scholarly journals Gene Therapy for Heart Disease: Modified mRNA Perspectives

2021 ◽  
Author(s):  
Lior Zangi ◽  
Ravinder K. Kaundal ◽  
Keerat Kaur
Keyword(s):  
Gene Therapy ◽  
Heart Disease ◽  
Molecular Mechanisms ◽  
Cardiac Repair ◽  
The Body ◽  
Therapeutic Approaches ◽  
Delivery Methods ◽  
Future Directions ◽  
Promising Alternative ◽  
Compositional Changes

Ischemic heart disease (IHD) presents a gigantic clinical challenge that demands effective therapeutic approaches. With increasing knowledge of the basic molecular mechanisms guiding the progress of this disease, it is now possible to target the key pathological players through gene therapy. Modified mRNA-based gene delivery presents a promising alternative to traditional gene therapy, because modRNA approaches have high potency, non-immunogenicity, greater efficiency and controlled nucleic acid transfer to the body. However, until recently the therapeutic applications of mRNA have been limited, as naturally occurring mRNA is rapidly degraded and cleared from the circulation. In this chapter, we outline the compositional changes made to mRNA to enhance its translational capacity and discuss the available carrier molecules currently being employed to deliver modRNA to the heart. We provide a detailed overview of modRNA applicability for cardiac repair and regeneration and consider future directions for novel delivery methods that can facilitate its cardiac therapeutic use.

scholarly journals Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Nicholas Asiimwe ◽  
Seung Geun Yeo ◽  
Min-Sik Kim ◽  
Junyang Jung ◽  
Na Young Jeong
Keyword(s):  
Nitric Oxide ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
The Body ◽  
Bioactive Molecules ◽  
Therapeutic Approaches ◽  
Cellular Debris ◽  
And Oxidative Stress ◽  
Proinflammatory Factors

Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.

scholarly journals Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

2021 ◽  
Author(s):  
Lydia M. Castelli ◽  
Wan-Ping Huang ◽  
Ya-Hui Lin ◽  
Kung-Yao Chang ◽  
Guillaume M. Hautbergue
Keyword(s):  
Molecular Mechanisms ◽  
Low Complexity ◽  
Spinocerebellar Ataxia Type ◽  
Rna Structures ◽  
Therapeutic Approaches ◽  
Future Directions ◽  
Coding Regions ◽  
Hexanucleotide Repeat ◽  
Ran Translation

Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

Competitive Precinct Projects: The Five Consistent Criticisms of “Global” Mixed-Use Megaprojects

2017 ◽  
Vol 48 (6) ◽  
pp. 76-92 ◽  
Author(s):  
Mike Harris
Keyword(s):  
The Body ◽  
Government Officials ◽  
Successful Management ◽  
Delivery Methods ◽  
Future Directions ◽  
The Past ◽  
Project Outcomes ◽  
Mixed Use ◽  
Global Consistency ◽  
Significant Barrier

Mixed-use megaprojects on state-owned land have been increasingly occurring around the world over the past few decades. This article reviews the body of literature that has emerged on these projects during this period and investigates a number of projects more deeply by reviewing original planning documents and undertaking interviews with government officials, consultants, and other insiders. Project motives, delivery methods, and built outcomes have been examined in order to contextualize their emergence and proliferation, leading to a typological understanding, defined in this article as competitive precinct projects. A content analysis of 30 reviews covering 42 mixed-use megaprojects in 20 countries reveals remarkable global consistency in thematic criticisms. Framed in this article as the “five consistent criticisms of ‘global’ mixed-use megaprojects,” they pose a significant barrier to addressing increasingly complex urban challenges as well as to their successful management from inception to delivery. While the consistent criticisms represent patterns that have endured within a globally active urban development type for over three decades, this research shows that rather than being a neoliberal hegemony, there are mixed political and ideological aims and outcomes across projects and sometimes within the same project. A typological understanding allows patterns to be examined and understood, variances and hybridity to be evaluated, and more sophisticated future directions to be mapped out in the pursuit of broader based and city-scale project outcomes.

scholarly journals Revolution in Gene Medicine Therapy and Genome Therapy

2018 ◽  
Author(s):  
David Jiang ◽  
Christine L. Xu ◽  
Stephen H. Tsang
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Viral Vectors ◽  
The Body ◽  
Promising Alternative ◽  
Retinal Dystrophies ◽  
Target Gene Therapy ◽  
Induced Pluripotent ◽  
Surgical Treatments

