Lidia Sautebin - Academia.edu (original) (raw)
Papers by Lidia Sautebin
Mediators of Inflammation, 1996
The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor... more The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor-α release in J774 macrophages has been studied. Both prostaglandin E2and iloprost inhibited, in a concentration-dependent fashion, the lipopolysaccharide-induced generation of nitric oxide and tumour necrosis factor-α. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO-20-1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E2and iloprost in lipopolysaccharide-activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor-α generation, which in turn is likely to be mediated by cAMP.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Oct 1, 2017
Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vit... more Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vitamin A, although the mechanisms behind the sustained kinase activation are diffuse. To investigate the role of cellular lipids as targetable factors in Akt signaling, we combined mass spectrometry-based lipidomics with immunologic detection of Akt (Ser473) phosphorylation. A screening campaign revealed retinol (vitamin A alcohol) and all- retinoic acid (vitamin A acid) (RA) as hits that time-dependently (≥24 h) deplete phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PCs) from NIH-3T3 mouse fibroblasts while inducing Akt activation (EC ≈ 0.1-1 µM). Other mitogenic and stress-regulated kinases were hardly affected. Organized in a coregulated phospholipid subcluster, PUFA-PCs compensated for the RA-induced loss of cellular PUFA-PCs and diminished Akt activation when supplemented. The counter-regulation of phospholipids and Akt by RA was mimicked by knockdown of lysophosphatidylc...
Scientific reports, Jan 24, 2017
Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxyge... more Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH. Diflapolin inhibited 5-LOX product formation in intact human monocytes and neutrophils with IC50 = 30 and 170 nM, respectively, and suppressed the activity of isolated sEH (IC50 = 20 nM). Characteristic for FLAP inhibitors, diflapolin (I) failed to inhibit isolated 5-LOX, (II) blocked 5-LOX product formation in HEK cells only when 5-LOX/FLAP was co-expressed, (III) lost potency in inta...
Pharmacological Research, Feb 28, 2009
Psychopharmacology, 1996
Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whethe... more Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses of NG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P < 0.001) without influencing total fluid consumption or feeding behavior. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.
Inflamm Research, 1999
The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipo... more The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipopolysaccharide (LPS)- stimulated J774 macrophages has been investigated. Murine monocyte/macrophage J774 cell line. Cells were incubated with AA or LPS and the amount of 8-epi-PGF2alpha, 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) and prostaglandin E2 (PGE2) released in the incubation media measured by radioimmunoassay (RIA) or, in some experiments, by enzyme immunoassay (EIA). The effect of dexamethasone (DXM), cycloheximide (CXM) and 5,5 dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 (COX-2) selective inhibitor, on LPS-induced generation of AA metabolites was assessed. AA induced a significant production of 6-ketoPGF1alpha and PGE2, whereas LPS caused a concentration- and time-dependent increase of 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2. DXM (2 microM) as well as CXM (1 microM) significantly decreased (p<0.001; n = 4) the LPS-stimulated production of 8-epi-PGF2alpha (by 86% and 82%, respectively), 6-ketoPGF1alpha (by 78% and 74%, respectively) and PGE2 (by 83% and 78%, respectively). Immunostimulated production of AA metabolites was also inhibited by DFU (IC50 0.3+/-0.04 microM; 0.16 +/- 0.02 microM and 0.11 +/- 0.05 microM for 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2, respectively. These results demonstrate the role of COX-2 in the generation of 8-epi-PGF2alpha by LPS-stimulated J774 macrophages. The relevance of these findings requires further elucidation.
