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American Journal of Physiology. Cell... Feb 2019As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and... (Review)
Review
As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain Ischemia; Endothelial Cells; Humans; Inflammation Mediators; Oxidative Stress; Permeability; Stroke; Tight Junctions
PubMed: 30379577
DOI: 10.1152/ajpcell.00136.2018 -
Brain Research Aug 2022The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic... (Review)
Review
The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic microenvironment. All constituent cell types play indispensable roles in the BBB's integrity, and other structural BBB components, such as tight junction proteins, adherens junctions, and junctional proteins, can control the barrier permeability. Regarding the need to exchange nutrients and toxic materials, solute carriers, ATP-binding case families, and ion transporter, as well as transcytosis regulate the influx and efflux transport, while the difference in localisation and expression can contribute to functional differences in transport properties. Numerous chemical mediators and other factors such as non-physicochemical factors have been identified to alter BBB permeability by mediating the structural components and barrier function, because of the close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into the maintenance and disruption of the BBB. A better understanding of the factors influencing BBB permeability could contribute to supporting promising potential therapeutic targets for protecting the BBB and the delivery of central nervous system drugs via BBB permeability interventions under pathological conditions.
Topics: Biological Transport; Blood-Brain Barrier; Brain; Humans; Permeability; Tight Junction Proteins; Tight Junctions
PubMed: 35568085
DOI: 10.1016/j.brainres.2022.147937 -
Physiological Reviews Apr 2013Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction... (Review)
Review
Claudins are tight junction membrane proteins that are expressed in epithelia and endothelia and form paracellular barriers and pores that determine tight junction permeability. This review summarizes our current knowledge of this large protein family and discusses recent advances in our understanding of their structure and physiological functions.
Topics: Animals; Claudins; Epithelium; Gene Expression Regulation; Humans; Permeability; Signal Transduction; Tight Junctions
PubMed: 23589827
DOI: 10.1152/physrev.00019.2012 -
Cold Spring Harbor Perspectives in... Jan 2018Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste... (Review)
Review
Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.
Topics: Animals; Humans; Immunity, Mucosal; Interleukin-13; Intestinal Mucosa; Mucous Membrane; Myosin-Light-Chain Kinase; Permeability; Tight Junctions; Zonula Occludens-1 Protein
PubMed: 28507021
DOI: 10.1101/cshperspect.a029314 -
Neurogastroenterology and Motility Jun 2012Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal... (Review)
Review
Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…
Topics: Humans; Intestinal Diseases; Intestinal Mucosa; Intestines; Tight Junctions
PubMed: 22583600
DOI: 10.1111/j.1365-2982.2012.01921.x -
Animal Science Journal = Nihon Chikusan... 2020Tight junctions (TJs) play an important role in intestinal barrier function. TJs in intestinal epithelial cells are composed of different junctional molecules, such as... (Review)
Review
Tight junctions (TJs) play an important role in intestinal barrier function. TJs in intestinal epithelial cells are composed of different junctional molecules, such as claudin and occludin, and regulate the paracellular permeability of water, ions, and macromolecules in adjacent cells. One of the most important roles of the TJ structure is to provide a physical barrier to luminal inflammatory molecules. Impaired integrity and structure of the TJ barrier result in a forcible activation of immune cells and chronic inflammation in different tissues. According to recent studies, the intestinal TJ barrier could be regulated, as a potential target, by dietary factors to prevent and reduce different inflammatory disorders, although the precise mechanisms underlying the dietary regulation remain unclear. This review summarizes currently available information on the regulation of the intestinal TJ barrier by food components.
Topics: Animal Nutritional Physiological Phenomena; Animals; Body Water; Claudins; Epithelial Cells; Food; Inflammation; Intestines; Nutrients; Permeability; Tight Junctions
PubMed: 32219956
DOI: 10.1111/asj.13357 -
International Journal of Molecular... Sep 2020Constant remodeling of tight junctions to regulate trans-epithelial permeability is essential in maintaining intestinal barrier functions and thus preventing diffusion... (Review)
Review
Constant remodeling of tight junctions to regulate trans-epithelial permeability is essential in maintaining intestinal barrier functions and thus preventing diffusion of small molecules and bacteria to host systemic circulation. Gut microbiota dysbiosis and dysfunctional gut barrier have been correlated to a large number of diseases such as obesity, type 2 diabetes and inflammatory bowel disease. This led to the hypothesis that gut bacteria-epithelial cell interactions are key regulators of epithelial permeability through the modulation of tight junctions. Nevertheless, the molecular basis of host-pathogen interactions remains unclear mostly due to the inability of most in vitro models to recreate the differentiated tissue structure and components observed in the normal intestinal epithelium. Recent advances have led to the development of a novel cellular model derived from intestinal epithelial stem cells, the so-called organoids, encompassing all epithelial cell types and reproducing physiological properties of the intestinal tissue. We summarize herein knowledge on molecular aspects of intestinal barrier functions and the involvement of gut bacteria-epithelial cell interactions. This review also focuses on epithelial organoids as a promising model for epithelial barrier functions to study molecular aspects of gut microbiota-host interaction.
