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  • 1
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    Online Resource
    Comparative lipidomic analysis of inflammatory mediators in the aqueous humor and tear fluid of humans and rabbits
    Springer Science and Business Media LLC ; 2020
    In:  Metabolomics Vol. 16, No. 2 ( 2020-02)
    Details
    In: Metabolomics, Springer Science and Business Media LLC, Vol. 16, No. 2 ( 2020-02)
    Type of Medium: Online Resource
    ISSN: 1573-3882 , 1573-3890
    URL: Article
    DOI: 10.1007/s11306-020-1650-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2182289-X
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  • 2
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    Mechanisms and Treatment of Light-Induced Retinal Degeneration-Associated Inflammation: Insights from Biochemical Profiling of the Aqueous Humor
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 3 ( 2020-01-21), p. 704-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 3 ( 2020-01-21), p. 704-
    Abstract: Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21030704
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 3
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    Oxylipin Profiles as Functional Characteristics of Acute Inflammatory Responses in Astrocytes Pre-Treated with IL-4, IL-10, or LPS
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 5 ( 2020-03-05), p. 1780-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 5 ( 2020-03-05), p. 1780-
    Abstract: Functional phenotypes, which cells can acquire depending on the microenvironment, are currently the focus of investigations into new anti-inflammatory therapeutic approaches. Glial cells, microglia, and astrocytes are major participants in neuroinflammation, but their roles differ, as microglia are cells of mesodermal origin, while astrocytes are cells of ectodermal origin. The inflammatory phenotype of cells can be modulated by ω-6- and ω-3-polyunsaturated fatty acid-derived oxylipins, although data on changes in oxylipin profiles in different cell adaptations to pro- and anti-inflammatory stimuli are scarce. Our study aimed to compare UPLC-MS/MS-measured oxylipin profiles in various rat astrocyte adaptation states. We used cells treated for 24 h with lipopolysaccharide (LPS) for classical pro-inflammatory adaptation and with interleukin 4 (IL-4) or 10 (IL-10) for alternative anti-inflammatory adaptation, with the resulting phenotypes characterized by quantitative real-time PCR (RT-PCR). We also tested long-term, low-concentration LPS treatment (endotoxin treatment) as a model of astrocyte adaptations. The functional response of astrocytes was estimated by acute (4 h) LPS-induced cell reactivity, measured by gene expression markers and oxylipin synthesis. We discovered that, as well as gene markers, oxylipin profiles can serve as markers of pro- (A1-like) or anti-inflammatory (A2-like) adaptations. We observed predominant involvement of ω-6 polyunsaturated fatty acid (PUFA) and the cyclooxygenase branch for classical (LPS) pro-inflammatory adaptations and ω-3 PUFA and the lipoxygenase branch for alternative (IL-4) anti-inflammatory adaptations. Treatment with IL-4, but not IL-10, primes the ability of astrocytes to activate the innate immunity signaling pathways in response to LPS. Endotoxin-treated astrocytes provide an alternative anti-inflammatory adaptation, which makes cells less sensitive to acute LPS stimulation than the IL-4 induced adaptation. Taken together, the data reveal that oxylipin profiles associate with different states of polarization to generate a pro-inflammatory or anti-inflammatory phenotype. This association manifests itself both in native cells and in their responses to a pro-inflammatory stimulus.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21051780
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 4
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    Multi-Omics Approach Points to the Importance of Oxylipins Metabolism in Early-Stage Breast Cancer
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 8 ( 2022-04-18), p. 2041-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 8 ( 2022-04-18), p. 2041-
    Abstract: The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism’s level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14082041
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 5
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    Modulation of the Primary Astrocyte-Enriched Cultures’ Oxylipin Profiles Reduces Neurotoxicity
    MDPI AG ; 2021
    In:  Metabolites Vol. 11, No. 8 ( 2021-07-30), p. 498-
    Details
    In: Metabolites, MDPI AG, Vol. 11, No. 8 ( 2021-07-30), p. 498-
    Abstract: Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries and neurodegenerative diseases. Astrocytes can release several substances, which may exert neurotoxic or neuroprotective effects, but the nature of these substances is still largely unknown. In the present work, we tested the hypothesis that these effects may be attributed to oxylipins, which are synthesized from n-3 or n-6 polyunsaturated fatty acids (PUFAs). We used astrocyte-enriched cultures and found that: (1) lipid fractions secreted by lipopolysaccharide (LPS)—stimulated rat primary astrocyte-enriched cultures—possessed neurotoxic activity in rat primary neuronal cultures; (2) both of the tested oxylipin synthesis inhibitors, ML355 and Zileuton, reduce the LPS-stimulated release of interleukin 6 (IL-6) by astrocyte cultures, but only ML355 can change lipid fractions from neurotoxic to non-toxic; and (3) oxylipin profiles, measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from neurotoxic and non-toxic lipid fractions, reveal a group of n-3 docosahexaenoic acid derivatives, hydroxydocosahexaenoic acids (HdoHEs)-4-HdoHE, 8-HdoHE, and 17-HdoHE, which may reflect the neuroprotective features of lipid fractions. Regulating the composition of astrocyte oxylipin profiles may be suggested as an approach for regulation of neurotoxicity in inflammatory processes.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo11080498
