesulfonamides-as-potent-and-selective-inhibitors-of-cytosolic-hca-ii-and-membrane-bound-hca-ix-isoforms
#6
Mikhail Krasavin, Anton Shetnev, Tatyana Sharonova, Sergey Baykov, Tiziano Tuccinardi, Stanislav Kalinin, Andrea Angeli, Claudiu T Supuran
A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic hCA II and membrane-bound hCA IX isoforms. Due to a different cellular localization of the two target enzymes, the compounds can be viewed as selective inhibition tools for either isoform, depending on the cellular permeability profile. The SAR findings revealed in this study has been well rationalized by docking simulation of the key compounds against the crystal structures of the relevant hCA isoforms...
October 16, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29152410/ultrasound-triggered-local-anaesthesia
#7
Alina Y Rwei, Juan L Paris, Bruce Wang, Weiping Wang, Christopher D Axon, María Vallet-Regí, Robert Langer, Daniel S Kohane
On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve block in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve block to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produces reactive oxygen species that react with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin...
2017: Nature biomedical engineering
https://www.readbyqxmd.com/read/29150974/reciprocal-interactions-between-bile-acids-and-gut-microbiota-in-human-liver-diseases
#8
REVIEW
Tadashi Ikegami, Akira Honda
The gut microbiota (GM) play a central role in their hosts' metabolism of bile acids (BAs) by regulating deconjugation, dehydroxylation, dehydrogenation, and epimerization reactions to generate unconjugated free BAs and secondary BAs. These BAs generated by the GM are potent signaling molecules that interact with BA receptors, such as the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). Each BA has a differential affinity to these receptors; therefore, alterations in BA composition by GM could modify the intensity of receptor signaling...
November 18, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/29150838/gi-530159-a-novel-selective-mechano-sensitive-k2p-channel-opener-reduces-rat-dorsal-root-ganglion-drg-neuron-excitability
#9
Alexandre J C Loucif, Pierre-Philippe Saintot, Jia Liu, Brett M Antonio, Shannon G Zellmer, Katrina Yoger, Emma L Veale, Anna Wilbrey, Kiyoyuki Omoto, Lishuang Cao, Alex Gutteridge, Neil A Castle, Edward B Stevens, Alistair Mathie
BACKGROUND AND PURPOSE: TREK two pore domain potassium channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study we describe a new, selective opener of TREK channels, GI-530159 (4,4'-(Hexafluoroisopropylidene)bis(p-phenyleneoxy)dianiline)...
November 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29150508/community-composition-and-ultrastructure-of-a-nitrate-dependent-anaerobic-methane-oxidizing-enrichment-culture
#10
Lavinia Gambelli, Simon Guerrero-Cruz, Rob J Mesman, Geert Cremers, Mike S M Jetten, Huub J M Op den Camp, Boran Kartal, Claudia Lueke, Laura van Niftrik
Methane is a very potent greenhouse gas and can be oxidized aerobically or anaerobically through microbial-mediated processes, thus decreasing methane emissions to the atmosphere. Using a complementary array of methods including phylogenetic analysis, physiological experiments, and light and electron microscopy techniques (including electron tomography), we investigated the community composition and ultrastructure of a continuous bioreactor enrichment culture, in which anaerobic methane oxidation (AOM) was coupled to nitrate reduction...
November 17, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29150433/tyrosine-phosphorylation-of-munc18-1-inhibits-synaptic-transmission-by-preventing-snare%C3%A2-assembly
#11
Marieke Meijer, Bernhard Dörr, Hanna Ca Lammertse, Chrysanthi Blithikioti, Jan Rt van Weering, Ruud Fg Toonen, Thomas H Söllner, Matthijs Verhage
Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29146185/biomarker-identification-for-statin-sensitivity-of-cancer-cell-lines
#12
Vineet K Raghu, Colin H Beckwitt, Katsuhiko Warita, Alan Wells, Panayiotis V Benos, Zoltán N Oltvai
Statins are potent cholesterol reducing drugs that have been shown to reduce tumor cell proliferation in vitro and tumor growth in animal models. Moreover, retrospective human cohort studies demonstrated decreased cancer-specific mortality in patients taking statins. We previously implicated membrane E-cadherin expression as both a marker and mechanism for resistance to atorvastatin-mediated growth suppression of cancer cells; however, a transcriptome-profile-based biomarker signature for statin sensitivity has not yet been reported...
November 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29145073/target-induced-proximity-ligation-triggers-recombinase-polymerase-amplification-and-transcription-mediated-amplification-to-detect-tumor-derived%C3%A2-exosomes-in-nasopharyngeal-carcinoma-with-high-sensitivity
#13
Wanli Liu, Jianpei Li, Yixian Wu, Shan Xing, Yanzhen Lai, Ge Zhang
Tumor-derived exosomes (TEXs) are extracellular vesicles that are continuously released into the blood by tumor cells and carry specific surface markers of the original tumor cells. Substantial evidence has implicated TEXs as attractive diagnostic markers for cancer. However, the detection of TEXs in blood at an early tumor stage is challenging due to their very low concentration. Here, we established a method called PLA-RPA-TMA assay that allows TEXs to be detected with high sensitivity and specificity. Based on two proximity ligation assay (PLA) probes that recognize a biomarker on a TEX, we generated a unique surrogate DNA signal for the specific biomarker, which was synchronously amplified twice by recombinase polymerase amplification (RPA) coupled with transcription-mediated amplification (TMA), and then the products of the RPA-TMA reaction were quantitatively detected using a gold nanoparticle-based colorimetric assay...
