A hypotensive procyanidin-glycoside from Rhamnus lycioides ssp. lycioides.

A lyophilized hot water extract of the aerial parts of Rhamnus lycioides L. (Rhamnaceae) produced a lowering of systemic arterial blood pressure in normotensive anaesthetized Wistar rats. An activity-guided fractionation of the methanolic extract led to the isolation of a tetrameric procyanidin-glycoside which produced a clear dose-dependent hypotensive response (1.5-6 mg/kg i.v.). This principle was characterized using acid hydrolysis, thiolytic degradation and spectroscopic methods. It consisted of four flavanol units with a 2,3-cis configuration and with a O-beta-d-glucosylpyranoside function on the epicatechin terminal unit. The interflavan linkage was (4-8).

Nitric oxide synthase and cyclo-oxygenase pathways in the inflammatory response induced by zymosan in the rat air pouch

1. We have studied the participation of nitric oxide (NO) in an animal model of inflammation, the rat air pouch stimulated with zymosan. 2. Saline or zymosan was injected into 6-day rat air pouches at different time points and measurements were made of cell migration, levels of nitrite/nitrate (NO2/NO3-), prostaglandin E2 (PGE2), leukotriene B4 (L.TB4) and secretory phospholipase A2 (sPLA2) in exudates. Nitric oxide synthase (NOS) activity was determined in high speed supernatants from cells present in pouch exudates. Western blot analysis was also performed on these samples. 3. Zymosan injection induced a time-dependent increase in leukocyte infiltration, NO2/NO3- levels and cellular NOS a…

Synthesis and evaluation of diverse thio avarol derivatives as potential UVB photoprotective candidates.

Semisynthesis of 13 new thio avarol derivatives (4-16) and in vitro evaluation on the photodamage response induced by UVB irradiation are described. Their ability to inhibit NF-kappaB activation and TNF-alpha generation in HaCaT cells as well as their antioxidant capacity in human neutrophils has also been studied. Among them we have identified two monophenyl thio avarol derivatives (4-5) lacking cytotoxicity which can be considered promising UVB photoprotective agents through the potent inhibition of NF-kappaB activation with a mild antioxidant pharmacological profile.

Type-IIA secreted phospholipase A2 is an endogenous antibiotic-like protein of the host.

International audience; Type-IIA secreted phospholipase A(2) (sPLA(2)-IIA) has been proposed to play a role in the development of inflammatory diseases. It has been shown to release arachidonic acid, the precursor of proinflammatory eicosanoids, to hydrolyze phospholipids of pulmonary surfactant, and to bind to specific receptors located on cell surface membranes. However, the most established biological role of sPLA(2)-IIA is related to its potent bactericidal property in particular toward Gram-positive bacteria. This enzyme is present in animal and human biological fluids at concentrations sufficient to kill bacteria. Human recombinant sPLA(2)-IIA is able to kill Gram-positive bacteria at…

Hypotensive Effect ofPistacia lentiscusL

AbstractThe present studies were undertaken to confirm the hypotensive effect of Pistacia lentiscus L. in normotensive urethane anaesthetized Wistar rats. It was shown that lyophilized aqueous extract caused a dose-dependent decreased of the systemic arterial blood pressure. Acute toxicity was also determined. Phytochemical analysis revealed the presence of steroids-triterpenes, catechin tannins, flavonoids, sugars, resins and saponins.

Synthesis and inhibitory activity of dimethylamino-chalcone derivatives on the induction of nitric oxide synthase.

A series of nine dimethylamino-chalcone derivatives (1,3-diaryl-propenones) was synthesized and screened as potential inhibitors of NO and PGE(2) production in the RAW 264.7 macrophage cell line. 4-Dimethylamino-2',5'-dimethoxychalcone (6) was found to be the most potent and dual inhibitor (IC(50s) in the submicromolar range) of NO and PGE(2) production. 2',6'-Dimethoxylation appeared to be an effective requirement for selective and potent inhibition of nitric oxide synthase induction as it was confirmed by Western blot analysis. Chalcone (6) at 25 mg kg(-1) by oral route, inhibited significantly the formation of oedema in the carrageenan-induced model of inflammation in mice.

Suppression of leukotriene B4 and tumour necrosis factor alpha release in acute inflammatory responses by novel prenylated hydroquinone derivatives.

