scholarly journals Inflammasomes and Proteostasis Novel Molecular Mechanisms Associated With Atrial Fibrillation

2020 ◽  
Vol 127 (1) ◽  
pp. 73-90 ◽  
Author(s):  
Na Li ◽  
Bianca J.J.M. Brundel
Keyword(s):  
Atrial Fibrillation ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Cytoskeletal Proteins ◽  
Age Related ◽  
Research Findings ◽  
Shock Proteins

Atrial fibrillation (AF), the most common progressive and age-related cardiac arrhythmia, affects millions of people worldwide. AF is associated with common risk factors, including hypertension, diabetes mellitus, and obesity, and serious complications such as stroke and heart failure. Notably, AF is progressive in nature, and because current treatment options are mainly symptomatic, they have only a moderate effect on prevention of arrhythmia progression. Hereto, there is an urgent unmet need to develop mechanistic treatments directed at root causes of AF. Recent research findings indicate a key role for inflammasomes and derailed proteostasis as root causes of AF. Here, we elaborate on the molecular mechanisms of these 2 emerging key pathways driving the pathogenesis of AF. First the role of NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome on AF pathogenesis and cardiomyocyte remodeling is discussed. Then we highlight pathways of proteostasis derailment, including exhaustion of cardioprotective heat shock proteins, disruption of cytoskeletal proteins via histone deacetylases, and the recently discovered DNA damage-induced nicotinamide adenine dinucleotide + depletion to underlie AF. Moreover, potential interactions between the inflammasomes and proteostasis pathways are discussed and possible therapeutic targets within these pathways indicated.

scholarly journals Cellular and mitochondrial mechanisms of atrial fibrillation

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Fleur E. Mason ◽  
Julius Ryan D. Pronto ◽  
Khaled Alhussini ◽  
Christoph Maack ◽  
Niels Voigt
Keyword(s):  
Atrial Fibrillation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Specific Treatment ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Mitochondrial Activity ◽  
Atp Production

AbstractThe molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

scholarly journals Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia: A Mini-Review

Gerontology ◽  
2017 ◽  
Vol 63 (6) ◽  
pp. 580-589 ◽  
Author(s):  
Juan Diego Naranjo ◽  
Jenna L. Dziki ◽  
Stephen F. Badylak
Keyword(s):  
Regenerative Medicine ◽  
Treatment Options ◽  
The Elderly ◽  
Signaling Molecules ◽  
Current Treatment ◽  
Muscle Physiology ◽  
Age Related ◽  
Increased Risk ◽  
And Function ◽  
Age Related Changes

Sarcopenia is a complex and multifactorial disease that includes a decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls. Treatment options are suboptimal and consist of exercise and nutrition as the cornerstone of therapy. Current treatment principles involve identification and modification of risk factors to prevent the disease, but these efforts are of limited value to the elderly individuals currently affected by sarcopenia. The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. The present paper reviews regenerative medicine strategies that seek to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach that is discussed herein.

scholarly journals Vulpinic Acid as a Natural Compound Inhibits the Proliferation of Metastatic Prostate Cancer Cell by Inducing Apoptosis

2021 ◽  
Author(s):  
Demet Cansaran Duman ◽  
Gamze Guney Eskiler ◽  
Betül Çolak ◽  
Elif Sozen Kucukkara
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Annexin V ◽  
Current Treatment ◽  
Pcr Analysis ◽  
G1 Arrest ◽  
Advanced Analysis ◽  
Induced Apoptosis

Abstract Lichen secondary metabolites have drawn considerable attention in recent years due to limitations of current treatment options. Vulpinic acid (VA) obtained from Letharia vulpina lichen species exerts a remarkable cytotoxic effect on different cancer types. However, the therapeutic efficacy of VA in metastatic prostate cancer (mPC) cells has not been investigated. In the present study, we aimed to identify VA-mediated cytotoxicity in PC-3 mPC cells compared with control cells. After identification of the cytotoxic concentrations of VA, VA induced apoptosis was analyzed by Annexin V, cell cycle, acridine orange and propidium iodide staining and RT-PCR analysis. Our findings showed that VA significantly decreased the viability of PC-3 cells (p < 0.01) and caused a considerable early apoptotic effect through G0/G1 arrest, nuclear bleebing and the activation of particularly initiator caspases. Therefore, VA may be a potential treatment option for mPC patients. However, the underlying molecular mechanisms of VA-induced apoptosis with advanced analysis should be further performed.

