Isolation, characterization and evaluation of antimicrobial and cytotoxic activity of estragole, obtained from the essential oil of Croton zehntneri (Euphorbiaceae).

Croton zehntneri (Euphorbiaceae) is a native aromatic plant from Northeast region of Brazil. The monoterpenoid estragole (ESL) has been isolated by classical chromatographic methods from the essential oil (EO) of C. zehnteneri leaves and characterized by GC-FID and GC-MS, its antimicrobial and cytotoxic potentials being assessed. The analysis of the EO enabled the identification of 100% of the integrated constituents, of which yield was about 1.8%. The main components identified were: eucalyptol, estragole (84.7%) and spathulenol. The dosage of 50 µg/disk of ESL presented fairly significant zones of inhibition against Gram-positive bacteria and fungi. The ESL presented toxicity against Artemia salina with LC50 and LC90 of 4,54 and 8,47 µg mL-1. However, in tumor inhibition assays (human cells), there were no rewarding inhibition in any of the human cancer cell lines (MCF-7, HEP-2 and NCI-H292).

Antischistosomal activity of the terpene nerolidol.

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people worldwide. Since the treatment of this disease currently relies on a single drug, praziquantel, new and safe schistosomicidal agents are urgently required. Nerolidol, a sesquiterpene present in the essential oils of several plants, is found in many foods and was approved by the U.S. Food and Drug Administration. In this study we analysed the in vitro antiparasitic effect of nerolidol on Schistosoma mansoni adult worms. Nerolidol at concentrations of 31.2 and 62.5 µM reduced the worm motor activity and caused the death of all male and female schistosomes, respectively. In addition, confocal laser scanning microscopy revealed morphological alterations on the tegument of worms such as disintegration, sloughing and erosion of the surface, and a correlation between viability and tegumental damage was observed. In conclusion, nerolidol may be a promising lead compound for the development of antischistosomal natural agents.

In vitro antioxidant and cytotoxic activity of some synthetic riparin-derived compounds.

This study aimed to study the in vitro antioxidant activity and cytotoxicity on tumor cells lines of six synthetic substances derived from riparins. All the substances showed antioxidant activity and riparins C, D, E, F presented cell growth inhibition rates greater than 70%, suggesting that these molecules have antitumor properties. These substances also caused greater than 80% releases of cytoplasmic lactate dehydrogenase enzyme (LDH). Although the antioxidant and antitumor properties presented herein require further assessment, the outcomes indicate that these novel riparins are promising biologically active compounds.

Evidence for the involvement of spinal cord-inhibitory and cytokines-modulatory mechanisms in the anti-hyperalgesic effect of hecogenin acetate, a steroidal sapogenin-acetylated, in mice.

Hecogenin is a steroidal sapogenin largely drawn from the plants of the genus Agave, commonly known as 'sisal', and is one of the important precursors used by the pharmaceutical industry for the synthesis of steroid hormones. Hecogenin acetate (HA) is a steroidal sapogenin-acetylated that produces antinociceptive activity. Thus, we evaluate the antihyperalgesic profile of HA in mice in inflammatory models, as well as its possible involvement with c-fos expression on spinal cord area and cytokines to produces analgesic profile. Acute pretreatment with HA (5, 10, or 20 mg/kg; i.p.) inhibited the development of mechanical hyperalgesia induced by carrageenan, TNF-α, dopamine and PGE2. Additionally, the immunofluorescence data demonstrated that acute pretreatment with HA, at all doses tested, significantly inhibited Fos-like expression in the spinal cord dorsal horn normally observed after carrageenan-inflammation. Moreover, HA did not affect the motor performance of the mice as tested in the Rota rod test. This antinociceptive profile seems to be related, at least in part, to a reduction of pro-inflammatory cytokines, as IL-1ß. The present results suggest that HA attenuates mechanical hyperalgesia by blocking the neural transmission of pain at the spinal cord levels and by cytokines-inhibitory mechanisms.

Anxiolytic properties of new chemical entity, 5TIO1.

