Adriana Catalli - Academia.edu (original) (raw)
Papers by Adriana Catalli
The FASEB Journal, 2015
Ursolic acid is a constituent of the American cranberry (Vaccinium macrocarpon) and other Vaccini... more Ursolic acid is a constituent of the American cranberry (Vaccinium macrocarpon) and other Vaccinium fruit found primarily in the peel. In this study, the effects of ursolic acid (UA) on the cell cycle behaviour of DU145 human prostate cancer cells in vitro was examined. Following treatment of cells with UA (50 μM) for 6 hours, the cellular viability of the cells decreased. UA treatment increased the proportion of cells in the G1 phase of the cell cycle. The relative proportion of cells in G2-M phase was similar in both control and UA-treated cells. UA treatment also caused a decrease in the proportion of cells in S-phase relative to untreated cells. These cell cycle alterations were associated with changes in expression of cell cycle associated regulatory proteins. UA decreased the protein expression levels of cyclin A, cyclin D, p16 , pRBp107 and increased the expression of CDK2, CDK4, cyclin E, p21, p27 and pRBp130. CyclinB1 protein expression levels were apparently unaffected by UA. These findings demonstrate that ursolic acid can affect the cell growth behaviour of human prostate cancer cells in vitro. [Cranberry Institute (Wisconsin Board) & Telus MRFD Prostate Cancer Research Fund (PEI Division) funded
Journal of biological regulators and homeostatic agents, 2018
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the p... more Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, ...
Http Dx Doi Org 10 1080 01635581 2014 951736, Sep 29, 2014
Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide.... more Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.
European Journal of Pharmacology, Nov 1, 2004
We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prosta... more We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prostaglandin E(2) in porcine tracheal smooth muscle. Both autacoids completely reversed cholinergic tone; blockade of thromboxane A(2) receptors had no effect on relaxations to either compound. 8-iso-prostaglandin E(2) and prostaglandin E(2) suppressed outward K(+) currents while the thromboxane A(2) receptor agonist U46619 (9, 11-dideoxy-9a,11a-methanoepoxy prostaglandin F(2alpha)) had no significant effect. During thromboxane A(2) receptor antagonism, however, 8-iso-prostaglandin E(2) markedly augmented K(+) currents while prostaglandin E(2) no longer suppressed K(+) currents, indicating that the inhibition of K(+) currents by both compounds was thromboxane A(2) receptor-mediated. Furthermore, the observation that K(+) currents were augmented by 8-iso-prostaglandin E(2) but not by prostaglandin E(2) suggests that the salutory effect is not exerted through a prostaglandin E receptor. Additionally, our observations argue against any causal role for K(+) current activation in mediating relaxations evoked by isoprostanes or by prostaglandin E(2). We conclude that 8-iso-prostaglandin E(2) relaxes porcine tracheal smooth muscle independent of K(+) current activity, and that 8-iso-prostaglandin E(2) may also act at a non-thromboxane A(2)/non-prostaglandin E receptor to augment K(+) currents.
J Allerg Clin Immunol, 2010
The Journal of Immunology, May 1, 2012
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid mediators which are derived from 5-l... more Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability, increased mucus secretion, decreased mucociliary clearance, eosinophil migration, and increased eosinophil survival. We now report that peripheral blood CD34+ progenitor-derived human mast cells and the human mast cell line (LAD2) express both CysLT receptors (CysLT1R and CysLT2R), the G protein-coupled receptors that bind CysLTs. LTC4, LTD4 and LTE4 activated LAD2 to produce MIP-1β and MCP-1 and production of these chemokines was inhibited by the CysLT1R inhibitor, monelukast. LAD2 activated by IgE/anti-IgE produced CysLT (980 + 55 pg/million cells) but LAD2 activated by substance P, a neuropeptide that also binds a G protein-coupled receptor, did not produce CysLT. Montelukast had no effect on SP-mediate...