Topics: Animals; Cell Membrane Permeability; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Intestinal Mucosa; Tight Junctions
PubMed: 32899147
DOI: 10.3390/ijms21176402 -
American Journal of Physiology. Cell... Sep 2018The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely controls cerebral homeostasis. It also plays a central role in the regulation of... (Review)
Review
The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely controls cerebral homeostasis. It also plays a central role in the regulation of blood-to-brain flux of endogenous and exogenous xenobiotics and associated metabolites. This is accomplished by molecular characteristics of brain microvessel endothelial cells such as tight junction protein complexes and functional expression of influx and efflux transporters. One of the pathophysiological features of ischemic stroke is disruption of the BBB, which significantly contributes to development of brain injury and subsequent neurological impairment. Biochemical characteristics of BBB damage include decreased expression and altered organization of tight junction constituent proteins as well as modulation of functional expression of endogenous BBB transporters. Therefore, there is a critical need for development of novel therapeutic strategies that can protect against BBB dysfunction (i.e., vascular protection) in the setting of ischemic stroke. Such strategies include targeting tight junctions to ensure that they maintain their correct structure or targeting transporters to control flux of physiological substrates for protection of endothelial homeostasis. In this review, we will describe the pathophysiological mechanisms in cerebral microvascular endothelial cells that lead to BBB dysfunction following onset of stroke. Additionally, we will utilize this state-of-the-art knowledge to provide insights on novel pharmacological strategies that can be developed to confer BBB protection in the setting of ischemic stroke.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain Ischemia; Endothelial Cells; Humans; Membrane Transport Proteins; Stroke; Tight Junction Proteins; Tight Junctions
PubMed: 29949404
DOI: 10.1152/ajpcell.00095.2018 -
International Journal of Molecular... Jun 2020For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after...
For a long time, the tight junction (TJ) was known to form and regulate the paracellular barrier between epithelia and endothelial cell sheets. Starting shortly after the discovery of the proteins forming the TJ-mainly, the two families of claudins and TAMPs-several other functions have been discovered, a striking one being the surprising finding that some claudins form paracellular channels for small ions and/or water. This Special Issue covers numerous dedicated topics including pathogens affecting the TJ barrier, TJ regulation via immune cells, the TJ as a therapeutic target, TJ and cell polarity, the function of and regulation by proteins of the tricellular TJ, the TJ as a regulator of cellular processes, organ- and tissue-specific functions, TJs as sensors and reactors to environmental conditions, and last, but not least, TJ proteins and cancer. It is not surprising that due to this diversity of topics and functions, the still-young field of TJ research is growing fast. This Editorial gives an introduction to all 43 papers of the Special Issue in a structured topical order.
Topics: Animals; Claudins; Humans; Occludin; Tight Junction Proteins; Tight Junctions
PubMed: 32610530
DOI: 10.3390/ijms21134612 -
Advanced Drug Delivery Reviews Apr 2021Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g.,... (Review)
Review
Intercellular tight junctions represent a formidable barrier against paracellular drug absorption at epithelia (e.g., nasal, intestinal) and the endothelium (e.g., blood-brain barrier). In order to enhance paracellular transport of drugs and increase their bioavailability and organ deposition, active excipients modulating tight junctions have been applied. First-generation of permeation enhancers (PEs) acted by unspecific interactions, while recently developed PEs address specific physiological mechanisms. Such target specific tight junction modulators (TJMs) have the advantage of a defined specific mechanism of action. To date, merely a few of these novel active excipients has entered into clinical trials, as their lack in safety and efficiency in vivo often impedes their commercialisation. A stronger focus on the development of such active excipients would result in an economic and therapeutic improvement of current and future drugs.
Topics: Animals; Drug Administration Routes; Drug Delivery Systems; Humans; Tight Junctions
PubMed: 33617902
DOI: 10.1016/j.addr.2021.02.008