2-[(2,6-dichlorobenzylidene)amino]-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile), 5TIO1, is a new 2-aminothiophene derivative with a promising pharmacological activity. The aim of this work was to evaluate the potential anxiolytic effect of 5TIO1 in animal models. In the elevated plus-maze test, 5TIO1 (0.1, 1.0 and 10.0 mg/kg, i.p) increased the time of permanence and the number of entries in the open arms. In the light/dark box test, 5TIO1 at dose of 0.1 mg/kg (i.p) also showed anxiolytic-like effect indicated by an increase in the time spent in the light box, similar to diazepam 2.0 mg/kg (i.p). 5TIO1 groups did not change locomotor and coordination activities in open field and rotarod tests, respectively, when compared to vehicle. Dose dependent process was not observed and the anxiolytic effects demonstrated were not completely reversed by flumazenil 25 mg/kg (i.p). Our results suggest that 5TIO1 can bind with other receptors, besides the benzodiazepine site of the GABA receptor in mouse brain.

Anthelmintic activity of the natural compound (+)-limonene epoxide against Schistosoma mansoni.

Blood fluke of the genus Schistosoma are the etiological agents of human schistosomiasis, an important neglected tropical disease that afflicts over 200 million people worldwide. The treatment for this disease relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new antischistosomal drugs. Currently, natural products have been a good source for drug development. (+)-Limonene epoxide is a mixture of cis and trans isomers found in many plants. Here, we report the in vitro effect of this natural compound on the survival time of Schistosoma mansoni adult worms. In addition, we examined alterations on the tegumental surface of adult schistosomes by means of confocal laser scanning microscopy. The effects of (+)-limonene epoxide at 25 µg/mL on S. mansoni adult worms were similar to those of the positive control (praziquantel), with reduction in motility and death of all worms after 120 h. Confocal laser scanning microscopy revealed that (+)-limonene epoxide-mediated worm killing was associated with tegumental destruction. Our results, along with the low toxicity of the (+)-limonene epoxide, suggest that this natural compound might be promising for the development of new schistosomicidal agents.

Phytochemical profile and qualification of biological activity of an isolated fraction of Bellis perennis.

This study describes the isolation and identification of apigenin-7-O-ghicopyranoside, a flavonoid isolated from the flowers of Bellis perennis L., Asteraceae, an species with a broad spectrum of biological activities. The in vitro antioxidant activity and the inhibition of the enzyme acetylcholinesterase were evaluated. The flavonoid showed strong in vitro antioxidant potential, because of the capacity of removal of hydroxyl radicals and nitric oxide, and also prevented the formation of thiobarbituric acid-reactive substances. These parameters were inhibited at the highest concentration of ApG at rates of 77.7%, 72% and 73.4%, respectively, in addition to inhibiting acetylcholinesterase, suggesting potential use in the treatment of neurodegenerative diseases.

Neuroprotective actions of vitamin C related to decreased lipid peroxidation and increased catalase activity in adult rats after pilocarpine-induced seizures.

In the present study, we examined the neuroprotective effects of vitamin C in adult rats after pilocarpine-induced seizures. Vitamin C is an exogenous antioxidant that can be used in treatment of seizures. It can alter oxidative stress and damage neuronal induced by seizures. Its antioxidant properties can be proved in epilepsy models, such as pilocarpine-induced seizures in adult rats. In order to investigate neuroprotective effects of vitamin C, adult male rats (2 months-old) were pretreated with vitamin C (VIT C 250 mg/kg, i.p.) 30 min before receiving pilocarpine (400 mg/kg, s.c., P400 group). The other three groups were treated with vitamin C (VIT C group) and saline 0.9 (control group) alone. The pretreatment with vitamin C increased the latency to first seizures and reduced mortality rate after pilocarpine-induced seizures. Pretreatment with vitamin C alone decrease lipid peroxidation levels when compared to pilocarpine group and P400+VIT C. In P400, P400+VIT C and VIT C groups were observed an increased hippocampal catalase activity when compared to control group. Our results can suggest that neuroprotective effects of vitamin C in adult rats can be the result of reduced lipid peroxidation levels and increase of catalase activity after seizures and status epilepticus induced by pilocarpine.

