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Modulatory effect of lipid compositions on phospholipase A2 activityChiou, Yi-ling 17 July 2012 (has links)
The goal of the present study is to elucidate the modulatory effect of lipid compositions on phospholipase A2 (PLA2) activity. Sphingomyelin (SM) incorporation inhibited catalytic activity and membrane-damaging activity of native and mutated PLA2 toward egg yolk phosphatidylcholine (EYPC) vesicles. The inhibitory effects were through the reduction of membrane fluidity and modulation of the mode of membrane binding of PLA2 at water/lipid interface. The modulated effect of SM depended on inherent structural elements of PLA2. Moreover, cholesterol (Chol) incorporation into EYPC/egg yolk sphingomyelin (EYSM) vesicles relieved the inhibitory effect of sphingomyelin on PLA2 activity via lipid domain formation by SM and Chol. The effects on the interactive mode of PLA2 with phospholipids induced by the physical state changes of membrane bilayers abolished the inhibition of SM on catalytic activity and membrane-damaging activity of PLA2. Additionally, quercetin incorporation increased PLA2 activity and membrane-damaging activity toward EYPC/SM vesicles via its raft-making effect. Quercetin incorporation reduced PLA2 activity and membrane-damaging activity toward EYPC/SM/Chol vesicles via its raft-breaking effect. Membrane-inserted quercetin affected on membrane structure and membrane-bound mode of PLA2 to modulate PLA2 interfacial activity and membrane-damaging activity. Finally, studies on the effects of phosphatidylserine (PS) content on the sensitivity of lipid vesicles mimicking inner and outer plasma membrane toward PLA2 activity revealed that the membrane-binding mode adopted by PLA2 depended on the lipid composition. The effects of PS content on the extent of lipid domain formation and the conformation of PLA2 adopted at water-lipid interface modulate PLA2 catalytic activity. Collectively, these results indicate that lipid composition modulates PLA2 activity via its effects on membrane structure and membrane-bound mode of PLA2
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The effect of different modulators on the transport of rhodamine 123 across rat jejunum using the sweetana-grass diffusion method / C.J. LamprechtLamprecht, Christian Johannes January 2004 (has links)
P-glycoprotein (Pgp), which leads to multidrug resistance in tumour cells,
is an ATP-dependent secretory drug efflux pump. In the intestine, as well as at specific
other epithelial and endothelial sites, P-glycoprotein expression is localised to the apical
membrane, consistent with secretory detoxifying and absorption limitation functions.
The primary function of Pgp is to clear the membrane lipid bilayer of lipophilic drugs.
Results from in vitro studies with human Caco-2 cells provide direct evidence for Pgp
limiting drug absorption. Limitation has non-linear dependence of absorption on
substrate (eg. vinblastine) concentration, increased absorption upon saturation of
secretion and increased absorption upon inhibition of Pgp function, with modulators such
as verapamil. The aim of this study was to investigate the effect of a known Pgp
inhibitor (verapamil) and grapefruit juice components (naringenin, quercetin and
bergamottin) on the transport of Rhodamine 123 across rat jejunum and to compare
these results with those obtained in similar studies done in Caco-2 cells and in rat
intestine (monodirectional). Verapamil, naringenin (442 µM, 662 µM and 884
µM), quercetin (73 µM, 183 µM and 292 µM) and bergamottin (12 µM, 30 µM and 48 µM)
were evaluated as modulators of rhodamine 123 transport across rat jejunum using
Sweetana-Grass diffusion cells. This study was done bidirectionally, with three cells
measuring transport in the apical to basolateral direction (AP / BL) and three cells
measuring transport in the basolateral to apical direction (BL / AP). The rate of transport
was expressed as the apparent permeability coefficient (Papp) and the extent of active
transport was expressed by calculating the ratio of BL/AP to AP/BL.
