scholarly journals Difructose anhydride III and sodium caprate activate paracellular transport via different intracellular events in Caco-2 cells

Life Sciences ◽  
2006 ◽  
Vol 79 (4) ◽  
pp. 401-410 ◽  
Author(s):  
Takuya Suzuki ◽  
Hiroshi Hara
Keyword(s):  
Paracellular Transport ◽  
Sodium Caprate

Claudin Tight Junction Proteins: Novel Aspects in Paracellular Transport

2008 ◽  
Vol 28 (6) ◽  
pp. 577-584 ◽  
Author(s):  
Constanze Will ◽  
Michael Fromm ◽  
Dominik Müller
Keyword(s):  
Tight Junction ◽  
Solute Transport ◽  
Molecular Mechanisms ◽  
Family Members ◽  
Transport Processes ◽  
Paracellular Transport ◽  
Solute Flux ◽  
Solute Fluxes ◽  
Essential Components ◽  
Renal Tubular

Claudins are essential components of the intercellular tight junction and major determinants of paracellular solute fluxes across epithelia and endothelia. Many members of this family display a distinct charge or size specificity, whereas others render the epithelium impermeable to transport. Due to intercellular localization, claudin-mediated transport processes are passive and driven by an electrochemical gradient. In epithelial tissues, claudins exhibit a temporal–spatial expression pattern corresponding with regional and local solute transport profiles. Whereas paracellular transport mechanisms in organs such as intestine and kidney have been extensively investigated, little is known about the molecular mechanisms determining solute transport in the peritoneum, and thus the determinants of peritoneal dialysis. Given the ubiquitous expression of claudins in endothelia and epithelia, it is predictable that claudins also contribute to pore formation and determination in the peritoneum, and that they are involved in solute flux. Therefore, we review the basic characteristics of claudin family members and their function as exemplified in renal tubular transport and give an outlook to what extent claudin family members might be of importance for solute reabsorption across the peritoneal membrane.

scholarly journals Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

2009 ◽  
Vol 297 (2) ◽  
pp. L219-L227 ◽  
Author(s):  
Charlie Wray ◽  
Ying Mao ◽  
Jue Pan ◽  
Anita Chandrasena ◽  
Frank Piasta ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tight Junction ◽  
Pulmonary Edema ◽  
Barrier Function ◽  
Mapk Pathway ◽  
Paracellular Transport ◽  
Epithelial Barrier ◽  
Altered Expression ◽  
Alveolar Epithelial

Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPEBD). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPEBD decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

scholarly journals Intestinal Absorption Profile of Three Polygala Oligosaccharide Esters in Polygalae Radix and the Effects of Other Components in Polygalae Radix on Their Absorption

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
YinYing Ba ◽  
MengLin Wang ◽  
KunFeng Zhang ◽  
QiJun Chen ◽  
JiaJia Wang ◽  
...  
Keyword(s):  
Future Research ◽  
Active Components ◽  
Sodium Caprate ◽  
P Glycoprotein ◽  
Paracellular Absorption ◽  
Underlying Mechanisms ◽  
The Relationship ◽  
Rat Gut ◽  
Human Nervous System

Oligosaccharide esters, which are among the main active components of Polygalae Radix (PR), demonstrate significant pharmacological activities in the human nervous system. In our previous research, some other constituents in PR were able to improve the bioavailability of oligosaccharide esters such as sibiricose A5 (SA5), sibiricose A6 (SA6), and 3,6′-disinapoyl sucrose (DISS), but the related components and their underlying mechanisms remain unknown. The present study aimed to investigate the intestinal absorptive profile of SA5, SA6, and DISS and the absorptive behavior influenced by the coadministration of polygalaxanthone III and total saponins of PR (TS) using an in vitro everted rat gut sac model, along with the possible mechanisms that may influence absorption. The results showed that TS could significantly enhance the absorption of SA5, SA6, and DISS monomers. Verapamil, a P-glycoprotein inhibitor, was able to elevate the absorption of SA5 and SA6, and an absorption experiment using Rho123 led us to conclude that TS influenced the absorption of SA5 and SA6 in a manner similar to that of a P-glycoprotein inhibitor. Sodium caprate, a paracellular absorption enhancer, was found to increase the absorption of SA5, SA6, and DISS. Results showed that the absorption mechanisms of SA5 and SA6 may combine active transport with paracellular passive penetration, while DISS’s absorption was dominated by paracellular passive penetration. However, the relationship between polygala saponins and the absorption of SA5, SA6, and DISS by paracellular passive penetration remain to be examined. This is the direction of our future research.