Cyclohexene-fused 1,3-oxazines with selective antibacterial and antiparasitic action and low cytotoxic effects.

Oxazine derivatives, a class of heterocyclic compounds, exhibit a variety of biological properties, such as anticonvulsant and antitumor activities. In this study, we evaluated the effect of two cyclohexene-fused 1,3-oxazines (cis­1-benzyl-N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (1) and trans­N-phenyl-1,4,4a,5,8,8a-hexahydro-3,1-benzoxazin-2-imine (2)) in cultures of Bacillus cereus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Serratia marcescens, Shigella flexneri and Staphylococcus aureus by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC). Additionally, the ex vivo antiparasitic activity of oxazines was assessed against Schistosoma mansoni, a helminth that is one of the major agents of the disease schistosomiasis Also, oxazines were evaluated on three tumor cell lines, NCI-H292 (human lung carcinoma), MCF-7 (human breast adenocarcinoma) and HEp-2 (human cervix carcinoma), and two normal cell lines (Vero and red blood cells). Bioassays revealed that oxazine 2 is more effective against bacteria than oxazine 1, with the lowest MIC and MBC values of 3.91 and 32.5µg/mL, respectively. Similarly, compound 2 demonstrated higher antiparasitic activity than 1, and scanning electron microscopy analysis showed several morphological alterations in the tegument of worms in a concentration-dependent manner. In contrast, both oxazines exhibited low cytotoxic effects on cancer and normal cell lines. These results indicated that oxazines exerted direct effects on bacteria and parasite schistosomes. More importantly, since schistosomiasis control programs rely on one drug, praziquantel, oxazines may have the potential to become new antischistosomal agents.

Expression of muscarinic and dopaminergic receptors and monoamine levels frontal cortex of epileptic rats.

Apart from stroke, epilepsy is the most common neurological disorder with 0.5% of prevalence. The present study was performed in order to determine the monoamine levels, (M(1)-like) muscarinic and (D(1)- and D(2)-like) dopaminergic receptor changes in frontal cortex of adult rats after pilocarpine-induced status epilepticus (SE). Male Wistar rats were treated with a single dose of pilocarpine (400 mg/kg, s.c.) and the control group received 0.9% saline (s.c.). Both groups were sacrificed 1 h after treatment. The frontal cortex was dissected for neurochemical assays. The results show a downregulation of 27% in M(1) muscarinic receptor density, but in the dissociation constant (K(d)) value remained unaltered. D(1) and D(2) dopaminergic receptor densities and their K(d) values remained unaltered. Monoamine and metabolites levels presented decreases of 44%, 27%, 30% and 42% in dopamine (DA), homovanilic acid (HVA), norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) contents, respectively. Moreover, in serotonin (5-HT) level remained unaltered and the 4-hydroxy-3-methoxy-phenylacetic acid (DOPAC) concentration was augmented by 34%. The results suggest that dopaminergic system in this area studied may not be directly involved in the seizures and status epilepticus, but different monoamines and metabolites can be modified in this cerebral area during seizure process. In conclusion, the neurochemical alterations that occur in frontal cortex of adult rats observed during the establishment of the status epilepticus induced by pilocarpine are decrease in M(1) receptor density concentration and a reduction in DA and NE levels.

Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats.