The BL-AP/AP-BL ratio calculated for Rhodamine 123 with no modulators added was 2.31. The
known modulator verapamil decreased the BL-AP/AP-BL ratio to 1.52. This was
statistically significant and inhibition of active transport was clearly demonstrated. All
modulators inhibited active transport. Only naringenin 884 µM, quercetin 183 µM and
bergamottin 30 µM did not show a statistically significant decrease in the BL-AP/AP-BL
ratio. All three components of grapefruit juice showed inhibition of active
transport and should have an effect on the bioavailability of the substrates of Pgp and
other active transporters. The results obtained in this study are similar to the results
found in Caco-2 cells, which suggests that Sweetana-Grass diffusion method can be
used for diffusion studies. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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83 |
The effect of selected hydroxy flavonoids on the in vitro efflux transport of rhodamine 123 using rat jejunum / S. van HuyssteenVan Huyssteen, Stephanie January 2005 (has links)
Background: Multidrug resistance (MDR) is resistance of cancer cells to multiple
classes of chemotherapeutic drugs that can be structurally unrelated. MDR involves
altered membrane transport that results in a lower cell concentration of cytotoxic drugs
which plays an important role during cancer treatment. P-glycoprotein (Pgp) is localised
at the apical surface of epithelial cell in the intestine and it functions as a biological
barrier by extruding toxic substances and xenobiotics out of cells (Lin, 2003:54). The
ATP-binding-cassette superfamily is a rapidly growing group of membrane transport
proteins and are involved in diverse physiological processes which include antigen
presentation, drug efflux from cancer cells, bacterial nutrient uptake and cystic fibrosis
(Germann, 1996:928; Kerr, 2002:47). A number of drugs have been identified which are
able to reverse the effects of Pgp, multidrug resistance protein (MRPI) and their
associated proteins on multidrug resistance. The first MDR modulators discovered and
studied during clinical trials were associated with definite pharmacological actions, but
the doses required to overcome MDR were associated with the occurrence of
unacceptable side effects. As a consequence, more attention has been given to the
development of modulators with proper potency, selectivity and pharmacokinetic
characteristics that it can be used at a lower dose. Several novel MDR reversing agents
(also known as chemosensitisers) are currently undergoing clinical evaluation for the
treatment of resistant tumours (Teodori et al., 2002:385). Aim: The aim of this study was
to investigate the effect of selected flavonoids (morin, galangin, kaempferol and
quercetin) at two different concentrations (10 μM and 20 μM) on the transport of a known
Pgp substrate, Rhodamine 123 (Rho 123) across rat intestine (jejunum) and to
investigate structure activity relationships (SAR) of the selected flavonoids with
reference to the inhibition of Pgp. Methods: Morin, galangin, kaempferol and quercetin
were evaluated as potential modulators of Rho 123 transport, each at a concentration of
10 μM and 20 μM across rat jejunum using Sweetana-Grass diffusion cells. This study
was done bidirectionally, with two cells measuring transport in the apical to basolateral
direction (AP-BL) and two cells measuring transport in the basolateral to apical direction
(BL-AP). The rate of transport was expressed as the apparent permeability coefficient
(Pap,) and the extent of active transport was expressed by calculating the ratio of BL-AP
to AP-BL. Results: The BL-AP to AP-BL ratio calculated for Rho 123 with no
modulators added was 3.29. Morin decreased the BL-AP to AP-BL ratio to 1.88 at a
concentration of 10 μM and to 1.49 at a concentration of 20 μM. Galangin decreased
the BL-AP to AP-BL ratio to 1.60 at a concentration of 20 μM. These two flavonoids
showed statistically significant results and inhibition of active transport were clearly
demonstrated. However, the other flavonoids inhibited active transport of Rho 123 but
according to statistical analysis, the results were not significantly different. The two
different concentrations (10 μM and 20 μM) indicated that galangin, kaempferol and
quercetin showed practically significant differences according to the effect sizes. Morin,
however, did not show any practically significant differences at the different
concentrations. Regarding .the SAR, it was shown by Boumendjel and co-workers
(2002:512) that the presence of a 5-hydroxyl group and a 3-hydroxyl group as well as
the C2-C3 double bond are required for high potency binding to the nucleotide binding
domain (NBD) of Pgp. All the flavonoids tested had the above-mentioned
characteristics. Conclusion: All the selected flavonoids showed inhibition of active
transport of Rho 123 and should have an effect on the bioavailability of the substrates of
Pgp and other active transporters. This study described the inhibitory interaction of
selected flavonoids on Pgp activity. Practical significant differences between the same
modulator at different concentrations were also observed. Structure activity
relationships were identified describing the inhibitory potency of the flavonoids based on
hydroxyl group positioning / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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84 |
ANTIOXIDANT AND CYTOPROTECTIVE PROPERTIES OF LONG CHAIN FATTY ACID ACYLATED DERIVATIVES OF QUERCETIN-3-O-GLUCOSIDEWarnakulasuriya, Sumudu Nirosha 09 August 2013 (has links)
Quercetin-3-O-glucoside (Q3G), a glycosylated derivative of quercetin, is a polyphenolic compound known to possess diverse biological activities. Its moderately hydrophilic nature is a critical factor governing the accessibility to the active sites of oxidative damages in vivo. It was hypothesized that biological activities of Q3G can be further enhanced by regioselective acylation with fatty acids which gives more lipophilicity. Q3G was acylated with six selected long chain fatty acids: stearic acid, oleic acid, linoleic acid, ?-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), using Candida antactica lipase. The derivatives were evaluated for their potential in inhibiting lipid oxidation in food systems and human low density lipoprotein (LDL), and cytoprotection and anti-inflammatory effect in cell culture model systems. The fatty acid derivatives of Q3G possessed greater effectiveness in inhibiting lipid oxidation in oil-in-water emulsions, and better cytoprotective effect against H2O2- and cigarette smoke toxicant-induced cytotoxicity when compared to Q3G.