![Research paper thumbnail of Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E2 synthase-1](https://attachments.academia-assets.com/71606080/thumbnails/1.jpg)
](Bioorganic Medicinal Chemistry, 2009
Inflamm Research, 1999
The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipo... more The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipopolysaccharide (LPS)- stimulated J774 macrophages has been investigated. Murine monocyte/macrophage J774 cell line. Cells were incubated with AA or LPS and the amount of 8-epi-PGF2alpha, 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) and prostaglandin E2 (PGE2) released in the incubation media measured by radioimmunoassay (RIA) or, in some experiments, by enzyme immunoassay (EIA). The effect of dexamethasone (DXM), cycloheximide (CXM) and 5,5 dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 (COX-2) selective inhibitor, on LPS-induced generation of AA metabolites was assessed. AA induced a significant production of 6-ketoPGF1alpha and PGE2, whereas LPS caused a concentration- and time-dependent increase of 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2. DXM (2 microM) as well as CXM (1 microM) significantly decreased (p<0.001; n = 4) the LPS-stimulated production of 8-epi-PGF2alpha (by 86% and 82%, respectively), 6-ketoPGF1alpha (by 78% and 74%, respectively) and PGE2 (by 83% and 78%, respectively). Immunostimulated production of AA metabolites was also inhibited by DFU (IC50 0.3+/-0.04 microM; 0.16 +/- 0.02 microM and 0.11 +/- 0.05 microM for 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2, respectively. These results demonstrate the role of COX-2 in the generation of 8-epi-PGF2alpha by LPS-stimulated J774 macrophages. The relevance of these findings requires further elucidation.
Archiv Fur Experimentelle Pathologie Und Pharmakologie, Apr 1, 2002
European journal of medicinal chemistry, Jan 28, 2015
A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and th... more A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-...
The Journal of Pharmacology and Experimental Therapeutics, 2000
The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithr... more The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithromycin) on the generation of some mediators and cytokines involved in the inflammatory process has been studied both in vivo and in vitro. Rat carrageenin pleurisy was used as a model of acute inflammation, and the macrolides were administered (10, 20, and 40 mg/kg p.o.) 1 h before the carrageenin challenge. Exudate volume and leukocyte accumulation were both dose-dependently reduced by roxithromycin, clarithromycin and erythromycin in either normal or adrenalectomized animals. Furthermore, in normal rats, prostaglandin (PG)E(2), nitrate plus nitrite, and tumor necrosis factor-alpha levels in pleural exudate were significantly reduced by these macrolides. Roxithromycin appeared more effective than erythromycin and clarithromycin, whereas azithromycin only slightly affected the inflammatory reaction. None of the macrolides were able to modify leukotriene B(4) exudate levels. In vitro experiments have shown that the four macrolides (5-80 microM) reduced in a concentration-dependent manner the production of 6-keto-PGF(1alpha), NO(2)(-), tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the inhibition of 6-keto-PGF(1alpha) and NO(2)(-) production by roxithromycin and erythromycin was not dependent on direct inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activity because it appears to be related to the inhibition of cyclooxygenase-2 and inducible nitric oxide synthase protein expression. In conclusion, the present study shows that macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokines, and suggest that these agents, particularly roxithromycin, can exert therapeutic effects independently of their antibacterial activity.
Pharmacological Research, 2015
Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human bod... more Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human body causing temporary or permanent sensory and/or motor system deficit, particularly hind limb locomotor function impairment. At present, steroidal inflammatory drugs, in particular methylprednisolone sodium succinate (MPSS) are the first line choice treatment of acute SCI. Despite progress in pharmacological, surgical and rehabilitative treatment approaches, SCI still remains a very complex medical and psychological challenge, with no curative therapy available. The aim of the present study was to compare the efficacy of MPSS in respect to other GCs such as dexamethasone (Dex) and mometasone furoate (MF) in an in vitro suitable model of LPS-induced inflammation in J774 cells as well as in an in vivo experimental mouse SCI (compression model). In both the in vitro and in vivo experiments, MF resulted surprisingly more potent than Dex and MPSS. In detail, mice sacrificed seven days after induction of SCI trauma resulted not only in tissue damage, cellular infiltration, fibrosis, astrocyte activation, iNOS expression, extracellular signal regulated kinase 1/2 phosphorylation in injured tissue, poly (ADP-ribose) polymerase 1 (PARP-1) activation but also apoptosis (Bax and Bcl-2 expression). All three GCs demonstrated the ability to modulate inflammatory, oxidative as well as apoptotic pathways, but MF demonstrated the best efficacy, while Dex and MPSS showed alternative potency with a different degree of protection. Therefore, we can conclude that MF is the best candidate for post-traumatic chronic treatment, since it ameliorates different molecular pathways involved in the damage's propagation to the surrounding areas of the injured spinal cord.
