scholarly journals Mitochondrial Membrane Intracellular Communication in Healthy and Diseased Myocardium

2020 ◽  
Vol 8 ◽  
Author(s):  
Vishnu K. Kumar ◽  
Atreju Lackey ◽  
Jonathan Snyder ◽  
Sunil Karhadkar ◽  
Ajay D. Rao ◽  
...  
Keyword(s):  
Cardiac Disease ◽  
Past Research ◽  
Mechanisms Of Action ◽  
First Century ◽  
Apoptosis Induction ◽  
Pharmacological Treatments ◽  
Intracellular Communication ◽  
Intracellular Organelle ◽  
Physical Interactions ◽  
Cellular Bioenergetics

Research efforts in the twenty-first century have been paramount to the discovery and development of novel pharmacological treatments in a variety of diseases resulting in improved life expectancy. Yet, cardiac disease remains a leading cause of morbidity and mortality worldwide. Over time, there has been an expansion in conditions such as atrial fibrillation (AF) and heart failure (HF). Although past research has elucidated specific pathways that participate in the development of distinct cardiac pathologies, the exact mechanisms of action leading to disease remain to be fully characterized. Protein turnover and cellular bioenergetics are integral components of cardiac diseases, highlighting the importance of mitochondria and endoplasmic reticulum (ER) in driving cellular homeostasis. More specifically, the interactions between mitochondria and ER are crucial to calcium signaling, apoptosis induction, autophagy, and lipid biosynthesis. Here, we summarize mitochondrial and ER functions and physical interactions in healthy physiological states. We then transition to perturbations that occur in response to pathophysiological challenges and how this alters mitochondrial–ER and other intracellular organelle interactions. Finally, we discuss lifestyle interventions and innovative therapeutic targets that may be used to restore beneficial mitochondrial and ER interactions, thereby improving cardiac function.

Recent Advances in the Development of Broad-Spectrum Antiprotozoal Agents

2020 ◽  
Vol 27 ◽  
Author(s):  
Antonio Moreno-Herrera ◽  
Sandra Cortez-Maya ◽  
Virgilio Bocanegra-Garcia ◽  
Bimal Krishna Banik ◽  
Gildardo Rivera
Keyword(s):  
Giardia Lamblia ◽  
Heterocyclic Compounds ◽  
Trichomonas Vaginalis ◽  
Mechanisms Of Action ◽  
Parasitic Infections ◽  
Parasitic Diseases ◽  
Pharmacological Treatments ◽  
Preclinical Development ◽  
Leishmania Spp ◽  
Effective Drugs

: Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatment is limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.

scholarly journals The use of ivabradine in a patient with inappropriate sinus tachycardia and cardiomyopathy due to limb girdle muscular dystrophy type 2I

2020 ◽  
Vol 13 (1) ◽  
pp. e230647
Author(s):  
Rajkumar Rajendram ◽  
Fahad AlDhahri ◽  
Naveed Mahmood ◽  
Mubashar Kharal
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cardiac Disease ◽  
Sinus Tachycardia ◽  
Prognostic Significance ◽  
Mechanisms Of Action ◽  
Limb Girdle Muscular Dystrophy ◽  
Muscular Dystrophies ◽  
Appropriate Use ◽  
Inappropriate Sinus Tachycardia

Muscular dystrophies are a heterogeneous group of disorders that commonly involve cardiac and skeletal muscle. Comprehensive guidelines for the management of cardiac failure and arrhythmias are available. However, the studies from which their recommendations are derived did not include any patients with muscular dystrophy. Some medications (eg, betablockers) may have significant side effects in this cohort. In some situations the use of agents with unique mechanisms of action such as ivabradine (a ‘funny’ channel inhibitor) may be more appropriate. Use of ivabradine has not previously been reported in limb girdle muscular dystrophy (LGMD). We describe the course of a patient with LGMD type 2I, cardiomyopathy and inappropriate sinus tachycardia treated with ivabradine. As advances in respiratory support have improved the outcomes of patients with muscular dystrophy; the prognostic significance of cardiac disease has increased. Ivabradine is tolerated and may reduce symptoms, morbidity and mortality in this cohort.

