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https://www.readbyqxmd.com/read/28822969/preconditioning-with-the-bkca-channel-activator-ns-1619-prevents-ischemia-reperfusion-induced-inflammation-and-mucosal-barrier-dysfunction-ros-and-ho-1
#1
Hongyan Dai, Meifang Wang, Parag N Patel, Theodore J Kalogeris, Yajun Liu, William Durante, Ronald J Korthuis
Activation of large conductance, calcium-activated potassium (BKCa) channels evokes cell survival programs that mitigate intestinal ischemia and reperfusion (I/R) inflammation and injury 24 hours later. The goal of the current study was to determine the role of reactive oxygen species (ROS) and heme oxygenase (HO)-1 in delayed acquisition of tolerance to I/R induced by pretreatment with the BKCa channel opener NS-1619. Superior mesentery arteries were occluded for 45 min followed by reperfusion for 70 min in wild type (WT) or HO-1 null (HO-1(-/-)) mice that were pretreated with NS-1619 or saline vehicle 24 hrs earlier...
August 19, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28822958/therapeutic-molecules-against-type-2-diabetes-what-we-have-and-what-are-we-expecting
#2
REVIEW
Ashwini Kumar, Sudhanshu Kumar Bharti, Awanish Kumar
World Health Organization (WHO) has identified diabetes as one of the fastest growing non-communicable diseases with 422 million patients around the world in 2014. Diabetes, a metabolic disease, is characterized primarily by hyperglycemia which results in various macrovascular and microvascular complications like cardiovascular disease and neuropathies which can significantly deteriorate the quality of life. The body either does not manufactures enough insulin (type 1 diabetes or T1DM) or becomes insensitive to physiologically secreted insulin or both (type 2 diabetes or T2DM)...
April 9, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28822686/the-role-of-human-monoacylglycerol-lipase-hmagl-binding-pocket-in-breakup-of-unsaturated-phospholipid-membranes
#3
Ioannis Karageorgos, Vitalii I Silin, Nikolai Zvonok, John Marino, David R Janero, Alexandros Makriyannis
Human monoacylglycerol lipase (hMAGL) plays a key role in homeostatic tuning of the endocannabinoid signaling system and supports aggressive tumorogenesis, making this enzyme a promising therapeutic target. hMAGL features a membrane-associated lid domain that regulates entry of endocannabinoid lipid substrates into the hydrophobic channel accessing the active site, likely from the membrane bilayer. The present work applied simultaneous surface plasmon resonance and electrochemical impedance spectroscopy measurements to show that, in absence of the substrate, hMAGL can remove phospholipid molecules from the membrane and, thereby, disintegrate pre-formed, intact, tethered phospholipid bilayer membrane mimetics (tBLMs) composed of unsaturated phosphatidylcholines...
August 16, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/28821851/mass-production-of-bulk-artificial-nacre-with-excellent-mechanical-properties
#4
Huai-Ling Gao, Si-Ming Chen, Li-Bo Mao, Zhao-Qiang Song, Hong-Bin Yao, Helmut Cölfen, Xi-Sheng Luo, Fu Zhang, Zhao Pan, Yu-Feng Meng, Yong Ni, Shu-Hong Yu
Various methods have been exploited to replicate nacre features into artificial structural materials with impressive structural and mechanical similarity. However, it is still very challenging to produce nacre-mimetics in three-dimensional bulk form, especially for further scale-up. Herein, we demonstrate that large-sized, three-dimensional bulk artificial nacre with comprehensive mimicry of the hierarchical structures and the toughening mechanisms of natural nacre can be facilely fabricated via a bottom-up assembly process based on laminating pre-fabricated two-dimensional nacre-mimetic films...
August 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28821612/syndecan-2-cytoplasmic-domain-upregulates-matrix-metalloproteinase-7-expression-via-protein-kinasec%C3%AE-mediated-fak-erk-signaling-pathway-in-colon-cancer
#5
Bohee Jang, Hyejung Jung, Sojoong Choi, Young Hun Lee, Seung-Taek Lee, Eok-Soo Oh
The syndecan family of heparan sulfate proteoglycans contribute to cell adhesion and communication by serving as co-receptors for cell signaling and extracellular matrix molecules. Syndecan-2 is located at the cell surface, and we previously reported that it induces matrix metalloproteinase-7 (MMP-7) expression in colon cancer cells. However, the underlying regulatory mechanisms are unknown. Here, we report that over-expression of syndecan-2 in HT-29 colon cancer cells increases the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) in parallel with upregulated MMP-7 expression, but a syndecan-2 mutant lacking the cytoplasmic domain showed significant reductions in these effects...