Drug safety, 2008
Currently, cosmetics and toiletries are very popular and their use continues to increase because ... more Currently, cosmetics and toiletries are very popular and their use continues to increase because consumers consider physical appearance important and, at the same time, these products are considered to be safe. However, in spite of their safety and tolerability, during recent decades, we have become aware that adverse effects can occur. The number of adverse effects known so far is very low indeed. This is partly because such adverse effects are underestimated as a result of self-diagnosis and self-medication, which are common behaviours in the presence of mild-to-moderate reactions, as in the case of cosmetics. Moreover, such effects are underestimated because of the absence of formal and reliable monitoring systems ('cosmetovigilance'). This requires the creation of a standard reporting form, as well as resolution concerning professional categories authorized to report and the subsequent validation/evaluation of the collected forms. All these items are of great importance,...
Journal of agricultural and food chemistry, Jan 27, 2007
Feijoa sellowiana Berg. fruits and especially the acetonic extract have been shown to possess bio... more Feijoa sellowiana Berg. fruits and especially the acetonic extract have been shown to possess biological activities, although the responsible compounds have never been identified. The present study was designed to evaluate the anti-inflammatory activity of an acetonic extract from F. sellowiana Berg. fruits on the nitric oxide (NO) pathway, which plays an important role in inflammation. To this aim the J774 cell line, which expresses inducible nitric oxide synthase (iNOS) following stimulation with lipopolysaccharide (LPS), has been utilized, and the effects of this extract and its fractions on NO production, iNOS protein expression, and signal pathways involved in its regulation have been evaluated. This study demonstrates that at least some part of the anti-inflammatory activity of the acetonic extract is due to the suppression of NO production by flavone and stearic acid. The mechanism of this inhibition seems to be related to an action on the expression of the enzyme iNOS throug...
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2002
The effect of an ethanolic extract of propolis, with and without CAPE, and some of its components... more The effect of an ethanolic extract of propolis, with and without CAPE, and some of its components on cyclooxygenase (COX-1 and COX-2) activity in J774 macrophages has been investigated. COX-1 and COX-2 activity, measaured as prostaglandin E2 (PGE2) production, were concentration-dependently inhibited by propolis (3 x 10(-3) - 3 x 10(2) microgml(-1)) with an IC50 of 2.7 microgml(-1) and 4.8 x 10(-2) microgml(-1), respectively. Among the compounds tested pinocembrin and caffeic, ferulic, cinnamic and chlorogenic acids did not affect the activity of COX isoforms. Conversely, CAPE (2.8 x 10(-4) - 28 microgml(-1); 10(-9) - 10(-4) M) and galangin (2.7 x 10(-4) - 27 microgml(-1); 10(-9) - 10(-4) M) were effective, the last being about ten-twenty times less potent. In fact the IC50 of CAPE for COX-1 and COX-2 were 4.4 x 10(-1) microgml(-1) (1.5 x 10(-6) M) and 2 x 10(-3) microgml(-1) (6.3 x 10(-9) M), respectively. The IC50 of galangin were 3.7 microgml(-1) (15 x 10(-6) M) and 3 x 10(-2) mi...
