Most Cited Article – Comparative Genomic and Network Analysis of nNOS by Using Different Bioinformatics Approaches

Author(s):Nymphaea AroraVikash PrasharTania AroraRandeep SinghAnshul MishraPriya GodaraArpita BanerjeeArti Sharma* and Jyoti Parkash*

Volume 18, Issue 1, 2021

Published on: 16 June, 2021

Page: [24 – 38]

Abstract:

Introduction: Nitric Oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis (growth of new blood vessels) and development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms, including nNOS (neuronal NOS), eNOS (endothelial NOS) and iNOS (inducible NOS). NOS1 is localized on chromosome 12 consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles and penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases.

Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as physiological inter/intra-cellular messenger in central as well as peripheral nervous systems. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in brain, it is involved in differentiation, development, synaptic plasticity and neurosecretion.

Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as therapeutic target in various neurodegenerative disorders that can surely provide ways to regulate its activity in different aspects.

Materials and Methods: In this study, we employed various bioinformatics tools and databases initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence (GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post translational modifications, enhancing the research by network analysis (STRING), leading to its functional enrichment (Panther).

Results: The results positively support the hypothesis of its role in various pathways related to neurodegeneration and its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis.

Conclusion: This study considered evolutionary trend of physical, chemical and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research. Read Now: https://bit.ly/3ONZli9

Editor’s Choice Article | Statins and the Brain: More than Lipid Lowering Agents?

Journal Name: Current Neuropharmacology

Author(s): Anna Fracassi, Martina Marangoni, Pamela Rosso, Valentina Pallottini, Marco Fioramonti, Silvia Siteni, Marco Segatto*.

Graphical Abstract:

Abstract:

Background: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions.

Objective: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information.

Methods: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke.

Results: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect.

Conclusion: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

 

 

Read out more at: http://www.eurekaselect.com/153651/article

MOST ACCESSED ARTICLE – Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Author(s): Ylenia Cau, Daniela Valensin, Mattia Mori, Sara Draghi, Maurizio Botta*.

 

Abstract:

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

 

Read more here: http://www.eurekaselect.com/151895

OPEN ACCESS ARTICLE – Does Ceruloplasmin Defend Against Neurodegenerative Diseases?

Journal Name: Current Neuropharmacology

Author(s): Bo Wang , Xiao-Ping Wang*.

 

 

Abstract:

Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson’s disease, Alzheimer’s disease and Parkinson’s disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.

 

Read more here: http://www.eurekaselect.com/161925 

OPEN ACCESS ARTICLE – Review Article Genetics and Therapies for GM2 Gangliosidosis

Journal Name: Current Gene Therapy

Author(s): Maria Begona Cachon-Gonzalez*, Eva Zaccariotto, Timothy Martin Cox.

 

Abstract:

Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from diseasecausing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.

 

Read more here: http://www.eurekaselect.com/161003

PRESS RELEASE – Gene transfer alters the neurodegenerative course of GM2 gangliosidosis

The article by Dr. María Begona Cachon-Gonzalez et al. is published in Current Gene Therapy, Volume 18, 2018

Since its clinical description in 1881, Tay-Sachs disease has had almost totemic significance as a cruel and relentless genetic condition that destroys the developing brain of babies and young children. Formerly considered to be restricted to Ashkenazy Jews, it can occur at almost any age and in any ethnic group. Moreover, with its close relatives, Sandhoff disease and the exceptionally rare GM2 activator deficiency, Tay-Sachs often masquerades as other neurological illnesses. There is no treatment beyond palliative care, and with a pressing medical need so typical of countless other nervous diseases, there is a pressing need and a formidable challenge in contemporary research.

This article considers the history, social context and scientific complexities of Tay-Sachs disease: not only does it represent a metabolic defect of glycosphingolipids but it is, par excellence, a lysosomal disease and so a tantalising target for treatment by functional complementation. Lysosomes were discovered by Christian de Duve; but even though he had had training as a physician, the founding father of Cell Biology had little time for studying the pathogenesis of inborn lysosomal diseases. However, de Duve realised that lysosomes could be readily accessed from outside the cell and, at the end of his life, stated that his research had been motivated by his wish to cure diseases such as Tay-Sachs disease, which progressively destroys nerve cells. In considering Tay-Sachs and related lysosomal diseases, after a prolonged period of therapeutic research, gene therapy at last offers a highly promising and tractable stratagem. This sanguine conclusion emphasises the accuracy of de Duve’s insights and the striking boldness of his vision.

The GM2 gangliosidoses comprise Tay-Sachs and Sandhoff disease as well as the ultra-rare GM2 activator protein deficiency, intimately linked biochemically, pathologically and clinically. Their manifestations result from defects in one of three genes: HEXA, HEXB and GM2A, which code for the α- and β-subunits of β-hexosaminidase and GM2 activator protein, respectively. The integrity of this triad, which cooperate to hydrolyse ganglioside GM2 in the lysosome, is an absolute requirement; and when one or other of the genes is dysfunctional, GM2 ganglioside accumulates progressively in tissues rich in this sphingolipid such as the brain. Disease onset correlates roughly with residual enzymatic activity. Typically, in the acute infantile form arrest of neurodevelopment followed by regression of attained milestones progress inexorably, with death occurring at around 3 years of age, whereas in late-onset forms variable presentations occur that often resemble better-known neurodegenerative conditions.