November 9, 2017: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/29141539/comparative-selectively-targeted-anti-neoplastic-cytotoxicity-of-three-immunopharmaceuticals-with-covalently-bound-fludarabine-gemcitabine-and-dexamethasone-moieties-synthesized-utilizing-organic-chemistry-reactions-in-a-multi-phase-regimen
#14
Cody P Coyne, Lakshmi Narayanan
Background - Unintentional passive diffusion of conventional small molecular weight pharmaceuticals across intact membranes of normal healthy cells in tissues and organ systems induces sequelae that limit therapeutic dosage and duration of administration. Selective "targeted" delivery of pharmaceuticals is a molecular strategy that can potentially provide heightened margins-of-safety with greater potency and improved efficacy. Materials-and-Methods - Monophosphate analogs of fludarabine, gemcitabine, and dexamethasone were combined with a carbodiimide reagent in the presence of imidazole to produce reactive intermediates that were subsequently covalently bound to monoclonal anti-IGF-1R or anti-EGFR IgG-immunoglobulin...
November 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29140786/selection-of-an-anticalin%C3%A2-against-the-membrane-form-of-hsp70-via-bacterial-surface-display-and-its-theranostic-application-in-tumour-models
#15
Lars Friedrich, Petra Kornberger, Claudia T Mendler, Gabriele Multhoff, Markus Schwaiger, Arne Skerra
We describe the selection of Anticalins against a common tumour surface antigen, human Hsp70, using functional display on live E. coli cells as fusion with a truncated EspP autotransporter. While found intracellularly in normal cells, Hsp70 is frequently exposed in a membrane-bound state on the surface of tumour cells and, even more pronounced, in metastases or after radiochemotherapy. Employing a recombinant Hsp70 fragment comprising residues 383-548 as target, Anticalins were selected from a naive bacterial library...
November 27, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/29139202/lego-inspired-drug-design-unveiling-of-the-novel-class-of-benzo-d-thiazole-containing-a-3-4-dihydroxyphenyl-moiety-as-plasma-membrane-h-atpase-inhibitors
#16
Truong Thanh Tung, Dao Trong Tuan, Marta Grifell Junyent, Michael Palmgren, Thomas Günther-Pomorski, Anja Thoe Fuglsang, Søren Brøgger Christensen, John Nielsen
The fungal plasma membrane H+-ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure-activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for design, synthesis and discovery of benzo[d]thiazoles containing a 3,4-dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2-(benzo[d]thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanones was found to inhibit Pma1p with the most potent IC50 of 8 µM in an in vitro plasma membrane H+-ATPase assay...
November 15, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29133055/green-unexpected-synthesis-of-bis-coumarin-derivatives-as-potent-anti-bacterial-and-anti-inflammatory-agents
#17
Bahubali M Chougala, S Samundeeswari, Megharaja Holiyachi, Nirmala S Naik, Lokesh A Shastri, Suneel Dodamani, Sunil Jalalpure, Sheshagiri R Dixit, Shrinivas D Joshi, Vinay A Sunagar
A green and efficient protocol has been developed and a series of coumarin based pyrano[3,2-c]chromene derivatives (2) have been synthesized using multi-component reaction (MCR) approach. Unexpected 3-coumarinyl-3-pyrazolylpropanoic acids (3) and C4-C4 chromenes (5) have been isolated instead of expected product 4 by the reaction of compound (2) in formic acid at 90 °C for about 4-5 h and at 130 °C for about 8-10 h respectively. Further, C4-C4chromenes (5) formation was confirmed by intramolecular cyclization of compounds (3)...
October 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29133052/design-and-synthesis-of-short-amphiphilic-cationic-peptidomimetics-based-on-biphenyl-backbone-as-antibacterial-agents
#18
Rajesh Kuppusamy, Muhammad Yasir, Thomas Berry, Charles G Cranfield, Shashidhar Nizalapur, Eugene Yee, Onder Kimyon, Aditi Taunk, Kitty K K Ho, Bruce Cornell, Mike Manefield, Mark Willcox, David StC Black, Naresh Kumar
Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3'-amino-[1,1'-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29133047/discovery-of-new-potent-molecular-entities-able-to-inhibit-mpges-1
#19
Simone Di Micco, Stefania Terracciano, Vincenza Cantone, Katrin Fischer, Andreas Koeberle, Antonio Foglia, Raffaele Riccio, Oliver Werz, Ines Bruno, Giuseppe Bifulco
mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE2 levels induced by inflammatory stimuli, with neither affecting PGE2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects...
October 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29131945/enantioselectivity-of-2-2-3-5-6-pentachlorobiphenyl-pcb-95-atropisomers-toward-ryanodine-receptors-ryrs-and-their-influences-on-hippocampal-neuronal-networks
#20
Wei Feng, Jing Zheng, Gaelle Robin, Yao Dong, Makoto Ichikawa, Yoshihisa Inoue, Tadashi Mori, Takeshi Nakano, Isaac N Pessah
Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets are not understood. PCB 95 (2,2',3,5',6-pentachlorobiphenyl), a chiral PCB of current environmental relevance, is among the most potent towards modifying ryanodine receptors (RyR) function and Ca2+ signaling. PCB 95 atropisomers are separated and assigned aR- and aS-PCB 95 using 3 chiral-columns HPLC and circular dichroism spectroscopy. Studies of RyR1-enriched microsomes show aR-PCB 95 with >4X greater potency (EC50=0...
November 13, 2017: Environmental Science & Technology
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