Molecular medicine (Cambridge, Mass.), 2001
We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitri... more We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitric oxide synthetase (iNOS) activity in selected model systems such as macrophages, microglia, smooth muscle cells, and proposed that this effect might be associated with an anti-inflammatory activity of this hormone. Here we investigate the effects of endogenous estrogens in rats subjected to carrageenan-induced pleurisy. Adult female rats were ovariectomized 3 weeks before the experiments to deplete circulating estrogens. Selected inflammatory markers, landmarks of the delayed phase of carrageenan-induced pleurisy, were measured in intact (N-OVX), and ovariectomized (OVX) female rats. In addition, the effect of hormone replacement was evaluated in ovariectomized rats with intraperitoneal injection of 17beta-estradiol (E2; 50 microg/kg) 1 hr before carrageenan treatment (OVX + E2). Ovariectomy enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte mig...
Journal of immunology (Baltimore, Md. : 1950), 1999
In the present study we used IL-6 knockout mice (IL-6KO) to evaluate the role of IL-6 in the infl... more In the present study we used IL-6 knockout mice (IL-6KO) to evaluate the role of IL-6 in the inflammatory response caused by injection of carrageenan into the pleural space. Compared with carrageenan-treated IL-6 wild-type (IL-6WT) mice, carrageenan-treated IL-6KO mice exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase activity and lipid peroxidation were significantly reduced in IL-6KO mice compared with those in IL-6WT mice treated with carrageenan. Immunohistochemical analysis for nitrotyrosine and poly(A)DP-ribose polymerase revealed a positive staining in lungs from carrageenan-treated IL-6WT mice. No positive staining for nitrotyrosine or PARS was found in the lungs of the carrageenan-treated IL-6KO mice. Staining of lung tissue sections obtained from carrageenan-treated IL-6WT mice with an anti-cyclo-oxygenase-2 Ab showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthas...
Mediators of Inflammation, 1996
The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor... more The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor-α release in J774 macrophages has been studied. Both prostaglandin E2and iloprost inhibited, in a concentration-dependent fashion, the lipopolysaccharide-induced generation of nitric oxide and tumour necrosis factor-α. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO-20-1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E2and iloprost in lipopolysaccharide-activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor-α generation, which in turn is likely to be mediated by cAMP.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Oct 1, 2017
Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vit... more Protein kinases, including the serine/threonine kinase Akt, mediate manifold bioactivities of vitamin A, although the mechanisms behind the sustained kinase activation are diffuse. To investigate the role of cellular lipids as targetable factors in Akt signaling, we combined mass spectrometry-based lipidomics with immunologic detection of Akt (Ser473) phosphorylation. A screening campaign revealed retinol (vitamin A alcohol) and all- retinoic acid (vitamin A acid) (RA) as hits that time-dependently (≥24 h) deplete phosphatidylcholine-bound polyunsaturated fatty acids (PUFA-PCs) from NIH-3T3 mouse fibroblasts while inducing Akt activation (EC ≈ 0.1-1 µM). Other mitogenic and stress-regulated kinases were hardly affected. Organized in a coregulated phospholipid subcluster, PUFA-PCs compensated for the RA-induced loss of cellular PUFA-PCs and diminished Akt activation when supplemented. The counter-regulation of phospholipids and Akt by RA was mimicked by knockdown of lysophosphatidylc...
Scientific reports, Jan 24, 2017
Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxyge... more Arachidonic acid (AA) is metabolized to diverse bioactive lipid mediators. Whereas the 5-lipoxygenase-activating protein (FLAP) facilitates AA conversion by 5-lipoxygenase (5-LOX) to pro-inflammatory leukotrienes (LTs), the soluble epoxide hydrolase (sEH) degrades anti-inflammatory epoxyeicosatrienoic acids (EETs). Accordingly, dual FLAP/sEH inhibition might be advantageous drugs for intervention of inflammation. We present the in vivo pharmacological profile and efficiency of N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea (diflapolin) that dually targets FLAP and sEH. Diflapolin inhibited 5-LOX product formation in intact human monocytes and neutrophils with IC50 = 30 and 170 nM, respectively, and suppressed the activity of isolated sEH (IC50 = 20 nM). Characteristic for FLAP inhibitors, diflapolin (I) failed to inhibit isolated 5-LOX, (II) blocked 5-LOX product formation in HEK cells only when 5-LOX/FLAP was co-expressed, (III) lost potency in inta...