scholarly journals Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers

2001 ◽  
Vol 281 (2) ◽  
pp. C388-C397 ◽  
Author(s):  
C. J. Watson ◽  
M. Rowland ◽  
G. Warhurst
Keyword(s):  
Cell Lines ◽  
Pore Radius ◽  
Intestinal Cell ◽  
Sodium Caprate ◽  
Cell Monolayers ◽  
Functional Regulation ◽  
Glycol Oligomers ◽  
Molecular Radius ◽  
Sieving Model

Despite significant advances in the characterization of tight junction (TJ) proteins, little is known about how molecular changes relate to function due primarily to the limitations of conventional paracellular probes. To address this, the paracellular pathway in Caco-2 and T84 cell lines was profiled by measuring the permeabilities of 24 polyethylene glycols (PEG) of increasing molecular radius (3.5–7.4 Å) analyzed by mass spectrometry. When combined with a paracellular sieving model, these data provided quantitative descriptors of the pathway under control conditions and after exposure to TJ modulators. PEG profiles in both cell lines conformed to a biphasic process involving a restrictive pore (radius 4.3–4.5 Å) and a nonrestrictive component responsible for permeability of larger molecules. PEG profiling revealed significant differences between the effects of EGTA and sodium caprate (C10). The restrictive component of EGTA-treated cells lost all size discrimination due to an increase in pore radius. Sodium caprate had no effect on pore radius but increased permeability via a different mechanism possibly involving increased numbers of functional pores. PEG profiling provides a useful tool for probing the functional regulation of the paracellular route.

scholarly journals Preparation, characterization and evaluation of the in vivo trypanocidal activity of ursolic acid-loaded solid dispersion with poloxamer 407 and sodium caprate

2015 ◽  
Vol 51 (1) ◽  
pp. 101-109 ◽  
Author(s):  
Josimar Oliveira Eloy ◽  
Juliana Saraiva ◽  
Sérgio de Albuquerque ◽  
Juliana Maldonado Marchetti
Keyword(s):  
Ursolic Acid ◽  
Solid Dispersion ◽  
Oral Absorption ◽  
Solid Dispersions ◽  
Poloxamer 407 ◽  
Drug Dissolution ◽  
Limiting Factors ◽  
Sodium Caprate ◽  
Trypanocidal Activity

Ursolic acid is a promising candidate for treatment of Chagas disease; however it has low aqueous solubility and intestinal absorption, which are both limiting factors for bioavailability. Among the strategies to enhance the solubility and dissolution of lipophilic drugs, solid dispersions are growing in popularity. In this study, we employed a mixture of the surfactants poloxamer 407 with sodium caprate to produce a solid dispersion containing ursolic acid aimed at enhancing both drug dissolution and in vivo trypanocidal activity. Compared to the physical mixture, the solid dispersion presented higher bulk density and smaller particle size. Fourier Transform Infrared Spectroscopy results showed hydrogen bonding intermolecular interactions between drug and poloxamer 407. X-ray diffractometry experiments revealed the conversion of the drug from its crystalline form to a more soluble amorphous structure. Consequently, the solubility of ursolic acid in the solid dispersion was increased and the drug dissolved in a fast and complete manner. Taken together with the oral absorption-enhancing property of sodium caprate, these results explained the increase of the in vivo trypanocidal activity of ursolic acid in solid dispersion, which also proved to be safe by cytotoxicity evaluation using the LLC-MK2 cell line.

scholarly journals Effect of Sodium Caprate against Physical Characteristics and Absorption on Sustained Release Progesterone Suppositories.

2001 ◽  
Vol 27 (2) ◽  
pp. 137-142 ◽  
Author(s):  
Masanori Iwata ◽  
Sachiko Komiya ◽  
Kouji Nakamura ◽  
Masakazu Kiuch ◽  
Yoshie Maitani ◽  
...  
Keyword(s):  
Sustained Release ◽  
Physical Characteristics ◽  
Sodium Caprate

An oral antisense oligonucleotide for PCSK9 inhibition

2021 ◽  
Vol 13 (593) ◽  
pp. eabe9117
Author(s):  
Peter Gennemark ◽  
Katrin Walter ◽  
Niclas Clemmensen ◽  
Dinko Rekić ◽  
Catarina A.M. Nilsson ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Antisense Oligonucleotide ◽  
Oral Delivery ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Sodium Caprate ◽  
Subcutaneous Dose

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.

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