August 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28819643/membrane-localization-of-acetylated-cnk1-mediates-a-positive-feedback-on-raf-erk-signaling
#6
Adrian Fischer, Wignand W D Mühlhäuser, Bettina Warscheid, Gerald Radziwill
Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)-binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28817272/cysteine-isocyanide-in-multicomponent-reaction-synthesis-of-peptido-mimetic-1-3-azoles
#7
Thimmalapura M Vishwanatha, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Alexander Dömling
An alternative approach towards the simple and robust synthesis of highly substituted peptidic thiazole derivatives by using Ugi-multicomponent reaction (U-MCR) is described. Thus, we introduced the enantiopure (R)-2-methyl-2-isocyano-3-(tritylthio)propanoate as novel class of isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of bis-heterocyclic rings were also synthesized through the proper choice of the aldehyde component in the U-4CR...
August 17, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28815933/an-%C3%AE-iib-%C3%AE-3-antagonist-prevents-thrombosis-without-causing-fc%C3%AE-riia-mediated-thrombocytopenia
#8
Yu-Ju Kuo, Ying-Ru Chen, Chun-Chieh Hsu, Hui-Chin Peng, Tur-Fu Huang
BACKGROUND: Thrombocytopenia, a common side effect of Arg-Gly-Asp (RGD)-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin αIIb β3 . OBJECTIVE: To explore the correlation between αIIb β3 binding epitopes and induction of DDAb binding to conformation-altered αIIb β3 , we examined whether two purified disintegrins TMV-2 and TMV-7 with distinct binding motifs that have different effects on induction of αIIb β3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory monoclonal antibody (mAb) raised against αIIb β3 ...
August 16, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28815651/peptide-mimetic-drugs-for-modulating-thrombosis-and-hemostasis
#9
Kimberly Nellenbach, Ashley C Brown
Preclinical Research Hemostasis is the complex physiological process that stems bleeding at an injury site while simultaneously maintaining unobstructed circulation in other areas of the body. This system is kept in balance with finely tuned regulation by pro- and antithrombotic agents. When this balance is thrown out of equilibrium, uncontrolled bleeding, or thrombotic complications can occur. Because of the high number of hemostatic disorders, researchers are continually searching for improved technologies for controlling coagulation...
August 16, 2017: Drug Development Research
https://www.readbyqxmd.com/read/28813980/human-mimetic-forearm-mechanism-towards-bionic-arm
#10
Minsang Seo, Hogyun Kim, Youngjin Choi
The paper presents a mechanical forearm mechanism to extend the pronation and supination (P/S) movement of the trans-radial amputee when he/she is able to conduct the P/S motion partially with his/her remaining forearm. The P/S motions of the existing prostheses and robotic arms developed till now are completely different from those of the human. When we are to develop the robotic prostheses for the amputees, two important issues should be considered such as cosmetic issue to look like normal arm and motion harmony issue between robotic prosthesis and the amputated living arm...
July 2017: IEEE ... International Conference on Rehabilitation Robotics: [proceedings]
https://www.readbyqxmd.com/read/28809779/application-of-solution-nmr-to-structural-studies-on-%C3%AE-helical-integral-membrane-proteins
#11
REVIEW
Dae-Won Sim, Zhenwei Lu, Hyung-Sik Won, Seu-Na Lee, Min-Duk Seo, Bong-Jin Lee, Ji-Hun Kim
A large portion of proteins in living organisms are membrane proteins which play critical roles in the biology of the cell, from maintenance of the biological membrane integrity to communication of cells with their surroundings. To understand their mechanism of action, structural information is essential. Nevertheless, structure determination of transmembrane proteins is still a challenging area, even though recently the number of deposited structures of membrane proteins in the PDB has rapidly increased thanks to the efforts using X-ray crystallography, electron microscopy, and solid and solution nuclear magnetic resonance (NMR) technology...
August 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28809398/precision-medicine-for-suicidality-from-universality-to-subtypes-and-personalization
#12
A B Niculescu, H Le-Niculescu, D F Levey, P L Phalen, H L Dainton, K Roseberry, E M Niculescu, J O Niezer, A Williams, D L Graham, T J Jones, V Venugopal, A Ballew, M Yard, T Gelbart, S M Kurian, A Shekhar, N J Schork, G E Sandusky, D R Salomon
Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies...
August 15, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28808806/brca1-mimetic-compound-nsc35446-hcl-inhibits-ikkb-expression-by-reducing-estrogen-receptor-%C3%AE-occupancy-in-the-ikkb-promoter-and-inhibits-nf-%C3%AE%C2%BAb-activity-in-antiestrogen-resistant-human-breast-cancer-cells
#13
Shyam Nathan, Yongxian Ma, York A Tomita, Eliseu De Oliveira, Milton L Brown, Eliot M Rosen
PURPOSE: We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity ("BRCA1-mimetics"), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 ("NSC35446.HCl"), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action...
