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The AA-5-LOX-LTs pathway. The arachidonic acid (AA) produced by cPLA2 in the membranous fraction is presented by 5-lipoxygenase activating protein to 5-LOX and thus catalyzed into 5-HETE. 5-HETE is a very unstable compound, which may soon be degraded in the plasma, but normally it will soon be catalyzed by 5-LOX again to LTA4, and then further catalyzed into LTB4 or/and LTC4 depending on the types of the cells. What’s more, the AA produced by cPLA2 may also translocate to the nucleus to be catalyzed by the 5-LOX in the inner nuclear membrane
Source publication
Inflammation secondary to tissue injuries serves as a double-edged sword that determines the prognosis of tissue repair. As one of the most important enzymes controlling the inflammation process by producing leukotrienes, 5-lipoxygenase (5-LOX, also called 5-LO) has been one of the therapeutic targets in regulating inflammation for a long time. Alt...
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Purpose
This study aimed to evaluate the association between polymorphisms in the ferroptosis-related genes apolipoprotein E (APOE), BCL3 transcription coactivator (BCL3) and arachidonate 5-lipoxygenase activating protein (ALOX5AP) and the risk of thyroid cancer.
Methods
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Citations
... In vivo, AA primarily exists in the form of phospholipids on cell membranes, and its release occurs when stimulated by various phospholipases [47]. The lipoxygenase (LOX) catalyzes the formation of HETEs from AA. Inflammatory stimuli can significantly enhance LOX-5 activation, leading to a substantial increase in HETE levels [48]. Prostaglandin H2 and Prostaglandin F2a are members of the prostaglandin (PG) group, which participate in the regulation and control of numerous physiological processes and play a crucial role in the development of inflammation. ...
Purpose
The impact of dietary nutrients on body growth performance and the composition of gut microbes and metabolites is well-established. In this study, we aimed to determine whether dietary protein can regulate the physiological indexes and changes the intestinal tissue morphology in rats, and if dietary protein was a crucial regulatory factor for the composition, function, and metabolic pathways of the gut microbiota.
Method
A total of thirty male Sprague Dawley (SD) rats (inbred strain, weighted 110 ± 10 g) were randomly assigned to receive diets containing animal-based protein (whey protein, WP), plant-based protein (soybean protein, SP), or a blended protein (soybean-whey proteins, S-WP) for a duration of 8 weeks. To investigate the effects of various protein supplement sources on gut microbiota and metabolites, we performed a high throughput 16S rDNA sequencing association study and fecal metabolomics profiling on the SD rats. Additionally, we performed analyses of growth indexes, serum biochemical indexes, and intestinal morphology.
Results
The rats in S-WP and WP group exhibited a significantly higher body weight and digestibility of dietary protein compared to the SP group (P < 0.05). The serum total protein content of rats in the WP and S-WP groups was significantly higher (P < 0.05) than that in SP group, and the SP group exhibited significantly lower (P < 0.05) serum blood glucose levels compared to the other two groups. The morphological data showed the rats in the S-WP group exhibited significantly longer villus height and shallower crypt depth (P < 0.05) than the SP group. The gut microbial diversity of the SP and S-WP groups exhibited a higher level than that of the WP group, and the microbiomes of the WP and S-WP groups are more similar compared to those of the SP group. The Arachidonic acid metabolism pathway is the most significant KEGG pathway when comparing the WP group and the SP group, as well as when comparing the SP group and the S-WP group.
Conclusion
The type of dietary proteins exerted a significant impact on the physiological indices of SD rats. Intake of S-WP diet can enhance energy provision, improve the body’s digestion and absorption of nutrients, as well as promote intestinal tissue morphology. In addition, dietary protein plays a crucial role in modulating fecal metabolites by regulating the composition of the gut microbiota. Metabolomics analysis revealed that the changes in the levels of arachidonic acid metabolites and secondary bile acid metabolite induced by Clostridium_sensu_stricto_1 and [Eubacterium]_coprostanoligenes_group maybe the primarily causes of intestinal morphological differences.
