scholarly journals Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

2014 ◽  
Vol 222 (1) ◽  
pp. R11-R24 ◽  
Author(s):  
Syed Jalal Khundmiri
Keyword(s):  
Heart Failure ◽  
Intracellular Signaling ◽  
Cardiac Contractility ◽  
Myocardial Cell ◽  
Renal Tubules ◽  
Intracellular Signaling Pathway ◽  
Body Sodium ◽  
Membrane Bound ◽  
Total Body

Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na+/K+ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na+/K+ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na+/K+ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na+/K+ATPase activity, cell signaling, and blood pressure regulation.

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

2017 ◽  
Vol 63 (4) ◽  
pp. 545-556
Author(s):  
Natalya Oskina ◽  
Aleksandr Shcherbakov ◽  
Maksim Filipenko ◽  
Nikolay Kushlinskiy ◽  
L. Ovchinnikova
Keyword(s):  
Genetic Disease ◽  
Intracellular Signaling ◽  
Somatic Mutations ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Phosphatidylinositol 3 Kinase ◽  
Intracellular Signaling Pathway ◽  
Metabolic Activities ◽  
Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

Microglia in cerebral ischemia: molecular actions and interactionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Aaron Y. Lai ◽  
Kathryn G. Todd
Keyword(s):  
Cerebral Ischemia ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Extracellular Signals ◽  
Messenger Molecules ◽  
Membrane Bound ◽  
The Subject ◽  
Survey Review ◽  
Selection Of

The precise role of microglia in stroke and cerebral ischemia has been the subject of debate for a number of years. Microglia are capable of synthesizing numerous soluble and membrane-bound biomolecules, some known to be neuroprotective, some neurotoxic, whereas others have less definitive bioactivities. The molecular mechanisms through which microglia activate these molecules have thus become an important area of ischemia research. Here we provide a survey review that summarizes the key actions of microglial factors in cerebral ischemia including complement proteins, chemokines, pro-inflammatory cytokines, neurotrophic factors, hormones, and proteinases, as well several important messenger molecules that play a part in how these factors respond to extracellular signals during ischemic injuries. We also provide some new perspectives on how microglial intracellular signaling may contribute to the seemingly contradictory roles of several microglial effector molecules.

Novel Non-Pharmaceutical Advancements in Heart Failure Management: The Emerging Role of Technology

2021 ◽  
Vol 17 ◽  
Author(s):  
Mark T. Nolan ◽  
Neville Tan ◽  
Christopher J. Neil
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Baroreflex Activation Therapy ◽  
Public Health Burden ◽  
Heart Failure Care ◽  
Cardiac Devices ◽  
Randomized Controlled Studies ◽  
Technological Advances ◽  
Activation Therapy

Purpose of Review: To summarise and discuss the implications of recent technological advances in heart failure care. Recent Findings: Heart failure remains a significant source of morbidity and mortality in the US population despite multiple classes of approved pharmacological treatments. Novel cardiac devices and technologies may offer an opportunity to improve outcomes. Baroreflex Activation Therapy and Cardiac Contractility Remodelling may improve myocardial contractility by altering neurohormonal stimulation of the heart. Implantable Pulmonary Artery Monitors and Biatrial Shunts may prevent heart failure admissions by altering the trajectory of progressive congestion. Phrenic Nerve Stimulation offers potentially effective treatment for comorbid conditions. Smartphone applications offer an intriguing strategy for improving medication adherence. Summary: Novel heart failure technologies offer promise for reducing this public health burden. Randomized controlled studies are indicated for assessing the future role of these novel therapies.

scholarly journals Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 38 ◽  
Author(s):  
Nicolas Ricard ◽  
Jiasheng Zhang ◽  
Zhen W. Zhuang ◽  
Michael Simons
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Clinical Importance ◽  
Macrophage Infiltration ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Ischemic Event ◽  
Intracellular Signaling Pathway ◽  
First Time

Despite the clinical importance of arteriogenesis, this biological process is poorly understood. ERK1 and ERK2 are key components of a major intracellular signaling pathway activated by vascular endothelial growth (VEGF) and FGF2, growth factors critical to arteriogenesis. To investigate the specific role of each ERK isoform in arteriogenesis, we used mice with a global Erk1 knockout as well as Erk1 and Erk2 floxed mice to delete Erk1 or Erk2 in endothelial cells, macrophages, and smooth muscle cells. We found that ERK1 controls macrophage infiltration following an ischemic event. Loss of ERK1 in endothelial cells and macrophages induced an excessive macrophage infiltration leading to an increased but poorly functional arteriogenesis. Loss of ERK2 in endothelial cells leads to a decreased arteriogenesis due to decreased endothelial cell proliferation and a reduced eNOS expression. These findings show for the first time that isoform-specific roles of ERK1 and ERK2 in the control of arteriogenesis.

