The Role of HCN Channels on Membrane Excitability in the Nervous System

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP2, and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons.

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Isoform-Selective PI3K Inhibitors for Various Diseases

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200106141717 ◽

2020 ◽

Vol 20 (12) ◽

pp. 1074-1092 ◽

Cited By ~ 4

Author(s):

Rammohan R.Y. Bheemanaboina

Keyword(s):

Intracellular Signaling ◽

Kinase Inhibitors ◽

Therapeutic Potential ◽

Type I ◽

Selective Inhibitors ◽

Pi3k Inhibitors ◽

Wide Range ◽

Lipid Kinases ◽

Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

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Structure, Function and Interactions of Tau: Particular Focus on Potential Drug Targets for the Treatment of Tauopathies

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180525112008 ◽

2018 ◽

Vol 17 (5) ◽

pp. 325-337 ◽

Cited By ~ 2

Author(s):

Hojjat Borna ◽

Kasim Assadoulahei ◽

Gholamhossein Riazi ◽

Asghar Beigi Harchegani ◽

Alireza Shahriary

Keyword(s):

Tau Protein ◽

Drug Targets ◽

Brain Injuries ◽

Potential Drug ◽

Microtubule Network ◽

Wide Range ◽

Potential Risk Factors ◽

Range Of Functions ◽

Potential Drug Targets

Background & Objective: Neurodegenrative diseases are among the most widespread lifethreatening disorders around the world in elderly ages. The common feature of a group of neurodegenerative disorders, called tauopathies, is an accumulation of microtubule associated protein tau inside the neurons. The exact mechanism underlying tauopathies is not well-understood but several factors such as traumatic brain injuries and genetics are considered as potential risk factors. Although tau protein is well-known for its key role in stabilizing and organization of axonal microtubule network, it bears a broad range of functions including DNA protection and participation in signaling pathways. Moreover, the flexible unfolded structure of tau facilitates modification of tau by a wide range of intracellular enzymes which in turn broadens tau function and interaction spectrum. The distinctive properties of tau protein concomitant with the crucial role of tau interaction partners in the progression of neurodegeneration suggest tau and its binding partners as potential drug targets for the treatment of neurodegenerative diseases. Conclusion: This review aims to give a detailed description of structure, functions and interactions of tau protein in order to provide insight into potential therapeutic targets for treatment of tauopathies.

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Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

International Journal of Molecular Sciences ◽

10.3390/ijms22052754 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2754

Author(s):

Naila Qayyum ◽

Muhammad Haseeb ◽

Moon Suk Kim ◽

Sangdun Choi

Keyword(s):

Interacting Protein ◽

Thioredoxin Interacting Protein ◽

Signaling Complex ◽

Current Review ◽

Wide Range ◽

Range Of Functions ◽

Species Production ◽

And Oxidative Stress ◽

Significant Attention

Thioredoxin-interacting protein (TXNIP), widely known as thioredoxin-binding protein 2 (TBP2), is a major binding mediator in the thioredoxin (TXN) antioxidant system, which involves a reduction-oxidation (redox) signaling complex and is pivotal for the pathophysiology of some diseases. TXNIP increases reactive oxygen species production and oxidative stress and thereby contributes to apoptosis. Recent studies indicate an evolving role of TXNIP in the pathogenesis of complex diseases such as metabolic disorders, neurological disorders, and inflammatory illnesses. In addition, TXNIP has gained significant attention due to its wide range of functions in energy metabolism, insulin sensitivity, improved insulin secretion, and also in the regulation of glucose and tumor suppressor activities in various cancers. This review aims to highlight the roles of TXNIP in the field of diabetology, neurodegenerative diseases, and inflammation. TXNIP is found to be a promising novel therapeutic target in the current review, not only in the aforementioned diseases but also in prolonged microvascular and macrovascular diseases. Therefore, TXNIP inhibitors hold promise for preventing the growing incidence of complications in relevant diseases.

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Characterization of proteins with Siaα2-3/6Gal-linked glycans from bovine milk and role of their glycans against influenza A virus

Food & Function ◽

10.1039/c8fo00950c ◽

2018 ◽

Vol 9 (10) ◽

pp. 5198-5208 ◽

Cited By ~ 4

Author(s):

Hanjie Yu ◽

Yaogang Zhong ◽

Zhiwei Zhang ◽

Xiawei Liu ◽

Kun Zhang ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Bovine Milk ◽

Milk Proteins ◽

Biological Functions ◽

Wide Range ◽

Range Of Functions ◽

Bovine Milk Proteins

The bovine milk proteins have a wide range of functions, but the role of the attached glycans in their biological functions has not been fully understood yet.

