Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral inflammation can aggravate local brain inflammation and neuronal death. The blood-brain barrier (BBB) is a key player in the event. On a relevant in vitro model of primary rat brain endothelial cells co-cultured with primary rat astroglia cells lipopolysaccharide (LPS)-induced changes in several BBB functions have been investigated. LPS-treatment resulted in a dose- and time-dependent decrease in the integrity of endothelial monolayers: transendothelial electrical resistance dropped, while flux of permeability markers fluorescein and albumin significantly increased. Immunostaining for junctional proteins ZO-1, claudin-5 and beta-catenin was significantly weaker in LPS-treated endothelial cells than in control monolayers. LPS also reduced the intensity and changed the pattern of ZO-1 immunostaining in freshly isolated rat brain microvessels. The activity of P-glycoprotein, an important efflux pump at the BBB, was also inhibited by LPS. At the same time production of reactive oxygen species and nitric oxide was increased in brain endothelial cells treated with LPS. Pentosan polysulfate, a polyanionic polysaccharide could reduce the deleterious effects of LPS on BBB permeability, and P-glycoprotein activity. LPS-stimulated increase in the production of reactive oxygen species and nitric oxide was also decreased by pentosan treatment. The protective effect of pentosan for brain endothelium can be of therapeutical significance in bacterial infections affecting the BBB.
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PMID:Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages. 1699 27

Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar-Hannover rats were injected with lipopolysaccharide (LPS(+)) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS(-)). After LPS(+), proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS(-) group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS(+), a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney.
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PMID:Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia. 1728

It is well known that pharmacokinetics is often altered by changing the expression and activity of P-glycoprotein during sepsis. However, there have been few reports about expression and activity of P-glycoprotein in the small intestine during sepsis. We examined the levels of intestinal P-glycoprotein expression and activity using a rat sepsis model induced by lipopolysaccharide (LPS, from Escherichia coli). LPS was administered to male Wistar/ST rats intraperitonealy (i.p.) at 5 mg/kg. The small intestine was excised before and 1, 3 and 7 days after LPS administration, and the intestinal P-glycoprotein expression was determined using Western blot analysis. The activity of P-glycoprotein was evaluated by measuring the efflux of rhodamine-123 (Rho123) in rats using an in situ single perfusion method. The changes of permeability via the paracellular route were evaluated by measuring the amount of fluorescein isothicyanate-dextran 4400 (FD-4) in a similar way. On Day 1 after LPS administration, both the level of P-glycoprotein expression and the total amount of Rho123 excreted into the intestinal lumen decreased significantly, but levels of both AUC2-95 and CLtot were not significantly different as compared with the control group. On Day 3, the total P-glycoprotein, including intestinal P-glycoprotein, might have been induced by sepsis, and then the excretion of P-glycoprotein substrate drugs into the intestinal lumen increased more than that of the control group. On Day 7, all pharmacokinetic parameters returned to the control level. Thus the intestinal P-glycoprotein function recovered within 3 days of LPS administration.
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PMID:Effects of lipopolysaccharide on intestinal P-glycoprotein expression and activity. 1739 99

For drug absorption, intestinal drug permeability's through both the paracellular and transcellular routes were analyzed. Absorption enhancers, such as sodium caprate (C10), decanoylcarnitine (DC) and tartaric acid (TA), increased the paracellular permeability of water-soluble, low lipophilic and poorly absorbable drugs by enlargement of tight junction (TJ) adhering to the intercellular portion; that is, expansion of the paracellular routes. C10 increased the intracellular calcium level to induce contraction of calmodulin-dependent actin filaments. Although DC also increased the intracellular calcium level, the action was independent of calmodulin, and thus the action mechanism of DC was considered to differ from that of C10. DC and TA decreased the intracellular ATP level and the intracellular pH, suggesting that intracellular acidosis increases the calcium level through decrease in ATP level followed by opening TJ. TA had no effect on Western blot analysis, but TA significantly inhibited excretion of rhodamine 123, one of the P-glycoprotein (P-gp) substrates, from the serosal to mucosal side, suggesting that TA increases the intestinal absorption of P-gp substrates, possibly by inhibiting the P-gp function without changing the expression of P-gp. During ischemia/reperfusion (I/R) injury during small intestine grafting, TJ opening and decrease in P-gp function simultaneously occurred. The in vitro model of I/R showed that lipid peroxidation is a trigger of the injury, and superoxide and iron ion participate in TJ opening and decrease in P-gp function. Colonic epithelial cells have the specific transcellular transport systems for lipopolysaccharide (LPS), one of which shows substrate specificity in the interaction with CD14 and/or that of TLR4. In the infective disease induced by LPS, the mucosal LPS sensitive transport capability was decreased and in the secretory direction, the receptor-mediated uptake mechanism disappeared. LPS taken up into the cells can be excreted by P-gp or mrp. The expression levels and function of the secretory transporters were considered to be increased in the infective condition. In conclusion, changes in TJ as the membrane structure and P-gp as the membrane function are important factors controlling intestinal membrane transport.
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PMID:Mechanistic analysis for drug permeation through intestinal membrane. 1749 13