A series of prenyl hydroquinone derivatives synthesized as structural analogs of marine products were tested for their effects on inflammatory responses in vitro and in vivo. 2-Prenyl-1,4-hydroquinone (H1), 2-diprenyl-1,4-hydroquinone (H2), 2-triprenyl-1,4-hydroquinone (H3) and 2-tetraprenyl-1,4-hydroquinone (H4) scavenged reactive oxygen species and inhibited 5-lipoxygenase (5-LO) activity in human neutrophils. The inhibition of 5-LO activity was demonstrated in vivo in the mouse air pouch injected with zymosan and arachidonic acid-induced ear inflammation. The four compounds suppressed the production of tumour necrosis factor alpha (TNFalpha) in J774 cells stimulated with lipopolysacchari…

Inhibition of the NF-κB Signaling Pathway Mediates the Anti-inflammatory Effects of Petrosaspongiolide M

Petrosaspongiolide M (PT) is a potent secretory phospholipase A(2) inhibitor and anti-inflammatory agent. This marine metabolite reduced the production of nitrite, prostaglandin E(2), and tumor necrosis factor-alpha in the mouse air pouch injected with zymosan. These effects were also observed in mouse peritoneal macrophages stimulated with zymosan. Inhibition of these inflammatory mediators was related to reductions in inducible nitric oxide synthase, cyclo-oxygenase-2, and tumor necrosis factor-alpha expression. Since nuclear factor-kappaB (NF-kappaB) appears to play a central role in the transcriptional regulation of these proteins by macrophages, we investigated the effects of PT on thi…

ChemInform Abstract: Dysidotronic Acid, a New and Selective Human Phospholipase A2 Inhibitor from the Sponge Dysidea sp.

Abstract A new bioactive sesquiterpenoid, named dysidotronic acid 1, with a rearranged drimane skeleton has been isolated from the sponge Dysidea sp. from Vanuatu islands, along with bolinaquinone 2. The chemical structure of 1 was determined on the basis of spectroscopic data. Dysidotronic acid significantly inhibited human synovial phospholipase A2 (PLA2) at 10 μM, with an IC50 value of 2.6 μM and a higher selectivity and potency towards this enzyme than the reference inhibitor manoalide.

Flavonoids ofRhamnus lycioides; Part 2

Diterpenoids from Tetraclinis articulata that Inhibit Various Human Leukocyte Functions

Ten new compounds, eight of them pimarane derivatives (1-8), together with a menthane dimer (9) and a totarane diterpenoid (10), were isolated from the leaves and wood of Tetraclinis articulata. The structures of 1-10 were established by using spectroscopic techniques, including 2D NMR spectra. Pimaranes 1-5 were found to possess an unusual cis interannular union of the B and C rings, which, from a biogenetic perspective, could be derived from the hydration of a carbocation at C-8. Compounds 4-6 and a mixture of 7 and 11 modulated different human leukocyte functions at a concentration of 10 microM, mainly the degranulation process measured as myeloperoxidase release and, to a lesser extent,…

Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase.

In a previous study, we reported a new bioactive sesquiterpenoid, named dysidotronic acid, to be a potent, selective human synovial phospholipase A(2) inhibitor. Dysidotronic acid is a novel, non-complex manoalide analogue lacking the pyranofuranone ring. We now investigate the effect of this compound on cytokine, nitric oxide and prostanoid generation on the mouse macrophage cell line RAW 264.7, where it showed a dose-dependent inhibition with inhibitory concentration 50% values in the micromolar range. This effect was also confirmed in the mouse air pouch injected with zymosan. Dysidotronic acid inhibited the production of tumor necrosis factor alpha and interleukin-1 beta as well as the …

Synthesis and pharmacological evaluation of 2'-hydroxychalcones and flavones as inhibitors of inflammatory mediators generation.

2'-Hydroxy-3,4-dimethoxy-3',4'-dimethylchalcone (3a), 2'-hydroxy-3',4',3,4-tetramethoxychalcone (3b), and their corresponding flavones, 3',4'-dimethoxy-7,8-dimethylflavone (4a) and 3',4',7,8-tetramethoxyflavone (4b), were prepared from 3,4-dimethoxycinnamic acid and the respective phenol. The four compounds inhibited enzymic lipid peroxidation and showed weak peroxyl scavenging activity. They also reduced LTB 4 release from human neutrophils stimulated by A23187. The chalcone 3b was the only compound able to inhibit in a concentration-dependent way, synovial human recombinant phospholipase A 2 activity, human platelet TXB 2 generation, and human neutrophil degranulation. This chalcone exert…

Modulatory effect of bolinaquinone, a marine sesquiterpenoid, on acute and chronic inflammatory processes