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662251-8
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  • 6
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    Inhibitor of Hyaluronic Acid Synthesis 4-Methylumbelliferone as an Anti-Inflammatory Modulator of LPS-Mediated Astrocyte Responses
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 21 ( 2020-11-02), p. 8203-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 21 ( 2020-11-02), p. 8203-
    Abstract: Astrocytes are glial cells that play an important role in neuroinflammation. Astrocytes respond to many pro-inflammatory stimuli, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4). Regulatory specificities of inflammatory signaling pathways are still largely unknown due to the ectodermal origin of astrocytes. Recently, we have shown that hyaluronic acid (HA) may form part of astrocyte inflammatory responses. Therefore, we tested 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, as a possible regulator of LPS-mediated responses. Rat primary astrocytes were treated with LPS with and without 4-MU and gene expression levels of inflammatory (interleukins 1β, (IL-1β), 6, (IL-6), tumor necrosis factor alpha TNFα,) and resolution interleukin 10 (IL-10) markers were evaluated via real-time PCR and western blot. The release of cytokines and HA was determined by ELISA. Oxylipin profiles were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Our data show that 4-MU (i) has anti-inflammatory effects in the course of TLR4 activation, decreasing the cytokines level TNFα, IL-6 and IL-1β and increasing IL-10, (ii) downregulates prostaglandin synthesis but not via cyclooxygenases COX-1 and COX-2 pathways, (iii) modulates HA synthesis and decreases LPS-induced HA synthase mRNA expression (HAS-1, HAS-2) but does not have an influence on HAS-3, HYAL1 and HYAL2 mRNAs; (iv) the effects of 4-MU are predominantly revealed via JNK but not p38, ERK mitogen-activated protein kinases (MAPKs) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways. For the first time, it is shown that 4-MU possesses the useful potential to regulate an inflammatory astrocyte response.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21218203
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 7
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    Comparison of PPAR Ligands as Modulators of Resolution of Inflammation, via Their Influence on Cytokines and Oxylipins Release in Astrocytes
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 24 ( 2020-12-16), p. 9577-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 24 ( 2020-12-16), p. 9577-
    Abstract: Neuroinflammation is a key process of many neurodegenerative diseases and other brain disturbances, and astrocytes play an essential role in neuroinflammation. Therefore, the regulation of astrocyte responses for inflammatory stimuli, using small molecules, is a potential therapeutic strategy. We investigated the potency of peroxisome proliferator-activated receptor (PPAR) ligands to modulate the stimulating effect of lipopolysaccharide (LPS) in the primary rat astrocytes on (1) polyunsaturated fatty acid (PUFAs) derivative (oxylipins) synthesis; (2) cytokines TNFα and interleukin-10 (IL-10) release; (3) p38, JNK, ERK mitogen-activated protein kinase (MAPKs) phosphorylation. Astrocytes were exposed to LPS alone or in combination with the PPAR ligands: PPARα (fenofibrate, GW6471); PPARβ (GW501516, GSK0660); PPARγ (rosiglitazone, GW9662). We detected 28 oxylipins with mass spectrometry (UPLC-MS/MS), classified according to their metabolic pathways: cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), lipoxygenase (LOX) and PUFAs: arachidonic (AA), docosahexaenoic (DHA), eicosapentaenoic (EPA). All tested PPAR ligands decrease COX-derived oxylipins; both PPARβ ligands possessed the strongest effect. The PPARβ agonist, GW501516 is a strong inducer of pro-resolution substances, derivatives of DHA: 4-HDoHE, 11-HDoHE, 17-HDoHE. All tested PPAR ligands decreased the release of the proinflammatory cytokine, TNFα. The PPARβ agonist GW501516 and the PPARγ agonist, rosiglitazone induced the IL-10 release of the anti-inflammatory cytokine, IL-10; the cytokine index, (IL-10/TNFα) was more for GW501516. The PPARβ ligands, GW501516 and GSK0660, are also the strongest inhibitors of LPS-induced phosphorylation of p38, JNK, ERK MAPKs. Overall, our data revealed that the PPARβ ligands are a potential pro-resolution and anti-inflammatory drug for targeting glia-mediated neuroinflammation.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21249577
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 8
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    High Glucose Shifts the Oxylipin Profiles in the Astrocytes towards Pro-Inflammatory States
    MDPI AG ; 2021
    In:  Metabolites Vol. 11, No. 5 ( 2021-05-13), p. 311-
    Details
    In: Metabolites, MDPI AG, Vol. 11, No. 5 ( 2021-05-13), p. 311-
