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…

A pyrroloquinazoline derivative with anti-inflammatory and analgesic activity by dual inhibition of cyclo-oxygenase-2 and 5-lipoxygenase

Abstract In a previous study, we reported a new pyrroloquinazoline derivative, 3-(4′-acetoxy-3′,5′-dimethoxy)benzylidene-1,2-dihydropyrrolo[2,1- b ]quinazoline-9-one (PQ), which inhibited human purified 5-lipoxygenase activity and prostaglandin E 2 release in lipopolysaccharide-stimulated RAW 264.7 cells. In the present work, we show that PQ inhibits cyclo-oxygenase-2 activity in intact cell assays (human monocytes) and purified enzyme preparations (ovine isoenzymes) without affecting cyclo-oxygenase-1 activity. This behaviour was confirmed in vivo by using the zymosan-injected mouse air pouch model, where PQ caused a marked reduction in cell migration and leukotriene B 4 levels at 4 h, as …

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…

Novel anti-inflammatory chalcone derivatives inhibit the induction of nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages

AbstractIn a previous work, we tested a series of chalcone derivatives as possible anti-inflammatory compounds. We now investigate the effects of three of those compounds, CH1, CH8 and CH12, on nitric oxide and prostanoid generation in mouse peritoneal macrophages stimulated with lipopolysaccharide and in the mouse air pouch injected with zymosan, where they showed a dose-dependent inhibition with inhibitory concentration 50% values in the μM range. This effect was not the consequence of a direct inhibitory action on enzyme activities. Our results demonstrated that chalcone derivatives inhibited de novo inducible nitric oxide synthase and cyclooxygenase-2 synthesis, being a novel therapeuti…

A new pyrazolo pyrimidine derivative inhibitor of cyclooxygenase-2 with anti-angiogenic activity

In a previous study, we reported a new pyrazolo pyrimidine derivative, N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-6,4-diamine (DPP), which inhibited potently cyclooxygenase-2 activity in intact cell assays with minor activity against cyclooxygenase-1 (IC(50)=0.9 nM for cyclooxygenase-2 versus IC(50)=59.6 nM for cyclooxygenase-1). In the present work, this behaviour was confirmed in vivo by using the 24-h zymosan-injected mouse air pouch model (ID(50)=1.36 nM/pouch for prostaglandin E(2) level). We also studied the possible beneficial effect of DPP in the angiogenesis-dependent murine air pouch granuloma and rat paw carrageenan-induced hyperalgesia models. DP…

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…

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…

Anti-inflammatory activity in selected Antarctic benthic organisms

Antarctic benthos was prospected in search for anti-inflammatory activity in polar benthic invertebrates, in two different geographical areas: deep-bottoms of the Eastern Weddell Sea and shallow-waters of the South Shetland Islands. A total of 36 benthic algae and invertebrate species were selected to perform solubility tests in order to obtain extracts that were soluble at an innocuous ethanol concentration (0.2%) for cell culture, and further test them for anti-inflammatory activity. From these, ethanol extracts of ten species from five different phyla resulted suitable to be studied in cell macrophage cultures (RAW 264.7). Cytotoxicity (MTT method) and production of inflammatory mediator…

Inside Cover: A Boron Dipyrromethene (BODIPY)-Based CuII-Bipyridine Complex for Highly Selective NO Detection (Chem. Eur. J. 44/2015)

Synthesis and anti-inflammatory activity of chalcone derivatives

Chalcones and their derivatives were synthesized and evaluated for their anti-inflammatory activity. In vitro, chalcones 2, 4, 8, 10 and 13 inhibited degranulation and 5-lipoxygenase in human neutrophils, whereas 11 behaved as scavenger of superoxide. Only four compounds (4-7) inhibited cyclo-oxygenase-2 activity. The majority of these samples showed anti-inflammatory effects in the mouse air pouch model.

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…

A Boron Dipyrromethene (BODIPY)-Based Cu(II) -Bipyridine Complex for Highly Selective NO Detection.

[EN] A BODIPY-containing Cu-II-bipyridine complex for the simple selective fluorogenic detection of NO in air and in live cells is reported. The detection mechanism is based on NO-promoted Cu-II to Cu-I reduction, followed by demetallation of the complex, which results in the clearly enhanced emission of the boron dipyrromethene (BODIPY) unit.

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…

Inhibition of phospholipase A2 activities and some inflammatory responses by the marine product ircinin

The marine product ircinin has been tested for its effects on secretory and cytosolic phospholipase A2 (PLA2) activities in vitro as well as for inhibition of cellular functions in human neutrophils and inflammatory responses in mice. Ircinin inhibited Naja naja venom, human synovial recombinant, bee venom and zymosan-injected rat air pouch PLA2 with IC50 values in the microM range, similar to those of the known inhibitor scalaradial. On the other hand, ircinin was less active on cytosolic PLA2 from human monocytes and decreased potently the release of LTB4 in human neutrophils. This marine product affected weakly human neutrophil functions like superoxide generation and degranulation. In t…