The marine metabolite bolinaquinone is a novel inhibitor of secretory phospholipase A(2) (sPLA(2)), with a potency on the human synovial enzyme (group II) higher than that of manoalide. This activity on the sPLA(2) was confirmed in vivo in the 8-h zymosan rat air pouch on the secretory enzyme accumulation in the pouch exudate. Additionally, bolinaquinone decreased potently the synthesis and release of leukotriene B(4) (LTB(4)) in calcimycin (A23187)-stimulated human neutrophils as a consequence of the inhibition of 5-lipoxygenase activity, as well as PGE(2) and NO production on zymosan-stimulated mouse peritoneal macrophages. This compound exerted anti-inflammatory effects by topical and or…

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A2B receptors, human epidermal keratinocytes also express A2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A2A receptors by CGS-21680 induces keratinocyte proliferation via p38–mitogen-activated protein…

Cavernolide

Abstract The inhibitory effect of cavernolide, a novel C 21 terpene lactone isolated from the sponge Fasciospongia cavernosa , on PLA 2 and other enzyme activities involved in the inflammatory process was studied. Cavernolide inhibited human synovial sPLA 2 in a concentration-dependent manner with an IC 50 value of 8.8 μM. Besides, this compound decreased in the nanomolar range the myeloperoxidase degranulation process using different stimuli. Cavernolide also inhibited TNFα, NO and PGE 2 production in intact cell experiments. NO and PGE 2 reduction was the consequence of the inhibition on iNOS and COX-2 expression because it did not affect inducible nitric oxide synthase and cyclooxygenase…

Dysidotronic acid, a new and selective human phospholipase A2 inhibitor from the sponge Dysidea sp.

Abstract A new bioactive sesquiterpenoid, named dysidotronic acid 1, with a rearranged drimane skeleton has been isolated from the sponge Dysidea sp. from Vanuatu islands, along with bolinaquinone 2. The chemical structure of 1 was determined on the basis of spectroscopic data. Dysidotronic acid significantly inhibited human synovial phospholipase A2 (PLA2) at 10 μM, with an IC50 value of 2.6 μM and a higher selectivity and potency towards this enzyme than the reference inhibitor manoalide.

Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation

Polymethoxylated flavones and C-glycosyl derivatives isolated from medicinal plants besides other flavonoid compounds were studied for their influence on lipid peroxidation induced by FeSO4+ cysteine in rat liver microsomes. A number of hydroxyflavones (e.g. luteolin); C-glycosyl-flavones (e.g. orientin); methoxyflavones (e.g. gardenin D) and flavonols (e.g. datiscetin), as well as the flavanol leucocyanidol and the biflavone amentoflavone behaved as inhibitors of non-enzymic lipid peroxidation. Structure-activity relationships were established and it was observed that the structural features for active polyhydroxylated compounds were different from those of polymethoxylated flavones, antip…

A study of the novel anti-inflammatory agent florifenine topical anti-inflammatory activity and influence on arachidonic acid metabolism and neutrophil functions

We have evaluated the effects of the novel anti-inflammatory agent florifenine, 2-(1-Pyrrolidinyl)ethyl N-[7-(trifluoromethyl)-4-quinolyl]anthranilate, on topical inflammation in mice, free radical-mediated reactions, arachidonic acid metabolism and some neutrophil functions. Topical administration of florifenine produced dose-related anti-inflammatory activity in 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear oedema and with a lower potency, in the response induced by arachidonic acid (AA). Florifenine also inhibited neutrophil migration and PGE2 content in the inflammed ears. In human whole blood, florifenine was a potent and selective inhibitor of TXB2 generation. This anti-infla…

ChemInform Abstract: The Synthesis and Effect of Fluorinated Chalcone Derivatives on Nitric Oxide Production.

Abstract Dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, were synthesized and evaluated for their influence on nitric oxide production. Some of them, chalcones 1 , 5 , 7 , 10 , 11 and 17 , inhibited NO production with an IC 50 in the submicromolar range; 17 is especially noteworthy because of its potency (IC 50 30 nM). These effects were not the consequence of a direct inhibitory action on enzyme activity but the inhibition of enzyme expression.