Pharmacological Research, Feb 28, 2009
Psychopharmacology, 1996
Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whethe... more Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses of NG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P < 0.001) without influencing total fluid consumption or feeding behavior. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.
Inflamm Research, 1999
The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipo... more The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipopolysaccharide (LPS)- stimulated J774 macrophages has been investigated. Murine monocyte/macrophage J774 cell line. Cells were incubated with AA or LPS and the amount of 8-epi-PGF2alpha, 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) and prostaglandin E2 (PGE2) released in the incubation media measured by radioimmunoassay (RIA) or, in some experiments, by enzyme immunoassay (EIA). The effect of dexamethasone (DXM), cycloheximide (CXM) and 5,5 dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 (COX-2) selective inhibitor, on LPS-induced generation of AA metabolites was assessed. AA induced a significant production of 6-ketoPGF1alpha and PGE2, whereas LPS caused a concentration- and time-dependent increase of 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2. DXM (2 microM) as well as CXM (1 microM) significantly decreased (p<0.001; n = 4) the LPS-stimulated production of 8-epi-PGF2alpha (by 86% and 82%, respectively), 6-ketoPGF1alpha (by 78% and 74%, respectively) and PGE2 (by 83% and 78%, respectively). Immunostimulated production of AA metabolites was also inhibited by DFU (IC50 0.3+/-0.04 microM; 0.16 +/- 0.02 microM and 0.11 +/- 0.05 microM for 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2, respectively. These results demonstrate the role of COX-2 in the generation of 8-epi-PGF2alpha by LPS-stimulated J774 macrophages. The relevance of these findings requires further elucidation.
Bioorganic Medicinal Chemistry, 2009
Inflamm Research, 1999
The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipo... more The generation of 8-epiprostaglandin F2alpha (8-epi-PGF2alpha) by arachidonic acid (AA)- and lipopolysaccharide (LPS)- stimulated J774 macrophages has been investigated. Murine monocyte/macrophage J774 cell line. Cells were incubated with AA or LPS and the amount of 8-epi-PGF2alpha, 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) and prostaglandin E2 (PGE2) released in the incubation media measured by radioimmunoassay (RIA) or, in some experiments, by enzyme immunoassay (EIA). The effect of dexamethasone (DXM), cycloheximide (CXM) and 5,5 dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 (COX-2) selective inhibitor, on LPS-induced generation of AA metabolites was assessed. AA induced a significant production of 6-ketoPGF1alpha and PGE2, whereas LPS caused a concentration- and time-dependent increase of 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2. DXM (2 microM) as well as CXM (1 microM) significantly decreased (p<0.001; n = 4) the LPS-stimulated production of 8-epi-PGF2alpha (by 86% and 82%, respectively), 6-ketoPGF1alpha (by 78% and 74%, respectively) and PGE2 (by 83% and 78%, respectively). Immunostimulated production of AA metabolites was also inhibited by DFU (IC50 0.3+/-0.04 microM; 0.16 +/- 0.02 microM and 0.11 +/- 0.05 microM for 8-epi-PGF2alpha, 6-keto-PGF1alpha and PGE2, respectively. These results demonstrate the role of COX-2 in the generation of 8-epi-PGF2alpha by LPS-stimulated J774 macrophages. The relevance of these findings requires further elucidation.
Archiv Fur Experimentelle Pathologie Und Pharmakologie, Apr 1, 2002
European journal of medicinal chemistry, Jan 28, 2015
A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and th... more A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-...
