Modulation of Cox-1, 5-, 12- and 15-Lox by popular herbal remedies used in southern Italy against psoriasis and other skin diseases.

Acanthus mollis (Acanthaceae), Achillea ligustica, Artemisia arborescens and Inula viscosa (Asteraceae) are used in Southern Italy against psoriasis and other skin diseases that occur with an imbalanced production of eicosanoids. We here assessed their in vitro effects upon 5-, 12-, 15-LOX and COX-1 enzymes as well as NFκB activation in intact cells as their possible therapeutic targets. All methanol crude extracts inhibited both 5-LOX and COX-1 activities under 200 µg/mL, without significant effects on the 12-LOX pathway or any relevant in vitro free radical scavenging activity. NFκB activation was prevented by all extracts but A. mollis. Interestingly, A. ligustica, A. arborescens and A. mollis increased the biosynthesis of 15(S)-HETE, an anti-inflammatory eicosanoid. A. ligustica (IC50 =49.5 µg/mL) was superior to Silybum marianum (IC50 =147.8 µg/mL), which we used as antipsoriatic herbal medicine of reference. Its n-hexane, dichloromethane and ethyl acetate fractions had also inhibitory effects on the LTB4 biosynthesis (IC50 s=9.6, 20.3 and 68 µg/mL, respectively) evidencing that the apolar extracts of A. ligustica are promising active herbal ingredients for future phytotherapeutical products targeting psoriasis

Genetic Markers for Differentiating Aspirin-Hypersensitivity

Aspirin-induced asthma (AIA) and aspirin-induced urticaria/angioedema (AIU) are two major aspirin-related allergies. We summarize recent findings related to their molecular genetic mechanisms in order to identify genetic susceptibility markers for differentiating AIU and AIA. The overproduction of cysteinyl leukotriene has been suggested as a mechanism in both AIU and AIA. Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU. An HLA study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are markers for AIU susceptibility. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, FcεRIβ, and TBXA2R were associated with AIA, while an FcεRIα promoter polymorphism was associated with AIU. The functional studies of the key genes involved in AIA and AIU are summarized. The identification and functional study of genetic markers for AIA and AIU susceptibility would further elucidate the pathogenic mechanisms and facilitate the development of early diagnostic markers to establish therapeutic targets

Sulfasalazine Blocks the Development of Tactile Allodynia in Diabetic Rats

OBJECTIVE—Diabetic neuropathy is manifested either by loss of nociception (painless syndrome) or by mechanical hyperalgesia and tactile allodynia (pain in response to nonpainful stimuli). While therapies with vasodilators or neurotrophins reverse some functional and metabolic abnormalities in diabetic nerves, they only partially ameliorate neuropathic pain. The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes

Anti-Inflammatory properties of Salograviolide A purified from Lebanese plant Centaurea ainetensis

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Evidence of effectiveness of herbal medicinal products in the treatment of arthritis

Herbal medicinal products (HMPs) that interact with the mediators of inflammation are used in the treatment of rheumatoid arthritis (RA). The aim of this study was to update a previous systematic review published in 2000. We searched electronic databases (MEDLINE, EMBASE, CISCOM, AMED, CINAHL, Cochrane registers) to June 2007, unrestricted by date or language, and included randomized controlled trials that compared HMPs with inert (placebo) or active controls in patients with rheumatoid arthritis. Five reviewers contributed to data extraction. Disagreements were discussed and resolved by consensus with reference to Cochrane guidelines and advice from the Cochrane Collaboration. Twenty studies (10 identified for this review update, and 10 of the 11 studies of the original review) investigating 14 HMPs were included. Meta-analysis was restricted to data from previous seven studies with oils from borage, blackcurrant and evening primrose containing gamma linolenic acid (GLA). GLA doses equal or higher than 1400 mg/day showed benefit in the alleviation of rheumatic complaints whereas lower doses (∼500 mg) were ineffective. Three studies compared products from Tripterygium wilfordii (thunder god vine) to placebos and returned favorable results but data could not be pooled because the interventions and measures differed. Serious adverse effects occurred in one study. In a follow-up study all side effects were mild to moderate and resolved after the intervention ceased, but time to resolution was variable. Two studies comparing Phytodolor N R to placebo were of limited use because some measures were poorly defined. The remaining studies, each considering differing HMPs, were assessed individually. For most HMPs used in the treatment of RA, the evidence of effectiveness was insufficient to either recommend or discourage their use. Interventions with HMPs containing GLA or Tripterygium wilfordii extract appear to produce therapeutic effects but further investigations are warranted to prove their effectiveness and safety. Copyright © 2009 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64567/1/3006_ftp.pd

Studies on the formation of leukotriene C4 and lipoxins from leukotriene A4 in human platelets