Isoprostanes are a large group of prostaglandin-like compounds produced via free radical peroxida... more Isoprostanes are a large group of prostaglandin-like compounds produced via free radical peroxidation of the membrane phospholipid arachidonic acid. Production of these molecules increases during periods of oxidative stress associated with various diseases. With mounting evidence of isoprostane-induced biological activity, it is becoming apparent that these compounds may contribute to disease pathology. ^ Most research regarding the physiological activity of
Open Journal of Immunology, 2012
Resveratrol, a polyphenol abundant in peanuts, red wine and the skin of grapes, has been shown to... more Resveratrol, a polyphenol abundant in peanuts, red wine and the skin of grapes, has been shown to have anti-cancer, anti-oxidant and anti-inflammatory activities, and may also have beneficial effects on allergic inflammation. We investigated the effects of resveratrol on human mast cell activation in comparison to the anti-allergy drug tranilast. In LAD2 mast cells, both resveratrol and tranilast inhibited degranulation induced by the mast cell activators substance P, IgE/anti-IgE, and compound 48/80. Resveratrol inhibition was immediate, preventing degranulation when added simultaneously to physiological stimuli, and the effect was sustained for up to 24 hrs. The inhibitory effect was not cAMP dependent, but may be attributable to calcium modulation, as resveratrol, and to a lesser extent tranilast, prevented substance P-induced increases in intracellular calcium. Resveratrol attenuated substance P-induced TNF and MCP-1 production and inhibited IgE-mediated release of cysteinyl leukotrienes, whereas tranilast was ineffective. Furthermore, both resveratrol and tranilast reduced expression of the high affinity IgE receptor, FcεRI, on LAD2 cells. The effects of resveratrol on mast cell activation were more marked in human primary CD34 +-derived mast cells (HuMC), and the polyphenol was significantly more efficacious than tranilast in these cells. In conclusion, resveratrol inhibited key aspects of human mast cell activation to physiological stimuli, and was comparable, if not more efficacious than the anti-allergy drug tranilast. Thus, resveratrol may be an effective therapeutic agent for the treatment of allergic disease.
Allergy Frontiers: Classification and Pathomechanisms, 2009
Allergic airways diseases are a leading cause of morbidity and mortality both in Canada and globa... more Allergic airways diseases are a leading cause of morbidity and mortality both in Canada and globally, and as such, highlight the pressing need for effective pharmacotherapy to adequately control these conditions. Asthma is a chronic inflammatory disease characterized by variable bronchial obstruction, airway hyperresponsiveness (AHR) and infiltration of the airways by activated pro-inflammatory cells, predominantly eosinophils implicated as prime effector
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2010
Polysaccharides are receiving increased attention due to their clinical applications in tissue en... more Polysaccharides are receiving increased attention due to their clinical applications in tissue engineering, vaccine development, nutritional supplementation and antimicrobial biopolymer engineering. The most abundant polysaccharides include fungal cell wall components chitin and-1,3-glucans. Recent evidence has shown that these polysaccharides modulate airway inflammation, making them the basis of several drug discovery platforms. Small to intermediate chitin fragments (< 70 μm) are protective in allergic inflammatory models, skewing T cell immunity towards Th1 responses, and reducing the production of Th2 cytokines. As such, chitin prevents the development of the quintessential features of asthmatic disease including chronic airway inflammation, airway hyperresponsiveness and pathological remodeling changes in mouse models of allergy. In contrast, the in vivo effects of-glucans in animal models of airway inflammation are often contradictory, and the number of human studies is limited.-1,3-glucans are both proand anti-inflammatory, preventing and enhancing allergic inflammation depending on the preparation, purity and species origin of the-glucans. This review summarizes recent studies of chitin and-glucans in models of atopy and airway inflammation and examines the possible reasons for the apparently contradictory observations. Recent relevant patents are also highlighted.
The Journal of pharmacology and experimental therapeutics, 2000
Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and ... more Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly...
American journal of physiology. Lung cellular and molecular physiology, 2002
Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isop... more Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isoprostanes in canine and porcine airway smooth muscle. 8-Isoprostaglandin E1 and 8-isoprostaglandin E2 (8-iso PGE2) reversed cholinergic tone in a concentration-dependent manner, whereas the F-ring isoprostanes were ineffective. Desensitization with 8-iso-PGE2 and PGE2 implicated isoprostane activity at the PGE2 receptor (EP). We found that the inhibitory E-ring isoprostane responses were significantly augmented by rolipram (a type IV phosphodiesterase inhibitor), while 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) had no effect, suggesting a role for cAMP in isoprostane-mediated relaxations. 8-Iso-PGE2 did not reverse KCl tone, suggesting that voltage-dependent Ca2+ influx and myosin light chain kinase are not suppressed by isoprostanes. Patch-clamp studies showed marked suppression of K+ currents by 8-iso-PGE2. We conclude that E-ring isoprostanes exert PGE...
Nutrition and Cancer, 2014
Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide.... more Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.
PLoS ONE, 2014
Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for ... more Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 mM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/ anti-IgE. Degranulation was measured by the release of b-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n = 3, P, .05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n = 3, P,.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n = 4, P,.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma.
Nutrition Research, 2014
Both quercetin glycosides and omega-3 polyunsaturated fatty acids (n-3 PUFA) are well established... more Both quercetin glycosides and omega-3 polyunsaturated fatty acids (n-3 PUFA) are well established for their individual health benefits in ameliorating metabolic disease. However, their combined effects are not well documented. It was hypothesized that the beneficial properties of quercetin glycosides can be enhanced when provided in combination with n-3 PUFA. Therefore, the aim of the present study was to investigate the effects of apple flavonols (AF) and fish oil (FO), alone and in combination, on proinflammatory biomarkers and lipid profiles in rats fed a high-fat diet. Sixty male Wistar rats were randomly divided into 5 groups (n = 12) and fed a high-fat diet for 4 weeks. One of the 5 groups of rats was used as the high-fat control. The other 4 groups of rats were injected with lipopolysaccharide (LPS) (5 mg/kg body weight) intraperitoneally, 5 hours before euthanization. One of these 4 groups was used as the hypercholerolemic and inflammatory control (high-fat with lipopolysaccharide [HFL]), and the other 3 received AF (HFL + 25 mg/kg per day AF), FO (HFL + 1 g/kg per day FO), or the combination (HFL + AF + FO). Compared to the HFL group, the AF, FO, and AF + FO groups showed lower serum concentrations of interleukin-6 and C-reactive protein (CRP) levels. The AF, FO, and AF + FO also had lowered serum triacylglycerol and non-high-density lipoprotein cholesterol (HDL-C) concentrations, but higher HDL-C levels relative to the HFL group. An additive effect was observed on serum CRP in the AF + FO group as compared with the AF or FO groups. The results demonstrated that AF and FO inhibited the production of proinflammatory mediators and showed an improved efficacy to lower serum CRP when administered in combination, and they significantly improved blood lipid profiles in rats with diet-induced hyperlipidemia and LPS-induced acute inflammation.
Mucosal Immunology, 2014
Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are stru... more Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are structurally and functionally similar to cathelicidins, one of the major CAP families. As cathelicidins stimulate mast cell chemotaxis and mediator release, we postulated that pleurocidins similarly activate mast cells. A screen of 20 pleurocidin peptides revealed that some were capable of degranulating the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). Pleurocidin NRC-04 caused LAD2 to adhere, migrate, degranulate, and release cysteinyl leukotrienes and prostaglandin D2. Moreover, pleurocidin increased intracellular Ca(2+) mobilization in mast cells and induced the production of proinflammatory chemokines such as monocyte chemotactic protein-1/C-C motif chemokine ligand 2 (CCL2) and macrophage inflammatory protein-1β/CCL4. Our evaluation of possible cellular mechanisms suggested that G proteins, phosphoinositol-3 kinase (PI3K), phospholipase C (PLC), and phosphokinase C (PKC) were involved in pleurocidin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G protein inhibitor), wortmanin (PI3K inhibitor), U-73122 (PLC inhibitor), and Ro-31-8220 (PKC inhibitor), respectively. We also found that human mast cells expressed the N-formyl-peptide receptor 1 (FPRL1) receptor and FPRL1-specific inhibitor affected pleurocidin-mediated activation of mast cell. Our finding that the novel CAP pleurocidin activated human mast cell through G protein-coupled receptor signaling suggests that this peptide might have immunomodulatory functions.
Journal of Neuroimmunology, 2010
The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly under... more The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly understood. In this study, SP effects on human MC expression of the high affinity IgE receptor (FcεRI) were characterized. SP downregulated expression of FcεRI mRNA and protein by approximately 50% and in a concentration dependent manner, the effect was partially mediated by engagement of the neurokinin-1 receptor (NK1R) and resulted in reduced mast cell activation. Sensitization of MC with IgE prior to SP exposure protected MC from SP-mediated FcεRI downregulation. SP release may inhibit MC responses to allergens and these results may have implications in neuroinflammatiion and stress.