The Journal of Pharmacology and Experimental Therapeutics, 2000
The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithr... more The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithromycin) on the generation of some mediators and cytokines involved in the inflammatory process has been studied both in vivo and in vitro. Rat carrageenin pleurisy was used as a model of acute inflammation, and the macrolides were administered (10, 20, and 40 mg/kg p.o.) 1 h before the carrageenin challenge. Exudate volume and leukocyte accumulation were both dose-dependently reduced by roxithromycin, clarithromycin and erythromycin in either normal or adrenalectomized animals. Furthermore, in normal rats, prostaglandin (PG)E(2), nitrate plus nitrite, and tumor necrosis factor-alpha levels in pleural exudate were significantly reduced by these macrolides. Roxithromycin appeared more effective than erythromycin and clarithromycin, whereas azithromycin only slightly affected the inflammatory reaction. None of the macrolides were able to modify leukotriene B(4) exudate levels. In vitro experiments have shown that the four macrolides (5-80 microM) reduced in a concentration-dependent manner the production of 6-keto-PGF(1alpha), NO(2)(-), tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the inhibition of 6-keto-PGF(1alpha) and NO(2)(-) production by roxithromycin and erythromycin was not dependent on direct inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activity because it appears to be related to the inhibition of cyclooxygenase-2 and inducible nitric oxide synthase protein expression. In conclusion, the present study shows that macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokines, and suggest that these agents, particularly roxithromycin, can exert therapeutic effects independently of their antibacterial activity.
Pharmacological Research, 2015
Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human bod... more Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human body causing temporary or permanent sensory and/or motor system deficit, particularly hind limb locomotor function impairment. At present, steroidal inflammatory drugs, in particular methylprednisolone sodium succinate (MPSS) are the first line choice treatment of acute SCI. Despite progress in pharmacological, surgical and rehabilitative treatment approaches, SCI still remains a very complex medical and psychological challenge, with no curative therapy available. The aim of the present study was to compare the efficacy of MPSS in respect to other GCs such as dexamethasone (Dex) and mometasone furoate (MF) in an in vitro suitable model of LPS-induced inflammation in J774 cells as well as in an in vivo experimental mouse SCI (compression model). In both the in vitro and in vivo experiments, MF resulted surprisingly more potent than Dex and MPSS. In detail, mice sacrificed seven days after induction of SCI trauma resulted not only in tissue damage, cellular infiltration, fibrosis, astrocyte activation, iNOS expression, extracellular signal regulated kinase 1/2 phosphorylation in injured tissue, poly (ADP-ribose) polymerase 1 (PARP-1) activation but also apoptosis (Bax and Bcl-2 expression). All three GCs demonstrated the ability to modulate inflammatory, oxidative as well as apoptotic pathways, but MF demonstrated the best efficacy, while Dex and MPSS showed alternative potency with a different degree of protection. Therefore, we can conclude that MF is the best candidate for post-traumatic chronic treatment, since it ameliorates different molecular pathways involved in the damage's propagation to the surrounding areas of the injured spinal cord.
Drug safety, 2008
Currently, cosmetics and toiletries are very popular and their use continues to increase because ... more Currently, cosmetics and toiletries are very popular and their use continues to increase because consumers consider physical appearance important and, at the same time, these products are considered to be safe. However, in spite of their safety and tolerability, during recent decades, we have become aware that adverse effects can occur. The number of adverse effects known so far is very low indeed. This is partly because such adverse effects are underestimated as a result of self-diagnosis and self-medication, which are common behaviours in the presence of mild-to-moderate reactions, as in the case of cosmetics. Moreover, such effects are underestimated because of the absence of formal and reliable monitoring systems ('cosmetovigilance'). This requires the creation of a standard reporting form, as well as resolution concerning professional categories authorized to report and the subsequent validation/evaluation of the collected forms. All these items are of great importance,...