Human platelets lack 5-lipoxygenase activity, but possess enzymatic capacity to transformthe unstable epoxide leukotriene (LT)A4 to the potent inflammatory agent LTC4 and lipoxins, agroup of trihydroxylated tetraene-containing eicosanoids, which recently have been suggestedto have an anti-inflammatory role. A novel pathway for the formation of lipoxin (LX)A4 via platelet lipoxygenation of SS,6R-diHETE and 5S,6S-diHETE, enzymatic/non-enzymatic hydrolysis products of LTA4, wasdiscovered in human platelets. In contrast, human platelets did not transform cysteinylleukotrienes to the corresponding cysteinyl lipoxins. The results indicated that platelet-dependent lipoxin formation from LTA4 can proceed both via a direct lipoxygenation, yielding15-OH-LTA4, and through initial hydrolysis to 5,6-diHETEs. The hydroxylation of LTA4 atC-15 was more efficiently catalysed by human platelet and porcine leukocyte 12-lipoxygenasesthan by rabbit reticulocyte and soybean 15-lipoxygenases. In kinetic studies, human platelet12-lipoxygenase was found to have a high affinity for LTA4, with a Km value comparable tothose earlier reported for arachidonic acid. Platelet activation resulted in elevated lipoxin synthesis. This activation was due to stimula-tion of 12-lipoxygenase by endogenous 12-HPETE, formed after calcium-dependentphospholipase activation and liberation of arachidonic acid. In contrast to the increased lipoxin formation, platelet activation attenuated the conversion ofLTA4 to LTC4. This inhibition of platelet LTC4 synthase activity was observed both afterreceptor-mediated activation of human platelets as well as after direct stimulation of PKC withPMA. These effects were blocked by pretreatment with the protein kinase inhibitor stauro-sporine, supporting the possible regulation of LTC4 synthase through phosphorylationpathways. This was further suggested by kinetic studies demonstrating non-competitiveinhibition of the enzyme after incubation of intact platelets with thrombin or PMA. However,receptor-mediated attenuation of LTC4 formation could not be reversed by specific PKCinhibitors, even though these drugs efficiently prevented the PMA-induced effect. Theseresults indicate that the LTC4 synthase activity in platelets is phosphoregulated, both via PKC-dependent and via receptor-mediated, PKC-independent mechanisms. Involvement of proteintyrosine phosphorylations in the latter process was suggested by the finding that a tyrosinephosphatase inhibitor induced dose-dependent inhibition of LTC4 production in plateletsonicates. In agreement with the findings in platelets, PKC-induced down-regulation of the LTC4synthase activity was also demonstrated in human granulocytes. Aspirin treatment in vivo was found to block attenuation of platelet LTC4 synthase activityinduced by arachidonic acid or collagen ex vivo. The results suggest that aspirin treatment canuncouple mechanisms that normally restrict the production of cysteinyl leukotrienes, which areimportant bronchoconstrictors and asthma mediators. These findings may therefore be relevantfor our understanding of the pathophysiology of aspirin-induced asthma. The effects of the anti-inflammatory drug sulfasalazine on the arachidonic acid cascade inhuman platelets and leukocytes were investigated. The drug was found to inhibit the produc-tion of leukotrienes and tromboxanes but allowed formation of prostaglandin E2. Thispharmacological profile may contribute to the clinical mechanism of action of this drug. In conclusion: Platelet 12-lipoxygenase is well suited to initiate the conversion of LTA4 tolipoxins, indicating a physiological role for this enzyme in lipoxin formation. Also, plateletactivation may lead to elevated formation of putative anti-inflammatory lipoxins paralleled bysuppressed formation of the pro-inflammatory LTC4. According to the present findings, regu-lation of LTC4 synthase activity can be exerted via receptor-mediated, phosphoregulatorymechanisms and may be of importance in aspirin-induced asthma. ISBN 91-628-2109-

The Effect of Pulse Width on Subjective Memory Impairment and Remission Rate 6 Months After Electroconvulsive Therapy

Objectives: The aim of this study was to compare the 0.5-millisecond pulse width with broader brief width stimulus and ultrabrief pulse width stimulus in respect to rates of subjective memory impairment and remission 6 months after completion of electroconvulsive therapy (ECT). Methods: This study used data from the Swedish National Quality Register for ECT. Inclusion criteria were bipolar or unipolar depression with or without psychosis, ECT with unilateral electrode placement, and data on the Montgomery-Asberg Depression Rating Scale-Self-Assessment and the memory item of the Comprehensive Psychopathological Rating Scale (CPRS-M) before and 6 months after ECT. The primary outcomes were the distributions of patients with a maximum of 10 on the Montgomery-Asberg Depression Rating Scale-Self-Assessment (remission) and a minimum of 2-step worsening in CPRS-M score according to the ECT pulse widths of &amp;lt;0.5, 0.5, and &amp;gt;0.5 millisecond. Result: This study included 312 patients. The distributions of patients with remission or a minimum of 2-step worsening on the CPRS-M 6 months after completion of ECT showed no significant differences between the 3 pulse width groups. Older age was associated with a significantly higher rate of remission 6 months after ECT. Conclusions: In this cohort of patients, no support was found for the previous research finding of lower rates of subjective memory disturbances 6 months after ultrabrief pulse width ECT in comparison with brief pulse width ECT. Older age was associated with higher remission rate 6 months after ECT. Large randomized studies are required to exclude the possibility of long-term differential effects between pulse widths.Funding Agencies|Region Orebro County</p