Introduction to nuclear cardiology

2011 ◽  
Author(s):  
Nikant Sabharwal ◽  
Chee Yee Loong ◽  
Andrew Kelion
Keyword(s):  
Nuclear Cardiology ◽  
Cardiac Disease ◽  
Imaging Technique ◽  
First Century ◽  
Imaging Modalities ◽  
Non Invasive ◽  
Early Twenty ◽  
Cardiac Imaging Technique ◽  
Wide Range ◽  
Electrocardiogram Ecg

Introduction 2Important milestones 4Relation to other imaging modalities 6The cardiologist of the early twenty-first century takes for granted the wide range of imaging modalities at his/her disposal, but it was not always so. At the beginning of the 1970s, invasive cardiac catheterization was the only reliable cardiac imaging technique. Subsequently, nuclear cardiology investigations led the way in the non-invasive assessment of cardiac disease. Some of the principles underlying these investigations [e.g. electrocardiogram (ECG)-triggered gating] have also been of great importance in the development of other imaging modalities....

scholarly journals Antitrypanosomal Activities and Mechanisms of Action of Novel Tetracyclic Iridoids from Morinda lucida Benth.

2016 ◽  
Vol 60 (6) ◽  
pp. 3283-3290 ◽  
Author(s):  
Kofi D. Kwofie ◽  
Nguyen Huu Tung ◽  
Mitsuko Suzuki-Ohashi ◽  
Michael Amoa-Bosompem ◽  
Richard Adegle ◽  
...  
Keyword(s):  
Human African Trypanosomiasis ◽  
Well Being ◽  
Mechanisms Of Action ◽  
Apoptosis Induction ◽  
Research Groups ◽  
Protein Subunit ◽  
Content Type ◽  
Lead Compounds ◽  
Cell Cycle Alteration ◽  
Economic Well Being

Trypanosoma bruceiparasites are kinetoplastid protozoa that devastate the health and economic well-being of millions of people in Africa through the disease human African trypanosomiasis (HAT). New chemotherapy has been eagerly awaited due to severe side effects and the drug resistance issues plaguing current drugs. Recently, there has been an emphasis on the use of medicinal plants worldwide.Morinda lucidaBenth. is a popular medicinal plant widely distributed in Africa, and several research groups have reported on the antiprotozoal activities of this plant. In this study, we identified three novel tetracyclic iridoids, molucidin, ML-2-3, and ML-F52, from the CHCl3fraction ofM. lucidaleaves, which possess activity against the GUTat 3.1 strain ofT. brucei brucei. The 50% inhibitory concentrations (IC50) of molucidin, ML-2-3, and ML-F52 were 1.27 μM, 3.75 μM, and 0.43 μM, respectively. ML-2-3 and ML-F52 suppressed the expression of paraflagellum rod protein subunit 2, PFR-2, and caused cell cycle alteration, which preceded apoptosis induction in the bloodstream form ofTrypanosomaparasites. Novel tetracyclic iridoids may be promising lead compounds for the development of new chemotherapies for African trypanosomal infections in humans and animals.

scholarly journals The Essential Need for a Validated Potency Assay for Cell-Based Therapies in Cardiac Regenerative and Reparative Medicine. A Practical Approach to Test Development

2021 ◽  
Author(s):  
Lidia Gómez-Cid ◽  
Lilian Grigorian-Shamagian ◽  
Ricardo Sanz-Ruiz ◽  
Ana S. de la Nava ◽  
Ana I. Fernández ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Treatment Efficacy ◽  
Scientific Evidence ◽  
Test Development ◽  
Mechanisms Of Action ◽  
First Century ◽  
Regulatory Agencies ◽  
Potency Assay ◽  
Target Disease ◽  
A Cell