scholarly journals Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 353
Author(s):  
Elena Tibaldi ◽  
Enrica Federti ◽  
Alessandro Matte ◽  
Iana Iatcenko ◽  
Anand B. Wilson ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Conformational Changes ◽  
Intracellular Signaling ◽  
Signal Transduction Pathways ◽  
Functional Connection ◽  
Intracellular Signaling Pathway ◽  
Hematological Disorders ◽  
Dynamic Coordination ◽  
Transduction Mechanisms

The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders.

Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1740-1742 ◽  
Author(s):  
Ingrid Pollet ◽  
Christy J. Opina ◽  
Carla Zimmerman ◽  
Kevin G. Leong ◽  
Fred Wong ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Bacterial Lipopolysaccharide ◽  
Intracellular Signaling Pathway ◽  
Necrosis Factor

AbstractThe intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor κB (NF-κB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-κB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)–induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.

Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure

2012 ◽  
Vol 44 (2) ◽  
pp. 162-172 ◽  
Author(s):  
Ida G. Lunde ◽  
Jan Magnus Aronsen ◽  
Heidi Kvaløy ◽  
Eirik Qvigstad ◽  
Ivar Sjaastad ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Novel Concept

Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively ( P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20–100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure.

scholarly journals How Can Malnutrition Affect Autophagy in Chronic Heart Failure? Focus and Perspectives

2021 ◽  
Vol 22 (7) ◽  
pp. 3332
Author(s):  
Giovanni Corsetti ◽  
Evasio Pasini ◽  
Claudia Romano ◽  
Carol Chen-Scarabelli ◽  
Tiziano M. Scarabelli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Myocardial Cell ◽  
The Body ◽  
Patient Death ◽  
Body Protein ◽  
Pathophysiological Role ◽  
Protein Components ◽  
Constituent Elements

Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.

scholarly journals Evolving Cardiac Electrical Therapies for Advanced Heart Failure Patients

2021 ◽  
Vol 14 (4) ◽  
Author(s):  
Zain I. Sharif ◽  
Vincent Galand ◽  
William J. Hucker ◽  
Jagmeet P. Singh
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Cardiac Resynchronization ◽  
Cardiac Contractility Modulation ◽  
Carotid Baroreceptor ◽  
Invasive Hemodynamic Monitoring ◽  
The Us ◽  
Baroreceptor Stimulation ◽  
Carotid Baroreceptor Stimulation

Symptomatic heart failure (HF) patients despite optimal medical therapy and advances such as invasive hemodynamic monitoring remain challenging to manage. While cardiac resynchronization therapy remains a highly effective therapy for a subset of HF patients with wide QRS, a majority of symptomatic HF patients are poor candidates for such. Recently, cardiac contractility modulation, neuromodulation based on carotid baroreceptor stimulation, and phrenic nerve stimulation have been approved by the US Food and Drug Administration and are emerging as therapeutic options for symptomatic HF patients. This state-of-the-art review examines the role of these evolving electrical therapies in advanced HF.

scholarly journals Problems of pain and quality of life in rheumatoid arthritis: focus on baricitinib

2020 ◽  
Vol 58 (4) ◽  
pp. 420-427
Author(s):  
A. E. Karateev
Keyword(s):  
Rheumatoid Arthritis ◽  
Intracellular Signaling ◽  
Janus Kinase ◽  
Effective Control ◽  
Signal Transducers ◽  
Intracellular Signaling Pathway ◽  
Autoimmune Inflammation ◽  
Immune Mediated

Modern therapy for rheumatoid arthritis (RA) allows not only to reduce the activity of immune-mediated inflammation and slow down the progression of the disease, but also to quickly eliminate the main symptoms that cause the most concern to patients, such as pain, functional disorders, fatigue. This action has an inhibitor of Janus kinases 1/ 2 – baricitinib, which quickly reduces the activity of inflammation, provides remission in RA, and has a high analgesic effect. The review discusses the role of autoimmune inflammation and the intracellular signaling pathway JAK/STAT (Janus kinase/signal transducers and activators of transcription) in the pathogenesis of chronic pain in RA, the role of baricitinib for effective control of pain intensity and fatigue. 

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