Anti-inflammatory and analgesic activity of a novel inhibitor of microsomal prostaglandin E synthase-1 expression

Abstract In a previous study, we reported a new γ-hydroxybutenolide derivative, 4-benzo[ b ]thiophen-2-yl-3-bromo-5-hydroxy-5 H -furan-2-one (BTH), as inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) expression in lypopolysaccharide (LPS) stimulated RAW 264.7 and TPH-1 cells, without affecting cyclooxygenase-2 (COX-2). In this study, we evaluated the in vivo effect of BTH on some acute and chronic inflammatory animal models in relation to its inhibitory profile on mPGES-1 expression. In the zymosan-induced mouse air pouch model, BTH produced a dose-dependent inhibition of prostaglandin E 2 (PGE 2 ) production and mPGES-1 protein expression in pouch exudates without any effect on…

Antipsoriatic effects of avarol-3′-thiosalicylate are mediated by inhibition of TNF-αgeneration and NF-κB activation in mouse skin

Background and purpose: Avarol is a marine sesquiterpenoid hydroquinone with anti-inflammatory and antipsoriatic properties. The aim of this study was to evaluate the in vitro and in vivo pharmacological behaviour of the derivative avarol-3′-thiosalicylate (TA) on some inflammatory parameters related to the pathogenesis of psoriasis. Experimental approach: Human neutrophils and monocytes as well as the human keratinocyte cell line HaCaT were used to study the effect of TA on oxidative stress, the arachidonic acid pathway, tumour necrosis factor-α (TNF-α) release and nuclear factor-κB (NF-κB) activation. All these parameters were also determined in vivo using the zymosan induced mouse air po…

ttCH, a selective inhibitor of inducible nitric oxide synthase expression with antiarthritic properties

In a previous work, we investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in lipopolysaccharide-stimulated murine RAW 264.7 cells. The present study was designed to determine if 2,4,6-trimethoxy-2'-trifluoromethylchalcone (ttCH) could modulate the production of nitric oxide (NO) and/or prostaglandins in vitro and in vivo. On the mouse macrophage cell line RAW 264.7, ttCH inhibited dose-dependently NO and prostaglandin E(2) production, with IC(50) in the micromolar range. This compound had no direct inhibitory effect on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 activities. …

Co-regulation between cyclo-oxygenase-2 and inducible nitric oxide synthase expression in the time-course of murine inflammation.

Many in vitro studies have used cell cultures to focus on the relationships between cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) isoforms. We have investigated the time-course of regulation and the role of COX-2 and iNOS in a model of experimental inflammation in mice, the air pouch injected with zymosan. This study demonstrates that there is an early acute phase (4 h) mediated mainly by eicosanoids, with high levels of prostaglandin E2 (PGE2) produced by cyclo-oxygenase-1. In addition, in the later phase (from 12 h) there is a participation of nitric oxide (NO) and PGE2 accompanied by co-induction of both iNOS and COX-2. These enzymes were detected in migrating leuk…

Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor-αby inhibiting nuclear factor-κB activation

The marine product cacospongionolide B, a sesterterpene isolated from the Mediterranean sponge Fasciospongia cavernosa, is an inhibitor of secretory phospholipase A2 with anti-inflammatory properties. In this work, we have studied the mechanism of action of this compound in the inflammatory response induced by zymosan in primary cells and in the mouse air pouch. In mouse peritoneal macrophages, cacospongionolide B was able to downregulate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), resulting in decreased production of NO and prostaglandin E2 (PGE2). This compound also reduced tumour necrosis factor-α (TNF-α) mRNA expression and TNF-α levels. Cacosp…

In vivo hypotensive activity ofPistacia lentiscus L

The present studies were undertaken to explain the mechanism of action of the hypothesive effect of Pistacia lentiscus L. aqueous extract. The potassium, calcium and magnesium content of the aqueous extract was determined and synthetic mixtures of salts evaluated in rats. The urinary excretion volume and the sodium and potassium concentrations in urine were also determined. In an effort to explain the effects of the extract, in vivo pharmacological experiments were conducted.

Therapeutic administration of 3,4,5-trimethoxy-4'-fluorochalcone, a selective inhibitor of iNOS expression, attenuates the development of adjuvant-induced arthritis in rats

We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in LPS-stimulated murine RAW 264.7. The present study was designed to determine if 3,4,5-trimethoxy-4'-fluorochalcone (CH 17) could modulate the production of NO and/or prostaglandins in vivo. On the mouse macrophage cell line RAW 264.7 CH 17 inhibited dose-dependently NO production, with an IC(50) value in the nanomolar range, and reduced PGE(2) levels by a 58% at 10 microM. This compound had no direct inhibitory effect on iNOS and COX-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS…

The synthesis and effect of fluorinated chalcone derivatives on nitric oxide production

Abstract Dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, were synthesized and evaluated for their influence on nitric oxide production. Some of them, chalcones 1 , 5 , 7 , 10 , 11 and 17 , inhibited NO production with an IC 50 in the submicromolar range; 17 is especially noteworthy because of its potency (IC 50 30 nM). These effects were not the consequence of a direct inhibitory action on enzyme activity but the inhibition of enzyme expression.

