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https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#1
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29780305/comparing-effects-of-transforming-growth-factor-%C3%AE-1-on-microglia-from-rat-and-mouse-transcriptional-profiles-and-potassium-channels
#2
Starlee Lively, Doris Lam, Raymond Wong, Lyanne C Schlichter
The cytokine, transforming growth factor β1 (TGFβ1), is up-regulated after central nervous system (CNS) injuries or diseases involving microglial activation, and it has been proposed as a therapeutic agent for treating neuroinflammation. Microglia can produce and respond to TGFβ1. While rats and mice are commonly used for studying neuroinflammation, very few reports directly compare them. Such studies are important for improving pre-clinical studies and furthering translational progress in developing therapeutic interventions...
2018: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/29773183/cytosolic-increased-labile-zn-2-contributes-to-arrhythmogenic-action-potentials-in-left-ventricular-cardiomyocytes-through-protein-thiol-oxidation-and-cellular-atp-depletion
#3
Sinan Degirmenci, Yusuf Olgar, Aysegul Durak, Erkan Tuncay, Belma Turan
Intracellular labile (free) Zn2+ -level ([Zn2+ ]i ) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn2+ ]i is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn2+ ]i on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn2+ ]i induced significant changes in action potential (AP) parameters, including depolarization in resting membrane-potential and prolongations in AP-repolarizing phases...
July 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29769580/kv1-3-activity-perturbs-the-homeostatic-properties-of-astrocytes-in-glioma
#4
Alfonso Grimaldi, Giuseppina D'Alessandro, Maria Amalia Di Castro, Clotilde Lauro, Vikrant Singh, Francesca Pagani, Luigi Sforna, Francesca Grassi, Silvia Di Angelantonio, Luigi Catacuzzeno, Heike Wulff, Cristina Limatola, Myriam Catalano
Glial cells actively maintain the homeostasis of brain parenchyma, regulating neuronal excitability and preserving the physiological composition of the extracellular milieu. Under pathological conditions, some functions of glial cells could be compromised, exacerbating the neurotoxic processes. We investigated if the homeostatic activities of astrocytes and microglia could be modulated by the voltage-gated K+ channel Kv1.3. To this end we used in vitro and in vivo systems to model cell-to-cell interactions in tumoral conditions, using a specific inhibitor of Kv1...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29760657/purkinje-cell-signaling-deficits-in-animal-models-of-ataxia
#5
REVIEW
Eriola Hoxha, Ilaria Balbo, Maria Concetta Miniaci, Filippo Tempia
Purkinje cell (PC) dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction...
2018: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/29740538/novel-mitochondria-targeted-furocoumarin-derivatives-as-possible-anti-cancer-agents
#6
Andrea Mattarei, Matteo Romio, Antonella Managò, Mario Zoratti, Cristina Paradisi, Ildikò Szabò, Luigi Leanza, Lucia Biasutto
Targeting small molecules to appropriate subcellular compartments is a way to increase their selectivity and effectiveness while minimizing side effects. This can be accomplished either by stably incorporating specific "homing" properties into the structure of the active principle, or by attaching to it a targeting moiety via a labile linker, i.e., by producing a "targeting pro-drug." Mitochondria are a recognized therapeutic target in oncology, and blocking the population of the potassium channel Kv1...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29678876/rapid-disinhibition-by-adjustment-of-pv-intrinsic-excitability-during-whisker-map-plasticity-in-mouse-s1
#7
Melanie A Gainey, Joseph W Aman, Daniel E Feldman
Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 day whisker deprivation drives rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing E-I conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, associated with an increase in low-threshold, voltage activated delayed rectifier (presumed Kv1) and A-type potassium currents...
April 20, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29652491/inhibition-of-voltage-gated-k-channel-kv1-5-by-anti-arrhythmic-drugs
#8
Rong Chen, Shin-Ho Chung
Molecular dynamics simulations are employed to determine the inhibitory mechanisms of three drugs, 5-(4- phenoxybutoxy)psoralen (PAP-1), vernakalant and flecainide, on the voltage-gated K+ channel Kv1.5, a target for the treatment of cardiac arrhythmia. At neutral pH, PAP-1 is neutral, whereas the other two molecules carry one positive charge. We show that PAP-1 forms stable dimers in water, primarily through the hydrophobic interactions between aromatic rings. All three molecules bind to the cavity between the Ile508 and Val512 residues from the four subunits of the channel...
April 13, 2018: Biochemistry
https://www.readbyqxmd.com/read/29650988/the-c-terminal-hret-sequence-of-kv1-3-regulates-gating-rather-than-targeting-of-kv1-3-to-the-plasma-membrane
#9
Orsolya Voros, Orsolya Szilagyi, András Balajthy, Sándor Somodi, Gyorgy Panyi, Péter Hajdu
Kv1.3 channels are expressed in several cell types including immune cells, such as T lymphocytes. The targeting of Kv1.3 to the plasma membrane is essential for T cell clonal expansion and assumed to be guided by the C-terminus of the channel. Using two point mutants of Kv1.3 with remarkably different features compared to the wild-type Kv1.3 (A413V and H399K having fast inactivation kinetics and tetraethylammonium-insensitivity, respectively) we showed that both Kv1.3 channel variants target to the membrane when the C-terminus was truncated right after the conserved HRET sequence and produce currents identical to those with a full-length C-terminus...
April 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29615878/elevated-anxiety-and-impaired-attention-in-super-smeller-kv1-3-knockout-mice
#10
Zhenbo Huang, Carlie A Hoffman, Brandon M Chelette, Nicolas Thiebaud, Debra A Fadool
It has long been recognized that olfaction and emotion are linked. While chemosensory research using both human and rodent models have indicated a change in emotion can contribute to olfactory dysfunction, there are few studies addressing the contribution of olfaction to a modulation in emotion. In mice, olfactory deficits have been linked with heightened anxiety levels, suggesting that there could be an inverse relationship between olfaction and anxiety. Furthermore, increased anxiety is often co-morbid with psychiatric conditions such as attention disorders...
