scholarly journals ATM Protein Kinase: Old and New Implications in Neuronal Pathways and Brain Circuitry

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1969 ◽  
Author(s):  
Lara Pizzamiglio ◽  
Elisa Focchi ◽  
Flavia Antonucci
Keyword(s):  
Ataxia Telangiectasia ◽  
Insulin Signalling ◽  
Point Of View ◽  
Motor Disability ◽  
Predominant Symptom ◽  
Brain Circuitry ◽  
Cognitive Diseases ◽  
The Central Nervous System ◽  
Atm Protein ◽  
Cycle Regulation

Despite that the human autosomal recessive disease ataxia telangiectasia (A-T) is a rare pathology, interest in the function of ataxia-telangiectasia mutated protein (ATM) is extensive. From a clinical point of view, the role of ATM in the central nervous system (CNS) is the most impacting, as motor disability is the predominant symptom affecting A-T patients. Coherently, spino-cerebellar neurodegeneration is the principal hallmark of A-T and other CNS regions such as dentate and olivary nuclei and brain stem are implicated in A-T pathophysiology. Recently, several preclinical studies also highlighted the involvement of ATM in the cerebral cortex and hippocampus, thus extending A-T symptomatology to new brain areas and pathways. Here, we review old and recent evidence that largely demonstrates not only the historical ATM account in DNA damage response and cell cycle regulation, but the multiple pathways through which ATM controls oxidative stress homeostasis, insulin signalling pathways, epigenetic regulation, synaptic transmission, and excitatory–inhibitory balance. We also summarise recent evidence on ATM implication in neurological and cognitive diseases beyond A-T, bringing out ATM as new pathological substrate and potential therapeutic target.

New Advanced Strategies for the Treatment of Lysosomal Diseases Affecting the Central Nervous System

2019 ◽  
Vol 25 (17) ◽  
pp. 1933-1950 ◽  
Author(s):  
Maria R. Gigliobianco ◽  
Piera Di Martino ◽  
Siyuan Deng ◽  
Cristina Casadidio ◽  
Roberta Censi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Polymeric Nanoparticles ◽  
Genetic Diseases ◽  
Point Of View ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Lysosomal Diseases ◽  
The Central Nervous System ◽  
Enzyme Delivery

Lysosomal Storage Disorders (LSDs), also known as lysosomal diseases (LDs) are a group of serious genetic diseases characterized by not only the accumulation of non-catabolized compounds in the lysosomes due to the deficiency of specific enzymes which usually eliminate these compounds, but also by trafficking, calcium changes and acidification. LDs mainly affect the central nervous system (CNS), which is difficult to reach for drugs and biological molecules due to the presence of the blood-brain barrier (BBB). While some therapies have proven highly effective in treating peripheral disorders in LD patients, they fail to overcome the BBB. Researchers have developed many strategies to circumvent this problem, for example, by creating carriers for enzyme delivery, which improve the enzyme’s half-life and the overexpression of receptors and transporters in the luminal or abluminal membranes of the BBB. This review aims to successfully examine the strategies developed during the last decade for the treatment of LDs, which mainly affect the CNS. Among the LD treatments, enzyme-replacement therapy (ERT) and gene therapy have proven effective, while nanoparticle, fusion protein, and small molecule-based therapies seem to offer considerable promise to treat the CNS pathology. This work also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs.

Herbal Medicine for Glioblastoma: Current and Future Prospects

2020 ◽  
Vol 16 (8) ◽  
pp. 1022-1043
Author(s):  
Imran Khan ◽  
Sadaf Mahfooz ◽  
Mustafa A. Hatiboglu
Keyword(s):  
Cell Proliferation ◽  
Survival Rates ◽  
Standard Of Care ◽  
Natural Compounds ◽  
Treatment Modalities ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cycle Regulation ◽  
Immense Potential

Background: Glioblastoma is one of the most aggressive and devastating tumours of the central nervous system with short survival time. Glioblastoma usually shows fast cell proliferation and invasion of normal brain tissue causing poor prognosis. The present standard of care in patients with glioblastoma includes surgery followed by radiotherapy and temozolomide (TMZ) based chemotherapy. Unfortunately, these approaches are not sufficient to lead a favorable prognosis and survival rates. As the current approaches do not provide a long-term benefit in those patients, new alternative treatments including natural compounds, have drawn attention. Due to their natural origin, they are associated with minimum cellular toxicity towards normal cells and it has become one of the most attractive approaches to treat tumours by natural compounds or phytochemicals. Objective: In the present review, the role of natural compounds or phytochemicals in the treatment of glioblastoma describing their efficacy on various aspects of glioblastoma pathophysiology such as cell proliferation, apoptosis, cell cycle regulation, cellular signaling pathways, chemoresistance and their role in combinatorial therapeutic approaches was described. Methods: Peer-reviewed literature was extracted using Pubmed, EMBASE Ovid and Google Scholar to be reviewed in the present article. Conclusion: Preclinical data available in the literature suggest that phytochemicals hold immense potential to be translated into treatment modalities. However, further clinical studies with conclusive results are required to implement phytochemicals in treatment modalities.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

Are we Ready for a “Microbiome-Guided Behaviour” Approach?

