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Seminars in Immunology Oct 2013Bioactive lipid mediators play crucial roles in promoting the induction and resolution of inflammation. Eicosanoids and other related unsaturated fatty acids have long... (Review)
Review
Bioactive lipid mediators play crucial roles in promoting the induction and resolution of inflammation. Eicosanoids and other related unsaturated fatty acids have long been known to induce inflammation. These signaling molecules can modulate the circulatory system and stimulate immune cell infiltration into the site of infection. Recently, DHA- and EPA-derived metabolites have been discovered to promote the resolution of inflammation, an active process. Not only do these molecules stop the further infiltration of immune cells, they prompt non-phlogistic phagocytosis of apoptotic neutrophils, stimulating the tissue to return to homeostasis. After the rapid release of lipid precursors from the plasma membrane upon stimulation, families of enzymes in a complex network metabolize them to produce a large array of lipid metabolites. With current advances in mass spectrometry, the entire lipidome can be accurately quantified to assess the immune response upon microbial infection. In this review, we discuss the various lipid metabolism pathways in the context of the immune response to microbial pathogens, as well as their complex network interactions. With the advancement of mass spectrometry, these approaches have also been used to characterize the lipid mediator response of macrophages and neutrophils upon immune stimulation in vitro. Lastly, we describe the recent efforts to apply systems biology approaches to dissect the role of lipid mediators during bacterial and viral infections in vivo.
Topics: Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Homeostasis; Humans; Infections; Lipid Metabolism; Macrophages; Mass Spectrometry; Neutrophils; Systems Biology
PubMed: 24084369
DOI: 10.1016/j.smim.2013.08.006 -
BMC Gastroenterology May 2022Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis. Intrahepatic bile duct stone (IBDS) is one of the key...
BACKGROUND
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy with poor prognosis. Intrahepatic bile duct stone (IBDS) is one of the key causes to ICC occurrence and can increase morbidity rate of ICC about forty times. However, the specific carcinogenesis of IBDS is still far from clarified. Insight into the metabolic phenotype difference between IBDS and ICC can provide potential mechanisms and therapeutic targets, which is expected to inhibit the carcinogenesis of IBDS and improve the prognosis of ICC.
METHODS
A total of 34 participants including 25 ICC patients and 9 IBDS patients were recruited. Baseline information inclusive of liver function indicators, tumor biomarkers, surgery condition and constitution parameters etc. from patients were recorded. ICC and IBDS pathological tissues, as well as ICC para-carcinoma tissues, were collected for GC-MS based metabolomics experiments. Multivariate analysis was performed to find differentially expressed metabolites and differentially enriched metabolic pathways. Spearman correlation analysis was then used to construct correlation network between key metabolite and baseline information of patients.
RESULTS
The IBDS tissue and para-carcinoma tissue have blurred metabolic phenotypic differences, but both of them essentially distinguished from carcinoma tissue of ICC. Metabolic differences between IBDS and ICC were enriched in linoleic acid metabolism pathway, and the level of 9,12-octadecadienoic acid in IBDS tissues was almost two times higher than in ICC pathological tissues. The correlation between 9,12-octadecadienoic acid level and baseline information of patients demonstrated that 9,12-octadecadienoic acid level in pathological tissue was negative correlation with gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) level in peripheral blood. These two indicators were all cancerization marker for hepatic carcinoma and disease characteristic of IBDS.
CONCLUSION
Long-term monitoring of metabolites from linoleic acid metabolism pathway and protein indicators of liver function in IBDS patients has important guiding significance for the monitoring of IBDS carcinogenesis. Meanwhile, further insight into the causal relationship between linoleic acid pathway disturbance and changes in liver function can provide important therapeutic targets for both IBDS and ICC.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Cholangiocarcinoma; Humans; Linoleic Acid
PubMed: 35637430
DOI: 10.1186/s12876-022-02354-2 -
Frontiers in Immunology 2024Various gut bacteria, including , possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from...
