Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo.

Based on its capacity to inhibit in vitro HIV-1 replication in T cells and the release of pro-inflammatory cytokines in monocytes, the prenylated heterodimeric phloroglucinyl α-pyrone arzanol was identified as the major anti-inflammatory and anti-viral constituent from Helichrysum italicum. We have now investigated the activity of arzanol on the biosynthesis of pro-inflammatory eicosanoids, evaluating its anti-inflammatory efficacy in vitro and in vivo. Arzanol inhibited 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC 1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E(2)in vitro (IC(50)=2.3-9μM). Detailed studies revealed that arzanol primarily inhibits microsomal PGE(2) synthase (mPGES)-1 (EC 5.3.99.3, IC(50)=0.4μM) rather than COX-2. In fact, arzanol could block COX-2/mPGES-1-mediated PGE(2) biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, but not the concomitant COX-2-derived biosynthesis of thromboxane B(2) or of 6-keto PGF(1α), and the expression of COX-2 or mPGES-1 protein was not affected. Arzanol potently suppressed the inflammatory response of the carrageenan-induced pleurisy in rats (3.6mg/kg, i.p.), with significantly reduced levels of PGE(2) in the pleural exudates. Taken together, our data show that arzanol potently inhibits the biosynthesis of pro-inflammatory lipid mediators like PGE(2)in vitro and in vivo, providing a mechanistic rationale for the anti-inflammatory activity of H. italicum, and a rationale for further pre-clinical evaluation of this novel anti-inflammatory lead

Myrtucommulone from Myrtus communis exhibits potent anti-inflammatory effectiveness in vivo.

Myrtucommulone a nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis), has been reported to suppress the biosynthesis of eicosanoids by inhibition of 5-lipoxygenase and cyclooxygenase-1 in vitro and to inhibit the release of elastase and the formation of reactive oxygen species in activated polymorphonuclear leukocytes. Here, in view of the ability of MC to suppress typical proinflammatory cellular responses in vitro, we have investigated the effects of MC in in vivo models of inflammation. MC was administered to mice intraperitoneally, and paw edema and pleurisy were induced by the subplantar and intrapleural injection of carrageenan, respectively. MC (0.5, 1.5, and 4.5 mg/kg i.p.) reduced the development of mouse carrageenan-induced paw edema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted anti-inflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC reduced: 1) the exudate volume and leukocyte numbers; 2) lung injury (histological analysis) and neutrophil infiltration (myeloperoxidase activity); 3) the lung intercellular adhesion molecule-1 and P-selectin immunohistochemical localization; 4) the cytokine levels (tumor necrosis factor-α and interleukin-1 β in the pleural exudate and their immunohistochemical localization in the lung; 5) the leukotriene B 4, but not prostaglandin E2, levels in the pleural exudates; and 6) lung peroxidation (thiobarbituric acid-reactant substance) and nitrotyrosine and poly (ADP-ribose) immunostaining. In conclusion, our results demonstrate that MC exerts potent anti-inflammatory effects in vivo and offer a novel therapeutic approach for the management of acute inflammation. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics

Therapeutic impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer

Background: Positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) is an accurate imaging modality for the staging of breast cancer. The aim of this study was to determine the potential therapeutic impact of pre- and postoperative FDG-PET in patients with clinically intermediate or high-risk breast cancer. Patients and methods: One hundred and fourteen patients with newly diagnosed breast cancer were examined before (73) or after (41) surgery. Patient data were translated into three scoring sheets corresponding to information available before positron emission tomography (PET), after PET and after further diagnostic tests. Three medical oncologists independently reviewed the retrospectively acquired patient data and prospectively made decisions on the theoretically planed treatment for each time point, according to the recommendations of St Gallen Consensus Guidelines 2005. Results: FDG-PET changed the planed treatment in 32% of 114 patients. In 20% of cases, therapeutic intention (curative versus palliative) was modified. Radiation treatment planning was changed in 27%, surgical planning in 9%, chemotherapy in 11% and intended therapy with bisphosphonates in 13% of all patients. Conclusion: Based on current treatment guidelines, FDG-PET, as a staging procedure in patients with newly diagnosed clinically intermediate or high-risk breast cancer examined pre- and postoperatively, may have a substantial therapeutic impact on treatment plannin

Vitamin E metabolites as potent inhibitors of 5-lipoxygenase

International audienc

Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E(2) synthase-1.

Selective inhibition of pro-inflammatory prostaglandin (PG)E2 formation via microsomal PGE2 synthase-1 (mPGES-1) might be superior over inhibition of all cyclooxygenase (COX)-derived products by non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. We recently showed that benzo[g]indol-3-carboxylates potently suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase. Here, we describe the discovery of benzo[g]indol-3-carboxylates as a novel class of potent mPGES-1 inhibitors (IC50 ≥ 0.1 μM). Ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 7a) inhibits human mPGES-1 in a cell-free assay (IC50 = 0.6 μM) as well as in intact A549 cells (IC50 = 2 μM), and suppressed PGE2 pleural levels in rat carrageenan-induced pleurisy. Inhibition of cellular COX-1/2 activity was significantly less pronounced. Compound 7a significantly reduced inflammatory reactions in the carrageenan-induced mouse paw edema and rat pleurisy. Together, based on the select and potent inhibition of mPGES-1 and 5-lipoxygenase, benzo[g]indol-3-carboxylates possess potential as novel anti-inflammatory drugs with a valuable pharmacological profile

SAR Studies on Curcumin's Pro-inflammatory Targets: Discovery of Prenylated Pyrazolocurcuminoids as Potent and Selective Novel Inhibitors of 5-Lipoxygenase.

The anticarcinogenic and anti-inflammatory properties of curcumin have been extensively investigated, identifying prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), key enzymes linking inflammation with cancer, as high affinity targets. A comparative structure-activity study revealed three modifications dissecting mPGES-1/5-LO inhibition, namely (i) truncation of the acidic, enolized dicarbonyl moiety and/or replacement by pyrazole, (ii) hydrogenation of the interaryl linker, and (iii) (dihydro)prenylation. The prenylated pyrazole analogue 11 selectively inhibited 5-LO, outperforming curcumin by a factor of up to 50, and impaired zymosan-induced mouse peritonitis along with reduced 5-LO product levels. Other pro-inflammatory targets of curcumin (i.e., mPGES-1, cyclooxygenases, 12/15-LOs, nuclear factor-κB, nuclear factor-erythroid 2-related factor-2, and signal transducer and activator of transcription 3) were hardly affected by 11. The strict structural requirements for mPGES-1 and 5-LO inhibition strongly suggest that specific interactions rather than redox or membrane effects underlie the inhibition of mPGES-1 and 5-LO by curcumin

Plectranthus zeylanicus: A rich source of secondary metabolites with antimicrobial, disinfectant and anti-inflammatory activities

Plectranthus zeylanicus Benth is used in Sri Lankan folk medicine as a remedy for inflammatory conditions and microbial infections. Our previous investigations revealed potent 5-lipoxygenase (5-LO) inhibitory activity in lipophilic extracts of this plant, supporting its anti-inflammatory potential. In-depth studies on the antimicrobial activity have not been conducted and the bioactive ingredients remained elusive. As a continuation of our previous work, the present investigation was undertaken to evaluate the antimicrobial activity of different extracts of P. zeylanicus and to isolate and characterize bioactive secondary metabolites. Different organic extracts of this plant were analyzed for their antibacterial activity, and the most active extract, i.e., dichloromethane extract, was subjected to bioactivity-guided fractionation, which led to the isolation of 7α-acetoxy-6β-hydroxyroyleanone. This compound displayed strong antibacterial activity against methicillin-resistant Staphylococcus aureus with a minimum inhibitory concentration of 62.5 µg/mL, and its disinfectant capacity was comparable to the potency of a commercial disinfectant. Moreover, 7α-acetoxy-6β-hydroxyroyleanone inhibits 5-LO with IC50 values of 1.3 and 5.1 µg/mL in cell-free and cell-based assays, respectively. These findings rationalize the ethnopharmacological use of P. zeylanicus as antimicrobial and anti-inflammatory remedy

Regeneration in starved planarians depends on TRiC/CCT subunits modulating the unfolded protein response

Planarians are able to stand long periods of starvation by maintaining adult stem cell pools and regenerative capacity. The molecular pathways that are needed for the maintenance of regeneration during starvation are not known. Here, we show that down‐regulation of chaperonin TRiC/CCT subunits abrogates the regeneration capacity of planarians during starvation, but TRiC/CCT subunits are dispensable for regeneration in fed planarians. Under starvation, they are required to maintain mitotic fidelity and for blastema formation. We show that TRiC subunits modulate the unfolded protein response (UPR) and are required to maintain ATP levels in starved planarians. Regenerative defects in starved CCT‐depleted planarians can be rescued by either chemical induction of mild endoplasmic reticulum stress, which leads to induction of the UPR, or by the supplementation of fatty acids. Together, these results indicate that CCT‐dependent UPR induction promotes regeneration of planarians under food restriction

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

Background: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). Patients and methods: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. Results: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. Conclusion: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trial

Machine intelligence decrypts β-lapachone as an allosteric 5-lipoxygenase inhibitor.

Using machine learning, targets were identified for β-lapachone. Resorting to biochemical assays, β-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of β-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies