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04/16/2003 Archived Entry: "Blood-Brain Barrier Cumulative Notes"
Blood-Brain Barrier Cumulative Notes:
BBB has significant implications; the topic is not getting deserved attention ... working notes continue.
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04/06/2003 Archived Entry: "BLOOD-BRAIN BARRIER"
BLOOD-BRAIN BARRIER - explore relationships between BLOOD-BRAIN BARRIER and disorders due to improper filters.
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04/08/2003 Archived Entry: "BLOOD-BRAIN BARRIER Zonulin and zot"
According to a University of Maryland Medical News Release:
The blood-brain barrier is a collection of cells that press together to block many substances from entering the brain, while allowing others to pass. For years, scientists knew little about how this barrier was regulated or why certain diseases are able to manipulate the barrier and infect the brain.Earlier research conducted at the University of Maryland School of Medicine found that two proteins, known as zonulin and zot, unlock the cell barrier in the intestine. The proteins attach themselves to receptors in the intestine to open the junctions between the cells and allow substances to be absorbed. The new research indicates that zonulin and zot also react with similar receptors in the brain.
At least according to Alessio Fasano, M.D., ... OH the press release is dated January 3, 2000, so I a little behind ... (did I say that correctly?) ... will the news hold? How come its not 80 point font on the NY Times front page?
continues earlier note. NEW NEW
Further readings on B3s
New Concepts of a Blood-Brain Barrier by John Greenwood
The Blood-Brain Barrier: Biology and Research Protocols (Methods in Molecular Medicine, 89) by Sukriti Nag
The Blood-Brain Barrier and Drug Delivery to the CNS by D. J. Begley
Brain Drug Targeting : The Future of Brain Drug Development by William M. Pardridge
Blood-Brain Barrier: Drug Delivery and Brain Pathology by Oholo Conference on Blood-Brain Barrier
Drug Transport Across the Blood-brain Barrier: In Vitro and In Vivo Techniques by A. G. De Boer (Editor), Win Sutanto (Editor)
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04/16/2003 Archived Entry: "Zonulin unappreciated, but important! Key to the blood-brain barrier."
WHAT DO YOU KNOW ABOUT ZONULIN? I have to admit, until a few days ago, I knew nothing about Zonulin ... its all about to change ... According to a University of Maryland Medical News press release (RESEARCHERS FIND INCREASED ZONULIN LEVELS AMONG CELIAC DISEASE PATIENTS):
Researchers at the University of Maryland School of Medicine have found that the human protein zonulin, which regulates the permeability of the intestine, is at increased levels during the acute phase of celiac disease. The discovery suggests that increased levels of zonulin are a contributing factor to the development of celiac disease and other autoimmune disorders such as insulin dependent diabetes, multiple sclerosis, and rheumatoid arthritis. The findings are published in the April 29 issue of the journal Lancet.
“Zonulin works like the traffic conductor or the gatekeeper of our body’s tissues,” says lead author Alessio Fasano, M.D., professor of pediatrics and physiology at the University of Maryland School of Medicine, and director of Pediatric Gastroenterology and Nutrition at the University of Maryland Hospital for Children. “Our largest gateway is the intestine with its billions of cells. Zonulin opens the spaces between cells allowing some substances to pass through while keeping harmful bacteria and toxins out,” explains Dr. Fasano.
Earlier research conducted by Dr. Fasano discovered that zonulin is also involved in the regulation of the impenetrable barrier between the blood stream and the brain, known as the blood-brain barrier.
FASANO REVIEWS THE TOPIC in "Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin." Ann N Y Acad Sci 2000;915:214-22
(ABSTRACT): "The intestinal epithelium represents the largest interface between the external environment and the internal host milieu and constitutes the major barrier through which molecules can either be absorbed or secreted. There is now substantial evidence that tight junctions (tj) play a major role in regulating epithelial permeability by influencing paracellular flow of fluid and solutes. Tj are one of the hallmarks of absorptive and secretory epithelia. Evidence now exists that tj are dynamic rather than static structures and readily adapt to a variety of developmental, physiological, and pathological circumstances. These adaptive mechanisms are still incompletely understood. Activation of PKC either by Zonula occludens toxin (Zot) or by phorbol esters increases paracellular permeability. Alteration of epithelial tj is a recently described property for infectious agents. Clostridium difficile toxin A and B and influenza and vesicular stomatitis viruses have been shown to loosen tj in tissue culture monolayers. Unlike what occurs after the Zot stimulus, these changes appear to be irreversible and are associated with destruction of the tj complex. On the basis of this observation, we postulated that Zot may mimic the effect of a functionally and immunologically related endogenous modulator of epithelial tj. We were able to identify an intestinal Zot analogue, which we named zonulin. It is conceivable that the zonulins participate in the physiological regulation of intercellular tj not only in the small intestine, but also throughout a wide range of extraintestinal epithelia as well as the ubiquitous vascular endothelium, including the blood-brain barrier. Disregulation of this hypothetical zonulin model may contribute to disease states that involve disordered intercellular communication, including developmental and intestinal disorders, tissue inflammation, malignant transformation, and metastasis
JOURNAL REFERENCES:
1: Marinaro M, Fasano A, De Magistris MT.
Zonula Occludens Toxin Acts as an Adjuvant through Different Mucosal Routes and
Induces Protective Immune Responses.
Infect Immun. 2003 Apr;71(4):1897-902.
2: Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR,
Drago S, Congia M, Fasano A.
Early effects of gliadin on enterocyte intracellular signalling involved in
intestinal barrier function.
Gut. 2003 Feb;52(2):218-23.
3: El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, Catassi C,
Fasano A, El Asmar R.
Host-dependent zonulin secretion causes the impairment of the small intestine
barrier function after bacterial exposure.
Gastroenterology. 2002 Nov;123(5):1607-15.
4: Fasano A.
Intestinal zonulin: open sesame!
Gut. 2001 Aug;49(2):159-62. No abstract available.
5: Di Pierro M, Lu R, Uzzau S, Wang W, Margaretten K, Pazzani C, Maimone F,
Fasano A.
Zonula occludens toxin structure-function analysis. Identification of the
fragment biologically active on tight junctions and of the zonulin receptor
binding domain.
J Biol Chem. 2001 Jun 1;276(22):19160-5.
6: Fasano A.
Regulation of intercellular tight junctions by zonula occludens toxin and its
eukaryotic analogue zonulin.
Ann N Y Acad Sci. 2000;915:214-22. Review.
7: Wang W, Uzzau S, Goldblum SE, Fasano A.
Human zonulin, a potential modulator of intestinal tight junctions.
J Cell Sci. 2000 Dec;113 Pt 24:4435-40.
8: Fasano A, Not T, Wang W, Uzzau S, Berti I, Tommasini A, Goldblum SE.
Zonulin, a newly discovered modulator of intestinal permeability, and its
expression in coeliac disease.
Lancet. 2000 Apr 29;355(9214):1518-9.
9: Lu R, Wang W, Uzzau S, Vigorito R, Zielke HR, Fasano A.
Affinity purification and partial characterization of the zonulin/zonula
occludens toxin (Zot) receptor from human brain.
J Neurochem. 2000 Jan;74(1):320-6.
Related Books:
Introduction to the Blood-Brain Barrier : Methodology, Biology and Pathology
by William M. Pardridge
Drug Transport Across the Blood-brain Barrier: In Vitro and In Vivo Techniques
by A. G. De Boer (Editor), Win Sutanto (Editor)
Membrane Transport of Antineoplastic Agents
by I. David
The Blood-Brain Barrier: Biology and Research Protocols (Methods in Molecular Medicine, 89)
by Sukriti Nag
New Concepts of a Blood-Brain Barrier
by John Greenwood
The Blood-Brain Barrier and Drug Delivery to the CNS
by D. J. Begley
The Cerebral Microvasculature: Investigation of the Blood-Brain Barrier
by Eisenberg
Replies: 4 comments
From: Nature 397, 569 - 570 (1999) - Stem cells: Breaking the brain-blood barrier (ANDERS BJORKLUND AND CLIVE SVENDSEN2)
We are used to associating stem cells with renewable tissues such as blood, gut and skin. But some cells in the adult central nervous system have the capacity to generate new neurons and glial cells (astrocytes and oligodendrocytes) and, as such, they are considered to be neural stem cells. These remarkable cells can be isolated from the subventricular zone in the wall of the lateral ventricle of the brain, and they divide in response to epidermal growth factor and fibroblast growth factor-2. But their exact nature has proved elusive. They have been proposed to reside in the subventricular zone, where they constitute a small population (0.1-1%) of relatively quiescent cells. On dividing (which is a rare event), they give rise to both neuronal and glial progeny.
It now comes as a surprise that these neural stem cells may reside not in the subventricular zone but, according to Johansson et al.1, in the overlying ventricular lining. This layer, the ependyma, has all the features of a differentiated, post-mitotic epithelium, and the authors provide compelling evidence that the ependymal cells are neural stem cells. These cells were found to express immature neural markers, consistent with a stem-cell function.