AbstractBiological treatments are one of the medical breakthroughs in the twenty-first century. The initial enthusiasm pushed the field towards indiscriminatory use of cell therapy regardless of the pathophysiological particularities of underlying conditions. In the reparative and regenerative cardiovascular field, the results of the over two decades of research in cell-based therapies, although promising still could not be translated into clinical scenario. Now, when we identified possible deficiencies and try to rebuild its foundations rigorously on scientific evidence, development of potency assays for the potential therapeutic product is one of the steps which will bring our goal of clinical translation closer. Although, highly challenging, the potency tests for cell products are considered as a priority by the regulatory agencies. In this paper we describe the main characteristics and challenges for a cell therapy potency test focusing on the cardiovascular field. Moreover, we discuss different steps and types of assays that should be taken into consideration for an eventual potency test development by tying together two fundamental concepts: target disease and expected mechanism of action. Graphical Abstract Development of potency assays for cell-based products consists in understanding the pathophysiology of the disease, identifying potential mechanisms of action (MoA) to counteract it and finding the most suitable cell-based product that exhibits these MoA. When applied, the potency assay needs to correlate bioactivity of the product, via a measurement related to the MoA, with treatment efficacy. However, in the cardiovascular field, the process faces several challenges and high requirements.

Results of researches of cases of sticking of wet snow and complex sediments on the territory of Ukraine during the second half of the XX - beginning of the XXI century. and the prospects for their further research

2018 ◽  
Vol 90 (2) ◽  
pp. 62-69
Author(s):  
Svitlana Pyasecka
Keyword(s):  
Climate Change ◽  
Global Warming ◽  
Past Research ◽  
First Century ◽  
Special Study ◽  
Current Trends ◽  
Synoptic Conditions ◽  
Wet Snow ◽  
Diagnostic Signs ◽  
Coherent Picture

The article presents the results of research on the physical characteristics of the formation of a number of ice-and-frost-free phenomena, in particular wet sticking (wet snow deposits on the wires of a standard ice-making machine) and complex sediments. The peculiarities of formation of such sediments in general (also categories of dangerous and natural) are analyzed. The synoptic conditions of their formation, diagnostic signs and peculiarities of distribution on the territory of Ukraine are indicated. The analyzed period covers mostly the second half of the twentieth century. and the beginning of the twenty-first century. The aim of the work is not only to analyze the results of past research, but also to draw the direction of further research on ice-damper deposits in Ukraine in the conditions of the modern climate for the development of recommendations for certain sectors of the economy that are most vulnerable to them in order to prevent or reduce losses. In view of further climate change in Ukraine on the background of global warming, the urgent need is to continue the study of changes in the distribution of various types of ice-and-cloud-bearing deposits, in particular, wet snow and complex deposits on the territory of Ukraine and the identification of their current trends in the regions of the country should cover a number of urgent tasks for further research, namely: it is necessary to identify the most active cells of such deferrals and to trace their dynamics, especially for deposits of the category of dangerous and natural. It is necessary to conduct a special study on the nature and amount of losses from such deposits in separate regions of Ukraine and to establish the most vulnerable territories. In order to create a coherent picture of modern features in the distribution and trends of ice-damper deposits in Ukraine, it is necessary to combine the results of the study of the present state of all three major types of sediment. On the basis of the revealed recent dynamics, the distribution of such deposits, taking into account the tendencies of losses from them, make recommendations for the most vulnerable territories of the country and the branches of government.