In the kidney, P-glycoprotein (Abcb1), an ATP-driven drug efflux pump, plays an important role in the detoxification of proximal tubule cells through the excretion of cationic and amphipathic organic compounds. We recently found that NO, produced by renal inducible NO synthase (iNOS), is involved in an up-regulation of P-glycoprotein during endotoxemia in rats. In the present study, we investigated the functional consequences of endotoxemia on the renal handling of rhodamine 123 by using isolated perfused rat kidneys. Wistar Hannover rats were injected intraperitoneally with 5 mg/kg body weight lipopolysaccharide (LPS) or with both LPS and the iNOS inhibitor, aminoguanidine. Despite an increased P-glycoprotein expression, we found a diminished urinary rhodamine 123 clearance 12 h after LPS (P<0.001). In addition, we found a diminished perfusate clearance (P<0.05) for rhodamine 123 after LPS treatment, suggesting a predominant role of influx carriers in urinary rhodamine 123 excretion. We examined the expression levels of organic cation transporter 1 (Slc22a1/Oct1) and Slc22a2/Oct2. Both appeared to be down-regulated at the mRNA and protein level, 12 h after LPS. Co-administration of aminoguanidine attenuated the down-regulation of both Oct1 and Oct2 protein expression and reversed the decrease in rhodamine 123 clearance (P<0.001). These findings indicate that NO, produced by iNOS, is responsible for a down-regulation of the influx carriers, Oct1 and Oct2.
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PMID:Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia. 1831 62

Increasingly, it is recognized that commensal microflora regulate epithelial cell processes through the dynamic interaction of pathogen-associated molecular patterns and host pattern recognition receptors such as Toll-like receptor 4 (TLR4). We therefore investigated the effects of bacterial lipopolysaccharide (LPS) on intestinal P-glycoprotein (P-gp) expression and function. Human SW480 (P-gp+/TLR4+) and Caco-2 (P-gp+/TLR4-) cells were treated with medium control or LPS (100 ng/ml) for 24 h prior to study. P-gp function was assessed by measuring the intracellular concentration of rhodamine 123 (Rh123). To confirm P-gp-specific effects, breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 2 (MRP-2/ABCC2) were also analyzed. Treatment of SW480 cells with LPS led to diminished P-gp activity, which could be prevented with polymyxin B (control: 207+/-16 versus LPS: 402+/-22 versus LPS+polymyxin B: 238+/-26 pmoles Rh123/mg protein, p<0.05 control versus LPS). These effects could be blocked by using polymyxin B and were not seen in the P-gp+/TLR4--Caco-2 cell line (control: 771+/-28 versus LPS: 775+/-59 pmoles Rh123/mg protein). Total cellular levels of P-gp did not change in LPS-treated SW480 cells; however, a significant increase in cell surface P-gp was detected. No change in activity, total protein, or apically located MRP-2 was detected following LPS treatment. Sequence analysis confirmed wild-type status of SW480 cells. These data suggest that activation of TLR4 in intestinal epithelial cells leads to an increase in plasma membrane P-gp that demonstrates a diminished capacity to transport substrate.
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PMID:Lipopolysaccharide increases cell surface P-glycoprotein that exhibits diminished activity in intestinal epithelial cells. 1868 2