Current Treatment Options in Atrial Fibrillation—A Changing Paradigm

2005 ◽  
Vol 2 (1) ◽  
pp. 186-190
Author(s):  
Jack Collier ◽  
Arthur J Labovitz
Keyword(s):  
Atrial Fibrillation ◽  
Treatment Options ◽  
Current Treatment

Chronic Myeloid Leukemia

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 132-152 ◽  
Author(s):  
Junia V. Melo ◽  
Timothy P. Hughes ◽  
Jane F. Apperley
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Philadelphia Chromosome ◽  
Current Treatment ◽  
Patient Specific ◽  
Imatinib Treatment ◽  
Molecular Monitoring ◽  
Cytogenetic Analyses

Abstract Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.

scholarly journals Chronic Constipation: Current Management and Challenges

2011 ◽  
Vol 25 (suppl b) ◽  
pp. 5B-6B ◽  
Author(s):  
Martin Storr
Keyword(s):  
Canadian Journal ◽  
Chronic Constipation ◽  
Initial Treatment ◽  
Unmet Needs ◽  
Treatment Options ◽  
Unmet Need ◽  
Current Treatment ◽  
Current Management ◽  
Novel Drugs ◽  
Canadian Market

Many challenges are associated with the diagnosis and management of patients with chronic constipation. Some of these challenges arise from the currently incomplete understanding of what causes constipation and from the difficulties in diagnosing and classifying the heterogeneous group of patients with chronic constipation. Despite the availability of different treatment options for constipation, an unmet need for drugs in the treatment of patients with chronic constipation remains. This holds especially true for patients who fail an initial treatment. With promising novel drugs either close to approval for the Canadian market or on the horizon, many of these unmet needs may be addressed. The present supplement toThe Canadian Journal of Gastroenterologyprovides an educational overview of the current understanding of the diagnosis, epidemiology, pathophysiology and management of chronic constipation, and summarizes current treatment options in light of current and newly available drugs.

scholarly journals New Therapies of Neovascular AMD – Beyond Anti VEGFs

2018 ◽  
Author(s):  
Praveen Yerramothu
Keyword(s):  
Tissue Factor ◽  
Treatment Options ◽  
Significant Risk ◽  
Current Treatment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
P450 Monooxygenase ◽  
New Therapies ◽  
Anti Vegf ◽  
Age Related

Neovascular age-related macular degeneration (nAMD) accounts for one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardised frequent administration of anti-VEGF injections only improves the vision in approximately 30%-40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has discovered novel therapeutic targets and angiogenic signalling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-&beta; signalling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NLRP3 inflammasome inhibition, targeted intraceptor nanoparticle therapy, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed to anti-VEGFs for the treatment of nAMD.

scholarly journals Age-related Macular Degeneration—Disease, Risk Factors, and Treatments

2014 ◽  
Vol 07 (02) ◽  
pp. 154
Author(s):  
Clyde Schultz ◽  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Genetic Factors ◽  
Progressive Disease ◽  
Disease Risk ◽  
Treatment Options ◽  
Current Treatment ◽  
Posterior Segment ◽  
Age Related Macular Degeneration ◽  
Age Related

Age-related macular degeneration (AMD) is a progressive disease of the posterior segment of the eye. It is has been diagnosed worldwide and primarily affects individuals over 50 years of age. The incidence of the disease increases with age and with the presence of certain genetic factors, which may indicate a disposition for disease progression. In addition to genetic factors and age, other factors may be involved in developing AMD. These include obesity and smoking, which are also linked to various cardiovascular conditions. There are two forms of AMD: wet and dry. Both forms may involve the build-up of drusen deposits in the posterior segment of the eye, but the wet form tends to be more severe due to the proliferation of blood vessels into the macula and retinal areas of the back of the eye, thus causing an individual’s vision to become ‘blocked’ or ‘shaded’ usually beginning at the center of the visual field. There are a variety of treatment options for AMD including surgery in the form of laser or photo therapy. The most current treatment options involve the injection of a biologic into the posterior segment of the eye. There are some severe adverse events with this approach but they tend to be rare.

Protein Microarrays: Valuable Tools for Ocular Diseases Research

2020 ◽  
Vol 27 (27) ◽  
pp. 4549-4566
Author(s):  
María Garranzo-Asensio ◽  
Ana Montero-Calle ◽  
Guillermo Solís-Fernández ◽  
Rodrigo Barderas ◽  
Ana Guzman-Aranguez
Keyword(s):  
Molecular Mechanisms ◽  
Protein Microarray ◽  
Unmet Need ◽  
Protein Microarrays ◽  
Specific Protein ◽  
Lifestyle Changes ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Age Related

: The eye is a complex organ comprised of several compartments with exclusive and specialized properties that reflect their diverse functions. Although the prevalence of eye pathologies is increasing, mainly because of its correlation with aging and of generalized lifestyle changes, the pathogenic molecular mechanisms of many common ocular diseases remain poorly understood. Therefore, there is an unmet need to delve into the pathogenesis, diagnosis, and treatment of eye diseases to preserve ocular health and reduce the incidence of visual impairment or blindness. Proteomics analysis stands as a valuable tool for deciphering protein profiles related to specific ocular conditions. In turn, such profiles can lead to real breakthroughs in the fields of ocular science and ophthalmology. Among proteomics techniques, protein microarray technology stands out by providing expanded information using very small volumes of samples. : In this review, we present a brief summary of the main types of protein microarrays and their application for the identification of protein changes in chronic ocular diseases such as dry eye, glaucoma, age-related macular degeneration, or diabetic retinopathy. The validation of these specific protein alterations could provide new biomarkers, disclose eye diseases pathways, and help in the diagnosis and development of novel therapies for eye pathologies.

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