Recently, there have been revolutions in the development of both gene therapy and genome surgical treatments for inherited diseases. Much of this progress has been centered around hereditary retinal dystrophies, because the eye is an immune-privileged and anatomically ideal target. Gene therapy treatments, already demonstrated to be safe and efficacious in numerous clinical trials, are benefitting from the development of new viral vectors, such as dual and triple AAVs. CRISPR/Ca9, which revolutionized the field of gene editing, is being adapted into more precise “high fidelity” and catalytically dead variants. New CRISPR endonucleases, such as CjCas9 and Cas12a, are generating excitement in the field as well. Stem cell therapy has emerged as a promising alternative, allowing human embryo derived stem cells and induced pluripotent stem cells to be edited precisely in vitro and then reintroduced into the body. This article highlights recent progress made in gene therapy and genome surgery for retinal disorders, and it provides an update on precision medicine FDA treatment trials.

scholarly journals Revolution in Gene Medicine Therapy and Genome Surgery

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 575 ◽  
Author(s):  
David J. Jiang ◽  
Christine L. Xu ◽  
Stephen H. Tsang
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Viral Vectors ◽  
The Body ◽  
Inherited Disorders ◽  
Promising Alternative ◽  
Target Gene Therapy ◽  
Induced Pluripotent ◽  
Surgical Treatments

Recently, there have been revolutions in the development of both gene medicine therapy and genome surgical treatments for inherited disorders. Much of this progress has been centered on hereditary retinal dystrophies, because the eye is an immune-privileged and anatomically ideal target. Gene therapy treatments, already demonstrated to be safe and efficacious in numerous clinical trials, are benefitting from the development of new viral vectors, such as dual and triple adeno-associated virus (AAV) vectors. CRISPR/Cas9, which revolutionized the field of gene editing, is being adapted into more precise “high fidelity” and catalytically dead variants. Newer CRISPR endonucleases, such as CjCas9 and Cas12a, are generating excitement in the field as well. Stem cell therapy has emerged as a promising alternative, allowing human embryo-derived stem cells and induced pluripotent stem cells to be edited precisely in vitro and then reintroduced into the body. This article highlights recent progress made in gene therapy and genome surgery for retinal disorders, and it provides an update on precision medicine Food and Drug Administration (FDA) treatment trials.

scholarly journals Sonodelivery in Skeletal Muscle: Current Approaches and Future Potential

2020 ◽  
Vol 7 (3) ◽  
pp. 107
Author(s):  
Richard E. Decker ◽  
Zachary E. Lamantia ◽  
Todd S. Emrick ◽  
Marxa L. Figueiredo
Keyword(s):  
Skeletal Muscle ◽  
Gene Therapy ◽  
Gene Delivery ◽  
Delivery Methods ◽  
Future Directions ◽  
Dna Injection ◽  
Polymeric Carriers ◽  
Future Potential ◽  
Ideal Technique ◽  
The Ideal

There are currently multiple approaches to facilitate gene therapy via intramuscular gene delivery, such as electroporation, viral delivery, or direct DNA injection with or without polymeric carriers. Each of these methods has benefits, but each method also has shortcomings preventing it from being established as the ideal technique. A promising method, ultrasound-mediated gene delivery (or sonodelivery) is inexpensive, widely available, reusable, minimally invasive, and safe. Hurdles to utilizing sonodelivery include choosing from a large variety of conditions, which are often dependent on the equipment and/or research group, and moderate transfection efficiencies when compared to some other gene delivery methods. In this review, we provide a comprehensive look at the breadth of sonodelivery techniques for intramuscular gene delivery and suggest future directions for this continuously evolving field.

Possibilities for treating aspirin-i lesions of the stomach and duodenum in patients with chronic coronary heart disease

2020 ◽  
Vol 98 (3) ◽  
pp. 231-235
Author(s):  
N. Yu. Borovkova ◽  
M. V. Buyanova ◽  
T. E. Bakka ◽  
M. P. Nistratova ◽  
T. V. Vlasova ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Proton Pump Inhibitor ◽  
Blood Serum ◽  
Proton Pump ◽  
The Body ◽  
Control Group ◽  
Pge2 Level ◽  
Endogenous Prostaglandins ◽  
Chronic Coronary Heart Disease

