The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) ...are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4-8 hrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE
than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response.
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that ...long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13'-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
(Fisch.) Bunge root is used as herbal medicine for its immunomodulating activities in Chinese medicine. Recently, beneficial properties of
on allergic diseases have been proposed. Here we ...investigated the role of a commercial extract of
, standardized to 16% polysaccharides, in regulating the immune-inflammatory response in vitro and in vivo and its therapeutic application in asthma.
extract inhibited prostaglandin E
and leukotriene C
production in stimulated J774 and peritoneal macrophages, respectively. The extract also reduced interlukin-1β, tumor necrosis factor-α, and nitrite production, affecting inducible nitric oxide synthase expression. In vivo experiments confirmed the anti-inflammatory properties of
, as evident by a reduction in zymosan-induced peritoneal cellular infiltration and pro-inflammatory mediator production. The efficacy of
extract in modulating the immune response was confirmed in a model of allergic airway inflammation. Extracts improve lung function by inhibiting airway hyperresponsiveness, airway remodeling, and fibrosis. Its anti-asthmatic effects were further sustained by inhibition of the sensitization process, as indicated by a reduction of ovalbumin-induced IgE levels and the mounting of a Th2 immune response. In conclusion, our data demonstrate the anti-inflammatory properties of the commercial extract of
and its beneficial effects on asthma feature development.
Alternative (M2)-polarized macrophages possess high capacities to produce specialized proresolving mediators (SPM; i.e., resolvins, protectins, and maresins) that play key roles in resolution of ...inflammation and tissue regeneration. Vacuolar (H
)-ATPase (V-ATPase) is fundamental in inflammatory cytokine trafficking and secretion and was implicated in macrophage polarization toward the M2 phenotype, but its role in SPM production and lipid mediator biosynthesis in general is elusive. In this study, we show that V-ATPase activity is required for the induction of SPM-biosynthetic pathways in human M2-like monocyte-derived macrophages (MDM) and consequently for resolution of inflammation. Blockade of V-ATPase by archazolid during IL-4-induced human M2 polarization abrogated 15-lipoxygenase-1 expression and prevented the related biosynthesis of SPM in response to pathogenic
, assessed by targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics. In classically activated proinflammatory M1-like MDM, however, the biosynthetic machinery for lipid mediator formation was independent of V-ATPase activity. Targeting V-ATPase in M2 influenced neither IL-4-triggered JAK/STAT6 nor the mTOR complex 1 signaling but strongly suppressed the ERK-1/2 pathway. Accordingly, the ERK-1/2 pathway contributes to 15-lipoxygenase-1 expression and SPM formation in M2-like MDM. Targeting V-ATPase in vivo delayed resolution of zymosan-induced murine peritonitis accompanied by decreased SPM levels without affecting proinflammatory leukotrienes or PGs. Together, our data propose that V-ATPase regulates 15-lipoxygenase-1 expression and consequent SPM biosynthesis involving ERK-1/2 during M2 polarization, implying a crucial role for V-ATPase in the resolution of inflammation.
Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have ...evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13′-carboxychromanol (α-T-13′-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA). We also have taken advantage of the metabolically stable α-T-13′-COOH derivative α-amplexichromanol (α-AC). Intraperitoneal treatment with α-T-13'-COOH reduced OVA-induced airway hyperreactivity (AHR) as well as peri-bronchial inflammatory cell infiltration. α-AC was more efficacious than α-T-13'-COOH, as demonstrated by better control of AHR and in reducing subepithelial. Both compounds exerted their protective function by reducing pulmonary leukotriene C4 levels. Beneficial effects of α-AC were coupled to inhibition of the sensitization process, as indicated by a reduction of IgE plasma levels, lung mast cell infiltration and Th2 immune response. Metabololipidomics analysis revealed that α-AC raises the pulmonary levels of prostanoids, their degradation products, and 12/15-lipoxygenase metabolites. Following oral administration, the pharmacodynamically different profile in α-T-13′-COOH and α-AC was abrogated as demonstrated by a similar and improved efficacy in controlling asthma features as well as by metabololipidomics analysis. In conclusion, this study highlights a role for LCM and of vitamin E derivatives as pharmacologically active compounds that ameliorate asthmatic features and defines an important role for endogenous vitamin E metabolites in regulating immune response underlying the sensitization process.
Display omitted
•Vitamin E long-chain metabolites relieve allergen-induced bronchial hyperreactivity.•Vitamin E long-chain metabolites inhibit Th2 immune response induced by allergen.•Vitamin E long-chain metabolites modulate anti- and pro-inflammatory lipid mediators
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.
L. is a highly consumed garden crop rich in biologically active phenolic and organosulfur compounds. This study aimed to assess the
bioaccessibility and anti-inflammatory effect of a chemically ...characterized
extract rich in quercetin and its derivatives. Different varieties of
were studied; based on the highest total phenolic content, the "Golden" variety was selected. Its extracts, obtained from the tunicate bulb, tunic, and bulb, were subjected to determination of quercetin and its derivatives with LC-MS analysis and based on the highest total quercetin content, the tunic extract was utilized for further experiments. The extraction method was optimized through a design of experiment (DoE) method via full factorial design, which showed that 40% ethanol and 1 g tunic/20 mL solvent are the best extraction conditions. HPLC analysis of the optimized tunic extract identified 14 flavonols, including 10 quercetin derivatives. As far as
bioaccessibility was concerned, the increases in some quercetin derivatives following the gastro-duodenal digestion process support the bioaccessibility of these bioactive compounds. Moreover, the extract significantly inhibited the production of PGE2 in stimulated J774 cell lines, while no effects of the tunic extract were observed against the release of IL-1β, TNF-α, and nitrites. The study provided insights into the optimized extraction conditions to obtain an
tunic extract rich in bioavailable quercetin derivatives with significant anti-inflammatory effects against PGE2.
5-Lipoxygenase initiates the biosynthesis of leukotrienes, lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Despite an obvious gender bias in ...leukotriene-related diseases (e.g., asthma), gender aspects have been neglected in studies on leukotrienes and 5-lipoxygenase. Here, we show that leukotriene formation in stimulated whole blood or neutrophils from males is substantially lower compared with females, accompanied by changed 5-lipoxygenase trafficking. This is due to gender-specific differential activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to variant male/female testosterone plus 5α-dihydrotestosterone levels, and addition of 5α-dihydrotestosterone to female blood or neutrophils reduced the high (female) LT biosynthesis capacity to low (male) levels. In conclusion, regulation of ERKs and leukotriene formation by androgens constitutes a molecular basis for gender differences in the inflammatory response, and in inflammatory diseases such as asthma.
There is evidence that an imbalance of extracellular purine levels may be associated with increased cardiovascular risk. Platelets play a pivotal role in vascular homeostasis and thrombosis and are ...important source of purine nucleotides and nucleosides. Hydrolysis of nucleotides ATP and ADP is regulated by two ectonucleotidases, triphosphate diphosphohydrolase-1 (NTPDase-1/CD39) and ecto-5'-nucleotidase (ecto-5'-NT/CD73). CD39 enzyme is expressed on the endothelium, circulating blood cells, and smooth muscle cells; there is evidence that changes in CD39 expression and activity affects the potential thrombogenic of a tissue. Gender difference in the cardiovascular risk has been extensively observed; however, while the age-dependent difference in the prevalence of cardiovascular events between men and women has been attributed to the loss of the protective effect of estrogens in the postmenopausal period, the physiological mechanism behind gender disparity is still unclear. Here, we evaluated comparatively male and female rat platelet reactivity and considered the possible role of CD39 at the basis of difference observed. We found a reduced
response to ADP (1-30 µM) of female compared to male platelets, associated to increased platelet CD39 expression and activity. Platelet response to ADP was strongly increased by incubation (10 min) with the CD39 inhibitor, ARL67156 (100 µM), while male platelet response was unaffected. Rat treatment with clopidogrel (30 mg/kg,
) inhibited ex vivo platelet aggregation. Bleeding time was prolonged in female compared to male. Taken together, our results suggest that platelet ATPase and ADPase activity might be a reliable predictor of platelet reactivity.
PDF
