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chloride channel activators

Juliana Porretti, Guillermo N Dalton, Cintia Massillo, Georgina D Scalise, Paula L Farré, Randolph Elble, Esther N Gerez, Paula Accialini, Ana M Cabanillas, Kevin Gardner, Paola De Luca, Adriana De Siervi
Prostate cancer (PCa) is the most common cancer among men. Metabolic syndrome (MeS) is associated with increased PCa aggressiveness and recurrence. Previously, we proposed C-terminal binding protein 1 (CTBP1), a transcripcional co-repressor, as a molecular link between these two conditions. Notably, CTBP1 depletion decreased PCa growth in MeS mice. The aim of this study was to investigate the molecular mechanisms that explain the link between MeS and PCa mediated by CTBP1. We found that CTBP1 repressed Chloride Channel Accessory 2 (CLCA2) expression in prostate xenografts developed in MeS animals...
March 14, 2018: International Journal of Cancer. Journal International du Cancer
Annalucia Carbone, Roberto Zefferino, Elisa Beccia, Valeria Casavola, Stefano Castellani, Sante Di Gioia, Valentina Giannone, Manuela Seia, Antonella Angiolillo, Carla Colombo, Maria Favia, Massimo Conese
We previously found that human amniotic mesenchymal stem cells (hAMSCs) in coculture with CF immortalised airway epithelial cells (CFBE41o- line, CFBE) on Transwell® filters acquired an epithelial phenotype and led to the expression of a mature and functional CFTR protein. In order to explore the role of gap junction- (GJ-) mediated intercellular communication (GJIC) in this rescue, cocultures (hAMSC : CFBE, 1 : 5 ratio) were studied for the formation of GJIC, before and after silencing connexin 43 (Cx43), a major component of GJs...
2018: Stem Cells International
Michael Malone, Abdul Waheed, Samiullah Samiullah
Functional lower gastrointestinal disorders include irritable bowel syndrome (IBS), functional constipation, functional fecal incontinence, and functional anorectal pain. These disorders are common and have significant medical and social effects. They also can be challenging to manage. Patients with mild symptoms may benefit from lifestyle modification. IBS is classified into two subtypes: diarrhea-predominant and constipation-predominant. Depending on the IBS subtype and its likely etiology, patients may benefit from treatment with antispasmodics, antidepressants, guanylate cyclase-C agonists, chloride channel activators, antidiarrheal agents, probiotics, and/or antibiotics...
March 2018: FP Essentials
Massimo Tosolini, Paolo Pengo, Paolo Tecilla
Natural and synthetic anionophores promote the trans-membrane transport of anions such as chloride and bicarbonate. This process may alter the cellular homeostasis with possible effects on internal ions concentration and pH levels triggering several and diverse biological effects. In this article an overview of the recent results on the study of anion-transporters, mainly acting with a carrier-type mechanism, is given with emphasis on the structure/activity relationship and on their biological activity as antibiotic and anticancer agents and in the development of new drugs for treating conditions derived by dysregulation of natural anion channels...
March 8, 2018: Current Medicinal Chemistry
Lisa Repsold, Anna Margaretha Joubert
Erythrocytes play an important role in oxygen and carbon dioxide transport. Although erythrocytes possess no nucleus or mitochondria, they fulfil several metabolic activities namely, the Embden-Meyerhof pathway, as well as the hexose monophosphate shunt. Metabolic processes within the erythrocyte contribute to the morphology/shape of the cell and important constituents are being kept in an active, reduced form. Erythrocytes undergo a form of suicidal cell death called eryptosis. Eryptosis results from a wide variety of contributors including hyperosmolarity, oxidative stress, and exposure to xenobiotics...
2018: BioMed Research International
Mandy Juarez, Alejandro Schcolnik-Cabrera, Alfonso Dueñas-Gonzalez
Drug repositioning is a highly studied alternative strategy to discover and develop anticancer drugs. This drug development approach identifies new indications for existing compounds. Ivermectin belongs to the group of avermectins (AVM), a series of 16-membered macrocyclic lactone compounds discovered in 1967, and FDA-approved for human use in 1987. It has been used by millions of people around the world exhibiting a wide margin of clinical safety. In this review, we summarize the in vitro and in vivo evidences demonstrating that ivermectin exerts antitumor effects in different types of cancer...