... In particular, this amino acid residue could bind to selective inhibitors with selective groups (usually through the sulfone of sulfonamide groups). Figure 5A shows that 7f enters the COX-1 active pocket surrounded by Tyr355, Arg120, Ser530, and Tyr385 [28,46], and combines Arg120 with hydrogen bonds. In Fig. 5B, the combining product of COX-1 enzyme and compound 7f was not similar to that of co-crystallized IMM. ...
The arachidonic acid metabolizing enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) have been considered to be associated with the occurrence and development of a variety of diseases, including inflammatory. Compared to classical NSAIDs, the dual COX-2/5-LOX inhibition is an effective strategy for designing compounds with more effective biological activities, fewer side effects, and a broader anti-inflammatory spectrum. In this study, we designed and synthesized a series of novel indole and indazole arylamide benzoic acid analogues as dual COX-2 / 5-LOX inhibitors and evaluated their anti-inflammatory properties in vivo. Compounds 7f and 7n showed significant anti-inflammatory activity in a xylene-induced mouse model of auricular edema. Furthermore, 7f and 7n exhibited moderate COX-2 inhibitory activity (IC50 = 537 and 321.5 nM) than celecoxib (IC50 = 10.04 nM) in vitro, among which 7n had higher COX-2 selectivity activity (selectivity index (COX-1/COX-2) = 7.89) and moderate 5-LOX inhibitory activity (IC50 = 222.1 nM). Compared to zileuton (IC50 = 36.46 nM), compound 7f was identified as the most potent 5-LOX inhibitor (IC50 = 77.37 nM). According to the biological results, compounds 7f and 7n have better inhibitory activities on the production of NO and PGE2 in LPS-induced RAW 264.7 cell macrophages than celecoxib and indomethacin. As demonstrated by docking studies, 7f and 7n have stronger interactions with key residues in the active pocket of COX-1 or COX-2, which is consistent with the activity results. Based on these results, further research into safer and more effective anti-inflammatory drugs might be possible using indole arylamide benzoic acid analogs.
Graphical abstract
... Since Alox12 expression was unaltered, its posttranscriptional modification could be involved. Among lipoxygenase family members, Alox5 is phosphorylated to be translocated to the nuclear membrane for its enzymatic function 41 . Alox12 phosphorylation was also reported although its role in regulating the enzymatic function remains to be elucidated 42,43 . ...
Severe and prolonged social stress induces mood and cognitive dysfunctions and precipitates major depression. Neuroinflammation has been associated with chronic stress and depression. Rodent studies showed crucial roles of a few inflammation-related lipid mediators for chronic stress-induced depressive-like behaviors. Despite an increasing number of lipid mediators identified, systematic analyses of synthetic pathways of lipid mediators in chronic stress models have not been performed. Using LC–MS/MS, here we examined the effects of chronic social defeat stress on multiple synthetic pathways of lipid mediators in brain regions associated with stress susceptibility in mice. Chronic social defeat stress increased the amounts of 12-lipoxygenase (LOX) metabolites, 12-HETE and 12-HEPE, specifically in the nucleus accumbens 1 week, but not immediately, after the last stress exposure. The increase was larger in stress-resilient mice than stress-susceptible mice. The S isomer of 12-HETE was selectively increased in amount, indicating the role of 12S-LOX activity. Among the enzymes known to have 12S-LOX activity, only Alox12 mRNA was reliably detected in the brain and enriched in brain endothelial cells. These findings suggest that chronic social stress induces a late increase in the amounts of 12S-LOX metabolites derived from the brain vasculature in the nucleus accumbens in a manner associated with stress resilience.
... This 15 epi-RvE4 could also be biosynthesized following acetylation of COX-2 by acetyl-CoA and sphingosine via sphingosine kinase 1 (SphK1) [94] and/or modified possibly by S-nitrosylation of COX-2 [95]. Since 5-LOX has been shown to be phosphorylated to produce 15R-HETE and further converted to 15R-lipoxin A 4 (LXA 4 ) [96][97][98], it is likely that, with EPA as a carbon 20:5 substrate like C20:4 arachidonate, phosphorylated 5-LOX can produce 15R-HEPE that can be subsequently converted to the novel 15R-RvE4 structure. Along these lines, RvE4 can be biosynthesized from EPA via several separate biosynthetic routes and can now be included in the E-series of pro-resolving mediators; see Table 2. ...