Journal of Cellular Biochemistry, 2010
Prostate cancer is one of the most common cancers in the Western world, and it is believed that a... more Prostate cancer is one of the most common cancers in the Western world, and it is believed that an individual's diet affects his risk of developing cancer. There has been an interest in examining phytochemicals, the secondary metabolites of plants, in order to determine their potential anti-cancer activities in vitro and in vivo. In this study we document the effects of proanthocyanidins (PACs) from the American Cranberry (Vaccinium macrocarpon) on matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells. Cranberry PACs decreased cellular viability of DU145 cells at a concentration of 25 mg/ml by 30% after 6 h of treatment. Treatment of DU145 cells with PACs resulted in an inhibition of both MMPs 2 and 9 activity. PACs increased the expression of TIMP-2, a known inhibitor of MMP activity, and decreased the expression of EMMPRIN, an inducer of MMP expression. PACs decreased the expression of PI-3 kinase and AKT proteins, and increased the phosphorylation of both p38 and ERK1/2. Cranberry PACs also decreased the translocation of the NF-kB p65 protein to the nucleus. Cranberry PACs increased c-jun and decreased c-fos protein levels. These results suggest that cranberry PACs decreases MMP activity through the induction and/or inhibition of specific temporal MMP regulators, and by affecting either the phosphorylation status and/or expression of MAP kinase, PI-3 kinase, NF-kB and AP-1 pathway proteins. This study further demonstrates that cranberry PACs are a strong candidate for further research as novel anti-cancer agents.
The FASEB Journal, 2015
Ursolic acid is a constituent of the American cranberry (Vaccinium macrocarpon) and other Vaccini... more Ursolic acid is a constituent of the American cranberry (Vaccinium macrocarpon) and other Vaccinium fruit found primarily in the peel. In this study, the effects of ursolic acid (UA) on the cell cycle behaviour of DU145 human prostate cancer cells in vitro was examined. Following treatment of cells with UA (50 μM) for 6 hours, the cellular viability of the cells decreased. UA treatment increased the proportion of cells in the G1 phase of the cell cycle. The relative proportion of cells in G2-M phase was similar in both control and UA-treated cells. UA treatment also caused a decrease in the proportion of cells in S-phase relative to untreated cells. These cell cycle alterations were associated with changes in expression of cell cycle associated regulatory proteins. UA decreased the protein expression levels of cyclin A, cyclin D, p16 , pRBp107 and increased the expression of CDK2, CDK4, cyclin E, p21, p27 and pRBp130. CyclinB1 protein expression levels were apparently unaffected by UA. These findings demonstrate that ursolic acid can affect the cell growth behaviour of human prostate cancer cells in vitro. [Cranberry Institute (Wisconsin Board) & Telus MRFD Prostate Cancer Research Fund (PEI Division) funded
Journal of biological regulators and homeostatic agents, 2018
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the p... more Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, ...
Http Dx Doi Org 10 1080 01635581 2014 951736, Sep 29, 2014
Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide.... more Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.
European Journal of Pharmacology, Nov 1, 2004
We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prosta... more We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prostaglandin E(2) in porcine tracheal smooth muscle. Both autacoids completely reversed cholinergic tone; blockade of thromboxane A(2) receptors had no effect on relaxations to either compound. 8-iso-prostaglandin E(2) and prostaglandin E(2) suppressed outward K(+) currents while the thromboxane A(2) receptor agonist U46619 (9, 11-dideoxy-9a,11a-methanoepoxy prostaglandin F(2alpha)) had no significant effect. During thromboxane A(2) receptor antagonism, however, 8-iso-prostaglandin E(2) markedly augmented K(+) currents while prostaglandin E(2) no longer suppressed K(+) currents, indicating that the inhibition of K(+) currents by both compounds was thromboxane A(2) receptor-mediated. Furthermore, the observation that K(+) currents were augmented by 8-iso-prostaglandin E(2) but not by prostaglandin E(2) suggests that the salutory effect is not exerted through a prostaglandin E receptor. Additionally, our observations argue against any causal role for K(+) current activation in mediating relaxations evoked by isoprostanes or by prostaglandin E(2). We conclude that 8-iso-prostaglandin E(2) relaxes porcine tracheal smooth muscle independent of K(+) current activity, and that 8-iso-prostaglandin E(2) may also act at a non-thromboxane A(2)/non-prostaglandin E receptor to augment K(+) currents.
