scholarly journals Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 146 ◽  
Author(s):  
Fahim Ahmad ◽  
Qian Sun ◽  
Deven Patel ◽  
Jayne Stommel
Keyword(s):  
Brain Tumors ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
The Body ◽  
Adult Brain ◽  
Normal Brain ◽  
New Strategy ◽  
The Brain

Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

scholarly journals Vitamin C In Neuropsychiatry

2015 ◽  
Vol 16 (2) ◽  
pp. 157-161 ◽  
Author(s):  
Dragan M. Pavlović ◽  
Merdin Š. Markišić ◽  
Aleksandra M. Pavlović
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
The Body ◽  
Adult Brain ◽  
Normal Brain ◽  
Positive Effects ◽  
Normal Brain Function ◽  
High Concentrations ◽  
High Doses ◽  
The Brain

Abstract Vitamins are necessary factors in human development and normal brain function. Vitamin C is a hydrosoluble compound that humans cannot produce; therefore, we are completely dependent on food intake for vitamin C. Ascorbic acid is an important antioxidative agent and is present in high concentrations in neurons and is also crucial for collagen synthesis throughout the body. Ascorbic acid has a role in modulating many essential neurotransmitters, enables neurogenesis in adult brain and protects cells against infection. While SVCT1 enables the absorption of vitamin C in the intestine, SVCT2 is primarily located in the brain. Ascorbate deficiency is classically expressed as scurvy, which is lethal if not treated. However, subclinical deficiencies are probably much more frequent. Potential fields of vitamin C therapy are in neurodegenerative, cerebrovascular and affective diseases, cancer, brain trauma and others. For example, there is some data on its positive effects in Alzheimer’s disease. Various dosing regimes are used, but ascorbate is safe, even in high doses for protracted periods. Better designed studies are needed to elucidate all of the potential therapeutic roles of vitamin C.

scholarly journals Balancing cholesterol in the brain: from synthesis to disposal

2022 ◽  
pp. 1-27
Author(s):  
Lydia Qian ◽  
Amanda B. Chai ◽  
Ingrid C. Gelissen ◽  
Andrew J. Brown
Keyword(s):  
De Novo ◽  
Cholesterol Metabolism ◽  
Peripheral Circulation ◽  
The Body ◽  
Cholesterol Homeostasis ◽  
Myelin Sheaths ◽  
The Central Nervous System ◽  
Vital Component ◽  
The Brain ◽  
Limited Exchange

The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain.

Genetic defects in sterol synthesis, absorption, and degradation into bile acids

2011 ◽  
pp. 1673-1676
Author(s):  
Stefano Romeo
Keyword(s):  
Membrane Permeability ◽  
Bile Acids ◽  
Steroid Hormones ◽  
Cell Membranes ◽  
De Novo ◽  
Cholesterol Metabolism ◽  
The Body ◽  
Sterol Synthesis ◽  
Genetic Defects ◽  
And Function

Cholesterol is the most abundant steroid in animals. Not only is it a vital constituent of cell membranes, where it establishes proper membrane permeability and fluidity, but it is also the immediate metabolic precursor of all known steroid hormones and bile acids. Synthesized de novo in cells or absorbed from the diet, cholesterol circulates in the body in association with lipoproteins and is ultimately degraded into bile acids by the liver. Every perturbation of the numerous enzymes involved in cholesterol metabolism leads to impairment in the development and function of the gastrointestinal, cardiovascular, skeletal, and nervous systems.

scholarly journals The Steroidogenic Acute Regulatory Protein Is Expressed in Steroidogenic Cells of the Day-Old Brain

Endocrinology ◽  
2004 ◽  
Vol 145 (10) ◽  
pp. 4775-4780 ◽  
Author(s):  
Steven R. King ◽  
Stephen D. Ginsberg ◽  
Tomohiro Ishii ◽  
Roy G. Smith ◽  
Keith L. Parker ◽  
...  
Keyword(s):  
De Novo ◽  
Metastatic Lymph Node ◽  
Regulatory Protein ◽  
Cell Types ◽  
Adult Brain ◽  
Peripheral Tissues ◽  
Cytochrome P450scc ◽  
Star Protein ◽  
Steroidogenic Acute Regulatory ◽  
The Brain

Abstract Although recent research has focused on the fundamental role(s) of steroids synthesized de novo in the brain on development, the mechanism by which production of these neurosteroids is regulated remains unclear. Steroid production in peripheral tissues is acutely regulated by the steroidogenic acute regulatory (StAR) protein, which mediates the rate-limiting step in steroid biosynthesis: the intramitochondrial delivery of cholesterol to cytochrome P450scc for conversion to steroid. We recently demonstrated that StAR is present in discrete cell types in the adult brain, suggesting that neurosteroid production is mediated by StAR. Nevertheless, little is known regarding the presence of StAR in the developing brain. In the present study, the presence of StAR and for the first time, its homolog, the putative cholesterol transport protein metastatic lymph node 64 (MLN64), were defined in the neonatal mouse brain using immunocytochemical techniques. Both StAR and MLN64 were found to be present in the brain with staining patterns characteristic to each protein, indicating the authenticity of StAR and MLN64 immunoreactivity. Furthermore, we found MLN64 to be expressed in the adult brain as well, apparently at higher levels than StAR. Importantly, StAR protein is present in cells that also express P450scc. These data suggest that, as with the adult, neurosteroid production during development occurs through a StAR-mediated pathway.