Modulation of acute and chronic inflammatory processes by cacospongionolide B, a novel inhibitor of human synovial phospholipase A2

Cacospongionolide B is a novel marine metabolite isolated from the sponge Fasciospongia cavernosa. In in vitro studies, this compound inhibited phospholipase A2 (PLA2), showing selectivity for secretory PLA2 (sPLA2) versus cytosolic PLA2 (cPLA2), and its potency on the human synovial enzyme (group II) was similar to that of manoalide. This activity was confirmed in vivo in the 8 h zymosan-injected rat air pouch, on the secretory enzyme accumulating in the pouch exudate. Cacospongionolide B, that is bioavailable when is given orally, reduced the elevated levels of sPLA2 present in paw homogenates of rats with adjuvant arthritis. This marine metabolite showed topical anti-inflammatory activit…

A New Cacospongionolide Inhibitor of Human Secretory Phospholipase A2 from the Tyrrhenian Sponge Fasciospongia cavernosa and Absolute Configuration of Cacospongionolides

A new inhibitor of human secretory phospholipase A2 (PLA2), cacospongionolide E (4a), has been isolated from the Tyrrhenian sponge Fasciospongia cavernosa. The structure was proposed on the basis of spectroscopic data and by chemical transformations. The absolute configuration of cacospongionolides 2a-4a was established using the modified Mosher's method. Cacospongionolide E was the most potent inhibitor toward human synovial PLA2, showing higher potency than the reference compound manoalide and exerting no signs of toxicity on human neutrophils. It showed high activity in the Artemia salina bioassay and moderate toxicity in the fish (Gambusia affinis) lethality assay.

Protection against 2,4,6-trinitrobenzenesulphonic acid-induced colonic inflammation in mice by the marine products bolinaquinone and petrosaspongiolide M.

Proinflammatory mediators, namely eicosanoids, reactive oxygen and nitrogen species and cytokines, are clearly involved in the pathogenesis of intestinal bowel disease. bolinaquinone (BQ) and petrosaspongiolide M (PT), two marine products with potent anti-inflammatory action, have been shown to control the production of mediators in acute and chronic inflammatory processes. Hence, we have tested here the hypothesis that BQ and PT could ameliorate inflammation and oxidative stress parameters in 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis in Balb/c mice. BQ and PT were given orally in doses of 10 or 20mg/kg/day. Treatment of the animals with BQ or PT at the highest dose signifi…

Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation.

Contains fulltext : 49512schalkwijk.pdf (Publisher’s version ) (Closed access) Avarol, a marine sesquiterpenoid hydroquinone, and 14 avarol derivatives have shown interesting anti-inflammatory properties in previous studies. In this study, avarol and derivatives were evaluated in high-throughput keratinocyte culture models using cytokeratin 10 and SKALP/Elafin expression as markers for respectively normal and psoriatic differentiation. Avarol and five of its derivatives (5, 10, 13, 14 and 15) were selected for further study. Only 10, 13, 14 and 15 were able to inhibit keratinocyte cell growth. Changes in expression levels of 22 genes were assessed by quantitative real time PCR (qPCR). From …

Toward the Discovery of New Agents Able to Inhibit the Expression of Microsomal Prostaglandin E Synthase-1 Enzyme as Promising Tools in Drug Development

In our recent studies, we focused our attention on the synthesis of several γ-hydroxybutenolides designed on the basis of petrosaspongiolide M 1 (PM) structure that has been recognized to potently inhibit the inflammatory process through the selective PLA2 enzyme inhibition. By means of a combination of computational methods and efficient synthetic strategies, we generated small collections of PM modified analogs to identify new potent PLA2 inhibitors, suitable for clinical development. In the course of the biological screening of our compounds, we discovered a potent and selective inhibitor of mPGES-1 expression, the benzothiophene γ-hydroxybutenolide 2, which so far represents the only pr…

Defective Induction of COX-2 Expression by Psoriatic Fibroblasts Promotes Pro-inflammatory Activation of Macrophages

Fibroblasts play an important role as members of the innate immune system through the secretion of COX-2-derived inflammatory mediators such as prostaglandin E-2 (PGE(2)). However, it has been described that dermal fibroblasts behave like mesenchymal stem cells reducing lymphocyte recruitment and dendritic cell activation through PGE(2) release. As the role of fibroblasts in psoriasis remains poorly characterized, in the present study we have evaluated the possible influence of PGE(2) derived from dermal fibroblasts as modulator of the immune response in psoriatic skin. Our results indicate that under inflammatory conditions, psoriatic fibroblasts showed defective induction of COX-2, which …

Cycloamphilectenes, a new type of potent marine diterpenes: inhibition of nitric oxide production in murine macrophages.