J Allerg Clin Immunol, 2010
The Journal of Immunology, May 1, 2012
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid mediators which are derived from 5-l... more Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid mediators which are derived from 5-lipoxygenase activity. CysLTs mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability, increased mucus secretion, decreased mucociliary clearance, eosinophil migration, and increased eosinophil survival. We now report that peripheral blood CD34+ progenitor-derived human mast cells and the human mast cell line (LAD2) express both CysLT receptors (CysLT1R and CysLT2R), the G protein-coupled receptors that bind CysLTs. LTC4, LTD4 and LTE4 activated LAD2 to produce MIP-1β and MCP-1 and production of these chemokines was inhibited by the CysLT1R inhibitor, monelukast. LAD2 activated by IgE/anti-IgE produced CysLT (980 + 55 pg/million cells) but LAD2 activated by substance P, a neuropeptide that also binds a G protein-coupled receptor, did not produce CysLT. Montelukast had no effect on SP-mediate...
Isoprostanes are a large group of prostaglandin-like compounds produced via free radical peroxida... more Isoprostanes are a large group of prostaglandin-like compounds produced via free radical peroxidation of the membrane phospholipid arachidonic acid. Production of these molecules increases during periods of oxidative stress associated with various diseases. With mounting evidence of isoprostane-induced biological activity, it is becoming apparent that these compounds may contribute to disease pathology. ^ Most research regarding the physiological activity of
Open Journal of Immunology, 2012
Resveratrol, a polyphenol abundant in peanuts, red wine and the skin of grapes, has been shown to... more Resveratrol, a polyphenol abundant in peanuts, red wine and the skin of grapes, has been shown to have anti-cancer, anti-oxidant and anti-inflammatory activities, and may also have beneficial effects on allergic inflammation. We investigated the effects of resveratrol on human mast cell activation in comparison to the anti-allergy drug tranilast. In LAD2 mast cells, both resveratrol and tranilast inhibited degranulation induced by the mast cell activators substance P, IgE/anti-IgE, and compound 48/80. Resveratrol inhibition was immediate, preventing degranulation when added simultaneously to physiological stimuli, and the effect was sustained for up to 24 hrs. The inhibitory effect was not cAMP dependent, but may be attributable to calcium modulation, as resveratrol, and to a lesser extent tranilast, prevented substance P-induced increases in intracellular calcium. Resveratrol attenuated substance P-induced TNF and MCP-1 production and inhibited IgE-mediated release of cysteinyl leukotrienes, whereas tranilast was ineffective. Furthermore, both resveratrol and tranilast reduced expression of the high affinity IgE receptor, FcεRI, on LAD2 cells. The effects of resveratrol on mast cell activation were more marked in human primary CD34 +-derived mast cells (HuMC), and the polyphenol was significantly more efficacious than tranilast in these cells. In conclusion, resveratrol inhibited key aspects of human mast cell activation to physiological stimuli, and was comparable, if not more efficacious than the anti-allergy drug tranilast. Thus, resveratrol may be an effective therapeutic agent for the treatment of allergic disease.
Allergy Frontiers: Classification and Pathomechanisms, 2009
Allergic airways diseases are a leading cause of morbidity and mortality both in Canada and globa... more Allergic airways diseases are a leading cause of morbidity and mortality both in Canada and globally, and as such, highlight the pressing need for effective pharmacotherapy to adequately control these conditions. Asthma is a chronic inflammatory disease characterized by variable bronchial obstruction, airway hyperresponsiveness (AHR) and infiltration of the airways by activated pro-inflammatory cells, predominantly eosinophils implicated as prime effector
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, 2010
Polysaccharides are receiving increased attention due to their clinical applications in tissue en... more Polysaccharides are receiving increased attention due to their clinical applications in tissue engineering, vaccine development, nutritional supplementation and antimicrobial biopolymer engineering. The most abundant polysaccharides include fungal cell wall components chitin and-1,3-glucans. Recent evidence has shown that these polysaccharides modulate airway inflammation, making them the basis of several drug discovery platforms. Small to intermediate chitin fragments (< 70 μm) are protective in allergic inflammatory models, skewing T cell immunity towards Th1 responses, and reducing the production of Th2 cytokines. As such, chitin prevents the development of the quintessential features of asthmatic disease including chronic airway inflammation, airway hyperresponsiveness and pathological remodeling changes in mouse models of allergy. In contrast, the in vivo effects of-glucans in animal models of airway inflammation are often contradictory, and the number of human studies is limited.-1,3-glucans are both proand anti-inflammatory, preventing and enhancing allergic inflammation depending on the preparation, purity and species origin of the-glucans. This review summarizes recent studies of chitin and-glucans in models of atopy and airway inflammation and examines the possible reasons for the apparently contradictory observations. Recent relevant patents are also highlighted.