To evaluate possibilities of aspirin-induced gastroduodenopathy treatment in the patients with chronic ischemic heart disease by means of applying the internal endogenous prostaglandins stimulant.  Material and methods. 340 patients suffering from chronic coronary heart disease and receiving a long-term acetylsalicylic acid (ASA) therapy were examined on the base of the cardiovascular care unit of The Nizhny Novgorod Regional Clinical Hospital named after N.A. Semaschko. There were evaluated frequency, nature and severity of the aspirin-induced gastroduodenopathy. The patients with coronary heart disease and aspirin-induced gastroduodenopathy were divided in two groups. In the first group of patients there was applied rebamipide therapy (in a single daily dose 300 mg) in combination with the proton pump inhibitor (PPI) — pantoprazole. In the second group there was applied only pantoprazole therapy. For the purpose of specification of AIG pathogenetic mechanisms development, all the examined chronic coronary heart disease cases were tested on the prostaglandin E2 (PGE2) level in blood serum before the therapy beginning and after the treatment. The control group was formed of chronic coronary heart disease patients showing no AIG evidence. Statistical processing of the received data was fulfilled with the program «Statistika 10.0». Results. AIG was registered in 15% out of 340 chronic coronary heart disease patients. According to the endoscopic examination erosive disease of the body and antrum prevailed among the patients. The PGE2 level in the blood serum was significantly lower (р = 0,00087) in these patients in comparison with the control group. In association with PPI and rebamipide mixed therapy, esophagogastroduodenoscopy results showed no pathological findings in gastrointestinal mucosa and statistically significant (р = 0,00067) blood serum PGE2 level growing in all the treated patients. As a result of exclusive PPI therapy there was marked positive dynamics in endoscopic view in 19 out of 25 patients and a tendency to normalization of PGE2 level in the blood serum. However, PGE2 level growing was insignificant. Conclusion. The presented research demonstrates the possibility of AIG treatment with the use of internal endogenous prostaglandins stimulant — rebamipide in complex with proton pump inhibitor PPI therapy.

Alcohol Consumption and Risk of Uterine Fibroids

2020 ◽  
Vol 20 (4) ◽  
pp. 247-258 ◽  
Author(s):  
Hajra Takala ◽  
Qiwei Yang ◽  
Ahmed M. Abd El Razek ◽  
Mohamed Ali ◽  
Ayman Al-Hendy
Keyword(s):  
Alcohol Consumption ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Legal Status ◽  
Current Knowledge ◽  
Uterine Fibroids ◽  
Future Directions ◽  
Working Adults ◽  
The Us ◽  
Alcohol Related Problems

Lifestyle factors, such as alcohol intake, have placed a substantial burden on public health. Alcohol consumption is increasing globally due to several factors including easy accessibility of this addictive substance besides its legal status and social acceptability. In the US, alcohol is the third leading preventable cause of death (after tobacco, poor diet and physical inactivity) with an estimated 88,000 people dying from alcohol-related causes annually, representing 1 in 10 deaths among working adults. Furthermore, the economic burden of excess drinking costs the US around $249 billion ($191.1 billion related to binge drinking). Although men likely drink more than women do, women are at much higher risk for alcohol-related problems. Alcohol use is also considered to be one of the most common non-communicable diseases, which affects reproductive health. This review article summarizes the current knowledge about alcohol-related pathogenesis of uterine fibroids (UFs) and highlights the molecular mechanisms that contribute to the development of UFs in response to alcohol consumption. Additionally, the effect of alcohol on the levels of various factors that are involved in UFs pathogenesis, such as steroid hormones, growth factors and cytokines, are summarized in this review. Animal studies of deleterious alcohol effect and future directions are discussed as well.

Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders

2020 ◽  
Vol 20 (13) ◽  
pp. 1142-1153 ◽  
Author(s):  
Sreyashi Chandra ◽  
Md. Tanjim Alam ◽  
Jhilik Dey ◽  
Baby C. Pulikkaparambil Sasidharan ◽  
Upasana Ray ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
The Body ◽  
Therapeutic Approaches ◽  
Cns Disorders ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Present Understanding ◽  
Lateral Sclerosis

Background: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington’s disease (HD). Objective: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. Methods: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. Results: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. Conclusion: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

Toxicology

2017 ◽  
Author(s):  
Robert Laumbach ◽  
Michael Gochfeld
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Toxicity Testing ◽  
The Body ◽  
Toxic Substances ◽  
Basic Principles ◽  
Practical Applications ◽  
Mechanisms Of Toxicity ◽  
Body Distribution ◽  
Threshold Doses

This chapter describes the basic principles of toxicology and their application to occupational and environmental health. Topics covered include pathways that toxic substances may take from sources in the environment to molecular targets in the cells of the body where toxic effects occur. These pathways include routes of exposure, absorption into the body, distribution to organs and tissues, metabolism, storage, and excretion. The various types of toxicological endpoints are discussed, along with the concepts of dose-response relationships, threshold doses, and the basis of interindividual differences and interspecies differences in response to exposure to toxic substances. The diversity of cellular and molecular mechanisms of toxicity, including enzyme induction and inhibition, oxidative stress, mutagenesis, carcinogenesis, and teratogenesis, are discussed and the chapter concludes with examples of practical applications in clinical evaluation and in toxicity testing.

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