The inhibitory effect of a series of 6 cycloamphilectenes, novel marine diterpenes based on amphilectene skeletons and isolated from the Vanuatu sponge Axinella sp., on NO, PGE(2) and TNFalpha production in murine peritoneal macrophages was studied. These compounds reduced potently nitric oxide production in a concentration-dependent manner with IC(50) values in the submicromolar range (0.1-4.3 microM). Studies on intact cells and Western blot analysis showed that the more potent cycloamphilectenes reduced the expression of inducible nitric oxide synthase without affecting cyclo-oxygenase-2 expression. Among them cycloamphilectene 2, the unique compound bearing an exocyclic methylene group,…

Synthesis and comparison of the antiinflammatory activity of manoalide and cacospongionolide B analogues.

We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A 2 (PLA 2 ). The two series of compounds were tested for their inhibitory effects on secretory PLA 2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addi…

LAAE-14, a new anti-inflammatory drug, increases the survival ofCandida albicans-inoculated mice

LAAE-14, a lipidic acid-amido ether derivative, has been recently described as a new anti-inflammatory drug. We have studied the effect of treatment with this compound on the susceptibility of mice to in vivo experimental Candida albicans infection. ICR mice orally treated with LAAE-14 (25 mg kg(-1)) and experimentally intravenously infected showed a significantly increased survival as compared to control mice. In vitro, the compound did not inhibit the growth of C. albicans yeast cells or the yeast-to-hyphal transition. The in vitro production of prostaglandin E2 by peritoneal macrophages in response to the yeasts and hyphae of C. albicans was significantly decreased upon treatment with LA…

Inhibitory Effects of Various Extracts of Argentine Plant Species on Free-radical-mediated Reactions and Human Neutrophil Functions

Extracts of Argentine plant species used in folk medicine were evaluated for their antioxidant properties and ability to influence human neutrophil functions, including superoxide anion release and degranulation. The infusion and methanol extract of Achyrocline flaccida, and the infusion of Pterocaulon polystachium exhibited chain-breaking antioxidant activity in Fe 2+ /ascorbate-induced lipid peroxidation of rat liver microsomal fractions and scavenged peroxyl radicals in an aqueous assay system. Nevertheless their superoxide scavenging ability was lower. The dichloromethane extracts of Phyllanthus sellowianus, Achyrocline flaccida, Gamochaeta simplicicaulis, Pterocaulon polystachium and E…

Inhibition of inflammatory responses by epitaondiol and other marine natural products

The marine metabolites pacifenol, stypotriol triacetate and epitaondiol were tested for their effects on a number of inflammatory responses. Epitaondiol exhibited a potent topical anti-inflammatory activity related to inhibition of leukocyte accumulation. The other compounds showed a lower potency, similar to that of indomethacin. None of the compounds affected superoxide generation by human neutrophils but pacifenol effectively inhibited the degranulation response. This compound and epitaondiol decreased the release of eicosanoids with a higher potency on the cyclo-oxygenase pathway. Only epitaondiol inhibited human recombinant synovial phospholipase A2 activity in a concentration-dependen…

Effect of tormentic acid on insulin secretion in isolated rat islets of langerhans

Tonnentic acid was isolated as the hypoglycemic agent of Poterium ancistroides Desf. The present study reports effects of this compound on isolated islets of Langerhans. We demonstrate that tormentic acid in the presence of 1.66 mM glucose initiates insulin secretion by isolated rat islets of Langerhans in a dose-dependent fashion at concentrations ranging from 0.05 to 0.5 mM. However, the compound has no effect on the insulin-releasing capacity of 16.6 mM glucose. Similar results were obtained with the sulfonylurea glibenclamide (0.01 mM) used as a reference. These results suggest that the hypoglycemic effect of tormentic acid is due to a diect effect of the compound in vitro.

Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase A2 with anti-inflammatory activity

Abstract The flavanonylflavone morelloflavone inhibited secretory phospholipase A 2 (PLA 2 ) in vitro , with a high potency on the human recombinant synovial and bee venom enzymes ( IC 50 = 0.9 and 0.6 μM, respectively). The inhibition was apparently irreversible. In contrast, the compound was inactive on cytosolic PLA 2 activity from human monocytes. Morelloflavone scavenged reactive oxygen species generated by human neutrophils ( IC 50 = 2.7 and 1.8 μM for luminol and lucigenin, respectively) but did not modify cellular responses such as degranulation or eicosanoid release. This biflavonoid exerted anti-inflammatory effects in animal models, with a potent inhibition of 12-O-tetradecanoylp…

NF-κB and STAT3 Inhibition as a Therapeutic Strategy in Psoriasis: In Vitro and In Vivo Effects of BTH

Benzo[b]thiophen-2-yl-3-bromo-5-hydroxy-5H-furan-2-one (BTH) is a simple and interesting synthetic derivative of petrosaspongiolide M, a natural compound isolated from a sea sponge with demonstrated potent anti-inflammatory activity through inhibition of the NF-κB signaling pathway. In the present study, we report the in vitro and in vivo pharmacological effect of BTH on some parameters related to the innate and adaptive response in the pathogenesis of psoriasis. BTH inhibited the release of some of the key psoriatic cytokines such as tumor necrosis factor α, IL-8, IL-6, and CCL27 through the downregulation of NF-κB in normal human keratinocytes. Moreover, it impaired signal transducers and…

LAAE-14, a new in vitro inhibitor of intracellular calcium mobilization, modulates acute and chronic inflammation.

Abstract A new lipidic acid-amido ether derivative (LAAE-14) able to reduce dose-dependently the calcium increases mediated either by calcium ionophore ionomycin, by the endoplasmic reticular Ca 2+ -ATPase inhibitor thapsigargin, or by the chemotactic tripeptide N -formyl- l -methionyl- l -leucyl- l -phenylalanine (fMLP), in human neutrophils as well as in murine peritoneal macrophages, but not ATP, has been evaluated as a potential anti-inflammatory drug. This compound attenuated leukocyte activation by means of its inhibitory effect on the respiratory burst elicited in both types of cells by 12- O -tetradecanoyl phorbol 13-acetate, by inhibition of the degranulation process induced by cyt…

Perthamides C-F, potent human antipsoriatic cyclopeptides

Abstract Two new cyclopeptides, perthamides E and F were isolated from the polar extracts of the sponge Theonella swinhoei . The new structures, featuring an unprecedented β-amino acid unit (AHMOA), were determined by interpretation of NMR and MS data. The absolute configuration of the AHMOA residue was proposed on the basis of quantum chemical calculation of NMR chemical shifts. Perthamides were proved to inhibit TNF-α and IL-8 release in primary human keratinocytes cells and therefore could represent potentially leads for the treatment of psoriasis.

Study of the antioedema activity of some seaweed and sponge extracts from the mediterranean coast in mice

Chloroform and methanol extracts of ten marine species, seven seaweeds and three sponges, have been studied for possible, antioedema activities. The extracts were administered either topically or orally on TPA-induced mouse ear oedema and on carrageenan mouse paw oedema, respectively. The most interesting seaweed extracts were found to be from Corallina elongata, Galaxaura oblongata, Laurencia obtusa and Udotea petiolata, where both extracts of each species induced a large antioedema effect in both models employed. None of the sponges assayed demonstrated antiinflammatory effects on carrageenan mouse paw oedema, however, some extracts elicited an inhibition of the oedema developed by TPA.

Potential Antipsoriatic Avarol Derivatives as Antioxidants and Inhibitors of PGE2 Generation and Proliferation in the HaCaT Cell Line

The synthesis and structure-activity relationships for a series of 14 new avarol derivatives as antioxidants and inhibitors of cell proliferation and PGE(2) generation in human keratinocytes are described. Compound 6 (thiosalicylic derivative) was the most potent inhibitor of superoxide generation in human neutrophils and also potently inhibited PGE(2) generation in the human keratinocyte HaCaT cell line. Compound 7(3'-methylaminoavarone) presented the best antiproliferative profile, by the inhibition of (3)H-thymidine incorporation in HaCaT cells, with potency similar to the reference compound anthralin. None of the avarol derivatives showed any sign of cytotoxicity measured as LDH release…

Involvement of secretory phospholipase A2 activity in the zymosan rat air pouch model of inflammation.