Analysis of Dasatinib-Induced Molecular Mechanisms of Apoptosis in Hypoxia-Adopted CML Cells Utilizing Quantitative Proteomics Technology.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2773-2773
Author(s):  
Yoko Tabe ◽  
Linhua Jin ◽  
Hiroko Iwanami ◽  
Saiko Kazuno ◽  
Tsutomu Fujimura ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cytochrome C ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Apoptosis Induction ◽  
Cycle Arrest ◽  
Mitochondrial Chaperones

Abstract Abstract 2773 Development of the second-generation ABL tyrosine kinase inhibitor (TKI) dasatinib in CML aimed at overcoming resistance to imatinib, to eliminate persistent residual disease and thus prevent recurrence of active leukemia after TKI discontinuation in chronic myeloid leukemia (CML). Hypoxia has recently been reported as an essential component of the leukemia BM microenvironment that promotes leukemia cell homing, survival and chemoresistance (Benito et al, PlosOne 2011). In this study, we investigated the anti-CML efficacy and molecular mechanisms of action of dasatinib under hypoxic conditions. We developed a hypoxia-adopted subclone of the KBM5 CML cell line (KMB5-HA), which was selected under 1.0% oxygen conditions, and an imatinib-resistant KBM5 subline bearing the T315I mutation (KBM5-T315I). KBM5-HA cells cultured under hypoxia accumulated in G0/G1 and exhibited moderate spontaneous apoptosis compared to KBM5 parental cells in normoxia (sub G1 %: KBM5 3.8±0.8, KBM5-HA 8.7±0.9; p=0.01; proportion of cells in G0/G1: KBM5 36.5±1.1%, KBM5-HA 52.4±6.6%; p=0.02, PI analysis). These cells displayed higher sensitivity to dasatinib than parental KBM cells (IC50; 1.3 nM for KBM5, 0.3 nM for KBM5-HA, at 48hrs by MTT). Low-dose dasatinib (0.5nM) which failed to cause inhibition of proliferation in parental KBM5 cells, caused significant apoptosis induction with cell cycle arrest in KBM-HA cells (sub G1 %: control 8.7±0.9, datatinib 49.1±16.9; p=0.02, G0/G1 %: control 52.4±6.4%, dasatinib 74.1±3.5%; p=0.01). In KBM5-T315I cells, dasatinib induced more prominent cell growth inhibition under hypoxia compared to normoxia (IC50 at 48hrs: normoxia 16.2 nM, hypoxia 3.7 nM). Treatment with 5nM dasatinib, which did not affect KBM5-T315I cell growth under normoxia, induced significant apoptotic effects under hypoxia (sub G1 %: control 6.9±0.9, dasatinib 20.3±3.3; p=0.05, G0/G1 %: control 57.3±5.8, dasatinib 67.4±8.9; p=0.41). We next investigated dasatinib-induced changes of Stat-5 and ERK activation in CML cells by immunoblotting Treatment with 0.5 nM dasatinib resulted in marked down-regulation of phosphorylated (p-) Stat-5 and p-ERK in both, KBM5 and KBM5-T315I cells. In KBM5-HA cells, however, no baseline expression of p-Stat-5 or p-ERK was detected. These results suggest that in KBM5-HA cells dasatinib induces apoptosis and cell cycle arrest via Stat-5 or ERK-independent pathways. To investigate the candidate signaling factors responsible for dasatinib effects on KBM-HA, we performed the proteomic analysis utilizing proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ, Applied Biosystems) coupled with two-dimensional-liquid chromatography-tandem mass spectrometry. A total of 1,234 proteins were detected, and 296 proteins were found to be significantly up-regulated in response to dasatinib treatment in KBM5-HA cells. Among the up-regulated proteins, we found 39 proteins involved in apoptosis induction including Cytochrome C and Cytochrome C oxydase subunits (p<0.001). Mass spectrometry further revealed the up-regulation of apoptosis related mitochondrial chaperones HSP10 and HSP60 (p<0.001), suggesting a role of HSP60/HSP10 in mitochondrial membrane permeabilization. In summary, these findings unravel novel mechanisms of action of dasatinib under conditions mimicking the hypoxic BM microenvironment via induction of Cytochrome C oxydase and mitochondrial chaperones HSP10 and HSP60, which lead to loss of mitochondrial transmembrane potential and release of apoptogenic Cytochrome C in CML cells. Disclosures: Tabe: Bristol-Myers Squibb: Research Funding.

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