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https://www.readbyqxmd.com/read/28107195/a-new-hdac-inhibitor-cinnamoylphenazine-shows-antitumor-activity-in-association-with-intensive-macropinocytosis
#1
Bing-Yan Zhu, Bo-Yang Shang, Yue Du, Yi Li, Liang Li, Xian-Dong Xu, Yong-Su Zhen
Previous studies have shown that intensive macropinocytosis occurs in cancer cells and neutral red (NR) is noted for its capability to enter into the cell massively through a process mimetic to macropinocytosis. In addition, trans-cinnamic acid (tCA) has been found to be an inhibitor of histone deacetylase (HDAC). In the present study, cinnamoylphenazine (CA-PZ) that consists of NR and tCA moieties was synthesized and evaluated. As shown, CA-PZ massively entered into colon carcinoma HT-29 cells and pancreatic carcinoma MIA PaCa-2 cells and this entry was blocked by 5-(N-ethyl-N-isopropyl) amiloride (EIPA, an inhibitor of macropinocytosis), indicating a macropinocytosis-mediated uptake...
January 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28087701/the-ubiquitin-ligase-nedd4l-regulates-the-na-k-2cl-co-transporter-nkcc1-slc12a2-in-the-colon
#2
Chong Jiang, Hiroshi Kawabe, Daniela Rotin
The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na+ channel (ENaC) in salt absorbing epithelia in the kidney, lung, and other tissues. Its role in the distal colon, which also absorbs salt and fluid and expresses ENaC, is unknown. Using conditional knockout approach to knockout Nedd4L in mice intestinal epithelium (Nedd4Lf/f;Vil-CreERT2) we show here that Nedd4L depletion leads to a higher steady-state short circuit current (Isc) in mouse distal colon tissue relative to controls...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28062311/trpa1-and-trpv1-antagonists-do-not-inhibit-human-acidosis-induced-pain
#3
Matthias G Schwarz, Barbara Namer, Peter W Reeh, Michael J M Fischer
: Acidosis occurs in a variety of pathophysiological and painful conditions where it is thought to excite or contribute to excitation of nociceptive neurons. Despite potential clinical relevance the principal receptor for sensing acidosis is unclear, but several receptors have been proposed. We investigated the contribution of the acid sensing ion channels, TRPV1 and TRPA1 to peripheral pain signaling. We first established a human pain model using intra-epidermal injection of TRPA1 agonist carvacrol...
January 3, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28049146/dissecting-bacterial-cell-wall-entry-and-signaling-in-eukaryotic-cells-an-actin-dependent-pathway-parallels-platelet-activating-factor-receptor-mediated-endocytosis
#4
Lip Nam Loh, Geli Gao, Elaine I Tuomanen
: The Gram-positive bacterial cell wall (CW) peptidoglycan-teichoic acid complex is released into the host environment during bacterial metabolism or death. It is a highly inflammatory Toll-like receptor 2 (TLR2) ligand, and previous in vivo studies have demonstrated its ability to recapitulate pathological features of pneumonia and meningitis. We report that an actin-dependent pathway is involved in the internalization of the CW by epithelial and endothelial cells, in addition to the previously described platelet-activating factor receptor (PAFr)-dependent uptake pathway...
January 3, 2017: MBio
https://www.readbyqxmd.com/read/28039784/verteporfin-based-silica-nanoparticle-for-in-vitro-selective-inhibition-of-human-highly-invasive-melanoma-cell-proliferation
#5
Manuela Rizzi, Stelvio Tonello, Bianca Martins Estevão, Enrica Gianotti, Leonardo Marchese, Filippo Renò
Photodinamic therapy (PDT) has gained an increasing interest as a new tool to treat skin cancers such as melanoma. This clinical approach take advantage from the combination of a photosensitizer and a specific light wavelength able to induce singlet oxygen production. Mesoporous silica nanoparticles (MSNs) have been widely investigated as drug nanocarriers as their structure and morphology could be customized to produce suitable nanoplatforms enabling high cargo capacity. In the present study MSNs were successfully conjugated with the second generation photosensitizer verteporfin and the resulting nanoplatform (Ver-MSNs) was tested in an in vitro PDT model as a potential tool for melanoma treatment...
