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tight junction [keywords]
- Mechanisms of improvement of intestinal transport of baicalin and puerarin by extracts of Radix Angelicae Dahuricae. [JOURNAL ARTICLE]
- Phytother Res 2014 Oct 14.
Radix Angelicae Dahuricae is the dried root of Angelicae Dahurica (Fisch.ex Hoffm.)Benth.et Hook.f. var.formosana (Boiss.) Shan et Yuan (Fam.Umbelliferae). The total coumarins (Cou) and volatile oil (VO) were main active components that drived from Radix Angelicae Dahuricae. Our previous studies have shown that Cou and VO could increase intestinal absorption for transmucosal drug delivery with unknown mechanism. The aim of this study was to investigate the molecular mechanism of Radix Angelicae Dahuricae for improving drug intestinal transport. Caco-2 cell model was used to study the effect of Radix Angelicae Dahurica on transepithelial electrical resistance. Western blot was used to study its effect on the expression of the actin and ZO-1, tight junction proteins. The effect of Radix Angelicae Dahurica on the expression of P-gp protein was investigated using flow cytometry. VO (0.036-2.88 μL/mL) and Cou (0.027-0.54 mg/mL) caused a reversible, time- and dose-dependent decrease in transepithelial electrical resistance. VO and/or Cou could inhibit the expression of the tight junction protein, ZO-1 and actin. VO and/or Cou also could inhibit the expression of P-gp. These data suggested that Radix Angelicae Dahurica increased cell permeability by affecting the expression of actin, ZO-1 or P-gp, opening the tight junction or inhibiting the efflux induced by P-gp. Copyright © 2014 John Wiley & Sons, Ltd.
- Transplantation of human umbilical mesenchymal stem cells attenuates dextran sulfate sodium-induced colitis in mice. [JOURNAL ARTICLE]
- Clin Exp Pharmacol Physiol 2014 Oct 14.
Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) and increases the risk of the development of colorectal carcinoma. The anti-inflammatory and immunomodulatory properties of mesenchymal stem cells (MSCs) make them promising tools for treating immune-mediated and inflammatory diseases. However, the lack of robust technique for harvesting and expanding of MSCs has hampered the use of bone marrow and umbilical cord blood derived MSCs in clinical applications. In the present study, we investigated the intestinal protective effects of Wharton's jelly derived umbilical MSCs (UMSCs) on dextran sulfate sodium (DSS) induced colitis in mice. The severity of colitis in mice was assessed using body weight loss, stool consistency, rectal bleeding, colon shortening, and hematological parameters. Colonic myeloperoxidase (MPO) and proinflammatory cytokines levels were also measured. Furthermore, the expression of cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) in the colon were detected. In addition, intestinal permeability and tight junction proteins expressions in the colon were examined as well. The results showed that Wharton's jelly derived UMSCs significantly diminished the severity of colitis, reduced histolopathological score, and decreased MPO activity and cytokines levels. Furthermore, the UMSCs markedly decreased the expression of COX2 and iNOS in the colon. In addition, transplantation of UMSCs reduced intestinal permeability and up-regulated the expression of tight junction proteins. These results indicate the anti-inflammation and regulation of tight junction proteins by Wharton's jelly derived UMSCs ameliorates colitis. This article is protected by copyright. All rights reserved.
- Breastmilk, Microbiota and Intestinal Immune Homeostasis. [REVIEW]
- Pediatr Res 2014 Oct 13.
Newborns adjust to the extrauterine environment by developing intestinal immune homeostasis. Appropriate initial bacterial colonization is necessary for adequate intestinal immune development. An environmental determinant of adequate colonization is breast milk. Although the full term infant is developmentally capable of mounting an immune response, the effector immune component requires bacterial stimulation. Breast milk stimulates the proliferation of a well balanced and diverse microbiota which initially influences a switch from an intrauterine Th2 predominant to a Th1/Th2 balanced response and with activation of T-regulatory cells by breast milk-stimulated specific organisms (Bifidobacteria, Lactobacillus and Bacteroides). As an example of its effect, oligosaccharides in breast milk are fermented by colonic bacteria producing an acid milieu for bacterial proliferation. In addition, short chain fatty acids in breast milk activate receptors on T-reg cells and bacterial genes which preferentially mediate intestinal tight junction expression and anti-inflammation. Other components of breast milk (defensins, lactoferrin, etc.) inhibit pathogens and further contribute to microbiota composition. The breast milk influence on initial intestinal microbiota also prevents expression of immune-mediated diseases (asthma, IBD, type 1 diabetes) later in life through a balanced initial immune response, underscoring the necessity of breast feeding as the first source of nutrition.Pediatric Research (2014); doi:10.1038/pr.2014.160.
- Condition-specific role of colonic inflammatory molecules in persistent functional colorectal hypersensitivity in the mouse. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Oct 13.