The Journal of pharmacology and experimental therapeutics, 2000
Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and ... more Isoprostanes are generated nonenzymatically during free radical-mediated lipid peroxidation, and are used clinically and experimentally as markers of oxidative stress. However, their biological effects are poorly understood. We examined the effects of seven different 8-isoprostanes in human and canine airway smooth muscles. In large order airways (carina) of the human, several isoprostanes evoked powerful contractions, with 8-iso-prostaglandin (PG) E(2), 8-iso-PGF(1 alpha), and 8-iso-PGF(2 alpha) being the most efficacious (and with logEC(50) values of 7.0, 5.9, and 6.2 microM, respectively). These contractions were sensitive to the prostanoid TP receptor antagonist ICI 192,605 (0.1-1 microM), but not the EP prostanoid receptor antagonist AH-6809 (50 microM), or the leukotriene receptor antagonists monteleukast or ICI 198,615 (both 1 microM). Qualitatively similar results were obtained in small order human airways (<2 mm o.d.), except that the isoprostanes were generally slightly...
American journal of physiology. Lung cellular and molecular physiology, 2002
Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isop... more Using muscle bath techniques, we examined the inhibitory activities of several E- and F-ring isoprostanes in canine and porcine airway smooth muscle. 8-Isoprostaglandin E1 and 8-isoprostaglandin E2 (8-iso PGE2) reversed cholinergic tone in a concentration-dependent manner, whereas the F-ring isoprostanes were ineffective. Desensitization with 8-iso-PGE2 and PGE2 implicated isoprostane activity at the PGE2 receptor (EP). We found that the inhibitory E-ring isoprostane responses were significantly augmented by rolipram (a type IV phosphodiesterase inhibitor), while 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) had no effect, suggesting a role for cAMP in isoprostane-mediated relaxations. 8-Iso-PGE2 did not reverse KCl tone, suggesting that voltage-dependent Ca2+ influx and myosin light chain kinase are not suppressed by isoprostanes. Patch-clamp studies showed marked suppression of K+ currents by 8-iso-PGE2. We conclude that E-ring isoprostanes exert PGE...
Nutrition and Cancer, 2014
Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide.... more Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 μM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.
PLoS ONE, 2014
Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for ... more Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 mM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/ anti-IgE. Degranulation was measured by the release of b-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n = 3, P, .05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n = 3, P,.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n = 4, P,.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma.
Nutrition Research, 2014
Both quercetin glycosides and omega-3 polyunsaturated fatty acids (n-3 PUFA) are well established... more Both quercetin glycosides and omega-3 polyunsaturated fatty acids (n-3 PUFA) are well established for their individual health benefits in ameliorating metabolic disease. However, their combined effects are not well documented. It was hypothesized that the beneficial properties of quercetin glycosides can be enhanced when provided in combination with n-3 PUFA. Therefore, the aim of the present study was to investigate the effects of apple flavonols (AF) and fish oil (FO), alone and in combination, on proinflammatory biomarkers and lipid profiles in rats fed a high-fat diet. Sixty male Wistar rats were randomly divided into 5 groups (n = 12) and fed a high-fat diet for 4 weeks. One of the 5 groups of rats was used as the high-fat control. The other 4 groups of rats were injected with lipopolysaccharide (LPS) (5 mg/kg body weight) intraperitoneally, 5 hours before euthanization. One of these 4 groups was used as the hypercholerolemic and inflammatory control (high-fat with lipopolysaccharide [HFL]), and the other 3 received AF (HFL + 25 mg/kg per day AF), FO (HFL + 1 g/kg per day FO), or the combination (HFL + AF + FO). Compared to the HFL group, the AF, FO, and AF + FO groups showed lower serum concentrations of interleukin-6 and C-reactive protein (CRP) levels. The AF, FO, and AF + FO also had lowered serum triacylglycerol and non-high-density lipoprotein cholesterol (HDL-C) concentrations, but higher HDL-C levels relative to the HFL group. An additive effect was observed on serum CRP in the AF + FO group as compared with the AF or FO groups. The results demonstrated that AF and FO inhibited the production of proinflammatory mediators and showed an improved efficacy to lower serum CRP when administered in combination, and they significantly improved blood lipid profiles in rats with diet-induced hyperlipidemia and LPS-induced acute inflammation.