Since first descriptions of GM2 gangliosidosis in the late nineteenth century as unique and devastating disease entities principally of young children, attempts to eradicate the disease through prevention in at-risk populations has been rapid and highly successful, once the biochemical defects were understood. A testament of this success is demonstrated by the fact that disease prevalence is currently higher in the general population, largely due to a lack of widespread screening programmes.

In common with other lysosomal enzymes, those responsible for the most frequent forms of GM2 gangliosidosis, β-hexosaminidase A and B, are made in the endoplasmic reticulum and travel to the lysosome where they execute their function. However, it was discovered that a significant proportion of these enzymes is secreted into the extracellular space; remarkably, they can be re-captured by neighbouring cells and transported to the lysosome where they function normally – a property that can be exploited in therapeutic applications. Purified enzyme has been injected intravenously and into the cerebrospinal fluid of patients with disappointing results. Substrate reduction therapies to ameliorate the burden of the stored material and pharmacological chaperones have also failed to rescue the disease. This has been attributed principally to the low penetrance of these substances into the brain parenchyma due to the blood-brain-barrier.

The discovery of naturally occurring animal models of disease – several breeds of cat and sheep – together with the creation of mouse strains by genetic manipulation allows systematic evaluation of potential treatments. Gene therapy currently rates as number one stratagem to definitively impact the course of the disease. Impressive outcomes in the mouse model have now been replicated in the larger and more complex cat and sheep brains. Encouraged by these results a few centres around the world have embarked in the design of clinical trials using recombinant Adeno-associated viruses for gene transfer.

For more information, please visit: http://www.eurekaselect.com/161003/article

GLAUCOMA AND ALZHEIMER’S DISEASE

Bentham Science observes World Glaucoma Week from 8th to 15th March, 2018, with the world and presents full support for the victims of glaucoma through publishing the latest research developments to combat this dangerous eye disease. Glaucoma is a widely feared eye problem because it causes irreversible blindness. Eye researchers and ophthalmologists have mostly attributed glaucoma to the increase in intraocular pressure, i.e. the increase in fluid pressure inside the eye.

Glaucoma_banner

However there are cases where the glaucoma patients had normal intraocular pressure, which suggests that there are other factors that can cause or enhance the risk of contracting this disease. Researchers from the Ophthalmology Unit of the University of Rome Tor Vergata have recently discovered that the patients of Alzheimer’s were often found susceptible of getting glaucoma in their eyes. Alzheimer’s disease is the most common form of dementia in the elderly that hampers memory and understanding.

Both these neurodegenerative diseases were found to have very similar risk factors and often co-existed in the older people. The research is an important revelation and opens doors for future studies and possible progress in finding cure for both Alzheimer’s disease and glaucoma.

The research entitled, Glaucoma and Alzheimer Disease: One Age-Related Neurodegenerative Disease of the Brain, is published in the Bentham Science journal, Current Neuropharmacology.

MOST ACCESSED ARTICLE – Targeted Nanoparticles for the Treatment of Alzheimer’s Disease – Current Pharmaceutical Design

Journal: Current Pharmaceutical Design

Author(s): Rafael Martín-Rapun, Laura De Matteis, Alfredo Ambrosone, Sonia Garcia-Embid, Lucia Gutierrez, Jesus M. de la Fuente

Abstract:

Background: Alzheimer’s disease (AD) has a dramatic impact on society. The therapeutic targets are located in the central nervous system (CNS), which limits the efficacy of drugs systemically administered: the blood-brain barrier (BBB) selectively allows the permeation of just a few kinds of molecules from the systemic circulation to the CNS. On the other hand, local administration routes to CNS are highly invasive.

Methods: In this article, we have reviewed therapeutic approaches against AD, which are based on nanoparticles targeted to the brain and to the pathological hallmarks of the disease. The existing literature has been classified according to the AD feature that is addressed.

Results: Nanoparticles have been used for the targeted delivery of drugs aiming to reduce the AD symptoms or to reverse the course of the disease. For this task the multivalency of nanoparticles has allowed their functionalization with several kinds of targeting groups, to cross the BBB and to target the place of treatment. With this approach an increased drug bioavailability has been achieved in the CNS using intravenous administration in place of more invasive administration routes. Additionally, nanoparticles have also been used in the development of vaccines and therapeutic formulations for intranasal administration.
Conclusion: Targeted nanoparticles have been proved useful to enhance the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted nanoparticles for combined therapies.

To access the article, please visit: http://www.eurekaselect.com/148709

Editor’s Choice – “Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application”

Journal: Current Molecular Pharmacology

Author(s): Xiaodan Jiao, Niloufar Ashtari, Maryam Rahimi-Balaei, Qi Min Chen, Ilnaz Badbezanchi, Shahla Shojaei, Adel Marzban, Nima Mirzaei, Seunghyuk Chung, Teng Guan, Jiasi Li, Jerry Vriend, Shahram Ejtemaei Mehr, Jiming Kong, Hassan Marzban

Graphical Abstract:

 

Abstract:

The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders.

Read more here: http://www.eurekaselect.com/138465

Article by Disease – “Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism”

Article by Disease on “Metabolic Disorders”

Abstract:

Introduction: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission.

Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia.

Highlights: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

Read more: http://www.eurekaselect.com/node/138027/article 

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