2018: American Journal of Cancer Research
Stefanie Klinger, Gerhard Breves
BACKGROUND: Beneficial effects of Resveratrol (RSV) have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. METHODS: Porcine jejunum and ileum were incubated with RSV (300 µM, 30 min) in Ussing chambers (functional studies) and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs))...
March 3, 2018: Nutrients
Logan J Voss, Sebastian Karalus, Vilhelm Englund, James W Sleigh
BACKGROUND: Ketamine is a general anesthetic thought to act by antagonizing N-methyl-D-aspartate receptors. However, ketamine acts on multiple channels, many of which are potential targets-including hyperpolarization-activated cyclic nucleotide-gated and potassium channels. In this study we tested the hypothesis that potassium leak channels contribute to the anesthetic action of ketamine. METHODS: Adult mouse cortical slices (400 µm) were exposed to no-magnesium artificial cerebrospinal fluid to generate seizure-like event activity...
March 6, 2018: Anesthesiology
Meagan Milton, Patrice D Smith
An acute ischemic stroke is characterized by the presence of a blood clot that limits blood flow to the brain resulting in subsequent neuronal loss. Acute stroke threatens neuronal survival, which relies heavily upon proper function of astrocytes. Neurons are more susceptible to cell death when an astrocyte is unable to carry out its normal functions in supporting the neuron in the area affected by the stroke (Rossi et al., 2007; Takano et al., 2009). For example, under normal conditions, astrocytes initially swell in response to changes in extracellular osmotic pressure and then reduce their regulatory volume in response to volume-activated potassium (K+ ) and chloride channels (Vella et al...
2018: Frontiers in Cellular Neuroscience
C Altamura, G F Mangiatordi, O Nicolotti, D Sahbani, A Farinato, F Leonetti, M R Carratù, D Conte, J-F Desaphy, P Imbrici
BACKGROUND AND PURPOSE: Despite the fact that chloride channels are involved in several physiological processes and acquired diseases, the availability of compounds selectively targeting CLC proteins is rather limited. ClC-1 channels are responsible for sarcolemma repolarization after an action potential in skeletal muscle fibers and have been associated with myotonia congenita and myotonic dystrophy as well as with other muscular physiopathological conditions. To date only a few ClC-1 blockers have been discovered, such as anthracene-9-carboxylic acid (9-AC) and niflumic acid (NFA), whereas no useful activator exists...
March 3, 2018: British Journal of Pharmacology
Prosper N'Gouemo
Voltage-sensitive Ca2+ (CaV ) channels are the primary route of depolarization-induced Ca2+ entry in neurons and other excitable cells, leading to an increase in intracellular Ca2+ concentration ([Ca2+ ]i ). The resulting increase in [Ca2+ ]i activates a wide range of Ca2+ -dependent processes in neurons, including neurotransmitter release, gene transcription, activation of Ca2+ -dependent enzymes, and activation of certain K+ channels and chloride channels. In addition to their key roles under physiological conditions, CaV channels are also an important target of alcohol, and alcohol-induced changes in Ca2+ signaling can disturb neuronal homeostasis, Ca2+ -mediated gene transcription, and the function of neuronal circuits, leading to various neurological and/or neuropsychiatric symptoms and disorders, including alcohol withdrawal induced-seizures and alcoholism...
March 3, 2018: Handbook of Experimental Pharmacology
Yanmei Qi, Norbert Mair, Kai K Kummer, Michael G Leitner, María Camprubí-Robles, Michiel Langeslag, Michaela Kress
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in numerous physiological and pathophysiological processes. We have previously reported a S1P-induced nocifensive response in mice by excitation of sensory neurons via activation of an excitatory chloride current. The underlying molecular mechanism for the S1P-induced chloride conductance remains elusive. In the present study, we identified two CLCN voltage-gated chloride channels, CLCN3 and CLCN5, which mediated a S1P-induced excitatory Cl- current in sensory neurons by combining RNA-seq, adenovirus-based gene silencing and whole-cell electrophysiological voltage-clamp recordings...
2018: Frontiers in Molecular Neuroscience
Christian J Peters, John M Gilchrist, Jason Tien, Neville P Bethel, Lijun Qi, Tingxu Chen, Lynn Wang, Yuh Nung Jan, Michael Grabe, Lily Y Jan
Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating...
