scholarly journals Human CNS barrier-forming organoids with cerebrospinal fluid production

Science ◽  
2020 ◽  
Vol 369 (6500) ◽  
pp. eaaz5626 ◽  
Author(s):  
Laura Pellegrini ◽  
Claudia Bonfio ◽  
Jessica Chadwick ◽  
Farida Begum ◽  
Mark Skehel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Secretion ◽  
Fluid Production ◽  
New Compounds ◽  
High Degree ◽  
The Brain ◽  
Degree Of Similarity ◽  
By Products

Cerebrospinal fluid (CSF) is a vital liquid, providing nutrients and signaling molecules and clearing out toxic by-products from the brain. The CSF is produced by the choroid plexus (ChP), a protective epithelial barrier that also prevents free entry of toxic molecules or drugs from the blood. Here, we establish human ChP organoids with a selective barrier and CSF-like fluid secretion in self-contained compartments. We show that this in vitro barrier exhibits the same selectivity to small molecules as the ChP in vivo and that ChP-CSF organoids can predict central nervous system (CNS) permeability of new compounds. The transcriptomic and proteomic signatures of ChP-CSF organoids reveal a high degree of similarity to the ChP in vivo. Finally, the intersection of single-cell transcriptomics and proteomic analysis uncovers key human CSF components produced by previously unidentified specialized epithelial subtypes.

The influx of amino acids into the brain of the rat in vivo : the essential compared with some non-essential amino acids

1973 ◽  
Vol 183 (1070) ◽  
pp. 59-70 ◽  
Keyword(s):  
Amino Acids ◽  
Specific Activity ◽  
Essential Amino Acids ◽  
Transport Processes ◽  
Carrier Mediated Transport ◽  
A New Technique ◽  
High Degree ◽  
The Brain

The cerebral influx rates of fifteen amino acids were measured directly in living rats by means of a new technique which makes it possible to maintain a constant specific activity of a radioactively labelled amino acid in the bloodstream. A wide variation in the influx rates of the amino acids was found. These rates differed from those found by other workers using in vitro preparations, but are consistent with the theory that amino acids enter the brain mainly by carrier mediated transport processes with a high degree of specificity. There are a number of important differences between the behaviour of the transport processes in vivo and in vitro . The influx rates of the various amino acids were directly proportional to their concentra­tions in blood plasma (over the range of concentrations studied). All the nutritionally essential amino acids had relatively high influx rates as did other amino acids which the brain does not seem to be able to synthesize. On the other hand, amino acids that the brain can readily synthesize and two amino acids which are not normally found in mammalian tissues had low influx rates.

scholarly journals Direct Physical and Functional Interaction of the NuA4 Complex Components Yaf9p and Swc4p

2004 ◽  
Vol 3 (4) ◽  
pp. 976-983 ◽  
Author(s):  
Claudia B. Bittner ◽  
Deniz T. Zeisig ◽  
Bernd B. Zeisig ◽  
Robert K. Slany
Keyword(s):  
Transcriptional Activation ◽  
Dna Methyltransferase ◽  
Chromatin Modification ◽  
Gel Filtration ◽  
Dominant Negative ◽  
Yeast Homolog ◽  
High Degree ◽  
Degree Of Similarity

ABSTRACT Saccharomyces cerevisiae Yaf9p and the mammalian leukemia-associated protein ENL share a high degree of similarity. To investigate the biological function of Yaf9p, this protein was used to search for interacting proteins in a two-hybrid system. Here, we demonstrate that Yaf9p binds directly to Swc4p, the yeast homolog of the mammalian DNA-methyltransferase-associated protein 1. Yaf9p and Swc4p associate through C-terminal domains, and both proteins coprecipitate in vitro in pull-down experiments and in vivo by immunoprecipitation. In living cells, Swc4p is present in a megadalton protein complex that shows a fractionation behavior in gel filtration similar to that of Esa1p, the histone acetyltransferase of the NuA4 complex. Recruitment of Yaf9p to DNA leads to promoter-specific transcriptional activation that can be inhibited by dominant negative Swc4p lacking the Yaf9p binding domain. Interference with Swc4p function also increases sensitivity to the microtubule toxin benomyl, a trait that corresponds to the known phenotype of a yaf9 − knockout strain. In summary, the results suggest that Yaf9p and Swc4p form a protein pair that has a role in chromatin modification with possible implications also for the function of their mammalian counterparts.