The gut lactic acid bacteria metabolite, 10-oxo--6,-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling.
Various gut bacteria, including , possess several enzymes that produce hydroxy fatty acids (FAs), oxo FAs, conjugated FAs, and partially saturated FAs from polyunsaturated FAs as secondary metabolites. Among these derivatives, we identified 10-oxo--6,-11-octadecadienoic acid (γKetoC), a γ-linolenic acid (GLA)-derived enon FA, as the most effective immunomodulator, which inhibited the antigen-induced immunoactivation and LPS-induced production of inflammatory cytokines. The treatment with γKetoC significantly suppressed proliferation of CD4 T cells, LPS-induced activation of bone marrow-derived dendritic cells (BMDCs), and LPS-induced IL-6 release from peritoneal cells, splenocytes, and CD11c cells isolated from the spleen. γKetoC also inhibited the release of inflammatory cytokines from BMDCs stimulated with poly-I:C, R-848, or CpG. Further experiments using an agonist of GPR40/120 suggested the involvement of these GPCRs in the effects of γKetoC on DCs. We also found that γKetoC stimulated the NRF2 pathway in DCs, and the suppressive effects of γKetoC and agonist of GPR40/120 on the release of IL-6 and IL-12 were reduced in BMDCs. We evaluated the role of NRF2 in the anti-inflammatory effects of γKetoC in a dextran sodium sulfate-induced colitis model. The oral administration of γKetoC significantly reduced body weight loss, improved stool scores, and attenuated atrophy of the colon, in wild-type C57BL/6 and mice with colitis. In contrast, the pathology of colitis was deteriorated in mice even with the administration of γKetoC. Collectively, the present results demonstrated the involvement of the NRF2 pathway and GPCRs in γKetoC-mediated anti-inflammatory responses.
Topics: Animals; NF-E2-Related Factor 2; Mice; Receptors, G-Protein-Coupled; Signal Transduction; Gastrointestinal Microbiome; Mice, Inbred C57BL; Inflammatory Bowel Diseases; Mice, Knockout; Cytokines; Disease Models, Animal; Dextran Sulfate; Oleic Acids; Lactobacillus plantarum; Colitis; Dendritic Cells; Male
PubMed: 38745644
DOI: 10.3389/fimmu.2024.1374425 -
Chemical & Pharmaceutical Bulletin 2020Oxo-octadecadienoic acids (OxoODEs) act as peroxisome proliferator-activated receptor (PPAR) agonists biologically, and are known to be produced in the...
Catalytic Production of Oxo-fatty Acids by Lipoxygenases Is Mediated by the Radical-Radical Dismutation between Fatty Acid Alkoxyl Radicals and Fatty Acid Peroxyl Radicals in Fatty Acid Assembly.
Oxo-octadecadienoic acids (OxoODEs) act as peroxisome proliferator-activated receptor (PPAR) agonists biologically, and are known to be produced in the lipoxygenase/linoleate system. OxoODEs seem to originate from the linoleate alkoxyl radicals that are generated from (E/Z)-hydroperoxy octadecadienoic acids ((E/Z)-HpODEs) by a pseudoperoxidase reaction that is catalyzed by ferrous lipoxygenase. However, the mechanism underlying the conversion of alkoxyl radical into OxoODE remains obscure. In the present study, we confirmed that OxoODEs are produced in the lipoxygenase/linoleate system in an oxygen-dependent manner. Interestingly, we revealed a correlation between the (E/Z)-OxoODEs content and the (E/E)-HpODEs content in the system. (E/E)-HpODEs could have been derived from (E/E)-linoleate peroxyl radicals, which are generated by the reaction between a free linoleate allyl radical and an oxygen molecule. Notably, the ferrous lipoxygenase-linoleate allyl radical (LOx(Fe)-L·) complex, which is an intermediate in the lipoxygenase/linoleate system, tends to dissociate into LOx(Fe) and a linoleate allyl radical. Subsequently, LOx(Fe) converts (E/Z)-HpODEs to an (E/Z)-linoleate alkoxyl radical through one-electron reduction. Taken together, we propose that (E/Z)-OxoODEs and (E/E)-HpODEs are produced through radical-radical dismutation between (E/Z)-linoleate alkoxyl radical and (E/E)-linoleate peroxyl radical. Furthermore, the production of (E/Z)-OxoODEs and (E/E)-HpODEs was remarkably inhibited by a hydrophobic radical scavenger, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO). On the contrary, water-miscible radical scavengers, 4-hydroxyl-2,2,6,6-tetramethylpiperidine 1-oxyl (OH-TEMPO) and 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrroline-N-oxyl (CmΔP) only modestly or sparingly inhibited the production of (E/Z)-OxoODEs and (E/E)-HpODEs. These facts indicate that the radical-radical dismutation between linoleate alkoxyl radical and linoleate peroxyl radical proceeds in the interior of micelles.