The COVID-19 pandemic has raised international awareness of the importance of rigorous scientific evidence and the havoc caused by uncontrolled excessive inflammation. Here we consider the evidence on whether the specialized pro-resolving mediators (SPMs) are ready to meet this challenge as well as targeted metabololipidomics of the resolution-inflammation metabolomes. Specific stereochemical mechanisms in the biosynthesis of SPMs from omega-3 essential fatty acids give rise to unique local-acting lipid mediators. SPMs possess stereochemically defined potent bioactive structures that are high-affinity ligands for cognate G protein-coupled surface receptors that evoke the cellular responses required for efficient resolution of acute inflammation. The SPMs biosynthesized from the major omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are coined Resolvins (resolution phase interaction products; E series and D-series), Protectins and Maresins (macrophage mediators in resolving inflammation). Their biosynthesis and stereochemical assignments are established and confirmed (>1,441 resolvin publications in PubMed.gov) as well as their functional roles on innate immune cells and adaptive immune cells (both lymphocyte T-cell subsets and B-cells). The resolution of a protective acute inflammatory response is governed mainly by phagocytes that actively clear apoptotic cells, debris, blood clots and pathogens. These resolution phase functions of the acute inflammatory response are enhanced by SPMs, which together prepare the inflammatory loci for homeostasis and stimulate tissue regeneration via activating stem cells and the biosynthesis of novel cys-SPMs (e.g. MCTRs, PCTRs and RCTRs). These cys-SPMs also activate regeneration, are organ protective and stimulate resolution of local inflammation. Herein, we review the biosynthesis and functions of the E-series resolvins, namely resolvin E1 (the first n-3 resolvin identified), resolvin E2, resolvin E3 and resolvin E4 biosynthesized from their precursor eicosapentaenoic acid (EPA), and the critical role of total organic synthesis in confirming SPM complete stereochemistry, establishing their potent functions in resolution of inflammation, and novel structures. The physical properties of each biologically derived SPM, i.e., ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS²) fragmentation, were matched to SPMs biosynthesized and prepared by stereospecific total organic synthesis. We briefly review this approach, also used with the endogenous D-series resolvins, protectins and maresins confirming their potent functions in resolution of inflammation, that paves the way for their rigorous evaluation in human tissues and clinical trials. The assignment of complete stereochemistry for each of the E and D series Resolvins, Protectins and Maresins was a critical and required step that enabled human clinical studies as in SPM profiling in COVID-19 infections and experimental animal disease models that also opened the promise of resolution physiology, resolution pharmacology and targeted precision nutrition as new areas for monitoring health and disease mechanisms.
... Human 5-LOX comprises two domains, an N-terminal regulatory C2like domain (residues 1-112) which consists of two antiparallel β-sheets and C-terminal catalytic domain (residues 126-673) which is made up of predominant α-helices and ferrous ion located inside. Non-heme ferrous ion, essential for 5-LOX catalytic ability, is held inside by three conserved histidine residues (His367, His372, His550) and one carboxylate group of the C-terminal Ile673 ( Figure 2) [14]. ...
... This 15R-RvE4 could be biosynthesized either from the acetylation of COX-2 by acetyl-CoA and sphingosine via sphingosine kinase 1 (SphK1) (32) or modified by S-nitrosylation by inducible nitric oxide synthase (33). Also, since 5-LOX can be phosphorylated to produce 15R-HETE and further converted to 15R-lipoxin A 4 (LXA 4 ) (34)(35)(36), it is likely that with EPA as a substitute phosphorylated 5-LOX can produce 15R-HEPE and subsequently be converted to 15R-RvE4.Therefore RvE4 can be biosynthesized from EPA potentially via multiple biosynthetic routes and now can be included in the E-series of proresolving mediators; see Table 1. The 15-LOX initiated route of RvE4 biosynthesis simplifies the production and biosynthesis of this mediator that can occur in the absence of enzyme modification (i.e. ...
The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS²) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.