Cerebrospinal Fluid, Brain Electrolytes Balance, and the Unsuspected Intrinsic Property of Melanin to Dissociate the Water Molecule

2018 ◽  
Vol 17 (10) ◽  
pp. 743-756 ◽  
Author(s):  
Arturo Solís Herrera ◽  
Ghulam Md Ashraf ◽  
María del Carmen Arias Esparza ◽  
Vadim V. Tarasov ◽  
Vladimir N. Chubarev ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Extracellular Fluid ◽  
Intrinsic Property ◽  
Fluid Secretion ◽  
Current View ◽  
Formidable Challenge ◽  
Fluid Production ◽  
Fluid Transfer ◽  
The Brain

Background & Objective: Regulation of composition, volume and turnover of fluids surrounding the brain and damp cells is vital. These fluids transport all substances required for cells and remove the unwanted materials. This regulation tends to act as barrier to prevent free exchange of materials between the brain and blood. There are specific mechanisms concerned with fluid secretion of the controlled composition of the brain, and others responsible for reabsorption eventually to blood and the extracellular fluid whatever their composition is. The current view assumes that choroidal plexuses secrete the major part of Cerebrospinal Fluid (CSF), while the Blood-Brain Barrier (BBB) has a much less contribution to fluid production, generating Interstitial Fluid (ISF) that drains to CSF. The skull is a rigid box; thereby the sum of volumes occupied by the parenchyma with its ISF, related connective tissue, the vasculature, the meninges and the CSF must be relatively constant according to the Monroe-Kellie dogma. This constitutes a formidable challenge that normal organisms surpass daily. The ISF and CSF provide water and solutes influx and efflux from cells to these targeted fluids in a quite precise way. Microvessels within the parenchyma are sufficiently close to every cell where diffusion areas for solutes are tiny. Despite this, CSF and ISF exhibit very similar compositions, but differ significantly from blood plasma. Many hydrophilic substances are effectively prevented from the entry into the brain via blood, while others like neurotransmitters are extremely hindered from getting out of the brain. Anatomical principle of the barrier and routes of fluid transfer cannot explain the extraordinary accuracy of fluids and substances needed to enter or leave the brain firmly. There is one aspect that has not been deeply analyzed, despite being prevalent in all the above processes, it is considered a part of the CSF and ISF dynamics. This aspect is the energy necessary to propel them properly in time, form, space, quantity and temporality. Conclusion: The recent hypothesis based on glucose and ATP as sources of energy presents numerous contradictions and controversies. The discovery of the unsuspected intrinsic ability of melanin to dissociate and reform water molecules, similar to the role of chlorophyll in plants, was confirmed in the study of ISF and CSF biology.

scholarly journals Leukocyte Recruitment in the Cerebrospinal Fluid of Mice with Experimental Meningitis Is Inhibited by an Antibody to Junctional Adhesion Molecule (Jam)

1999 ◽  
Vol 190 (9) ◽  
pp. 1351-1356 ◽  
Author(s):  
Aldo Del Maschio ◽  
Ada De Luigi ◽  
Ines Martin-Padura ◽  
Manfred Brockhaus ◽  
Tamas Bartfai ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Adhesion Molecule ◽  
Brain Parenchyma ◽  
Immunoglobulin Superfamily ◽  
Leukocyte Transmigration ◽  
Leukocyte Accumulation ◽  
Brain Barrier Permeability ◽  
The Brain

The mechanisms that govern leukocyte transmigration through the endothelium are not yet fully defined. Junctional adhesion molecule (JAM) is a newly cloned member of the immunoglobulin superfamily which is selectively concentrated at tight junctions of endothelial and epithelial cells. A blocking monoclonal antibody (BV11 mAb) directed to JAM was able to inhibit monocyte transmigration through endothelial cells in in vitro and in vivo chemotaxis assays. In this study, we report that BV11 administration was able to attenuate cytokine-induced meningitis in mice. The intravenous injection of BV11 mAb significantly inhibited leukocyte accumulation in the cerebrospinal fluid and infiltration in the brain parenchyma. Blood–brain barrier permeability was also reduced by the mAb. We conclude that JAM may be a new target in limiting the inflammatory response that accompanies meningitis.

scholarly journals Glucocorticoids reset circadian clock in choroid plexus via period genes

2020 ◽  
Author(s):  
Karolína Liška ◽  
Martin Sládek ◽  
Vendula Čečmanová ◽  
Alena Sumová
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Glucocorticoid Receptors ◽  
Clock Gene ◽  
Time Of Day ◽  
The Body ◽  
Surgical Removal ◽  
The Brain

The epithelial cells of choroid plexus (CP) in brain ventricles produce cerebrospinal fluid and act as the blood-cerebrospinal fluid barrier. In this study, we confirmed that CP in the 4th ventricle is composed of cellular oscillators that all harbor glucocorticoid receptors and are mutually synchronized to produce a robust clock gene expression rhythm detectable at the tissue level in vivo and in vitro. Animals lacking glucocorticoids (GCs) due to surgical removal of adrenal glands had Per1, Per2, Nr1d1 and Bmal1 clock gene rhythmicity in their CP significantly dampened, whereas subjecting them to daily bouts of synthetic GC analog, dexamethasone (DEX), reinforced those rhythms. We verified these in vivo effects using an in vitro model of organotypic CP explants; depending on time of its application, DEX significantly increased the amplitude and efficiently reset the phase of the CP clock. The results are the first description of a PRC for a non-neuronal clock in the brain, demonstrating that CP clock shares some properties with the non-neuronal clocks elsewhere in the body. Finally, we found that DEX exhibited multiple synergic effects on the CP clock, including acute activation of Per1 expression and change of PER2 protein turnover rate. The DEX-induced shifts of the CP clock were partially mediated via PKA-ERK1/2 pathway. The results provide first evidence that the GC rhythm strengthens and entrains the clock in the CP helping thus fine-tune the brain environment according to time of day.

scholarly journals Apple Fermented Products: An Overview of Technology, Properties and Health Effects

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 223
Author(s):  
Raquel P. F. Guiné ◽  
Maria João Barroca ◽  
Teodora Emilia Coldea ◽  
Elena Bartkiene ◽  
Ofélia Anjos
Keyword(s):  
Alcoholic Fermentation ◽  
Sensory Profile ◽  
Physical Chemical ◽  
Health Promoting ◽  
Sensory Profiles ◽  
High Degree ◽  
Harmful Effects ◽  
By Products

As an easily adapted culture, with overloaded production in some parts of the globe, apples and their by-products are being redirected to pharmaceutical, canning and beverages industries, both alcoholic and non-alcoholic. Fermentation is generally considered to increase the bioavailability of bioactive compounds found in apple, by impacting, through a high degree of changes, the product’s properties, including composition and health-promoting attributes, as well as their sensory profile. Probiotic apple beverages and apple vinegar are generally considered as safe and healthy products by the consumers. Recently, contributions to human health, both in vivo and in vitro studies, of non-alcoholic fermented apple-based products have been described. This review highlighted the advances in the process optimization of apple-based products considering vinegar, cider, pomace, probiotic beverages and spirits’ technologies. The different processing impacts on physical-chemical, nutritional and sensory profiles of these products are also presented. Additionally, the harmful effects of toxic compounds and strategies to limit their content in cider and apple spirits are illustrated. New trends of fermented apple-based products applicability in tangential industries are summarized.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

2020 ◽  
Vol 17 (3) ◽  
pp. 229-245
Author(s):  
Gang Wang ◽  
Junjie Wang ◽  
Rui Guan
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Oral Delivery ◽  
Safe Delivery ◽  
Drug Delivery Vehicles ◽  
Therapeutic Benefits ◽  
Delivery Vehicles ◽  
The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

Electromagnetic field in Alzheimer’s disease: a literature review of recent preclinical and clinical studies

2020 ◽  
Vol 17 ◽  
Author(s):  
Reem Habib Mohamad Ali Ahmad ◽  
Marc Fakhoury ◽  
Nada Lawand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
In Vivo Studies ◽  
Key Factors ◽  
Potential Benefits ◽  
Preclinical And Clinical Studies ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive loss of neurons leading to cognitive and memory decay. The main signs of AD include the irregular extracellular accumulation of amyloidbeta (Aβ) protein in the brain and the hyper-phosphorylation of tau protein inside neurons. Changes in Aβ expression or aggregation are considered key factors in the pathophysiology of sporadic and early-onset AD and correlate with the cognitive decline seen in patients with AD. Despite decades of research, current approaches in the treatment of AD are only symptomatic in nature and are not effective in slowing or reversing the course of the disease. Encouragingly, recent evidence revealed that exposure to electromagnetic fields (EMF) can delay the development of AD and improve memory. This review paper discusses findings from in vitro and in vivo studies that investigate the link between EMF and AD at the cellular and behavioural level, and highlights the potential benefits of EMF as an innovative approach for the treatment of AD.

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