1. In the zymosan rat air pouch model of inflammation we have assessed the time dependence of phospholipase A2 (PLA2) accumulation in the inflammatory exudates as well as cell migration, myeloperoxidase activity, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels. 2. A significant increase in PLA2 activity was detected in 1,200 g supernatants of exudates 8 h after injection of zymosan into rat air pouch. This event coincided with peaks in cell accumulation (mainly neutrophils) and myeloperoxidase activity in exudates and was preceded by a rise in eicosanoid levels. 3. This enzyme (without further purification) behaved as a secretory type II PLA2 with an optimum pH at 7-8 units, lack o…

Development of a second generation of inhibitors of microsomal prostaglandin E synthase 1 expression bearing the γ-hydroxybutenolide scaffold

Petrosaspongiolide M (PM), a marine sesterterpene metabolite bearing the gamma-hydroxybutenolide scaffold and displaying a potent inhibitory activity toward PLA(2) enzyme, was selected by us as an attractive target in order to explore its mechanism of action at molecular level. In the course of our investigations we decided to synthetically modify the parent compound to clarify the structural determinants responsible for the activity; in fact, very recently, our research group reported the synthesis and the pharmacological properties of a first collection of PM analogues generated by Ludi approach. The synthesized compounds showed a poor or moderate activity toward PLA(2) enzymes, neverthel…

Effects of marine 2-polyprenyl-1,4-hydroquinones on phospholipase A2 activity and some inflammatory responses.

Three 2-polyprenyl-1,4-hydroquinone derivatives (2-heptaprenyl-1,4-hydroquinone: IS1, 2-octaprenyl-1,4-hydroquinone: IS2 and 2-[24-hydroxy]-octaprenyl-1,4-hydroquinone: IS3) isolated from the Mediterranean sponge Ircinia spinosula, were evaluated for effects on phospholipase A2 activity of different origin (Naja naja venom, human recombinant synovial fluid and bee venom), as well as on human neutrophil function and mouse ear oedema induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). IS1 interacted minimally with these responses. In contrast, IS2 and IS3 inhibited human recombinant synovial phospholipase A2 in a concentration-dependent manner, with minor effects on the rest of the enzymes…

Avarol inhibits TNF-a generation and NF-kB activation in human cells and in animal models

Avarol is a marine sesquiterpenoid hydroquinone with interesting pharmacological properties including anti-inflammatory and antipsoriatic effects. In the present study we evaluated the pharmacological effect of avarol on some inflammatory parameters related to the pathogenesis of psoriasis. Avarol inhibited tumor necrosis factor-alpha (TNF-alpha) generation in stimulated human monocytes (IC(50) 1 microM) and TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB)-DNA binding in keratinocytes. In the mouse air pouch model, administration of avarol produced a dose-dependent reduction of TNF-alpha generation (ED(50) 9.2 nmol/pouch) as well as of interleukin (IL)-1beta, prostaglandin …

Flavonoid Constituents of Rhamnus lycioides L.

Abstract From the aerial part of Rhamnus lycioides, which is used in folk medicine in eastern Spain as an antihypertensive drug, seven free flavonoid aglycones were isolated. They were structurally eluci­dated as rhamnazin. rhamnocitrin, isorhamnetin, kaempferol, quercetin. quercetin-3-methylether and taxifolin. by applying the principal spectroscopic methods and TLC with authentic markers.

Potential antipsoriatic effect of chondroitin sulfate through inhibition of NF-κB and STAT3 in human keratinocytes

Abstract Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1–3 linkage of d -glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal…

Coscinolactams A and B: new nitrogen-containing sesterterpenoids from the marine sponge Coscinoderma mathewsi exerting anti-inflammatory properties

Abstract Investigation of the marine sponge Coscinoderma mathewsi led to the isolation of two novel nitrogen-containing cheilanthane sesterterpenoids, coscinolactams A and B, together with known suvanine. The structures were elucidated by extensive spectroscopic measurements including NOE experiments to deduce the stereochemistry. The natural compounds, as well as a semisynthetic derivative, showed moderate anti-inflammatory activity measured as their capability to inhibit PGE2 and NO production. The suvanine aldehyde derivative 4 inhibited inducible nitric oxide protein expression with an IC50 value of 7.3 μM.

Antioxidant Profile of Mono-and Dihydroxylated Flavone Derivatives in Free Radical Generating Systems

Abstract A number of free radical generating systems were used to investigate the antioxidant properties and structure-activity relationships of a series of monohydroxylated and dihydrox­ylated flavones. Ortho-dihydroxylated flavones showed the highest inhibitory activity on en­ zymic and non-enzymic microsomal lipid peroxidation as well as on peroxyl radical scaveng­ing. Most flavones were weak scavengers of hydroxyl radical, while ortho-dihydroxylated flavones interacted with superoxide anion generated by an enzymic system or by human neutrophils. This series of compounds did not exert cytotoxic effects on these cells. Scaveng­ing of superoxide and peroxyl radicals may determ ine the anti…