scholarly journals The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling

2012 ◽  
Vol 367 (1607) ◽  
pp. 3264-3275 ◽  
Author(s):  
Melina Reisenberg ◽  
Praveen K. Singh ◽  
Gareth Williams ◽  
Patrick Doherty
Keyword(s):  
Dopaminergic Neurons ◽  
Cannabinoid Receptors ◽  
Homology Modelling ◽  
Detailed Examination ◽  
The Body ◽  
Adult Brain ◽  
And Migration ◽  
Regulatory Loop ◽  
Translational Mechanisms ◽  
The Brain

The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2-arachidonoylglycerol (2-AG), the most abundant ligand for the CB 1 and CB 2 cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB 1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity—however, key insights can be gleaned by homology modelling against other α/β hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function.

scholarly journals Cholesterol: Its Regulation and Role in Central Nervous System Disorders

Cholesterol ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Matthias Orth ◽  
Stefano Bellosta
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Metabolic Pathways ◽  
Cholesterol Metabolism ◽  
Major Constituent ◽  
Normal Brain ◽  
Lipoprotein Receptors ◽  
Brain Cholesterol ◽  
Brain Functions ◽  
The Brain

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

scholarly journals Effects of dietary cholesterol and fat on serum non-cholesterol sterols according to different apolipoprotein E subgroups among healthy men

2008 ◽  
Vol 100 (2) ◽  
pp. 373-379 ◽  
Author(s):  
Markku J. Nissinen ◽  
Helena Gylling ◽  
Tatu A. Miettinen
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Serum Levels ◽  
High Cholesterol ◽  
High Fat ◽  
Low Fat ◽  
Apo E ◽  
The Impact ◽  
Low Cholesterol

The impact of apo E phenotypes on applicability of relative cholesterol synthesis (lathosterol:cholesterol) and absorption (ratios of cholestanol, campesterol and sitosterol to cholesterol) during diets of various cholesterol and fat content is unclear. We examined and compared with each other both relative and absolute synthesis and absorption among twenty-nine men, of whom eight, nine and twelve had apo E phenotypes 2 (2/2, 2/3, 2/4), 3 (3/3) and 4 (3/4, 4/4), respectively. Serum lipids, lipoproteins, sterols and cholesterol metabolism were examined on four subsequent diets: high-cholesterol high-fat (home diet; HD), low-cholesterol low-fat (LCLF), high-cholesterol low-fat (HCLF) and low-cholesterol high-fat (LCHF). LDL-cholesterol (LDL-C) level was about 40 % lower (P < 0·05) in apo E2 than apo E3 and E4 groups irrespective of dietary fat and cholesterol. Serum proportions of phytosterols were determined apo E-dependently on LCLF and HCLF, and those of lathosterol, cholestanol and campesterol were increased in apo E2 and E3 groups (P < 0·05 for each v. HD). Serum proportion of sitosterol reflected almost consistently apo E phenotype (r range+0·308 to+0·383; P range 0·214–0·011). Relative cholesterol synthesis and absorption reflected respective absolute values during each diet in the apo E4 group (r range+0·713 to+0·893; P < 0·05 for each), but only during HD (r+0·594; P = 0·015) in the apo E2+E3 group. The consumption of a high amount of fat did not interfere with cholesterol metabolism or serum levels of LDL-C differently in apo E phenotypes. Surrogate sterol markers of cholesterol metabolism reflected absolute ones (especially in the apo E4 group) and apo E phenotypes despite variable amounts of dietary cholesterol and fat.

scholarly journals Interplay of Good Bacteria and Central Nervous System: Cognitive Aspects and Mechanistic Considerations

2021 ◽  
Vol 15 ◽  
Author(s):  
Mahmoud Salami
Keyword(s):  
Gut Microbiota ◽  
Cognitive Processing ◽  
Clinical Problem ◽  
The Body ◽  
Brain Diseases ◽  
Normal Brain ◽  
Beneficial Effects ◽  
Normal Brain Function ◽  
The Brain ◽  
Common Clinical Problem

The human gastrointestinal tract hosts trillions of microorganisms that is called “gut microbiota.” The gut microbiota is involved in a wide variety of physiological features and functions of the body. Thus, it is not surprising that any damage to the gut microbiota is associated with disorders in different body systems. Probiotics, defined as living microorganisms with health benefits for the host, can support or restore the composition of the gut microbiota. Numerous investigations have proved a relationship between the gut microbiota with normal brain function as well as many brain diseases, in which cognitive dysfunction is a common clinical problem. On the other hand, increasing evidence suggests that the existence of a healthy gut microbiota is crucial for normal cognitive processing. In this regard, interplay of the gut microbiota and cognition has been under focus of recent researches. In the present paper, I review findings of the studies considering beneficial effects of either gut microbiota or probiotic bacteria on the brain cognitive function in the healthy and disease statuses.

scholarly journals Anatomical Differences between Children and Adults

2020 ◽  
Vol 8 (05) ◽  
pp. 355-359
Author(s):  
Rengin Kosif ◽  
Rabia Keçialan
Keyword(s):  
Subcutaneous Tissue ◽  
Vastus Lateralis ◽  
Rectus Femoris ◽  
The Body ◽  
Adult Brain ◽  
Skeletal Structure ◽  
School Age ◽  
Pediatric Drug ◽  
Gynecological Examination ◽  
The Brain

In this review,   anatomical differences between  child   and   adult   were   mentioned.   These differences are especially apparent in infancy and preschool term. When the child reaches the school age term, the differences begin to decrease gradually.  When the child reaches the age of 18, the child has the same characteristics as the adult. The main differences include skin, subcutaneous tissue, total amount of water in the body, muscles preferred in pharmaceutical applications,   external   ear   structure,   Eustachian   tube,   anatomy   of   the   eye,   bone   skeletal structure, spinal cord and brain, respiratory tract, digestive organs, cardiovascular system and urinary system. The differences especially between child and adult brain structure are striking. The brain tissue in the child is more sensitive, calvarium is thinner, subarachnoid space is narrower.   Morover;   the   differences   in   gynecological   examination   and   lumber   puncture practices   were   also   reviewed.  In   adults,   gluteal   muscles   are   used   in   intramuscular applications, while in infants, rectus femoris and vastus lateralis muscles are commonly used. These anatomical differences are important for the diagnosis and treatment of the doctors. Nurses should take these differences into account in pediatric drug applications in the clinic and in the care of children. Clinicians should know that children are not small adults.

scholarly journals IMMU-13. CUSTOMIZABLE MULTI-LAMELLAR RNA-NANOPARTICLES FOR PEDIATRIC GLIOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i29-i30
Author(s):  
Hector Mendez-Gomez ◽  
James McGuiness ◽  
Adam grippin ◽  
Frances Weidert ◽  
Sheila Carrera-Justiz ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Brain Tumors ◽  
Messenger Rna ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Therapeutic Benefit ◽  
Cross Reactivity ◽  
Large Animal ◽  
Normal Brain ◽  
Lipid Nanoparticle

Abstract Background Since the preponderance of pediatric gliomas are mutationally ‘bland,’ immune checkpoint inhibitors are unlikely to mediate therapeutic benefit. Alternately, immunologic response can be induced de novo against pediatric gliomas with mRNA cancer vaccines. Messenger RNA represents a paradigm shift in vaccinology (i.e. COVID-19) given its flexibility, commercialization, and propensity to confer rapid protection with only a single vaccine. Objective We sought to develop a new mRNA platform with an optimized backbone for insertion of both personalized and/or “off the shelf’ (i.e. H3K27M) transcripts for rapid induction of anti-tumor activity against pediatric gliomas. Approach We synthesized an mRNA backbone with optimized 5’ and 3’ UTRs for delivery of gene transcripts pertinent to pediatric brain tumors using a lipid-nanoparticle (NP) delivery vehicle. This vaccine utilizes a novel engineering design that layers tumor derived mRNA into a lipid-nanoparticle (NP) “onion-like” or multi-lamellar package. Results We demonstrate immunogenicity of RNA-NPs delivering either personalized glioma mRNA or H3K27M mRNA. RNA-NPs localize to myeloid cells in murine KR158b brain tumors and activate dendritic cells that supplant regulatory intratumoral myeloid populations inducing antigen-recall response with long-term survivor benefit. Our optimized mRNA backbone yielded significantly improved anti-tumor efficacy compared with commercial backbones. We have shown this approach can be refined for co-delivery of immunomodulatory RNAs (i.e. GM-CSF) and/or delivery of siRNAs targeting immunoregulatory axes (PD-L1) in murine brain tumors (GL261). We have since established safety of RNA-NPs in acute/chronic murine GLP toxicity studies without cross-reactivity to normal-brain, and launched a large-animal canine brain tumor trial which demonstrated RNA-NPs to be feasible, safe and immunologically active. Conclusion RNA-NPs reprogram the brain tumor microenvironment while inducing a glioma-specific immune response. We have since received FDA-IND approval for first-in-human trials (IND#BB-19304) in pediatric patients with high-grade gliomas (PNOC020 study, NCT04573140).

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