We previously reported that the soy isoflavone daidzein (Dz) suppresses the intracellular replication of influenza virus and that arachidonic acid-derived oxidation product via lipid oxidase 5-lipoxygenase (5-LOX) is involved in its anti-viral effect. The activation of 5-LOX by Dz triggers anti-influenza activity; however, the mechanism of activation of 5-LOX remains unclear. Therefore, in this study, we aimed to clarify the activation mechanism using human monocyte-derived THP-1 cells differentiated using phorbol 12-myristate 13-acetate. THP-1 cells expressed 5-LOX endogenously and Dz did not induce 5-LOX expression. However, 8 h after treatment with Dz, the amount of 5-hydroxyeicosatetraenoic acid (5-HETE), an arachidonic acid oxidation product via 5-LOX, increased significantly suggesting that the enzyme is activated regardless of changes in 5-LOX protein levels. Intracellular Ca2+ content, ATP concentration, 5-LOX protein phosphorylation, and 5-LOX intracellular localization are known 5-LOX activation factors. The intracellular Ca2+ and ATP concentrations were not affected by Dz treatment. The enzymatic activity of 5-LOX is regulated by the phosphorylation of three serine residues and four tyrosine residues. Pre-treatment with inhibitors of each kinase revealed that Dz-induced 5-HETE production was suppressed by the MEK/ERK inhibitor. 5-LOX in which the Ser663 residue was phosphorylated was found to be increased in the nuclear fraction of Dz-treated THP-1 cells. Furthermore, immunocytochemistry showed that 5-LOX translocates to the nuclear envelope following Dz treatment. These results indicate that Dz activates 5-LOX by phosphorylating Ser663 via the MEK/ERK pathway. Thus, these results demonstrate that Dz exerts anti-influenza virus activity via the MEK/ERK signal transduction pathway.
Nine new cadinane-type sesquiterpenoids (1-9) and three new eucalyptane -type sesquiterpenes (10-12) were isolated from the ethyl acetate extract of Burdock leaves, which were commonly used for preventing or treating atherosclerosis in China. Their structures were confirmed by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis and ECD calculations. Compound 1 possessed the rare large conjugated skeleton. All the isolates were evaluated for anti-inflammatory and cholesterol-lowering activities by the LPS- and oxidized-low-density-lipoprotein-stimulated RAW 264.7 cells, respectively. As the results, all isolates could decrease the productions of NO, and down-regulate the accumulation of cholesterol. Among them, 4 showed the most potent cholesterol-lowering effect. For the high content of 4 in the herb, mechanistic study of 4 was performed and the results showed that 4 markedly reduced the release of pro-inflammatory mediators which was probably associated with inhibition of the PI3K/Akt and 5-LOX signaling pathways. The findings of this study demonstrated the anti-inflammatory/cholesterol-lowering effects of the new sesquiterpenes from burdock leaves, which provides chemical basis and scientific evidence for the herb used as anti-atherosclerosis agents for the further study. The sesquiterpene lactones of burdock leaves are expected to become new small molecule inhibitors for the treatment of AS.
This study aims to evaluate the clinical efficacy of curcumin versus chlorhexidine as adjuncts to scaling and root planing (SRP) for periodontitis treatment. We searched PubMed, EMbase, Cochrane Library, and ClinicalTrials.gov from inception to February 18, 2021 and identified studies with relevant randomized controlled trials (RCTs) using curcumin or chlorhexidine as an adjunct to SRP. Nine RCTs involving 420 patients/sites were included. A meta‐analysis with a random‐effects model revealed that curcumin and chlorhexidine, as an adjunct to SRP, reduced probing pocket depth (PPD) at similar levels during a 3‐, 4‐, 6‐, and 12‐week follow‐up. No significant differences were observed in reducing clinical attachment loss (CAL) between curcumin and chlorhexidine as an adjunct to SRP at 4 weeks and 6 weeks. Furthermore, gingival index (GI) and plaque index (PI) were similar using curcumin versus chlorhexidine as an adjunct to SRP at the 4‐week‐, 6‐week‐, and 12‐week follow‐up. Based on the available evidence in RCTs, compared with chlorhexidine as an adjunct to SRP, curcumin has a similar effect on reducing PPD, CAL, GI, and PI. The quality of evidence is low, limited by the number of studies and their limitations. Further studies are needed to firmly establish the clinical efficacy of curcumin.