A low-level inflammation has been hypothesized to mediate visceral hypersensitivity in functional bowel disorders that persist after or even in the absence of gut inflammation. We aimed to test the efficacy of a steroidal anti-inflammatory treatment, and identify local inflammatory molecules mediating post- and non-inflammatory colorectal hypersensitivity using two mouse models.Visceromotor responses to colorectal distension were quantified as a measure of colorectal sensitivity. On day 1, mice received intracolonic saline (control), trinitrobenzenesulfonic acid (postinflammatory on day 15), or acidified hypertonic saline (non-inflammatory). Colorectal sensitivity before (day 10) and after (day 15) 4-day dexamethasone (Dex) treatment was compared, and colonic gene expression of inflammatory molecules was quantified.Dexamethasone effectively inhibited gene expression of inflammatory molecules such as interleukin (IL)-1β and mast cell protease-1 in the colon, but did not attenuate colorectal hypersensitivity in either model. Gene expression of inflammatory molecules in the colon did not differ between control and the non-inflammatory model, but the postinflammatory model showed increased IL-10 and tight junction protein 2, and decreased IL-6, transforming growth factor (TGF)-β, a precursor of β-endorphin, occludin, and mucin 2. While no common molecule explained colorectal hypersensitivity in these models, hypersensitivity was positively correlated with TGF-β2 mRNA in control, and with IL-1β, inhibin βA, and prostaglandin E2 synthase in the Dex-treated postinflammatory model. In the non-inflammatory model, cyclooxygenase-2 mRNA was negatively correlated with colorectal sensitivity.These results suggest that persistent functional colorectal hypersensitivity is mediated by condition-specific mediators whose gene expression in the colon is not inevitably sensitive to steroidal anti-inflammatory treatment.
- Interferon-γ Safeguards Blood-Brain Barrier during Experimental Autoimmune Encephalomyelitis. [JOURNAL ARTICLE]
- Am J Pathol 2014 Oct 7.
The function of blood-brain barrier is often disrupted during the progression of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the molecular mechanism of blood-brain barrier modulation during neuroinflammation remains unclear. Herein, we show that the expression of interferon-γ (IFNγ) receptor on endothelial cells (ECs) protected mice from the brain inflammation during EAE. IFNγ stabilized the integrity of the cerebral endothelium and prevented the infiltration of leukocytes into the brain. Further analysis revealed that IFNγ increased the expression of tight junction proteins zonula occludens protein 1 and occludin, as well as membranous distribution of claudin-5, in brain ECs. Silencing claudin-5 abolished the IFNγ-mediated improvement of EC integrity. Taken together, our results show that IFNγ, a pleiotropic proinflammatory cytokine, stabilizes blood-brain barrier integrity and, therefore, prevents brain inflammation during EAE.
- Steroids and the blood-brain barrier: therapeutic implications. [Journal Article]
- Adv Pharmacol 2014.:361-90.
Steroids have a wide spectrum of impact, serving as fundamental regulators of nearly every physiological process within the human body. Therapeutic applications of steroids are equally broad, with a diverse range of medications and targets. Within the central nervous system (CNS), steroids influence development, memory, behavior, and disease outcomes. Moreover, steroids are well recognized as to their impact on the vascular endothelium. The blood-brain barrier (BBB) at the level of the brain microvascular endothelium serves as the principle interface between the peripheral circulation and the brain. Steroids have been identified to impact several critical properties of the BBB, including cellular efflux mechanisms, nutrient uptake, and tight junction integrity. Such actions not only influence brain homeostasis but also the delivery of CNS-targeted therapeutics. A greater understanding of the respective steroid-BBB interactions may shed further light on the differential treatment outcomes observed across CNS pathologies. In this chapter, we examine the current therapeutic implications of steroids respective to BBB structure and function, with emphasis on glucocorticoids and estrogens.
- Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. [Journal Article]
- Adv Pharmacol 2014.:203-43.
The blood-brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2-26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD.
- P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery. [Journal Article]
- Adv Pharmacol 2014.:25-44.
The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription.
- Paracellular barrier and channel functions of TJ claudins in organizing biological systems: Advances in the field of barriology revealed in knockout mice. [REVIEW]
- Semin Cell Dev Biol 2014 Oct 11.
Claudin was first identified as a four-transmembrane protein in the tight junctions (TJs) between epithelial cells. The claudin family has 27 members, which are specifically expressed depending on the epithelial cell type. Accumulating evidence has revealed that claudins are responsible for the paracellular barrier that prevents molecules from passing through epithelial cell sheets. In addition, the extracellular domains of some claudins enable them to act as a permselective paracellular channel for specific molecules, including ions and non-ionic solutes. Recent studies using claudin knockout mice revealed that the loss of claudins' specific paracellular barrier and/or channel functions affects particular biological functions and leads to pathological states. In this review, considering recent findings in vivo, we describe how, sometimes in concert with canonical transporters and channels, the paracellular barrier and channel functions of claudins sophisticatedly organize biological systems.
- Melatonin Treatment Protects Against Acute Spinal Cord Injury-Induced Disruption of Blood Spinal Cord Barrier in Mice. [JOURNAL ARTICLE]
- J Mol Neurosci 2014 Oct 11.
The spinal cord microcirculation plays a critically important role in maintaining the normal function of spinal cord neurons, glial cells, and axons. Previous researches were largely focused on improved neurological manifestations of spinal cord injury (SCI) while ignoring to improve spinal cord microcirculation disorder after melatonin treatment. Therefore, the mechanism of melatonin that affects blood spinal cord barrier (BSCB) integrity and microcirculation in SCI remains unclear. The present study was performed to investigate the effect of melatonin on the BSCB in a SCI mice model. Melatonin (5, 10, 25, 50, 100 mg/kg i.p.) was administered to mice immediately following SCI. Compared to the 48 h post-SCI group, mice treated with melatonin (50 mg/kg) exhibited significantly reduced BSCB permeability. Additionally, melatonin treatment restrained microvessel loss; attenuated edema; protected the tight junction proteins, endothelial cells, and pericytes; decreased the number of cell apoptosis; and reduced MMP3/AQP4/HIF-1α/VEGF/VEGFR2 expression after SCI. Above all, our results clearly demonstrated that melatonin could stabilize microvascular barrier function and microcirculation of SCI, whose mechanism was to promote the repair of the damaged BSCB.