December 22, 2016: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/28003213/molecular-mechanisms-underlying-active-desalination-and-low-water-permeability-in-the-esophagus-of-eels-acclimated-to-seawater
#6
Yoshio Takei, Marty Kwok-Shing Wong, Supriya Pipil, Haruka Ozaki, Yutaka Suzuki, Wataru Iwasaki, Makoto Kusakabe
Marine teleosts can absorb imbibed seawater (SW) to maintain water balance, with esophageal desalination playing an essential role. NaCl absorption from luminal SW was enhanced 10-fold in the esophagus of SW-acclimated eels, and removal of Na(+) or Cl(-) from luminal SW abolished the facilitated absorption, indicating coupled transport. Mucosal/serosal application of various blockers for Na(+)/Cl(-) transporters profoundly decreased the absorption. Among the transporter genes expressed in eel esophagus detected by RNA-seq, dimethyl amiloride-sensitive Na(+)/H(+) exchanger (NHE3) and 4,4'-diisothiocyano-2,2'-disulfonic acid-sensitive Cl(-)/HCO3(-) exchanger (AE) coupled by the scaffolding protein on the apical membrane of epithelial cells, and ouabain-sensitive Na(+)/K(+)-ATPases (NKA1α1c and NKA3α) and diphenylamine-2-carboxylic acid-sensitive Cl(-) channel (CLCN2) on the basolateral membrane, may be responsible for enhanced transcellular NaCl transport because of their profound upregulation after SW acclimation...
December 21, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28003157/asic-channel-inhibition-enhances-excitotoxic-neuronal-death-in-an-in-vitro-model-of-spinal-cord-injury
#7
Graciela L Mazzone, Priyadharishini Veeraraghavan, Carlota Gonzalez-Inchauspe, Andrea Nistri, Osvaldo D Uchitel
In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death...
December 19, 2016: Neuroscience
https://www.readbyqxmd.com/read/27989677/salt-controls-feeding-decisions-in-a-blood-sucking-insect
#8
Gina Pontes, Marcos H Pereira, Romina B Barrozo
Salts are necessary for maintaining homeostatic conditions within the body of all living organisms. Like with all essential nutrients, deficient or excessive ingestion of salts can result in adverse health effects. The taste system is a primary sensory modality that helps animals to make adequate feeding decisions in terms of salt consumption. In this work we show that sodium and potassium chloride salts modulate the feeding behavior of Rhodnius prolixus in a concentration-dependent manner. Feeding is only triggered by an optimal concentration of any of these salts (0...
December 15, 2016: Journal of Insect Physiology
https://www.readbyqxmd.com/read/27965209/effectiveness-of-chlorthalidone-plus-amiloride-for-the-prevention-of-hypertension-the-prever-prevention-randomized-clinical-trial
#9
Sandra Costa Fuchs, Carlos E Poli-de-Figueiredo, José A Figueiredo Neto, Luiz César N Scala, Paul K Whelton, Francisca Mosele, Renato Bandeira de Mello, José F Vilela-Martin, Leila B Moreira, Hilton Chaves, Marco Mota Gomes, Marcos R de Sousa, Ricardo Pereira E Silva, Iran Castro, Evandro José Cesarino, Paulo Cesar Jardim, João Guilherme Alves, André Avelino Steffens, Andréa Araujo Brandão, Fernanda M Consolim-Colombo, Paulo Ricardo de Alencastro, Abrahão Afiune Neto, Antônio C Nóbrega, Roberto Silva Franco, Dario C Sobral Filho, Alexandro Bordignon, Fernando Nobre, Rosane Schlatter, Miguel Gus, Felipe C Fuchs, Otávio Berwanger, Flávio D Fuchs
BACKGROUND: Prehypertension is associated with higher cardiovascular risk, target organ damage, and incidence of hypertension. The Prevention of Hypertension in Patients with PreHypertension (PREVER-Prevention) trial aimed to evaluate the efficacy and safety of a low-dose diuretic for the prevention of hypertension and end-organ damage. METHODS AND RESULTS: This randomized, parallel, double-blind, placebo-controlled trial was conducted in 21 Brazilian academic medical centers...
