Inhibition of 5‐Lipoxygenase‐Derived Leukotrienes and Hemiketals as a Novel Anti‐Inflammatory Mechanism of Urolithins

Giménez‐Bastida, Juan Antonio; González‐Sarrías, Antonio; Espı́n, Juan Carlos; Schneider, Claus

doi:10.1002/mnfr.202000129

Cited by 18 publications

(9 citation statements)

References 54 publications

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“…Recent studies on human primary leukocytes have shown that UA and iUA are potent to reduce the formation of the 5-LOX/COX-2 pathway products (HKE 2 and HKD 2 ) through the attenuation of COX-2 and PGE2, while urolithin C was shown to reduce 5-HETE and LTB4 via inhibition of 5-LOX. The respective glucuronide and sulfate conjugates of UA and iUA were inactive [44]. In the present study no activity towards the production of pro-and anti-inflammatory cytokines was observed for phase II conjugates of urolithins.…”

Section: Discussioncontrasting

confidence: 76%

Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

et al. 2020

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Purpose Ellagitannins are high molecular weight polyphenols present in high quantities in various food products. They are metabolized by human and animal gut microbiota to postbiotic metabolites-urolithins, bioavailable molecules of a low molecular weight. Following absorption in the gut, urolithins rapidly undergo phase II metabolism. Thus, to fully evaluate the mechanisms of their biological activity, the in vitro studies should be conducted for their phase II conjugates, mainly glucuronides. The aim of the study was to comparatively determine the influence of urolithin A, iso-urolithin A, and urolithin B together with their respective glucuronides on processes associated with the inflammatory response. Methods The urolithins obtained by chemical synthesis or isolation from microbiota cultures were tested with their respective glucuronides isolated from human urine towards modulation of inflammatory response in THP-1-derived macrophages, RAW 264.7 macrophages, PBMCs-derived macrophages, and primary neutrophils. Results Urolithin A was confirmed to be the most active metabolite in terms of LPS-induced inflammatory response inhibition (TNF-α attenuation, IL-10 induction). The observed strong induction of ERK1/2 phosphorylation has been postulated as the mechanism of its action. None of the tested glucuronide conjugates was active in terms of pro-inflammatory TNF-α inhibition and anti-inflammatory IL-10 and TGF-β1 induction. Conclusion Comparative studies of the most abundant urolithins and their phase II conjugates conducted on human and murine immune cells unambiguously confirmed urolithin A to be the most active metabolite in terms of inhibition of the inflammatory response. Phase II metabolism was shown to result in the loss of urolithins’ pharmacological properties.

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Section: Discussioncontrasting

confidence: 76%

Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

et al. 2020

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“…New in vitro studies using a range of relevant cell lines (with different features) and correctly designed [ 52 ] will be essential to enlarge our knowledge about further mechanisms of action. Based on the reported effects of caffeic acid on the well-defined 5-lypoxygenase (5-LOX) [ 53 ] and COX-2 (see above) pathways, an interesting approach could be the study of its effects on the formation of the more recently described 5-LOX/COX-2 hemiketal (HK) eicosanoids, HKE 2 and HKD 2 [ 54 , 55 , 56 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

et al. 2021

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Caffeic acid is one of the most abundant hydroxycinnamic acids in fruits, vegetables, and beverages. This phenolic compound reaches relevant concentrations in the colon (up to 126 µM) where it could come into contact with the intestinal cells and exert its anti-inflammatory effects. The aim of this investigation was to study the capacity of caffeic acid, at plausible concentrations from an in vivo point of view, to modulate mechanisms related to intestinal inflammation. Consequently, we tested the effects of caffeic acid (50–10 µM) on cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2, cytokines, and chemokines (IL-8, monocyte chemoattractant protein-1 -MCP-1-, and IL-6) biosynthesis in IL-1β-treated human myofibroblasts of the colon, CCD-18Co. Furthermore, the capacity of caffeic acid to inhibit the angiotensin-converting enzyme (ACE) activity, to hinder advanced glycation end product (AGE) formation, as well as its antioxidant, reducing, and chelating activity were also investigated. Our results showed that (i) caffeic acid targets COX-2 and its product PGE2 as well as the biosynthesis of IL-8 in the IL-1β-treated cells and (ii) inhibits AGE formation, which could be related to (iii) the high chelating activity exerted. Low anti-ACE, antioxidant, and reducing capacity of caffeic acid was also observed. These effects of caffeic acid expands our knowledge on anti-inflammatory mechanisms against intestinal inflammation.

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“…However, according to our analysis, only two studies have approached the effect of conjugated metabolites on 5-LOX and COX-2 using leukocytes ( Table S1 ). Among the conjugated metabolites tested, 3′- O -methyl-quercetin reduced the biosynthesis of LTB 4 (at 2 μM) and PGE 2 (IC 50 = 2 μM) [ 154 ], whereas the phase II conjugated urolithins (ellagic acid-derived metabolites) were inactive against 5-LOX, COX-2, and the 5-LOX/COX-2 crossover pathways [ 155 ]. Under the same conditions, their free forms (quercetin, Uro-A, IsoUro-A, and Uro-C) effectively decreased 5-HETE, LTB 4 , PGE 2 , HKE 2 , and HKD 2 levels in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…To date, no studies describe the in vitro effect of phenolic compounds or derived metabolites on lipoxin biosynthesis. Only two studies have investigated the effect of phenolics on the 5-LOX/COX-2 crossover pathway and found that curcumin and urolithins (Uro-A, IsoUro-A, and Uro-C) showed the capacity to inhibit HKE 2 and HKD 2 formation in a mixture of stimulated leukocytes [ 47 , 155 ]. This limited evidence underscores the need for future studies on the biosynthesis of complex 5-LOX dependent eicosanoids using isolated cell preparation or co-incubations (i.e., platelets with neutrophils) in the presence of phenolic compounds.…”

Section: Resultsmentioning

confidence: 99%

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

Giménez‐Bastida

González‐Sarrías

Llopis

et al. 2021

IJMS

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5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.

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Inhibition of 5‐Lipoxygenase‐Derived Leukotrienes and Hemiketals as a Novel Anti‐Inflammatory Mechanism of Urolithins

Cited by 18 publications

References 54 publications

Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

Comparative studies of urolithins and their phase II metabolites on macrophage and neutrophil functions

Caffeic Acid Modulates Processes Associated with Intestinal Inflammation

Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review

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