Posted by EM - additional notes @ 04/16/2003 09:57 PM CST
S. Fischer, A. Reinel, M. Wiesnet†, D. Renz and W. Schaper in "Effect of hypoxia on the expression of tight junction proteins in endothelial and epithelial cells" [The Journal of Physiology (2002). 539P 48P] find:
"Hypoxia is known to increase the permeability across endothelial as well as epithelial cell monolayers, which in vivo can lead to the development of vasogenic oedema. The paracellular permeability across these cell monolayers is regulated by specialized intercellular structures like the tight junctions (TJ). Tight junctions in epithelial cells are much stronger than those in endothelial cells, which was confirmed by measurements of the transcellular resistance values across cell monolayers consisting of murine submandibular gland carcinoma cells (CSG) and brain-derived microvascular endothelial cells (BMEC). Hypoxia-induced hyper-permeability of BMEC and CSG was prevented in the presence of a neutralizing antibody to vascular endothelial growth factor (VEGF) and by the nitric oxide synthase inhibitor N G-monomethyl-L-arginine, suggesting that hypoxia-induced permeability in CSG is mediated by a mechanism similar to that in BMEC."
Posted by EM reHypoxia and BBB @ 04/16/2003 10:06 PM CST
Zonulin is being marketed (http://www.qxhealth.com/licensing/cfml/Details.cfm?sum_ID=374) for Arthritis rheumatoid, Asthma, Diabetes insulin dependent, diabetes mellitus IDDM, Immune disorders, Inflammatory bowel disease IBD, Inflammatory disorders, Multiple sclerosis
Transplant rejection, cleiac disease Sijogren syndrome.
According to note, patent was applied for, Mechanism: Zonulin is an endogenous mammalian family of proteins which are well known to increase tight junction permeability in epithelial cells. Research has shown that these molecules inhibit macrophage-mediated antigen-specific lymphocyte proliferation in a dose-dependent manner. The mechanism involves specific and saturable binding of the zonulin molecule to a macrophage surface recptor, which appears to inhibit antigen uptake.
Additionally, its stated that "
Zonulin strongly suppresses tetanus toxin immune response in flow cytometry experiments ... and ... Zonulin inhibits FITC-dextran uptake by macrophages Zonulin induces cytokine production."
Analysis anyone?
Posted by EM re Zonulin marketing @ 04/16/2003 11:20 PM CST
From (http://www1.odn.ne.jp/~cam39380/epage/epage151.htm) [includes neat cartoon)
... Several years ago, while trying to develop a cholera vaccine, Alenso Fasano of the University of Maryland School of Medicine in Baltimore discovered that cholera bacteria (Vibrio cholerae) produced a toxin called zot. He found that this protein makes the wall of the small intestine more permeable by opening up the cell 'junction' that normally stop large molecules getting through the intestine walls.
"Fasano went on to show in animals that this protein could make the gut absorb large molecules such as insulin. A similar human protein called zonulin had the same effect.
"To find out if these protein also break Head guard: the blood-brain barrier stops drugs entering the brain down the BBB, Fasano treated brain tissue samples with zot and zonulin. Sure enough, both the proteins bound to receptors in the tissue that seem to open the junctions between cells. ...
Posted by EM: Cholera research leads to zot & zonulin @ 04/16/2003 11:36 PM CST
Replies: 1 Comment
"Always changing; everything for good, nothing for nothing."—Flying Hawk, Sioux Chief
From "The Blood-Brain Barrier
A Background Briefing by Dennis Blakeslee, PhD" - Posted May 5, 1997 on (http://www.ama-assn.org/special/hiv/newsline/briefing/bbb.htm>
)[no longer available on web]
... the barrier exists between the blood and the central nervous system, the brain and the spinal cord. A similar barrier exists between the blood and the retina of the eye
... the endothelial cell linings of the capillaries in the brain are tightly packed, with no gaps between them. As a result, no constituents of the blood, apart from water, can diffuse freely across the endothelial layer. Those elements required by the brain, such as glucose and other nutrients, are actively transported by the cells into the CSF and the thin layers of liquid that surround and bathe each brain cells ...
This barrier's most important function is to help provide neurons with their exact nutritional requirements. Glucose is the sole source of energy for these cells -- the adult brain converts about 100 g of glucose to energy each day -- and they depend on a steady supply at an exact concentration. Indeed, neurons exposed to levels of glucose even slightly higher or lower than the optimal concentration quickly begin to malfunction.
... Another important task of the blood-brain barrier is to maintain the proper ion balance within the brain ...
... Compounds that are highly water soluble are almost universally excluded from the brain. On the other hand, molecules that are soluble in lipids dissolve readily in the membranes of the endothelial cells, pass through the cells, and diffuse out the other side into the brain space. ... AZT, one of the few anti-HIV drugs that can enter the brain, is believed to be able to do so by its close resemblance to thymidine, one of the constituents of DNA and RNA
Posted by more notes @ 04/16/2003 10:56 PM CST