The work shows the effects of caffeine after the intrastriatal injection of 6-OHDA in rats, considered as a model of Parkinson disease (PD). Two weeks after the 6-OHDA lesion, rats exhibit a characteristic rotation behavior as a response to the apomorphine challenge. Our results showed significant increases in the number of apomorphine-induced rotations in 6-OHDA-lesioned rats, as compared to sham-operated animals. A partial recovery was observed in 6-OHDA-lesioned rats, after caffeine (10 and 20 mg/kg, i.p., daily for 14 days) treatment. The stereotaxic injection of 6-OHDA produced loss of striatal neurons, as indicated by the decrease in monoamines levels, in the ipsilateral side (75-85%) when compared to the contralateral side. Significant decreases in noradrenaline levels were seen in the ipsilateral side of 6-OHDA group (62%), and this effect was not significantly reversed in caffeine-treated groups. While significant decreases in dopamine levels were seen in the ipsilateral side of 6-OHDA group (78%), in the caffeine-treated group (10 and 20 mg/kg, i.p.) the decreases were only 53 and 18%, indicating significant recoveries. In conclusion, our data demonstrated beneficial effects of caffeine in this model of PD, suggesting the potential use of A2A antagonists as a novel treatment for this neurodegenerative disease.

Comparative efficacy and toxic effects of carvacryl acetate and carvacrol on sheep gastrointestinal nematodes and mice.

Carvacrol is a compound isolated from some essential oils. It has been reported to possess anthelmintic activity. Acetylation of this monoterpene has been proposed as a potential way to reduce the toxicity and enhance the pharmacological effects of carvacrol. This study aimed to evaluate the effect of carvacryl acetate (CA) using in vitro and in vivo assays with gastrointestinal nematodes of small ruminants. The egg hatching test (EHT), larval development test (LDT) and adult worm motility (AWM) assessment were conducted to evaluate the effect of the acetylated product and pure carvacrol on Haemonchus contortus eggs, larvae and adults. The structural changes induced in adult H. contortus were assessed using scanning electron microscopy (SEM). CA and carvacrol acute toxicity was evaluated in mice. Finally, the efficacy of 250 mg/kg CA and 2.5mg/kg monepantel (positive control) were evaluated in 30 sheep naturally infected with gastrointestinal nematodes by the fecal egg count reduction test (FECRT). In vitro tests were analyzed by analysis of variance (ANOVA) followed by comparison with Tukey's test. The efficacy was calculated by the Boot Street program using the arithmetic average. The number of eggs in feces (epg) of the groups were transformed to log (x+1) and subjected to ANOVA to compare differences among the groups by Tukey's test. The level of significance was P<0.05. CA and carvacrol inhibited larval hatching by 89.3 and 97.7% at doses of 8.0 and 1.0mg/ml, respectively. At the concentration of 2mg/ml, CA and carvacrol inhibited 100% of larval development. At a concentration of 200 µg/ml, CA and carvacrol inhibited the motility of adult worms by 100% and 58.3% at 24h post-exposure, respectively. CA caused cuticle and vulvar flap wrinkling and bubbles to emerge from the tegument. Carvacrol caused more discreet effects on the cuticle and vulvar flap. The LD10 and LD50 of CA were 566.7 mg/kg and 1544.5mg/kg, respectively. The LD10 and LD50 of carvacrol were 546.8 mg/kg and 919 mg/kg, respectively. CA and monepantel reduced the epg of sheep by 65.9 and 96.4%, respectively, at 16 days post-treatment. CA showed in vitro and in vivo anthelmintic activity and was less toxic than carvacrol.

Structural parameters, molecular properties, and biological evaluation of some terpenes targeting Schistosoma mansoni parasite.

The use of natural products has a long tradition in medicine, and they have proven to be an important source of lead compounds in the development of new drugs. Among the natural compounds, terpenoids present broad-spectrum activity against infective agents such as viruses, bacteria, fungi, protozoan and helminth parasites. In this study, we report a biological screening of 38 chemically characterized terpenes from different classes, which have a hydroxyl group connected by hydrophobic chain or an acceptor site, against the blood fluke Schistosoma mansoni, the parasite responsible for schistosomiasis mansoni. In vitro bioassays revealed that 3,7-dimethyl-1-octanol (dihydrocitronellol) (10) was the most active terpene (IC50 values of 13-52 µM) and, thus, we investigated its antischistosomal activity in greater detail. Confocal laser scanning microscopy revealed that compound 10 induced severe tegumental damage in adult schistosomes and a correlation between viability and tegumental changes was observed. Furthermore, we compared all the inactive compounds with dihydrocitronellol structurally by using shape and charge modeling. Lipophilicity (miLogP) and other molecular properties (e.g. molecular polar surface area, molecular electrostatic potential) were also calculated. From the 38 terpenes studied, compound 10 is the one with the greatest flexibility, with a sufficient apolar region by which it may interact in a hydrophobic active site. In conclusion, the integration of biological and chemical analysis indicates the potential of the terpene dihydrocitronellol as an antiparasitic agent.