February 16, 2018: Neuron
Man-Song Li, Elizabeth A Cowley, Yassine El Hiani, Paul Linsdell
The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that apparently has evolved from an ancestral active transporter. Key to CFTR's switch from pump to channel function may have been the appearance of one or more "lateral portals". Such portals connect the cytoplasm to the transmembrane channel pore, allowing a continuous pathway for the electro-diffusional movement of Cl- ions. However, these portals remain the least well-characterized part of the Cl- transport pathway; even the number of functional portals is uncertain, and if multiple portals do exist, their relative functional contributions are unknown...
February 23, 2018: Journal of Biological Chemistry
Gail Otulakowski, Doreen Engelberts, Martin Post, Claire Masterson, Brian P Kavanagh
BACKGROUND: Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. METHODS: We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group)...
February 23, 2018: Anesthesiology
Jennifer Danielsson, Joy Vink, Shunsuke Hyuga, Xiao Wen Fu, Hiromi Funayama, Ronald Wapner, Andrew M Blanks, George Gallos
BACKGROUND: Spontaneous preterm labor leading to preterm birth is a significant obstetric problem leading to neonatal morbidity and mortality. Current tocolytics are not completely effective and novel targets may afford a therapeutic benefit. OBJECTIVE: To determine whether the anoctamin (ANO) family, including the calcium-activated chloride channel ANO1, is present in pregnant human uterine smooth muscle (USM) and whether pharmacological and genetic modulation of ANO1 modulates USM contraction...
January 1, 2018: Reproductive Sciences
Ethan A Everington, Adina G Gibbard, Jerome D Swinny, Mohsen Seifi
Gamma aminobutyric acid (GABA) subtype A receptors (GABAA Rs) are integral membrane ion channels composed of five individual proteins or subunits. Up to 19 different GABAA R subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π, and ρ1-3) have been identified, resulting in anatomically, physiologically, and pharmacologically distinct multiple receptor subtypes, and therefore GABA-mediated inhibition, across the central nervous system (CNS). Additionally, GABAA R-modulating drugs are important tools in clinical medicine, although their use is limited by adverse effects...
2018: Frontiers in Molecular Neuroscience
Yuan-Yuan Qiang, Chang-Zhi Li, Rui Sun, Li-Sheng Zheng, Li-Xia Peng, Jun-Ping Yang, Dong-Fang Meng, Yan-Hong Lang, Yan Mei, Ping Xie, Liang Xu, Yun Cao, Wen-Wen Wei, Li Cao, Hao Hu, Qin Yang, Dong-Hua Luo, Ying-Ying Liang, Bi-Jun Huang, Chao-Nan Qian
BACKGROUND: CLCA2 was reported as a tumor suppressor and disregulated in breast cancer. However, its function in tumor growth and metastasis in NPC has rarely been reported. In this study, we investigated the functional and molecular mechanisms by which CLCA2 influences NPC. METHODS: CLCA2 expression in human NPC cell lines and tissues was examined via real-time PCR (RT-PCR), Western blot and IHC. The biological roles of CLCA2 in proliferative, migration and invasion of NPC cell lines was evaluated in 5-8F, S18, S26 and SUNE-1 cells...
February 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
Gabrielė Stakaitytė, Nnenna Nwogu, Jonathan D Lippiat, G Eric Blair, Krzysztof Poterlowicz, James R Boyne, Andrew Macdonald, Jamel Mankouri, Adrian Whitehouse
Ion channels regulate many aspects of cell physiology, including cell proliferation, motility, and migration, and aberrant expression and activity of ion channels is associated with various stages of tumor development, with K+ and Cl- channels now being considered the most active during tumorigenesis. Accordingly, emerging in vitro and preclinical studies have revealed that pharmacological manipulation of ion channel activity offers protection against several cancers. Merkel cell polyomavirus (MCPyV) is a major cause of Merkel cell carcinoma (MCC), primarily due to the expression of two early regulatory proteins termed small and large tumour antigens (ST and LT, respectively)...
February 8, 2018: Journal of Biological Chemistry
Kara R Vogel, Garrett R Ainslie, Dana C Walters, Alice McConnell, Sameer C Dhamne, Alexander Rotenberg, Jean-Baptiste Roullet, K Michael Gibson
We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option...
February 19, 2018: Journal of Inherited Metabolic Disease
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