Mucosal Immunology, 2014
Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are stru... more Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are structurally and functionally similar to cathelicidins, one of the major CAP families. As cathelicidins stimulate mast cell chemotaxis and mediator release, we postulated that pleurocidins similarly activate mast cells. A screen of 20 pleurocidin peptides revealed that some were capable of degranulating the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). Pleurocidin NRC-04 caused LAD2 to adhere, migrate, degranulate, and release cysteinyl leukotrienes and prostaglandin D2. Moreover, pleurocidin increased intracellular Ca(2+) mobilization in mast cells and induced the production of proinflammatory chemokines such as monocyte chemotactic protein-1/C-C motif chemokine ligand 2 (CCL2) and macrophage inflammatory protein-1β/CCL4. Our evaluation of possible cellular mechanisms suggested that G proteins, phosphoinositol-3 kinase (PI3K), phospholipase C (PLC), and phosphokinase C (PKC) were involved in pleurocidin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G protein inhibitor), wortmanin (PI3K inhibitor), U-73122 (PLC inhibitor), and Ro-31-8220 (PKC inhibitor), respectively. We also found that human mast cells expressed the N-formyl-peptide receptor 1 (FPRL1) receptor and FPRL1-specific inhibitor affected pleurocidin-mediated activation of mast cell. Our finding that the novel CAP pleurocidin activated human mast cell through G protein-coupled receptor signaling suggests that this peptide might have immunomodulatory functions.
Journal of Neuroimmunology, 2010
The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly under... more The effect of the neuropeptide substance P (SP) on human mast cell (MC) phenotype is poorly understood. In this study, SP effects on human MC expression of the high affinity IgE receptor (FcεRI) were characterized. SP downregulated expression of FcεRI mRNA and protein by approximately 50% and in a concentration dependent manner, the effect was partially mediated by engagement of the neurokinin-1 receptor (NK1R) and resulted in reduced mast cell activation. Sensitization of MC with IgE prior to SP exposure protected MC from SP-mediated FcεRI downregulation. SP release may inhibit MC responses to allergens and these results may have implications in neuroinflammatiion and stress.
Journal of Cellular Biochemistry, 2010
Prostate cancer is one of the most common cancers in the Western world, and it is believed that a... more Prostate cancer is one of the most common cancers in the Western world, and it is believed that an individual's diet affects his risk of developing cancer. There has been an interest in examining phytochemicals, the secondary metabolites of plants, in order to determine their potential anti-cancer activities in vitro and in vivo. In this study we document the effects of proanthocyanidins (PACs) from the American Cranberry (Vaccinium macrocarpon) on matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells. Cranberry PACs decreased cellular viability of DU145 cells at a concentration of 25 mg/ml by 30% after 6 h of treatment. Treatment of DU145 cells with PACs resulted in an inhibition of both MMPs 2 and 9 activity. PACs increased the expression of TIMP-2, a known inhibitor of MMP activity, and decreased the expression of EMMPRIN, an inducer of MMP expression. PACs decreased the expression of PI-3 kinase and AKT proteins, and increased the phosphorylation of both p38 and ERK1/2. Cranberry PACs also decreased the translocation of the NF-kB p65 protein to the nucleus. Cranberry PACs increased c-jun and decreased c-fos protein levels. These results suggest that cranberry PACs decreases MMP activity through the induction and/or inhibition of specific temporal MMP regulators, and by affecting either the phosphorylation status and/or expression of MAP kinase, PI-3 kinase, NF-kB and AP-1 pathway proteins. This study further demonstrates that cranberry PACs are a strong candidate for further research as novel anti-cancer agents.