Topics: Alcohols; Biocatalysis; Fatty Acids; Lipoxygenases; Molecular Structure; Oxygen; Peroxides
PubMed: 32115533
DOI: 10.1248/cpb.c19-00975 -
Frontiers in Plant Science 2022Cowpea aphid ( Koch) is a plant pest that causes serious damage to vegetable crops. Extensive use of synthetic chemical pesticides causes deleterious effects on...
Cowpea aphid ( Koch) is a plant pest that causes serious damage to vegetable crops. Extensive use of synthetic chemical pesticides causes deleterious effects on consumers as well as the environment. Hence, the search for environmentally friendly insecticides in the management of cowpea aphids is required. The present work aims to investigate the aphicidal activity of pomelo seed oil (PSO) on cowpea aphids, the possible insecticidal mechanisms, its chemical constituent profile, as well as the toxicity of its primary compounds. The results of the toxicity assay showed that PSO had significant insecticidal activity against aphids with a 72-hour LC value of 0.09 μg/aphid and 3.96 mg/mL in the contact and residual toxicity assay, respectively. The enzymatic activity of both glutathione S-transferase (GST) and acetyl cholinesterase (AChE) significantly decreased, as well as the total protein content, after PSO treatment, which suggested that the reduction of AChE, GST, and the total protein content in aphids treated with PSO might be responsible for the mortality of . The GC-MS analysis revealed that PSO contained limonene (22.86%), (9Z,12)-9,12-octadecadienoic acid (20.21%), -hexadecanoic acid (15.79%), (2,4)-2,4-decadienal (12.40%), and (2,4)-2,4-decadienal (7.77%) as its five major compounds. Furthermore, (9Z,12)-9,12-octadecadienoic acid showed higher toxicity to aphids than both PSO and thiamethoxam (positive control). This study emphasized the potential of PSO as a natural plant-derived insecticide in controlling cowpea aphids and also provided a novel approach for the value-added utilization of pomelo seed.
PubMed: 36426147
DOI: 10.3389/fpls.2022.1048814 -
Journal of the Science of Food and... Feb 2018The oxidative deterioration of vegetable oils is commonly measured by the peroxide value, thereby not considering the contribution of individual lipid hydroperoxide...
BACKGROUND
The oxidative deterioration of vegetable oils is commonly measured by the peroxide value, thereby not considering the contribution of individual lipid hydroperoxide isomers, which might have different bioactive effects. Thus, the formation of 9- and 13-hydroperoxy octadecadienoic acid (9-HpODE and 13- HpODE), was quantified after short-term heating and conditions representative of long-term domestic storage in samples of linoleic acid, canola, sunflower and soybean oil, by means of stable isotope dilution analysis-liquid chromatography-mass spectroscopy.