December 13, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/27941075/%C3%AE-%C3%AE-%C3%AE-enac-is-inhibited-by-cftr-but-stimulated-by-camp-in-xenopus-laevis-oocytes
#10
Robert Rauh, Christian Hoerner, Christoph Korbmacher
The epithelial sodium channel (ENaC) and the CFTR chloride channel critically regulate airway surface liquid by driving fluid absorption and secretion, respectively. Their functional interplay is complex and incompletely understood. ENaC is a heteromeric channel with three well characterised subunits (α, β, γ). In humans, an additional δENaC subunit exists in lung and several other tissues where it may replace the α-subunit to form δβγENaC. Little is known about the physiological role of δβγENaC and its possible interaction with CFTR...
December 9, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27934921/acid-sensing-ion-channels-are-expressed-in-the-ventrolateral-medulla-and-contribute-to-central-chemoreception
#11
Nana Song, Ruijuan Guan, Qian Jiang, Comron J Hassanzadeh, Yuyang Chu, Xiaomei Zhao, Xia Wang, Dawei Yang, Qijun Du, Xiang-Ping Chu, Linlin Shen
The role of acid-sensing ion channels (ASICs) in the ventrolateral medulla (VLM) remains uncertain. Here, we found that ASIC1a and ASIC2 are widely expressed in rat medulla, and the expression level is higher at neonatal stage as compared to adult stage. The two ASIC subunits co-localized in medualla neurons. Furthermore, pH reduction triggered typical ASIC-type currents in the medulla, including the VLM. These currents showed a pH50 value of 6.6 and were blocked by amiloride. Based on their sensitivity to psalmotoxin 1 (PcTx1) and zinc, homomeric ASIC1a and heteromeric ASIC1a/2 channels were likely responsible for acid-mediated currents in the mouse medulla...
December 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900368/whole-exome-sequencing-reveals-an-inherited-r566x-mutation-of-the-epithelial-sodium-channel-%C3%AE-subunit-in-a-case-of-early-onset-phenotype-of-liddle-syndrome
#12
Linda M Polfus, Eric Boerwinkle, Richard A Gibbs, Ginger Metcalf, Donna Muzny, Narayanan Veeraraghavan, Megan Grove, Sanjay Shete, Stephanie Wallace, Dianna Milewicz, Neil Hanchard, James R Lupski, Syed Shahrukh Hashmi, Monesha Gupta-Malhotra
To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27865862/impaired-mucus-clearance-exacerbates-allergen-induced-type-2-airway-inflammation-in-juvenile-mice
#13
Benedikt Fritzsching, Matthias Hagner, Lu Dai, Sandra Christochowitz, Raman Agrawal, Charlotte van Bodegom, Simone Schmidt, Jolanthe Schatterny, Stephanie Hirtz, Ryan Brown, Michelle Goritzka, Julia Duerr, Zhe Zhou-Suckow, Marcus A Mall
BACKGROUND: Type 2 airway inflammation plays a central role in the pathogenesis of allergen-induced asthma, but the underlying mechanisms remain poorly understood. Recently, we demonstrated that reduced mucociliary clearance, a characteristic feature of asthma, produces spontaneous type 2 airway inflammation in juvenile β-epithelial Na(+) channel (Scnn1b)-transgenic (Tg) mice. OBJECTIVE: We sought to determine the role of impaired mucus clearance in the pathogenesis of allergen-induced type 2 airway inflammation and identify cellular sources of the signature cytokine IL-13...
November 16, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27847440/gintonin-facilitates-catecholamine-secretion-from-the-perfused-adrenal-medulla
#14
Seung-Yeol Na, Ki-Hwan Kim, Mi-Sung Choi, Kang-Su Ha, Dong-Yoon Lim
The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M1 receptor antagonist), Ki14625 (10 µM, an LPA1/3 receptor antagonist), amiloride (1 mM, an inhibitor of Na(+)/Ca(2+) exchanger), a nicardipine (1 µM, a voltage-dependent Ca(2+) channel blocker), TMB-8 (1 µM, an intracellular Ca(2+) antagonist), and perfusion of Ca(2+)-free Krebs solution with 5mM EGTA (a Ca(2+)chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor)...