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The Effects of Cooked Whole Asparagus (Asparagus officinalis L.) and its Purified Bioactive, Rutin, on Symptoms of DSS-induced Acute Colitis and Recovery in C57BL/6 MiceLu, Jenifer Thi 17 January 2013 (has links)
This thesis explored the effects of cooked whole asparagus and its purified bioactive, rutin, on colitis symptoms and disease progression in mice using a chemically-induced model of colitis. This model mimics active colitis and recovery states of ulcerative colitis. C57BL/6 mice were fed a basal diet supplemented with 2% asparagus or 0.025% rutin for 3 weeks. Colitis was induced by 2% dextran sodium sulfate in drinking water for 7 days. Asparagus diet was determined to contain higher antioxidant capacities than rutin diet through antioxidant assays. During active colitis, consumption of asparagus alleviated some clinical symptoms (stool consistency, stool blood, and spleen hypertrophy) of colitis. In recovery, asparagus-fed mice were improving in terms of regenerating crypts, surface epithelial, and goblet cells, potentially due to its rutin content. Overall, these findings advocate that asparagus can be therapeutic in treating symptoms during active colitis and recovery phases of ulcerative colitis.
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Modulating the Pharmacokinetics of BioflavonoidsSmith, Adam John 01 January 2012 (has links)
One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. However, the technology is still very new and its effectiveness in certain conditions had previously not been evaluated.
The studies detailed herein investigated the ability of two different technology platforms for overcoming drug design challenges for two promising bioflavonoids: EGCg and quercetin. Studies have shown that EGCg might be useful for the treatment of Alzheimer's disease and other neurodegenerative diseases. Quercetin is being investigated for numerous bioactivities and is currently being marketed as an energy dietary supplement. Both of these bioflavonoids exhibit poor bioavailability and water solubilities that are at opposite ends of the spectrum. In the chapters to follow, nanoparticle technology was applied to EGCg and evaluated in cell models of AΒ production, a hallmark of Alzheimer's disease. Bioavailability improvements were also evaluated in rats. Additionally, new forms of both flavonoids were created using cocrystallization. These new cocrystals were characterized using powder and single crystal x-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Solubility and bioavailability changes were also evaluated. These data have strong implications in drug development since they elucidated the strengths and weaknesses of two major technologies in compounds with different design challenges.
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The effect of different modulators on the transport of rhodamine 123 across rat jejunum using the sweetana-grass diffusion method / C.J. LamprechtLamprecht, Christian Johannes January 2004 (has links)
P-glycoprotein (Pgp), which leads to multidrug resistance in tumour cells,
is an ATP-dependent secretory drug efflux pump. In the intestine, as well as at specific
other epithelial and endothelial sites, P-glycoprotein expression is localised to the apical
membrane, consistent with secretory detoxifying and absorption limitation functions.
The primary function of Pgp is to clear the membrane lipid bilayer of lipophilic drugs.
Results from in vitro studies with human Caco-2 cells provide direct evidence for Pgp
limiting drug absorption. Limitation has non-linear dependence of absorption on
substrate (eg. vinblastine) concentration, increased absorption upon saturation of
secretion and increased absorption upon inhibition of Pgp function, with modulators such
as verapamil. The aim of this study was to investigate the effect of a known Pgp
inhibitor (verapamil) and grapefruit juice components (naringenin, quercetin and
bergamottin) on the transport of Rhodamine 123 across rat jejunum and to compare
these results with those obtained in similar studies done in Caco-2 cells and in rat
intestine (monodirectional). Verapamil, naringenin (442 µM, 662 µM and 884
µM), quercetin (73 µM, 183 µM and 292 µM) and bergamottin (12 µM, 30 µM and 48 µM)
were evaluated as modulators of rhodamine 123 transport across rat jejunum using
Sweetana-Grass diffusion cells. This study was done bidirectionally, with three cells
measuring transport in the apical to basolateral direction (AP / BL) and three cells
measuring transport in the basolateral to apical direction (BL / AP). The rate of transport
was expressed as the apparent permeability coefficient (Papp) and the extent of active
transport was expressed by calculating the ratio of BL/AP to AP/BL.