2019 ◽  
Vol 28 (04) ◽  
pp. 708-724
Author(s):  
ANDREA LAVAZZA ◽  
VITTORIO A. SIRONI
Keyword(s):  
Fecal Microbiota Transplantation ◽  
Negative Attitude ◽  
Well Being ◽  
Fecal Microbiota ◽  
Point Of View ◽  
Brain Functioning ◽  
The Central Nervous System ◽  
The Individual ◽  
The Right ◽  
The Mind

Abstract:The microbiome is proving to be increasingly important for human brain functioning. A series of recent studies have shown that the microbiome influences the central nervous system in various ways, and consequently acts on the psychological well-being of the individual by mediating, among others, the reactions of stress and anxiety. From a specifically neuroethical point of view, according to some scholars, the particular composition of the microbiome—qua microbial community—can have consequences on the traditional idea of human individuality. Another neuroethical aspect concerns the reception of this new knowledge in relation to clinical applications. In fact, attention to the balance of the microbiome—which includes eating behavior, the use of psychobiotics and, in the treatment of certain diseases, the use of fecal microbiota transplantation—may be limited or even prevented by a biased negative attitude. This attitude derives from a prejudice related to everything that has to do with the organic processing of food and, in general, with the human stomach and intestine: the latter have traditionally been regarded as low, dirty, contaminated and opposed to what belongs to the mind and the brain. This biased attitude can lead one to fail to adequately consider the new anthropological conceptions related to the microbiome, resulting in a state of health, both physical and psychological, inferior to what one might have by paying the right attention to the knowledge available today. Shifting from the ubiquitous high-low metaphor (which is synonymous with superior-inferior) to an inside-outside metaphor can thus be a neuroethical strategy to achieve a new and unbiased reception of the discoveries related to the microbiome.

scholarly journals Stable Brain ATM Message and Residual Kinase-Active ATM Protein in Ataxia-Telangiectasia

2011 ◽  
Vol 31 (20) ◽  
pp. 7568-7577 ◽  
Author(s):  
J. Li ◽  
J. Chen ◽  
H. V. Vinters ◽  
R. A. Gatti ◽  
K. Herrup
Keyword(s):  
Ataxia Telangiectasia ◽  
Atm Protein

THE FAMILY HISTORY OF SPINA BIFIDA CYSTICA

PEDIATRICS ◽  
1965 ◽  
Vol 35 (4) ◽  
pp. 589-595
Author(s):  
John Lorber
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Spina Bifida ◽  
Index Case ◽  
Progressive Increase ◽  
Point Of View ◽  
The Family ◽  
History Of ◽  
The Central Nervous System ◽  
Spina Bifida Cystica

1. The family histories of 722 infants who were born with spina bifida cystica were studied. 2. The index cases were referred for surgical treatment and were not selected in any way from the genetic point of view. 3. Intensive inquiries were made to obtain a complete family pedigree, including a prospective follow-up of siblings born after the index case. 4. Of 1,256 siblings 85 or 6.8% had gross malformation of the central nervous system: spina bifida cystica in 54, anencephaly in 22, and uncomplicated hydrocephalus in 9. 5. Of 306 children born after the index case 25 (8%) or 1 in 12 were affected. 6. There was a progressive increase in multiple cases in the family with increasing family size. In sibships of five or more, multiple cases occurred in 24.1%. 7. In 118 families cases of gross malformation of the central nervous system were known to have occurred among members of the family other than siblings. Cases occurred in three generations. 8. It is possible that spina bifida cystica might be a recessively inherited condition.

scholarly journals Insights into the Toxicity and Degradation Mechanisms of Imidacloprid Via Physicochemical and Microbial Approaches

Toxics ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 65
Author(s):  
Shimei Pang ◽  
Ziqiu Lin ◽  
Yuming Zhang ◽  
Wenping Zhang ◽  
Nasser Alansary ◽  
...  
Keyword(s):  
Large Scale ◽  
Insect Pests ◽  
Point Of View ◽  
Emerging Contaminant ◽  
Human Beings ◽  
Degradation Mechanisms ◽  
The World ◽  
Neonicotinoid Insecticide ◽  
The Central Nervous System ◽  
Control Insect

Imidacloprid is a neonicotinoid insecticide that has been widely used to control insect pests in agricultural fields for decades. It shows insecticidal activity mainly by blocking the normal conduction of the central nervous system in insects. However, in recent years, imidacloprid has been reported to be an emerging contaminant in all parts of the world, and has different toxic effects on a variety of non-target organisms, including human beings, due to its large-scale use. Hence, the removal of imidacloprid from the ecosystem has received widespread attention. Different remediation approaches have been studied to eliminate imidacloprid residues from the environment, such as oxidation, hydrolysis, adsorption, ultrasound, illumination, and biodegradation. In nature, microbial degradation is one of the most important processes controlling the fate of and transformation from imidacloprid use, and from an environmental point of view, it is the most promising means, as it is the most effective, least hazardous, and most environmentally friendly. To date, several imidacloprid-degrading microbes, including Bacillus, Pseudoxanthomonas, Mycobacterium, Rhizobium, Rhodococcus, and Stenotrophomonas, have been characterized for biodegradation. In addition, previous studies have found that many insects and microorganisms have developed resistance genes to and degradation enzymes of imidacloprid. Furthermore, the metabolites and degradation pathways of imidacloprid have been reported. However, reviews of the toxicity and degradation mechanisms of imidacloprid are rare. In this review, the toxicity and degradation mechanisms of imidacloprid are summarized in order to provide a theoretical and practical basis for the remediation of imidacloprid-contaminated environments.

scholarly journals Characterization of ATM Expression, Localization, and Associated DNA-dependent Protein Kinase Activity

1998 ◽  
Vol 9 (9) ◽  
pp. 2361-2374 ◽  
Author(s):  
Dennis P. Gately ◽  
James C. Hittle ◽  
Gordon K. T. Chan ◽  
Tim J. Yen
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Ataxia Telangiectasia ◽  
Kinase Activity ◽  
Human Fibroblasts ◽  
Protein Kinase Activity ◽  
Dependent Manner ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Atm Protein

Ataxia telangiectasia–mutated gene (ATM) is a 350-kDa protein whose function is defective in the autosomal recessive disorder ataxia telangiectasia (AT). Affinity-purified polyclonal antibodies were used to characterize ATM. Steady-state levels of ATM protein varied from undetectable in most AT cell lines to highly expressed in HeLa, U2OS, and normal human fibroblasts. Subcellular fractionation showed that ATM is predominantly a nuclear protein associated with the chromatin and nuclear matrix. ATM protein levels remained constant throughout the cell cycle and did not change in response to serum stimulation. Ionizing radiation had no significant effect on either the expression or distribution of ATM. ATM immunoprecipitates from HeLa cells and the human DNA-dependent protein kinase null cell line MO59J, but not from AT cells, phosphorylated the 34-kDa subunit of replication protein A (RPA) complex in a single-stranded and linear double-stranded DNA–dependent manner. Phosphorylation of p34 RPA occurred on threonine and serine residues. Phosphopeptide analysis demonstrates that the ATM-associated protein kinase phosphorylates p34 RPA on similar residues observed in vivo. The DNA-dependent protein kinase activity observed for ATM immunocomplexes, along with the association of ATM with chromatin, suggests that DNA damage can induce ATM or a stably associated protein kinase to phosphorylate proteins in the DNA damage response pathway.

Pain, Painrelieving Mechanisms and Trauma

1987 ◽  
Vol 3 (1) ◽  
pp. 12-13
Author(s):  
B. Sjolund
Keyword(s):  
Spinal Cord ◽  
Great Britain ◽  
Nerve Fibers ◽  
Point Of View ◽  
Pain Sensation ◽  
Small Peptides ◽  
Periaqueductal Gray Matter ◽  
Nociceptive Afferents ◽  
The Central Nervous System ◽  
Areas Of Interest

Activity in nociceptive nerve fibers does not only trigger the sensation of pain but it also starts a variety of nocifensive reflexes to protect the organism from the noxious agent. Some of these reflexes may, if active long enough, be harmful themselves, causing ischemia in visceral organs or other inadvertent reactions. Recently, several endogenous mechanisms have been discovered that can inhibit the transmission of nerve impulses from nociceptive afferents to other nerve cells, thus not only preventing the pain sensation but also modulating the nocifensive reflex responses. Several such mechanisms may involve the release of endorphins. These are small peptides, with opiate-like activity that were first discovered in 1975 by Hughes and Kosterlitz in Great Britain and by Terenius in Sweden. The distribution of such endorphins in the central nervous system was first investigated by Hökfelt and his coworkers. They found terminals and cell bodies containing endorphins in several areas of interest from the point of view of nociception. Thus the dorsal horn of the spinal cord, the corresponding area of the fifth cranial nerve and the periaqueductal gray matter contained such material.

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