Sex hormone deprivation abolishes sex-specific differences in murine colon inflammation and related lipid mediator production.

Unresolved inflammation, due to unfavorable imbalances between pro-inflammatory and pro-resolving mediators, leads to chronic inflammatory pathologies that are often sex-biased and regulated by sex hormones, including inflammatory bowel disease. Lipid mediators (LM) produced from polyunsaturated fatty acids by various lipoxygenases (LOX) and cyclooxygenases govern all stages of inflammation, i.e., the initiation and progression by pro-inflammatory eicosanoids and its resolution by specialized pro-resolving mediators (SPM). Here, we reveal sex-specific differences in murine experimental colitis with male preponderance, which was abolished by sex hormone deprivation using gonadectomy, and this correlated to the levels of inflammation-relevant mediators in the colon. Oral dextran sodium sulfate administration caused more severe colon inflammation in male CD-1 mice than in female counterparts during the acute phase. Colitis in males yielded higher colonic cytokine/chemokine levels but lower 12-/15-LOX-derived LM including SPM compared to female animals in the resolving phase. Sex hormone deprivation in male mice by orchidectomy ameliorated colitis and impaired pro-inflammatory cytokine/chemokine levels but elevated 12-/15-LOX products including SPM, thus abolishing the observed sex differences. Conversely, ovariectomy impaired the levels of those LM that dominated in females and that were increased in males after gonadectomy. Our findings suggest that male sex hormones promote the development of colitis connected to the biosynthesis of inflammatory cytokines, chemokines, and certain LM, especially pro-resolving 12-/15-LOX products that appear to be suppressed in the male colon due to androgens.

Eicosanoid signaling in neuroinflammation associated with Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition affecting a substantial portion of the global population. It is marked by a complex interplay of factors, including the accumulation of amyloid plaques and tau tangles within the brain, leading to neuroinflammation and neuronal damage. Recent studies have underscored the role of free lipids and their derivatives in the initiation and progression of AD. Eicosanoids, metabolites of polyunsaturated fatty acids like arachidonic acid (AA), emerge as key players in this scenario. Remarkably, eicosanoids can either promote or inhibit the development of AD, and this multifaceted role is determined by how eicosanoid signaling influences the immune responses within the brain. However, the precise molecular mechanisms dictating the dual role of eicosanoids in AD remain elusive. In this comprehensive review, we explore the intricate involvement of eicosanoids in neuronal function and dysfunction. Furthermore, we assess the therapeutic potential of targeting eicosanoid signaling pathways as a viable strategy for mitigating or halting the progression of AD.

Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis.

BACKGROUND: In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. PURPOSE: In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. METHODS: We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. RESULTS: Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. CONCLUSION: This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.

Single and multiple inhibitors of the biosynthesis of 5-, 12-, 15-lipoxygenase products derived from cinnamyl-3,4-dihydroxy-α-cyanocinnamate: Synthesis and structure-activity relationship.

The involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure-activity study was carried out, which led to the discovery of several novel compounds (16a-c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5-, 12- and 15-LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA-approved 5-LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α-position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12- and 15-LO products. Compounds 16a, 17a far surpassed baicalein, a known 12-LO inhibitor, as inhibitors of 12-LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α-position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15-LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5-LO active site.

Integrated computational and experimental evaluation of phenolic constituents of Apricot fruit L. for antiqourum sensing, antibiofilm, antioxidant, and 15-lox inhibitory properties.