P-glycoprotein (P-gp) is a brain-to-blood efflux system that controls the ability of many drugs and endogenous substances to access the brain. In vitro work has shown that inflammatory states mediated through lipopolysaccharide (LPS) and tumor necrosis factor-alpha first impair and then stimulate P-gp activity. Here, we determined whether LPS can affect P-gp function in vivo. Mice treated with a single intraperitoneal injection of LPS (3 mg/kg) showed an inhibition of P-gp function. As assessed by brain perfusion, inhibition began 18 h after LPS administration and lasted until 36 h after administration. P-gp protein was increased by 44%, consistent with P-gp inhibition occurring through post-translational mechanisms. Unlike other effects of LPS on blood-brain barrier function, neither nitric oxide nor prostaglandin inhibition had an effect. We conclude that induction of proinflammatory states as exemplified by LPS treatment can inhibit P-gp function in vivo at the blood-brain barrier.
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PMID:Lipopolysaccharide impairs blood-brain barrier P-glycoprotein function in mice through prostaglandin- and nitric oxide-independent pathways. 1903 63

During endotoxemia, the ATP-dependent drug efflux pump P-glycoprotein (Abcb1/P-gp) is upregulated in kidney proximal tubule epithelial cells. The signaling pathway through which lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) regulates P-gp expression and activity was investigated further in the present study. Exposure of rat kidney proximal tubule cells to TNF-alpha alone or TNF-alpha and LPS increased P-gp gene and protein expression levels and efflux activity, suggesting de novo P-gp synthesis. Upon exposure to TNF-alpha in combination with LPS, P-gp activity in renal proximal tubule cells is increased under influence of nitric oxide (NO) produced by inducible NO synthase. Upon exposure to TNF-alpha alone, P-gp upregulation seems to involve TLR4 activation and nuclear factor kappaB (NF-kappaB) translocation, a pathway that is likely independent of NO. These findings indicate that at least two pathways regulate P-gp expression in the kidney during endotoxemia.
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PMID:Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. 2030 Apr 55

There have been many reports that P-glycoprotein expression and activity are altered during sepsis, but few of them have examined such changes over 72 h. In this study, we examined the effect of lipopolysaccharide (LPS, 5mg/kg, ip) on P-glycoprotein expression (Western blotting) and activity (rhodamine-123 (Rho123) pharmacokinetics) in liver and kidneys for 7 days. On day 1 after LPS administration, hepatic P-glycoprotein expression and activity significantly decreased. On day 3, hepatic P-glycoprotein expression significantly increased compared with the control group, while activity had returned to the control level. On day 7, hepatic P-glycoprotein expression returned to the control level. There were no significant changes in P-glycoprotein expression or activity in the kidneys after LPS administration. The amount of Rho123 excretion in urine remained unchanged with (4.2%) or without (4.0%) LPS administration, but the amount of Rho123 excretion in bile decreased from 2.0 to 0.7% with LPS administration. Our findings suggested that hepatic P-glycoprotein expression and activity decreased on day 1 but recovered within 3 days, but there were no significant differences in the kidneys after LPS administration. These results suggested that the change in P-glycoprotein activity might be due to change in P-glycoprotein expression in the liver rather than the kidneys.
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PMID:Effects of lipopolysaccharide on P-glycoprotein expression and activity in the liver and kidneys. 2035 68

Multidrug efflux transporters of the ATP-Binding cassette (ABC) family, P-glycoprotein (Pgp), multidrug-resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), located on endothelial cells lining brain vasculature play important roles in limiting movement of substances into and enhancing their efflux from the brain. Signals from the surrounding brain normally maintain such barrier function but these may become altered in CNS pathologies such as Alzheimer's disease (AD). Previous studies have reported decreases in the glucose transporter, Glut-1, in brain vasculature of AD patients. The present study investigates the status of the multidrug efflux transporters. Sections of frozen brain from hippocampal region obtained from male AD and age-matched non-demented cases were examined for amyloid plaques and Dkk-1 expression and subjected to dual fluorescence immunochemical staining using antibodies against Pgp, BCRP or MRP4 and von Willebrand factor. Protein expression of each transporter was assessed using confocal microscopy, quantifying peak fluorescence values of cross sectional profiles across brain microvessels. Results in brain microvessels revealed expression of Pgp protein to be significantly lower in hippocampal vessels of patients with AD compared to normal individuals whereas that of MRP4 or BCRP protein was not. By contrast, analysis of the sections at protein level via Western blotting or at transcript level by qRT-PCR did not reveal significantly lower expression for either Pgp or BCRP. Such analysis did however reveal higher than normal expression in the AD brains of MRP4, probably due to gliosis, MRP4 being present also in glial cells.
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PMID:ABC efflux transporters in brain vasculature of Alzheimer's subjects. 2072 60


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