2018: Frontiers in Behavioral Neuroscience
https://www.readbyqxmd.com/read/29608997/the-beneficial-effects-of-electroacupuncture-at-pc6-acupoints-neiguan-on-myocardial-ischemia-in-asic3-mice
#11
Ying-Wang, Wan-Shuang Zhao, Di Li, Ya-Han Xu, Meng-di Li, Jin Chen, Zhi-Jun Kou, Qi-Ge Wang, Yi-Guo Chen, Nsoa Dimitri Joseph
This study aims to investigate the possible mechanisms of electroacupuncture (EA) at PC6 to improve myocardial ischemia (MI) by regulating the cardiac transient outward potassium current channel (Ito). According to the random number table, the mice were divided into 6 groups of 6 mice each: control group, MI group, PC6, LU7 (Lieque-point), ST36 (Zusanli-point), and nonacupoint group. Mice in the control group were injected with saline (20mg/kg, 24 hours interval), and the other ASIC3 -/- mice were injected subcutaneously twice with isoproterenol (ISO) (20mg/kg, 24 hours interval)...
March 30, 2018: Journal of Acupuncture and Meridian Studies
https://www.readbyqxmd.com/read/29599640/the-effects-of-4-hydroxybenzoic-acid-identified-from-bamboo-dendrocalamus-asper-shoots-on-kv1-4-channel
#12
Jingli Zhang, Fatin H Mohamad, Jia Hui Wong, Habsah Mohamad, Abdul Hadi Ismail, Abdul Aziz Mohamed Yusoff, Hasnah Osman, Kok Tong Wong, Zamzuri Idris, Jafri Malin Abdullah
Background: Bamboo shoot has been used as a treatment for epilepsy in traditional Chinese medicine for generations to treat neuronal disorders such as convulsive, dizziness and headaches. 4-hydroxybenzoic acid (4-hba) is a non-flavonoid phenol found abundantly in Dendrocalamus asper shoots (bamboo), fruits (strawberries and apples) and flowers. Kv1.4 is a rapidly inactivating Shaker -related member of the voltage-gated potassium channels with two inactivation mechanisms; the fast N-type and slow C-type...
February 2018: Malaysian Journal of Medical Sciences: MJMS
https://www.readbyqxmd.com/read/29577640/a-kv1-3-channel-specific-blocker-alleviates-neurological-impairment-through-inhibiting-t-cell-activation-in-experimental-autoimmune-encephalomyelitis
#13
Xiao-Lu Yuan, Yi-Peng Zhao, Jie Huang, Jun-Chen Liu, Wen-Qian Mao, Jun Yin, Bi-Wen Peng, Wan-Hong Liu, Song Han, Xiao-Hua He
AIM: Multiple sclerosis (MS) is a neurological autoimmune disorder characterized by mistaken attacks of inflammatory cells against the central nervous system (CNS), resulting in demyelination and axonal damage. Kv1.3 channel blockers can inhibit T-cell activation and have been designed for MS therapy. However, little is known about the effects of Kv1.3 blockers on protecting myelin sheaths/axons in MS. This study aimed at investigating the neuroprotection efficacy of a selective Kv1.3 channel blocker ImKTx88 (ImK) in MS animal model...
March 25, 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29574670/voltage-gated-potassium-channel-kv1-3-is-upregulated-on-activated-astrocytes-in-experimental-autoimmune-encephalomyelitis
#14
Iva Bozic, Katarina Tesovic, Danijela Laketa, Marija Adzic, Marija Jakovljevic, Ivana Bjelobaba, Danijela Savic, Nadezda Nedeljkovic, Sanja Pekovic, Irena Lavrnja
Kv1.3 is a voltage gated potassium channel that has been implicated in pathophysiology of multiple sclerosis (MS). In the present study we investigated temporal and cellular expression pattern of this channel in the lumbar part of spinal cords of animals with experimental autoimmune encephalomyelitis (EAE), animal model of MS. EAE was actively induced in female Dark Agouti rats. Expression of Kv1.3 was analyzed at different time points of disease progression, at the onset, peak and end of EAE. We here show that Kv1...
March 24, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29496642/a-novel-padre-kv1-3-vaccine-effectively-induces-therapeutic-antibodies-and-ameliorates-experimental-autoimmune-encephalomyelitis-in-rats
#15
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 27, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29494279/a-multiplatform-strategy-for-the-discovery-of-conventional-monoclonal-antibodies-that-inhibit-the-voltage-gated-potassium-channel-kv1-3
#16
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
https://www.readbyqxmd.com/read/29468176/inhibition-of-the-potassium-channel-kv1-3-reduces-infarction-and-inflammation-in-ischemic-stroke
#17
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
https://www.readbyqxmd.com/read/29467644/use-of-peptides-for-the-management-of-alzheimer-s-disease-diagnosis-and-inhibition
#18
REVIEW
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
https://www.readbyqxmd.com/read/29415410/functional-role-of-kv1-1-and-kv1-3-channels-in-the-neoplastic-progression-steps-of-three-cancer-cell-lines-elucidated-by-scorpion-peptides
#19
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...
May 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29388859/inhibitory-effects-of-candesartan-on-kca3-1-potassium-channel-expression-and-cell-culture-and-proliferation-in-peripheral-blood-cd4-t-lymphocytes-in-kazakh-patients-with-hypertension-from-the-xinjiang-region
#20
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...
2018: Clinical and Experimental Hypertension: CHE
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