August 14, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28806505/co4n-nanowires-noble-metal-free-peroxidase-mimetic-with-excellent-salt-and-temperature-resistant-abilities
#14
Yu-Zhen Li, Tong-Tong Li, Wei Chen, Yan-Yan Song
Compared to natural enzymes, nanomaterial-based artificial enzymes have attracted immense attention because of their high stability and cost-effectiveness. In this study, cobalt nitride (Co4N) as a noble-metal-free artificial enzyme exhibiting highly intrinsic peroxidase-like activity and good stability was reported. Kinetic studies revealed that the resultant Co4N nanowires (NWs) exhibited a stronger affinity for 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2 than HRP. Compared to Co3O4 NWs, Co4N NWs exhibited highly improved catalytic activities, with H2O2 exhibiting an apparent Km approximately 2 orders of magnitude less than that of Co3O4...
August 14, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28804913/on-bh3-mimetics-and-ca-2-signaling
#15
Pawel E Ferdek, Monika A Jakubowska
Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca(2+) homeostasis, including Ca(2+) release from the intracellular stores as well as Ca(2+) fluxes across the plasma membrane...
August 13, 2017: Drug Development Research
https://www.readbyqxmd.com/read/28803935/tnf-%C3%AE-upregulates-hif-1%C3%AE-expression-in-pterygium-fibroblasts-and-enhances-their-susceptibility-to-vegf-independent-of-hypoxia
#16
Kyoung Woo Kim, Soo Jin Lee, Jae Chan Kim
The clinical manifestations of pterygium are characterized by rapid growth and postoperative recurrences. We had previously proposed that hypoxia-inducible factor (HIF)-1α recruits progenitor cells during the development and progression of pterygia. Recently, it was reported that various stimuli, including inflammation, could activate HIF-1α even under normoxic conditions. The ocular surface directly faces external environments, and is thus frequently exposed to inflammatory insults. First, we examined the gene expression of HIF-1α, its downstream molecule, vascular endothelial growth factor (VEGF)-A, and VEGF receptor (VEGFR)-2 in corneal and conjunctival cells compared with cultured human umbilical vein endothelial cells...
August 10, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28802072/fifty-years-of-benz-oxaphospholene-chemistry
#17
Jan Berton, Thomas Heugebaert, David Virieux, Chris Victor Stevens
The first synthesis of benzoxaphospholenes dates back to the 60s. Since then, the structural variety of reported (benz)oxaphospholenes has steadily increased. Organophosphorus compounds have caught the interest of synthetic chemists for a couple of decades now because of their interesting biological properties. Oxaphospholenes, in particular, could serve as carbohydrate mimetics, while benzoxaphospholenes have been reported to possess bactericidal, insecticidal, herbicidal and fungistatical properties. Transesterification reactions and addition of phosphorus nucleophiles to carbonyl compounds were reaction types that led to the production of the first (benz)oxaphospholenes...
August 12, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28802066/targeting-senescent-cholangiocytes-and-activated-fibroblasts-with-bcl-xl-inhibitors-ameliorates-fibrosis-in-mdr2-mice
#18
Anja Moncsek, Mohammed S Al-Suraih, Christy E Trussoni, Steven P O'Hara, Patrick L Splinter, Camille Zuber, Eleonora Patsenker, Piero V Valli, Christian D Fingas, Achim Weber, Yi Zhu, Tamar Tchkonia, James L Kirkland, Gregory J Gores, Beat Müllhaupt, Nicholas F LaRusso, Joachim C Mertens
Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASF), which are drivers of fibrosis. The activated phenotype of ASF is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASF and explored a combined targeting strategy to deplete senescent cholangiocytes and ASF from fibrotic tissue to ameliorate liver fibrosis...
August 12, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28801916/adenosine-and-dopamine-oppositely-modulate-a-hyperpolarization-activated-current-ih-in-chemosensory-neurons-of-the-rat-carotid-body-in-co-culture
#19
Min Zhang, Cathy Vollmer, Colin A Nurse
Adenosine and dopamine (DA) act as neurotransmitters or neuromodulators at the carotid body (CB) chemosensory synapse, however, their mechanisms of action are not fully understood. Using a functional co-culture model of rat CB chemoreceptor (type I) cell clusters and juxtaposed afferent petrosal neurons (PNs), we tested the hypothesis that adenosine and DA act postsynaptically to modulate a hyperpolarization-activated, cyclic nucleotide-gated (HCN) cation current (Ih ). In whole-cell recordings from hypoxia-responsive PNs, cAMP mimetics enhanced Ih whereas the HCN blocker ZD7288 (2 μm) reversibly inhibited Ih ...
August 12, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28801135/pyrrolo-2-1-f-1-2-4-triazines-from-c-nucleosides-to-kinases-and-back-again-the-remarkable-journey-of-a-versatile-nitrogen-heterocycle
#20
REVIEW
Gregory R Ott, David A Favor
Pyrrolo[2,1-f][1,2,4]triazine, a unique NN bond-containing heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chemistry until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets...
July 30, 2017: Bioorganic & Medicinal Chemistry Letters
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