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Cheng Fan, Rui Long, Ya You, Jue Wang, Xiaofang Yang, Shiyuan Huang, Yuling Sheng, Xu Peng, Hui Liu, Zhaohui Wang, Kun Liu
Previous studies have confirmed that selective blockade of Kv1.3 channels could modulate the activities of pathogenic T cells and microglia/macrophages, which play key roles in experimental autoimmune encephalomyelitis (EAE). In this study, we designed an anti-Kv1.3 vaccine (PADRE-Kv1.3) to explore its protective role in EAE rat models. When the vaccine was applied in EAE rats, clinical scores and several staining techniques were used to evaluate the severity of the disease. T cell subtypes and related cytokines, as well as microglia/macrophage activation were assayed through flow cytometry, qRT-PCR or immunofluorescence staining, respectively...
February 26, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Janna Bednenko, Rian Harriman, Lore Mariën, Hai M Nguyen, Alka Agrawal, Ashot Papoyan, Yelena Bisharyan, Joanna Cardarelli, Donna Cassidy-Hanley, Ted Clark, Darlene Pedersen, Yasmina Abdiche, William Harriman, Bas van der Woning, Hans de Haard, Ellen Collarini, Heike Wulff, Paul Colussi
Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein...
March 1, 2018: MAbs
Yi-Je Chen, Hai M Nguyen, Izumi Maezawa, Lee-Way Jin, Heike Wulff
Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1...
February 2018: Annals of Clinical and Translational Neurology
Mohammad H Baig, Khurshid Ahmad, Gulam Rabbani, Inho Choi
Alzheimer's disease (AD) is a form of dementia and the most common progressive neurodegenerative disease (ND). The targeting of amyloid-beta (Aβ) aggregation is one of the most widely used strategies to manage AD, and efforts are being made globally to develop peptide-based compounds for the early diagnosis and treatment of AD. Here, we briefly discuss the use of peptide-based compounds for the early diagnosis and treatment of AD and the use of peptide-based inhibitors targeting various Aβ aggregation checkpoints...
2018: Frontiers in Aging Neuroscience
Dorra Aissaoui, Saoussen Mlayah-Bellalouna, Jed Jebali, Zaineb Abdelkafi-Koubaa, Soumaya Souid, Wassim Moslah, Houcemeddine Othman, José Luis, Mohamed ElAyeb, Naziha Marrakchi, Khadija Essafi-Benkhadir, Najet Srairi-Abid
Voltage-gated potassium (Kv) channels are known to play a pivotal role in the progression of various cancer types and considered as new targets for designing anti-cancer therapy. However, the fact that many Kv channels are expressed in different cell lines makes it difficult to ascribe a functional role for a given Kv channel on a specific aspect of the tumorogenesis. In this work, we showed that although both Kv1.1 and Kv1.3 channels are expressed in U87 (glioblastoma), MDA-MB-231 (breast cancer) and LS174 (colon adenocarcinoma) cells, these respond differently to KAaH1 or KAaH2, two homologous Kv1 blockers from scorpion venom...
February 2, 2018: International Journal of Biological Macromolecules
Hui Li, Jun-Ling Zhao, Yuan-Ming Zhang, Su-Xia Han
BACKGROUND AND AIM: Increasing evidence confirms that potassium channels are essential for lymphocyte activation, suggesting an involvement in the development of hypertension. Moreover, chronic inflammation is regarded as a direct or indirect manifestation of hypertension, highlighting the theoretical mechanisms. In this study, we investigated changes in KCa3.1 potassium channel expression in the blood of hypertensive and healthy Kazakh people in north-west China. METHODS: Flow cytometry technology was used for T-lymphocyte subtype analysis...
February 1, 2018: Clinical and Experimental Hypertension: CHE
Heather Wood
No abstract text is available yet for this article.