RESULTS
Although heating of pure linoleic acid at 180 °C for 30 min led to an almost complete loss of 9-HpODE and 13-HpODE, heating of canola, sunflower and soybean oil resulted in the formation of 5.74 ± 3.32, 2.00 ± 1.09, 16.0 ± 2.44 mmol L 13-HpODE and 13.8 ± 8.21, 10.0 ± 6.74 and 45.2 ± 6.23 mmol L 9-HpODE. An almost equimolar distribution of the 9- and 13-HpODE was obtained during household-representative storage conditions after 56 days, whereas, under heating conditions, an approximately 2.4-, 2.8- and 5.0-fold (P ≤ 0.001) higher concentration of 9-HpODE than 13-HpODE was detected in canola, soybean and sunflower oil, respectively.
CONCLUSION
A temperature-dependent distribution of HpODE regioisomers could be shown in vegetable oils, suggesting their application as markers of lipid oxidation in oils used for short-term heating. © 2017 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Topics: Cooking; Food Additives; Food Storage; Hot Temperature; Linoleic Acids; Linolenic Acids; Oxidation-Reduction; Plant Oils; Stereoisomerism
PubMed: 29095495
DOI: 10.1002/jsfa.8766 -
An allene oxide and 12-oxophytodienoic acid are key intermediates in jasmonic acid biosynthesis by .Journal of Lipid Research Aug 2017Fungi can produce jasmonic acid (JA) and its isoleucine conjugate in large quantities, but little is known about the biosynthesis. Plants form JA from 18:3-3 by...
Fungi can produce jasmonic acid (JA) and its isoleucine conjugate in large quantities, but little is known about the biosynthesis. Plants form JA from 18:3-3 by 13-lipoxygenase (LOX), allene oxide synthase, and allene oxide cyclase. Shaking cultures of f. sp. released over 200 mg of jasmonates per liter. Nitrogen powder of the mycelia expressed 10-dioxygenase-epoxy alcohol synthase activities, which was confirmed by comparison with the recombinant enzyme. The 13-LOX of could not be detected in the cell-free preparations. Incubation of mycelia in phosphate buffer with [17,17,18,18,18-H]18:3-3 led to biosynthesis of a [H]12-oxo-13-hydroxy-9,15-octadecadienoic acid (α-ketol), [H]12-oxo-10,15-phytodienoic acid (12-OPDA), and [H]13-keto- and [H]13-hydroxyoctadecatrienoic acids. The α-ketol consisted of 90% of the 13 stereoisomer, suggesting its formation by nonenzymatic hydrolysis of an allene oxide with 13 configuration. Labeled and unlabeled 12-OPDA were observed following incubation with 0.1 mM [H]18:3-3 in a ratio from 0.4:1 up to 47:1 by mycelia of liquid cultures of different ages, whereas 10 times higher concentration of [H]13-hydroperoxyoctadecatrienoic acid was required to detect biosynthesis of [H]12-OPDA. The allene oxide is likely formed by a cytochrome P450 or catalase-related hydroperoxidase. We conclude that , like plants, forms jasmonates with an allene oxide and 12-OPDA as intermediates.
Topics: Alkenes; Cyclopentanes; Fatty Acids, Unsaturated; Fusarium; Mycelium; Oxidation-Reduction; Oxides; Oxylipins
PubMed: 28572515
DOI: 10.1194/jlr.M077305 -
Food Chemistry: X Jun 2019Lipid oxidation is a main source of reactive carbonyls, and these compounds have been shown both to degrade amino acids by carbonyl-amine reactions and to produce...
Formation of phenylacetic acid and benzaldehyde by degradation of phenylalanine in the presence of lipid hydroperoxides: New routes in the amino acid degradation pathways initiated by lipid oxidation products.
Lipid oxidation is a main source of reactive carbonyls, and these compounds have been shown both to degrade amino acids by carbonyl-amine reactions and to produce important food flavors. However, reactive carbonyls are not the only products of the lipid oxidation pathway. Lipid oxidation also produces free radicals. Nevertheless, the contribution of these lipid radicals to the production of food flavors by degradation of amino acid derivatives is mostly unknown. In an attempt to investigate new routes of flavor formation, this study describes the degradation of phenylalanine, phenylpyruvic acid, phenylacetaldehyde, and β-phenylethylamine in the presence of the 13-hydroperoxide of linoleic acid, 4-oxononenal (a reactive carbonyl derived from this hydroperoxide), and the mixture of both of them. The obtained results show the formation of phenylacetic acid and benzaldehyde in these reactions as a consequence of the combined action of carbonyl-amine and free radical reactions for amino acid degradation.