Oxidative stress in the hippocampus after pilocarpine-induced status epilepticus in Wistar rats.

The role of oxidative stress in pilocarpine-induced status epilepticus was investigated by measuring lipid peroxidation level, nitrite content, GSH concentration, and superoxide dismutase and catalase activities in the hippocampus of Wistar rats. The control group was subcutaneously injected with 0.9% saline. The experimental group received pilocarpine (400 mg.kg(-1), subcutaneous). Both groups were killed 24 h after treatment. After the induction of status epilepticus, there were significant increases (77% and 51%, respectively) in lipid peroxidation and nitrite concentration, but a 55% decrease in GSH content. Catalase activity was augmented 88%, but superoxide dismutase activity remained unaltered. These results show evidence of neuronal damage in the hippocampus due to a decrease in GSH concentration and an increase in lipid peroxidation and nitrite content. GSH and catalase activity are involved in mechanisms responsible for eliminating oxygen free radicals during the establishment of status epilepticus in the hippocampus. In contrast, no correlations between superoxide dismutase and catalase activities were observed. Our results suggest that GSH and catalase activity play an antioxidant role in the hippocampus during status epilepticus.

Antioxidant effect of nimodipine in young rats after pilocarpine-induced seizures.

Nimodipine (ND) is a centrally active calcium antagonist that blocks the voltage-dependent L-type channels. Its antiepileptic properties have been proved in various animal models, including pilocarpine-induced seizures in adult rats. In order to investigate protective effects of the ND (10 (ND10) and 30 mg/kg (ND30), i.p.), young male rats (21-day-old) received ND injections before pilocarpine administration (400 mg/kg, s.c., pilocarpine group (P400)). The pretreatment with ND10 and ND30 prolonged the latencies of seizures and death on this seizure model. ND pretreatment in two doses decreased the levels of lipid peroxidation when compared to pilocarpine group. The P400 administration increased the striatal catalase activity. However, the administration of ND, in dose of 30 mg/kg, 30 min before pilocarpine, preserved catalase activity in normal levels. On the other hand, no change was detected in the animals treated with the dose of 10 mg/kg. Our results confirm the neuroprotective effect of ND on the seizures in young rats, suggesting that this drug acts positively on lipid peroxidation. Our observations shows that nimodipine cannot induces these effects via blockade of Ca(2+)-channel.

Anticonvulsant and behavioral effects observed in mice following treatment with an ester derivative of ferulic acid: Isopentyl ferulate.

The objective of this study was to evaluate the potential anticonvulsant effect of isopentyl ferulate, a new ester derived from ferulic acid in mice (Mus musculus) subjected to two models of induced seizures. According to the results obtained, the IF at doses of 25, 50 and 75 mg/kg (i.p.) showed protective effect against induced seizures by pilocarpine (400 mg/kg, i.p.) and pentylenetetrazole (70 mg/kg, i.p.). In the two animal models of seizures, the pretreatment of the IF (25, 50 and 75 mg/kg) with flumazenil blocked the anticonvulsant effect, suggesting that the mechanism of action of this ester derived of ferulic acid may be related to activity in the benzodiazepine-binding site of the GABAA receptor (γ-aminobutyric acid, type A). In addition to the anticonvulsant effect, behavioral changes as neurotoxicity indication were assessed by using the rota rod and open field tests. The results obtained showed that the IF (25, 50 and 75 mg/kg) does not induce significant changes in locomotor activity and motor coordination when compared with the control group, unlike the results presented by diazepam. Thus, these results demonstrate a new pharmacological knowledge of IF with potential application against epileptic seizures. However, further studies are needed to elucidate other neurobiological mechanisms underlying epilepsy.