    Abstract: Hyperglycemia is associated with several complications in the brain, which are also characterized by inflammatory conditions. Astrocytes are responsible for glucose metabolism in the brain and are also important participants of inflammatory responses. Oxylipins are lipid mediators, derived from the metabolism of polyunsaturated fatty acids (PUFAs) and are generally considered to be a link between metabolic and inflammatory processes. High glucose exposure causes astrocyte dysregulation, but its effects on the metabolism of oxylipins are relatively unknown and therefore, constituted the focus of our work. We used normal glucose (NG, 5.5 mM) vs. high glucose (HG, 25 mM) feeding media in primary rat astrocytes-enriched cultures and measured the extracellular release of oxylipins (UPLC-MS/MS) in response to lipopolysaccharide (LPS). The sensitivity of HG and NG growing astrocytes in oxylipin synthesis for various serum concentrations was also tested. Our data reveal shifts towards pro-inflammatory states in HG non-stimulated cells: an increase in the amounts of free PUFAs, including arachidonic (AA), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, and cyclooxygenase (COX) mediated metabolites. Astrocytes cultivated in HG showed a tolerance to the LPS, and an imbalance between inflammatory cytokine (IL-6) and oxylipins release. These results suggest a regulation of COX-mediated oxylipin synthesis in astrocytes as a potential new target in treating brain impairment associated with hyperglycemia.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo11050311
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662251-8
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  • 9
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    Inflammation in Dry Eye Syndrome: Identification and Targeting of Oxylipin-Mediated Mechanisms
    MDPI AG ; 2020
    In:  Biomedicines Vol. 8, No. 9 ( 2020-09-11), p. 344-
    Details
    In: Biomedicines, MDPI AG, Vol. 8, No. 9 ( 2020-09-11), p. 344-
    Abstract: Dry eye syndrome (DES) is characterized by decreased tear production and stability, leading to desiccating stress, inflammation and corneal damage. DES treatment may involve targeting the contributing inflammatory pathways mediated by polyunsaturated fatty acids and their derivatives, oxylipins. Here, using an animal model of general anesthesia-induced DES, we addressed these pathways by characterizing inflammatory changes in tear lipidome, in correlation with pathophysiological and biochemical signs of the disease. The decline in tear production was associated with the infiltration of inflammatory cells in the corneal stroma, which manifested one to three days after anesthesia, accompanied by changes in tear antioxidants and cytokines, resulting in persistent damage to the corneal epithelium. The inflammatory response manifested in the tear fluid as a short-term increase in linoleic and alpha-linolenic acid-derived oxylipins, followed by elevation in arachidonic acid and its derivatives, leukotriene B4 (5-lipoxigenase product), 12-hydroxyeicosatetraenoic acid (12-lipoxigeanse product) and prostaglandins, D2, E2 and F2α (cyclooxygenase products) that was observed for up to 7 days. Given these data, DES was treated by a novel ophthalmic formulation containing a dimethyl sulfoxide-based solution of zileuton, an inhibitor of 5-lipoxigenase and arachidonic acid release. The therapy markedly improved the corneal state in DES by attenuating cytokine- and oxylipin-mediated inflammatory responses, without affecting tear production rates. Interestingly, the high efficacy of the proposed therapy resulted from the synergetic action of its components, namely, the general healing activity of dimethyl sulfoxide, suppressing prostaglandins and the more specific effect of zileuton, downregulating leukotriene B4 (inhibition of T-cell recruitment), as well as upregulating docosahexaenoic acid (activation of resolution pathways).
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines8090344
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2720867-9
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  • 10
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    Oxylipin Profiles in Plasma of Patients with Wilson’s Disease
    MDPI AG ; 2020
    In:  Metabolites Vol. 10, No. 6 ( 2020-05-29), p. 222-
    Details
    In: Metabolites, MDPI AG, Vol. 10, No. 6 ( 2020-05-29), p. 222-
    Abstract: Wilson’s disease (WD) is a rare autosomal recessive metabolic disorder resulting from mutations in the copper-transporting, P-type ATPase gene ATP7B gene, but influences of epigenetics, environment, age, and sex-related factors on the WD phenotype complicate diagnosis and clinical manifestations. Oxylipins, derivatives of omega-3, and omega-6 polyunsaturated fatty acids (PUFAs) are signaling mediators that are deeply involved in innate immunity responses; the regulation of inflammatory responses, including acute and chronic inflammation; and other disturbances related to any system diseases. Therefore, oxylipin profile tests are attractive for the diagnosis of WD. With UPLC-MS/MS lipidomics analysis, we detected 43 oxylipins in the plasma profiles of 39 patients with various clinical manifestations of WD compared with 16 healthy controls (HCs). Analyzing the similarity matrix of oxylipin profiles allowed us to cluster patients into three groups. Analysis of the data by VolcanoPlot and partial least square discriminant analysis (PLS-DA) showed that eight oxylipins and lipids stand for the variance between WD and HCs: eicosapentaenoic acid EPA, oleoylethanolamide OEA, octadecadienoic acids 9-HODE, 9-KODE, 12-hydroxyheptadecatrenoic acid 12-HHT, prostaglandins PGD2, PGE2, and 14,15-dihydroxyeicosatrienoic acids 14,15-DHET. The compounds indicate the involvement of oxidative stress damage, inflammatory processes, and peroxisome proliferator-activated receptor (PPAR) signaling pathways in this disease. The data reveal novel possible therapeutic targets and intervention strategies for treating WD.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo10060222
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662251-8
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