The BL-AP/AP-BL ratio calculated for Rhodamine 123 with no modulators added was 2.31. The
known modulator verapamil decreased the BL-AP/AP-BL ratio to 1.52. This was
statistically significant and inhibition of active transport was clearly demonstrated. All
modulators inhibited active transport. Only naringenin 884 µM, quercetin 183 µM and
bergamottin 30 µM did not show a statistically significant decrease in the BL-AP/AP-BL
ratio. All three components of grapefruit juice showed inhibition of active
transport and should have an effect on the bioavailability of the substrates of Pgp and
other active transporters. The results obtained in this study are similar to the results
found in Caco-2 cells, which suggests that Sweetana-Grass diffusion method can be
used for diffusion studies. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
|
88 |
The effect of selected hydroxy flavonoids on the in vitro efflux transport of rhodamine 123 using rat jejunum / S. van HuyssteenVan Huyssteen, Stephanie January 2005 (has links)
Background: Multidrug resistance (MDR) is resistance of cancer cells to multiple
classes of chemotherapeutic drugs that can be structurally unrelated. MDR involves
altered membrane transport that results in a lower cell concentration of cytotoxic drugs
which plays an important role during cancer treatment. P-glycoprotein (Pgp) is localised
at the apical surface of epithelial cell in the intestine and it functions as a biological
barrier by extruding toxic substances and xenobiotics out of cells (Lin, 2003:54). The
ATP-binding-cassette superfamily is a rapidly growing group of membrane transport
proteins and are involved in diverse physiological processes which include antigen
presentation, drug efflux from cancer cells, bacterial nutrient uptake and cystic fibrosis
(Germann, 1996:928; Kerr, 2002:47). A number of drugs have been identified which are
able to reverse the effects of Pgp, multidrug resistance protein (MRPI) and their
associated proteins on multidrug resistance. The first MDR modulators discovered and
studied during clinical trials were associated with definite pharmacological actions, but
the doses required to overcome MDR were associated with the occurrence of
unacceptable side effects. As a consequence, more attention has been given to the
development of modulators with proper potency, selectivity and pharmacokinetic
characteristics that it can be used at a lower dose. Several novel MDR reversing agents
(also known as chemosensitisers) are currently undergoing clinical evaluation for the
treatment of resistant tumours (Teodori et al., 2002:385). Aim: The aim of this study was
to investigate the effect of selected flavonoids (morin, galangin, kaempferol and
quercetin) at two different concentrations (10 μM and 20 μM) on the transport of a known
Pgp substrate, Rhodamine 123 (Rho 123) across rat intestine (jejunum) and to
investigate structure activity relationships (SAR) of the selected flavonoids with
reference to the inhibition of Pgp. Methods: Morin, galangin, kaempferol and quercetin
were evaluated as potential modulators of Rho 123 transport, each at a concentration of
10 μM and 20 μM across rat jejunum using Sweetana-Grass diffusion cells. This study
was done bidirectionally, with two cells measuring transport in the apical to basolateral
direction (AP-BL) and two cells measuring transport in the basolateral to apical direction
(BL-AP). The rate of transport was expressed as the apparent permeability coefficient
(Pap,) and the extent of active transport was expressed by calculating the ratio of BL-AP
to AP-BL. Results: The BL-AP to AP-BL ratio calculated for Rho 123 with no
modulators added was 3.29. Morin decreased the BL-AP to AP-BL ratio to 1.88 at a
concentration of 10 μM and to 1.49 at a concentration of 20 μM. Galangin decreased
the BL-AP to AP-BL ratio to 1.60 at a concentration of 20 μM. These two flavonoids
showed statistically significant results and inhibition of active transport were clearly
demonstrated. However, the other flavonoids inhibited active transport of Rho 123 but
according to statistical analysis, the results were not significantly different. The two
different concentrations (10 μM and 20 μM) indicated that galangin, kaempferol and
quercetin showed practically significant differences according to the effect sizes. Morin,
however, did not show any practically significant differences at the different
concentrations. Regarding .the SAR, it was shown by Boumendjel and co-workers
(2002:512) that the presence of a 5-hydroxyl group and a 3-hydroxyl group as well as
the C2-C3 double bond are required for high potency binding to the nucleotide binding
domain (NBD) of Pgp. All the flavonoids tested had the above-mentioned
characteristics. Conclusion: All the selected flavonoids showed inhibition of active
transport of Rho 123 and should have an effect on the bioavailability of the substrates of
Pgp and other active transporters. This study described the inhibitory interaction of
selected flavonoids on Pgp activity. Practical significant differences between the same
modulator at different concentrations were also observed. Structure activity
relationships were identified describing the inhibitory potency of the flavonoids based on
hydroxyl group positioning / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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Quercetin content in yellow onion (Allium cepa L.) : effects of cultivation methods, curing and storage /Mogren, Lars, January 2006 (has links) (PDF)
Diss. (sammanfattning) Alnarp : Sveriges lantbruksuniv., 2006. / Härtill 4 uppsatser.
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Antioxidant abilities of human plasma, buckwheat extracts and fractions, and quercetin metabolites in different biochemical assaysJanisch, Kerstin Maria. January 2003 (has links) (PDF)
München, Techn. Univ., Diss., 2003.
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