Garcinielliptone FC: antiparasitic activity without cytotoxicity to mammalian cells.

Garcinielliptone FC (GFC) is a natural prenylated benzophenone found in the seeds of Platonia insignis Mart. (Clusiaceae), a native Brazilian plant. It has been chemically characterized and it is known that GFC has several biological activities such as antioxidant and vasorelaxant properties. In this study, we report the in vitro effect of GFC against the blood fluke Schistosoma mansoni, the parasite responsible for schistosomiasis mansoni. The anti-S. mansoni activity and cytotoxicity toward mammalian cells were determined for the compound. GFC⩾6.25 µM showed antischistosomal activity and confocal laser scanning microscopy analysis demonstrated several morphological alterations on the tegument of worms, and a correlation between viability and tegumental damage was observed. In addition, at sub-lethal concentrations of GFC (⩽3.125 µM), the number of S. mansoni eggs was reduced. More importantly, GFC exhibited no activity toward mammalian cells and, therefore, there is an appreciable selectivity of this compound against the helminths. In conclusion, these findings indicate the potential of GFC as an antiparasitic agent.

Evaluation of toxic, cytotoxic, mutagenic, and antimutagenic activities of natural and technical cashew nut shell liquids using the Allium cepa and Artemia salina bioassays.

The cashew nut releases a substance that is known as cashew nut shell liquid (CNSL). There are both natural (iCNSL) and technical (tCNSL) cashew nut shell liquids. This study used an Artemia salina bioassay to evaluate the toxic effects of iCNSL and tCNSL cashew nut shell liquids. It also evaluated the toxicity, cytotoxicity, and mutagenicity of CNSL and its effects on the damage induced by copper sulfate (CuSO4·5H2O) on the meristems' root of Allium cepa. Effects of the damage induced by CuSO4·5H2O were evaluated before (pre-), during (co-), and after (post-) treatments. The iCNSL contained 94.5% anacardic acid, and the tCNSL contained 91.3% cardanol. The liquids were toxic to A. salina. Toxicity, cytotoxicity, and mutagenicity were observed with iCNSL compared with the negative control. Similarly, iCNSL failed to inhibit the toxicity and cytotoxicity of CuSO4·5H2O. The tCNSL was not toxic, cytotoxic, or mutagenic in any of the concentrations. However, the lowest iCNSL concentrations and all of the tCNSL concentrations had preventive, antimutagenic, and reparative effects on micronuclei and on chromosomal aberrations in the A. cepa. Therefore, protective, modulating, and reparative effects may be observed in the A. cepa, depending on the concentration and type of CNSL used.

Riparin B, a Synthetic Compound Analogue of Riparin, Inhibits the Systemic Inflammatory Response and Oxidative Stress in Mice.

The aim of our study was to evaluate the anti-inflammatory, anti-nociceptive, and anti-oxidant action of Riparin B in vivo. We performed experiments in which we induced paw edema by carrageenan and other mediators, carrageenan-induced peritonitis and the level of myeloperoxidase (MPO) activity, pro-inflammatory cytokines (TNF-α and IL-1ß), malondialdehyde (MDA) acid, and glutathione (GSH) from the peritoneal fluid. We also performed behavior tests such as acetic acid-induced writhing, formalin-induced linking, and the hot plate test. Among the doses tested of the Riparin B (1, 3, and 10 mg/kg), the dose of 10 mg/kg showed the strongest effect, and this dose was able to reduce the paw edema induced by carrageenan, dextran, histamine serotonin, bradykinin, 48/80, and PGE2. Similarly, the Riparin B in the same dose reduced cell migration and significantly decreased the nociception induced by formalin and acetic acid and reversed the parameters of the oxidative stress. Thus, we can infer that Riparin B exhibits anti-inflammatory, anti-nociceptive, and anti-oxidant actions in vivo.

Riparin A, a compound from Aniba riparia, attenuate the inflammatory response by modulation of neutrophil migration.

Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1ß) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.