January 29, 2018: Nature Reviews. Neurology
Sandra Cortes, Caroline Barette, Rémy Beroud, Michel De Waard, Béatrice Schaack
Using a cell-free expression system, we produced the Kv1.3 protein embedded in one step within detergent micelles. The protein was then purified and relipidated into mixed lipid bilayers. These proteoliposomes held an average of 0.8 protein per liposome. We examined channel forming activity using an oxonol VI fluorescent probe and verified its inhibition using margatoxin and ShK toxins. This assay was automatized and optimized so as to get a Z' statistical factor acceptable for venom fraction screening. We obtained a sensible amount of membrane protein using the cell-free assay, that proved to be active when embedded in liposomes...
January 20, 2018: Protein Expression and Purification
Tania Chernov-Rogan, Tianbo Li, Gang Lu, Henry Verschoof, Kuldip Khakh, Steven W Jones, Maureen H Beresini, Chang Liu, Daniel F Ortwine, Steven J McKerrall, David H Hackos, Daniel Sutherlin, Charles J Cohen, Jun Chen
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lei Huang, Kuo-Ho Wu, Liyong Zhang, Qinchuan Wang, Shuangbo Tang, Qiuping Wu, Pei-Hsiu Jiang, Jim Jung-Ching Lin, Jian Guo, Lin Wang, Shih-Hurng Loh, Jianding Cheng
BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization...
January 6, 2018: Journal of the American Heart Association
Antonio Serrano-Albarrás, Irene Estadella, Sergi Cirera-Rocosa, María Navarro-Pérez, Antonio Felipe
No abstract text is available yet for this article.
December 20, 2017: Expert Opinion on Therapeutic Targets
Jennifer Leigh Rodgers, Eva Samal, Subhra Mohapatra, Siva Kumar Panguluri
Hyperoxia, or supplemental oxygen, is regularly used in the clinical setting for critically ill patients in ICU. However, several recent studies have demonstrated the negative impact of this treatment in patients in critical care, including increased rates of lung and cardiac injury, as well as increased mortality. The purpose of this study was to determine the predisposition for arrhythmias and electrical remodeling in a type 2 diabetic mouse model (db/db), as a result of hyperoxia treatment. For this, db/db and their heterozygous controls were treated with hyperoxia (> 90% oxygen) or normoxia (normal air) for 72-h...
December 5, 2017: Heart and Vessels
R Zhang, L Xia, J Chen, Y Gong, L Zhang, P Li, H Liu, Z Xie, S Jiang
 The infections with duck hepatitis A virus type 3 (DHAV-3) become common in eastern Asia. To better understand the molecular evolution and genetic variation of DHAV-3, a total of 482 dead Cherry Valley duckling liver samples collected from Shandong province of China during 2012-2014 were tested, and the complete P1 coding sequences of 18 DHAV-3 strains were analyzed. The detection rate of DHAV-3 was 64.5% (311/482) in clinical liver samples and 73.0% (92/126) in duckling flocks. The P1 genes of the 18 DHAV-3 isolates shared 91...
2017: Acta Virologica
Vipin Sharma, Sooraj V Nair, Pooja Jaitley, Udayraj P Nakade, Abhishek Sharma, Soumen Choudhury, Satish Kumar Garg
Cellular coupling of beta3 -adrenoceptors (β3 -ADR) to potassium channels in myometrium is largely unknown. In vitro study was undertaken to unravel the presence of β3 -adrenergic receptors (ADR) and the role of K+ -channels in mediating β3 -ADR-induced relaxation in isolated myometrial strips from cyclic non-pregnant water buffaloes. Isometric tension was recorded in isolated myometrial strips using data acquisition system based physiograph. Compared to SR 59230A, BRL 37344 was found to be more potent in inducing β3 -dependent myometrial relaxation which was significantly (p < 0...
February 2018: Theriogenology
Martin Nybo Andersen, Lasse Skibsbye, Arnela Saljic, Martin Zahle Larsen, Hanne Borger Rasmussen, Thomas Jespersen
Over the last years extensive kinase-mediated regulation of a number of voltage-gated potassium (Kv) channels important in cardiac electrophysiology has been reported. This includes regulation of Kv1.5, Kv7.1 and Kv11.1 cell surface expression, where the kinase-mediated regulation appears to center around the ubiquitin ligase Nedd4-2. In the present study we examined whether Kv1.4, constituting the cardiac Ito,s current, is subject to similar regulation. In the epithelial Madin-Darby Canine Kidney (MDCK) cell line, which constitutes a highly reproducible model system for addressing membrane targeting, we find, by confocal microscopy, that Kv1...