PubMed: 31432020
DOI: 10.1016/j.fochx.2019.100037 -
Biomedicines Mar 2022Oxylipins play a critical role in regulating the onset and resolution phase of inflammation. Despite inflammation is a pathological hallmark in amyotrophic lateral...
Oxylipins play a critical role in regulating the onset and resolution phase of inflammation. Despite inflammation is a pathological hallmark in amyotrophic lateral sclerosis (ALS), the plasma oxylipin profile of ALS patients has not been assessed yet. Herein, we develop an oxylipin profile-targeted analysis of plasma from 74 ALS patients and controls. We found a significant decrease in linoleic acid-derived oxylipins in ALS patients, including 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE. These derivatives have been reported as important regulators of inflammation on different cell systems. In addition, some 5-lipoxygenase metabolites, such as 5-hydroxy- eicosatetraenoic acid also showed a significant decrease in ALS plasma samples. Isoprostanes of the F2α family were detected only in ALS patients but not in control samples, while the hydroxylated metabolite 11-HETE significantly decreased. Despite our effort to analyze specialized pro-resolving mediators, they were not detected in plasma samples. However, we found the levels of 14-hydroxy-docosahexaenoic acid, a marker pathway of the Maresin biosynthesis, were also reduced in ALS patients, suggesting a defective activation in the resolution programs of inflammation in ALS. We further analyze oxylipin concentration levels in plasma from ALS patients to detect correlations between these metabolites and some clinical parameters. Interestingly, we found that plasmatic levels of 13-HODE and 9-HODE positively correlate with disease duration, expressed as days since onset. In summary, we developed a method to analyze "(oxy)lipidomics" in ALS human plasma and found new profiles of metabolites and novel lipid derivatives with unknown biological activities as potential footprints of disease onset.
PubMed: 35327476
DOI: 10.3390/biomedicines10030674 -
Hepatology Communications Jun 2021Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis...
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited. Various bioactive lipid mediators have recently emerged as important factors in ALD pathogenesis. The current study aimed to examine alterations in linoleic acid (LA)-derived lipid metabolites in the plasma of individuals who are heavy drinkers and to evaluate associations between these molecules and markers of liver injury and systemic inflammation. Analysis of plasma LA-derived metabolites was performed on 66 individuals who were heavy drinkers and 29 socially drinking but otherwise healthy volunteers. Based on plasma alanine aminotransferase (ALT) levels, 15 patients had no liver injury (ALT ≤ 40 U/L), 33 patients had mild liver injury (ALT > 40 U/L), and 18 were diagnosed with moderate AH (mAH) (Model for End-Stage Liver Disease score <20). Lipoxygenase-derived LA metabolites (13-hydroxy-octadecadienoic acid [13-HODE] and 13-oxo-octadecadienoic acid) were markedly elevated only in patients with mAH. The cytochrome P450-derived LA epoxides 9,10-epoxy-octadecenoic acid (9,10-EpOME) and 12,13-EpOME were decreased in all patients regardless of the presence or absence of liver injury. LA-derived diols 9,10-dihydroxy-octadecenoic acid (9,10-DiHOME) and 12,13-DiHOME as well as the corresponding diol/epoxide ratio were elevated in the mAH group, specifically compared to patients with mild liver injury. We found that 13-HODE and 12,13-EpOME (elevated and decreased, respectively) in combination with elevated interleukin-1β as independent predictors can effectively predict altered liver function as defined by elevated bilirubin levels. Specific changes in LA metabolites in individuals who are heavy drinkers can distinguish individuals with mAH from those with mild ALD.
PubMed: 34141982
DOI: 10.1002/hep4.1686