Journal of agricultural and food chemistry, Jan 27, 2007
Feijoa sellowiana Berg. fruits and especially the acetonic extract have been shown to possess bio... more Feijoa sellowiana Berg. fruits and especially the acetonic extract have been shown to possess biological activities, although the responsible compounds have never been identified. The present study was designed to evaluate the anti-inflammatory activity of an acetonic extract from F. sellowiana Berg. fruits on the nitric oxide (NO) pathway, which plays an important role in inflammation. To this aim the J774 cell line, which expresses inducible nitric oxide synthase (iNOS) following stimulation with lipopolysaccharide (LPS), has been utilized, and the effects of this extract and its fractions on NO production, iNOS protein expression, and signal pathways involved in its regulation have been evaluated. This study demonstrates that at least some part of the anti-inflammatory activity of the acetonic extract is due to the suppression of NO production by flavone and stearic acid. The mechanism of this inhibition seems to be related to an action on the expression of the enzyme iNOS throug...
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2002
The effect of an ethanolic extract of propolis, with and without CAPE, and some of its components... more The effect of an ethanolic extract of propolis, with and without CAPE, and some of its components on cyclooxygenase (COX-1 and COX-2) activity in J774 macrophages has been investigated. COX-1 and COX-2 activity, measaured as prostaglandin E2 (PGE2) production, were concentration-dependently inhibited by propolis (3 x 10(-3) - 3 x 10(2) microgml(-1)) with an IC50 of 2.7 microgml(-1) and 4.8 x 10(-2) microgml(-1), respectively. Among the compounds tested pinocembrin and caffeic, ferulic, cinnamic and chlorogenic acids did not affect the activity of COX isoforms. Conversely, CAPE (2.8 x 10(-4) - 28 microgml(-1); 10(-9) - 10(-4) M) and galangin (2.7 x 10(-4) - 27 microgml(-1); 10(-9) - 10(-4) M) were effective, the last being about ten-twenty times less potent. In fact the IC50 of CAPE for COX-1 and COX-2 were 4.4 x 10(-1) microgml(-1) (1.5 x 10(-6) M) and 2 x 10(-3) microgml(-1) (6.3 x 10(-9) M), respectively. The IC50 of galangin were 3.7 microgml(-1) (15 x 10(-6) M) and 3 x 10(-2) mi...
Molecular medicine (Cambridge, Mass.), 2001
We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitri... more We have recently demonstrated that 17beta-estradiol (E2) inhibits the increase of inducible nitric oxide synthetase (iNOS) activity in selected model systems such as macrophages, microglia, smooth muscle cells, and proposed that this effect might be associated with an anti-inflammatory activity of this hormone. Here we investigate the effects of endogenous estrogens in rats subjected to carrageenan-induced pleurisy. Adult female rats were ovariectomized 3 weeks before the experiments to deplete circulating estrogens. Selected inflammatory markers, landmarks of the delayed phase of carrageenan-induced pleurisy, were measured in intact (N-OVX), and ovariectomized (OVX) female rats. In addition, the effect of hormone replacement was evaluated in ovariectomized rats with intraperitoneal injection of 17beta-estradiol (E2; 50 microg/kg) 1 hr before carrageenan treatment (OVX + E2). Ovariectomy enhanced the carrageenan-induced degree of pleural exudation and polymorphonuclear leukocyte mig...
Journal of immunology (Baltimore, Md. : 1950), 1999
In the present study we used IL-6 knockout mice (IL-6KO) to evaluate the role of IL-6 in the infl... more In the present study we used IL-6 knockout mice (IL-6KO) to evaluate the role of IL-6 in the inflammatory response caused by injection of carrageenan into the pleural space. Compared with carrageenan-treated IL-6 wild-type (IL-6WT) mice, carrageenan-treated IL-6KO mice exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase activity and lipid peroxidation were significantly reduced in IL-6KO mice compared with those in IL-6WT mice treated with carrageenan. Immunohistochemical analysis for nitrotyrosine and poly(A)DP-ribose polymerase revealed a positive staining in lungs from carrageenan-treated IL-6WT mice. No positive staining for nitrotyrosine or PARS was found in the lungs of the carrageenan-treated IL-6KO mice. Staining of lung tissue sections obtained from carrageenan-treated IL-6WT mice with an anti-cyclo-oxygenase-2 Ab showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthas...