184 Paf Acetylhydrolase and Arachidonic Acid Metabolite Levels in Patients With Sepsis

Takakuwa, T; Endo, S; Kasai,; Inada, Kazunori; Nakae, Hajime; Kikuchi, M; Suzuki, Takahiro; Taniguchi, Shuichi

doi:10.1097/00024382-199505000-00185

Cited by 4 publications

(7 citation statements)

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“…Thus, inhibition of COX-2 and LOX-5 appears to be responsible for the decreased biosynthesis of pro-inflammatory PGs and LTB4. Septic patients and animals treated with LPS have increased expression of pro-inflammatory cytokines and PGI2 synthase [54]. Since, PGI2 once formed rapidly gets converted into 6-ketoPGF1, and is involved in vasodilation resulting in reduced blood pressure, and can ultimately lead to sepsis [55].…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages

Mohammed

Ramana

2012

Free Radical Biology and Medicine

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Benfotiamine, a lipid-soluble analogue of vitamin B1, is a potent anti-oxidant that is used as a food supplement for the treatment of diabetic complications. Our recent study indicates a novel role of benfotiamine in the prevention of bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in murine macrophages. Nevertheless, it remains unclear how benfotiamine mediates anti-inflammatory effects. In this study, we investigated the anti-inflammatory role of benfotiamine in regulating the arachidonic acid (AA) pathway generated inflammatory lipid mediators in RAW 264.7 macrophages. Benfotiamine prevented the LPS-induced activation of cPLA2 and release of AA metabolites such as leukotrienes (LTB4), prostaglandin E2 (PGE2), thromboxanes 2 (TXB2) and prostacyclin (PGI2) in macrophages. Further, LPS-induced expressions of AA metabolizing enzymes such as COX-2, LOX-5, TXB synthase and PGI2 synthase were significantly blocked by benfotiamine. Furthermore, benfotiamine prevented the LPS-induced phosphorylation of ERK1/2 and expression of transcription factors NF-kB, and Egr-1. Benfotiamine also prevented the LPS-induced oxidative stress and protein-HNE adducts formation. Most importantly, as compared to specific COX-2 and LOX-5 inhibitors, benfotiamine significantly prevented the LPS-induced macrophage death and monocytes adhesion to endothelial cells. Thus, our studies indicate that the dual regulation of COX and LOX pathways in AA metabolism could be a novel mechanism by which benfotiamine exhibits its potential anti-inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages

Mohammed

Ramana

2012

Free Radical Biology and Medicine

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“…Further, COX and LOX enzymes metabolize AA into PGE 2 , TXB and LTB4, major inflammatory lipid mediators. As the pre-eminent AA metabolite, PGE 2 is implicated in various inflammatory diseases such as sepsis [36], allodynia [37] and fever [38]. Therefore, regulation of PGE 2 and other AA metabolites by inhibiting or decreasing the expression of AA metablic enzymes such as PLA 2 , COX-2 could be an effective mechanism for the prevention of inflammation and related pathologies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of sPLA2-IIA Prevents LPS-Induced Neuroinflammation by Suppressing ERK1/2-cPLA2α Pathway in Mice Cerebral Cortex

et al. 2013

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Neuroinflammation is involved in various central nervous system (CNS) disorders, including brain infections, ischemia, trauma, stroke, and degenerative CNS diseases. In the CNS inflammation, secretory phospholipase A2-IIA (sPLA2-IIA) acts as a mediator, resulting in the generation of the precursors of pro-inflammatory lipid mediators, such as prostaglandins (PGs) and leukotrienes (LTs). However, the role of sPLA2-IIA in neuroinflammation is more complicated and remains unclear yet. In the present study, we investigated the effect of sPLA2-IIA inhibition by specific inhibitor SC-215 on the inflammation in LPS-induced mice cerebral cortex and primary astrocytes. Our results showed that the inhibition of sPLA2-IIA alleviated the release of PGE2 by suppressing the activation of ERK1/2, cPLA2α, COX-2 and mPGES-1. These findings demonstrated that sPLA2-IIA showed the potential to regulate the neuroinflammation in vivo and in vitro, indicating that sPLA2-IIA might be a novel target for the treatment of acute neuroinflammation.

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“…Further, COX and LOX enzymes metabolize AA into PGE2, TXB and LTB4, major inflammatory lipid mediators. The products of AA metabolism are implicated in various inflammatory diseases such as sepsis [25] and endotoxemia. Therefore, regulation of AA metabolism by inhibiting or decreasing the expression of key AA metabolic enzymes such as cPLA2, COX-2 and LOX-5 could be an effective mechanism for the prevention of inflammation and related pathologies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

Mohammed

Yadav

Srivastava

et al. 2011

Free Radical Biology and Medicine

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Bacterial endotoxin, lipopolysaccharide (LPS) is known to induce release of arachidonic acid (AA) and its metabolic products which play important role in inflammatory process. We have shown earlier that LPS-induced signals in macrophages are mediated by aldose reductase (AR). Here we have investigated the role of AR in LPS-induced release of AA metabolites and their modulation using a potent pharmacological inhibitor fidarestat and AR-siRNA ablation in RAW 264.7 macrophages, and AR-knockout mice peritoneal macrophages and heart tissue. Inhibition or genetic ablation of AR prevented the LPS-induced synthesis and release of AA metabolites such as PGE2, TXB, PGI2 and LTBs in macrophages. LPS-induced activation of cPLA2 was also prevented by AR inhibition. Similarly, AR inhibition also prevented the calcium ionophore A23187 –induced cPLA2 and LTB4 in macrophages. Further, AR inhibition with fidarestat prevented the expression of AA metabolizing enzymes such as COX-2 and LOX-5 in RAW 264.7 cells and AR-knockout mice derived peritoneal macrophages. LPS-induced expression of AA metabolizing enzymes and their catalyzed metabolic products were significantly lower in peritoneal macrophages and heart tissue from AR-knockout mice. LPS-induced activation of redox-sensitive signaling intermediates such as MAPKs, transcription factor NF-kB as well as Egr-1, a transcription regulator of mPGES-1, which in collaboration with COX-2 leads to the production of PGE2, were also significantly prevented by AR inhibition. Taken together, our results indicate that AR mediates LPS-induced inflammation by regulating AA metabolic pathway and thus provide novel role of AR inhibition in preventing inflammatory complications such as sepsis.

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184 Paf Acetylhydrolase and Arachidonic Acid Metabolite Levels in Patients With Sepsis

Cited by 4 publications

References 0 publications

Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages

Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages

Inhibition of sPLA2-IIA Prevents LPS-Induced Neuroinflammation by Suppressing ERK1/2-cPLA2α Pathway in Mice Cerebral Cortex

Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages

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