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Decreased Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 Activity in a Rat Model of Absence Epilepsy and the Effect of ZD7288, an Ih Inhibitor, on the Spike-and-Wave Discharges

Pharmacology ◽

10.1159/000520059 ◽

2022 ◽

pp. 1-8

Author(s):

Melis Yavuz ◽

Banu Aydın ◽

Nihan Çarçak ◽

Filiz Onat

Keyword(s):

Rat Model ◽

Cyclic Nucleotide ◽

Total Duration ◽

Absence Epilepsy ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Hcn Channels ◽

Hcn Channel ◽

Gated Channel ◽

Channel Currents

Introduction: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents of Ih and absence epilepsy seizures are associated, but studies reveal differential results. Objective: In our study, we aimed to investigate the role of the HCN channels on the expression of spike-and-wave discharges (SWDs) using the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model. Methods: HCN isoform levels from isolated brains of both naïve nonepileptic Wistar and GAERS groups were evaluated by enzyme-linked immunosorbent assay. ZD7288, an Ih inhibitor as well as an HCN channel antagonist, was administered intracerebroventricularly to the adult GAERS groups, and to evaluate their SWD activities, electroencephalography was recorded. The effect of ZD7288 on the cumulative total duration and number of SWDs and the mean duration of each SWD complex was evaluated. Results: The HCN2 levels in the cortex and hippocampus of the GAERS group were lower compared to the naïve nonepileptic Wistar group (p < 0.05). ZD7288 increased the number of SWDs at the 20th and 120th min with the highest administered dose of 7 μg (p < 0.05). Conclusion: The Ih inhibitor ZD7288 increased the number of SWDs in a genetic absence epilepsy rat model, although this increase may not be significant due to the inconsistent time-dependent effects. In GAERS, the cortical and hippocampal HCN2 channel levels were significantly lower compared to the control group. Further studies are needed with higher doses of ZD7288 to determine if the effects will increase drastically.

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IMPORTANT ROLE OF TRACE ELEMENTS (MG AND ZN) IN THE SERUM OF PATIENTS SUFFERING FROM NON-ALCOHOLIC LIVER DISEASE AND COMPARE THEIR LEVEL WITH HEALTHY SUBJECTS OF RAJASTHAN

10.36106/ijsr/6928037 ◽

2021 ◽

pp. 29-31

Author(s):

halini Vyas ◽

RK Vyas ◽

Hemlata Sharma

Keyword(s):

Trace Elements ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Healthy Subjects ◽

Control Group ◽

P Value ◽

Wide Range ◽

Range Of Functions ◽

Serum Trace Elements

Liver is the largest major organ of our body. liver having a wide range of functions so, it is prone to many diseases which are very commonly seen in India. Any disturbance of liver function that causes illness is called liver disease. It is also known as hepatic disease. It is major leading cause of morbidity and mortality worldwide. Aim of this study was to nd out the role of Trace Elements (Mg & Zn) levels in diagnosis of Non-alcoholic liver disease. Material and methods: 200 subjects were selected out of them 100 were selected as study group (Non-alcoholic (NALD) and 100 were selected as control group and distributed according to their age and sex. Trace elements were estimated by Atomic adsorption spectrophotometer (AAS). Result: the serum trace elements level was decreased in non-alcoholic liver disease patients. P-value was found to be signicant when compared with healthy subjects. (P≤0.001). Conclusion: We came to the conclusion that serum level trace elements (Mg, Zn) activity looks specic and can be used for prognostic evolution of non-alcoholic liver disease.

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INTERNAL AUDIT - EFFECTIVE INSTUMENTY OF CORPORATE GOVERNANCE SYSTEM

Vestnik of Kazan state agrarin university ◽

10.12737/20645 ◽

2016 ◽

Vol 11 (2) ◽

pp. 95-99 ◽

Cited By ~ 1

Author(s):

Закирова ◽

Alsu Zakirova ◽

Клычова ◽

Augul Klychova ◽

Клычова ◽

...

Keyword(s):

Internal Control ◽

Internal Audit ◽

Governance System ◽

Internal Audit Function ◽

Wide Range ◽

Corporate Governance System ◽

Internal Control System ◽

Range Of Functions ◽

Domestic Companies

Today the debatable problem is the effectiveness of internal control system. That internal audit, as a part of interfarm monitoring systems, has a wide range of functions, that go beyond the range of issues, relating to internal control. In Russia, there are no laws and regulations, governing the internal audit organization. The absence of a rigid framework is a prerequisite for creating the most effective internal audit service. The establishment an internal audit function is also becoming increasingly necessary because of competition and integration of foreign and domestic companies. This article provides an irreplaceable role of internal audit in terms of its objectives and functions.

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Role of the Nrf2-ARE Pathway in Liver Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/763257 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 83

Author(s):

Sang Mi Shin ◽

Ji Hye Yang ◽

Sung Hwan Ki

Keyword(s):

Liver Diseases ◽

Target Genes ◽

Antioxidant Response ◽

Related Factor ◽

Genes Expression ◽

Wide Range ◽

Range Of Functions ◽

Central Organ ◽

Essential Transcription Factor

The liver is a central organ that performs a wide range of functions such as detoxification and metabolic homeostasis. Since it is a metabolically active organ, liver is particularly susceptible to oxidative stress. It is well documented that liver diseases including hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are highly associated with antioxidant capacity. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. It is activated in response to electrophiles and induces its target genes by binding to the antioxidant response element (ARE). Therefore, the roles of the Nrf2-ARE pathway in liver diseases have been extensively investigated. Studies from several animal models suggest that the Nrf2-ARE pathway collectively exhibits diverse biological functions against viral hepatitis, alcoholic and nonalcoholic liver disease, fibrosis, and cancer via target gene expression. In this review, we will discuss the role of the Nrf2-ARE pathway in liver pathophysiology and the potential application of Nrf2 as a therapeutic target to prevent and treat liver diseases.

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The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽

10.3390/cancers13164000 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4000

Author(s):

Esra’a Keewan ◽

Ksenia Matlawska-Wasowska

Keyword(s):

Intracellular Signaling ◽

Cell Communication ◽

Janus Kinase ◽

Signaling Cascades ◽

Cytokine Signaling ◽

Surface Receptors ◽

Wide Range ◽

Stat Signaling ◽

Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

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Distinct Populations of HCN Pacemaker Channels Produce Voltage-dependent and Voltage-independent Currents

The Journal of General Physiology ◽

10.1085/jgp.200509389 ◽

2006 ◽

Vol 127 (2) ◽

pp. 183-190 ◽

Cited By ~ 36

Author(s):

Catherine Proenza ◽

Gary Yellen

Keyword(s):

Channel Blocker ◽

Hcn Channels ◽

Hcn Channel ◽

Single Application ◽

Distinct Population ◽

Open Probability ◽

Pacemaker Channels ◽

Conduction Pathway ◽

Voltage Dependent

Hyperpolarization-activated HCN pacemaker channels are critical for the generation of spontaneous activity and the regulation of excitability in the heart and in many types of neurons. These channels produce both a voltage-dependent current (Ih) and a voltage-independent current (Iinst or VIC). In this study, we explored the molecular basis of the voltage-independent current. We found that for the spHCN isoform, VIC averaged ∼4% of the maximum HCN conductance that could be activated by hyperpolarization. Cyclic AMP increased the voltage-independent current in spHCN to ∼8% of maximum. In HCN2, VIC was ∼2% of the maximal current, and was little affected by cAMP. VIC in both spHCN and HCN2 was blocked rapidly both by ZD7288 (an HCN channel blocker that is thought to bind in the conduction pore) and by application of Cd2+ to channels containing an introduced cysteine in the pore (spHCN-464C or HCN2-436C). These results suggest that VIC flows through the main conduction pathway, down the central axis of the protein. We suspected that VIC simply represented a nonzero limiting open probability for HCN channels at positive voltages. Surprisingly, we found instead that the spHCN channels carrying VIC were not in rapid equilibrium with the channels carrying the voltage-dependent current, because they could be blocked independently; a single application of blocker at a depolarized potential essentially eliminated VIC with little change in Ih. Thus, VIC appears to be produced by a distinct population of HCN channels. This voltage-independent current could contribute significantly to the role of HCN channels in neurons and myocytes; VIC flowing through the channels at physiological potentials would tend to promote excitability by accelerating both depolarization and repolarization.

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