November 23, 2017: Channels
Yan Zou, Feng Zhang, Yaxian Li, Yuanfang Wang, Yi Li, Zhengtao Long, Shujuan Shi, Li Shuai, Jiukai Liu, Zhiyong Di, Shijin Yin
Background: Specific and selective peptidic blockers of Kv1.3 channels can serve as a valuable drug lead for treating T cell-mediated autoimmune diseases, and scorpion venom is an important source of kv1.3 channel inhibitors. Through conducting transcriptomic sequencing for the venom gland of Scorpiops pococki from Xizang province of China, this research aims to discover a novel functional gene encoding peptidic blocker of Kv1.3, and identify its function. Results: We screened out a new peptide toxin KTX-Sp4 which had 43 amino acids including six cysteine residues...
2017: Cell & Bioscience
Z Vysotskaya, B Chidipi, J L Rodgers, X Tang, E Samal, N Kolliputi, S Mohapatra, E S Bennett, S K Panguluri
Supplementation of 100% oxygen is a very common intervention in intensive care units (ICU) and critical care centers for patients with dysfunctional lung and lung disorders. Although there is advantage in delivering sufficient levels of oxygen, hyperoxia is reported to be directly associated with increasing in-hospital deaths. Our previous studies reported ventricular and electrical remodeling in hyperoxia treated mouse hearts, and in this article, for the first time, we are investigating the effects of hyperoxia on atrial electrophysiology using whole-cell patch-clamp electrophysiology experiments along with assessment of Kv1...
November 15, 2017: Journal of Cellular Physiology
Ann-Kathrin Diesch, Stephan Grissmer
BACKGROUND/AIMS: The human-voltage gated Kv1.3 channel (hKv1.3) is expressed in T- and B lymphocytes. Verapamil is able to block hKv1.3 channels. We characterized the effect of verapamil on currents through hKv1.3 channels paying special attention to the on-rate (kon) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. METHODS: Using the whole-cell patch clamp technique the action of verapamil on currents through wild-type and six hKv1...
November 6, 2017: Cellular Physiology and Biochemistry
Roberta Peruzzo, Andrea Mattarei, Matteo Romio, Cristina Paradisi, Mario Zoratti, Ildikò Szabò, Luigi Leanza
Previous results link the mitochondrial potassium channel Kv1.3 (mitoKv1.3) to the regulation of apoptosis. By synthesizing new, mitochondria-targeted derivatives (PAPTP and PCARBTP) of PAP-1, a specific membrane-permeant Kv1.3 inhibitor, we have recently provided evidence that both drugs acting on mitoKv1.3 are able to induce apoptosis and reduce tumor growth in vivo without affecting healthy tissues and cells. In the present article, by exploiting these new drugs, we addressed the question whether mitoKv1...
2017: Frontiers in Oncology
Judith Land, Lucas L Lintermans, Coen A Stegeman, Ernesto J Muñoz-Elías, Eric J Tarcha, Shawn P Iadonato, Peter Heeringa, Abraham Rutgers, Wayel H Abdulahad
B cells are central to the pathogenesis of granulomatosis with polyangiitis (GPA), exhibiting both (auto)antibody-dependent and -independent properties. Class-switched memory B cells in particular are a major source of pathogenic autoantibodies. These cells are characterized by high expression levels of Kv1.3 potassium channels, which may offer therapeutic potential for Kv1.3 blockade. In this study, we investigated the effect of the highly potent Kv1.3 blocker ShK-186 on B cell properties in GPA in vitro. Circulating B cell subsets were determined from 33 GPA patients and 17 healthy controls (HCs)...
2017: Frontiers in Immunology
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