November 2016: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/27829053/no-evidence-for-ionotropic-pheromone-transduction-in-the-hawkmoth-manduca-sexta
#15
Andreas Nolte, Petra Gawalek, Sarah Koerte, HongYing Wei, Robin Schumann, Achim Werckenthin, Jürgen Krieger, Monika Stengl
Insect odorant receptors (ORs) are 7-transmembrane receptors with inverse membrane topology. They associate with the conserved ion channel Orco. As chaperon, Orco maintains ORs in cilia and, as pacemaker channel, Orco controls spontaneous activity in olfactory receptor neurons. Odorant binding to ORs opens OR-Orco receptor ion channel complexes in heterologous expression systems. It is unknown, whether this also occurs in vivo. As an alternative to this ionotropic transduction, experimental evidence is accumulating for metabotropic odor transduction, implicating that insect ORs couple to G-proteins...
2016: PloS One
https://www.readbyqxmd.com/read/27827955/a-novel-role-of-dickkopf-related-protein-3-in-macropinocytosis-in-human-bladder-cancer-t24-cells
#16
Nonoka Tsujimura, Nami O Yamada, Yuki Kuranaga, Minami Kumazaki, Haruka Shinohara, Kohei Taniguchi, Yukihiro Akao
Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G₀/G₁ cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA)...
November 5, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27820820/asic1a-deficient-mice-show-unaltered-neurodegeneration-in-the-subacute-mptp-model-of-parkinson-disease
#17
Daniel Komnig, Silke Imgrund, Arno Reich, Stefan Gründer, Björn H Falkenburger
Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i...
2016: PloS One
https://www.readbyqxmd.com/read/27816051/molecular-features-of-the-cytotoxicity-of-an-nhe-inhibitor-evidence-of-mitochondrial-alterations-ros-overproduction-and-dna-damage
#18
Francesca Aredia, Sebastian Czaplinski, Simone Fulda, A Ivana Scovassi
BACKGROUND: NH exchangers (NHEs) play a crucial role in regulating intra/extracellular pH, which is altered in cancer cells, and are therefore suitable targets to alter cancer cell metabolism in order to inhibit cell survival and proliferation. Among NHE inhibitors, amiloride family members are commonly used in clinical practice as diuretics; we focused on the amiloride HMA, reporting a net cytotoxic effect on a panel of human cancer cell lines; now we aim to provide new insights into the molecular events leading to cell death by HMA...
November 5, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27802150/feeding-through-your-gills-and-turning-a-toxicant-into-a-resource-how-the-dogfish-shark-scavenges-ammonia-from-its-environment
#19
Chris M Wood, Marina Giacomin
Nitrogen (N) appears to be a limiting dietary resource for elasmobranchs, required not only for protein growth but also for urea-based osmoregulation. Building on recent evidence that the toxicant ammonia can be taken up actively at the gills of the shark and made into the valuable osmolyte urea, we demonstrate that the uptake exhibits classic Michaelis-Menten saturation kinetics with an affinity constant (Km) of 379 µmol l(-1), resulting in net N retention at environmentally realistic ammonia concentrations (100-400 µmol l(-1)) and net N loss through stimulated urea-N excretion at higher levels...
October 15, 2016: Journal of Experimental Biology
https://www.readbyqxmd.com/read/27787836/should-all-patients-with-resistant-hypertension-receive-spironolactone
#20
REVIEW
Ján Rosa, Tomáš Zelinka, Ondřej Petrák, Branislav Štrauch, Robert Holaj, Jiří Widimský
PURPOSE OF REVIEW: Resistant hypertension is a common clinical situation. Identification of true resistant hypertension (using 24-h ambulatory blood pressure monitoring to exclude white coat phenomenon, excluding secondary causes and non-adherence to treatment) is important mostly because of the application of a proper therapeutic approach and the higher cardiovascular risk of these patients. This review surveys recent studies, with a focus on mineralocorticoid receptor antagonists, including spironolactone, in the treatment of resistant hypertension...
November 2016: Current Hypertension Reports
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