The present study investigated the antioxidant profile together with the antibacterial potential of Apricot L. with the aim to find a functional food based anti-infective lead. Additionally the study evaluated the biofilm and QS inhibitory potential of the plant using Pseudomonas aeruginosa (ATCC 15442) and Chromo bacterium Violaceum (DSM 30191) respectively. Several fractions of the peel of Apricot were subjected to initial antimicrobial and antibiofilm screening. Among all the fractions, methanol and ethyl acetate fractions displayed significant antimicrobial activity against the strains selected with MIC values 1.25 mg/dL and 1.68 mg/dL respectively. Similarly, while evaluating antiqourum-sensing potential, methanol extract showed remarkable zone of inhibition (14mm) with Violaceum inhibition (58%) while aqueous part presented moderately good inhibition (32%) with zone of inhibition of (4mm). N-hexane fraction was least active in this regard. In case of free radicals scavenging aptitudes, Ethanolic fraction displayed the highest free radicals scavenging potential (IC50µg/mL 13.76 ± 23.61) while Aqueous and ethyl acetate part exhibited moderate to good antioxidant behaviors with IC50µg/mL of 26.74 ± 22.00 and 19.49 ± 2.91 respectively. Then the selected compounds were screened for putative binding sites and molecular docking studies followed by enzyme inhibition assays. The negative binding energies and close proximity to residues in the binding pocket of selected targets including human α- soybean lox (PDB ID 1IK3), quorum sensing regulators LasR (2UV0) were observed which indicated high affinity and tight binding capacity of compounds 1 and 5 towards the active sites of LasR 2UV0 and 15-lipoxygenase. The physicochemical characteristics and toxicity expectation were computationally accomplished. Bioactivity prediction study revealed that all of the selected Phytoconstituents displayed incredible Bioactivity score. None of the selected chemical compound was found to be toxic as discovered by toxicity studies. Compound 4 exhibited the highest inhibition of 15-lipoxygenase in vitro (69%, at 0.037 mM final concentration) and that is accompanied by compound 5 (60%) whereas in the biofilm inhibition assay, compound 1 was most active (IC50 0.05 mM), followed by compound 3 (IC50 0.07 mM). It was therefore determined that compounds 1 and 3 had the highest biofilm inhibitory activity, whereas compounds 4 and 5 were potent 15-lipoxygenase inhibitors with potentially anti-inflammatory properties. Future investigations are suggested for the characterization and formulation development.

Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations.

Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b-/-B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Molecular, in silico and expression studies on lipoxygenases (LOXs) in potato (Solanum tuberosum L.).

Lipoxygenases (LOXs) namely 9-LOXs and 13-LOXs catalyse the oxygenation of polyunsaturated fatty acids to produce fatty acid hydroperoxides which are crucial in growth, development and stress responses in plants. Here, we isolated and characterized a 2723-bp cDNA encoding a distinct 861-aa 9-LOX form, designated StKCLX-1, using tuber total RNA from an Indian potato cultivar, Kufri Chipsona-1 through RT-PCR. A total of 17 LOX genes distributed in different chromosomes were identified and characterized in the potato genome. Multiple sequence alignment revealed highly conserved amino acids in the crucial domains, motifs and variable N-terminal regions between the LOX classes. A total of 36 LOXs from potato, tomato and Arabidopsis were used in phylogenetic analysis. A 3-D structure of StKCLX-1 was predicted by AlphaFold tool, validated through the predicted local-distance difference test (pLDDT) and Ramachandran Plot. Molecular docking predicted the nature of receptor-ligand interactions. STRING database was used to predict the protein-protein interactions. Expression patterns of the LOXs in the potato organs were examined by Expression Atlas and semi-quantitative RT-PCR. 9-LOX activity was noticed at early stages of tuberization, and significantly increased in the freshly-harvested mature tubers. This report would be useful in gaining insights into the structure-function relationships of the LOXs and corresponding multigene family-prerequisites for understanding tuber development in potato.

The roles of lipoxygenases and autoxidation during mackerel (Scomberomorus niphonius) dry-cured processing.

The roles of enzymatic (Lipoxygenases, LOX) oxidation and autoxidation in the dry-cured processing of mackerel were investigated by adding exogenous substances in this study. Four groups, namely control, chlorogenic acid (inhibiting LOX activity), EDTA-2Na (inhibiting autoxidation), and exogenous LOX (adding eLOX), were assigned. The results showed that lipid oxidation of mackerel was reduced by inhibiting LOX activity and autoxidation, while adding eLOX promoted lipid oxidation. Inhibition of LOX activity and autoxidation suppressed fatty acid accumulation mainly in the air-drying and curing stage, respectively. The total contents of key flavors in the mackerel during dry-cured processing were decreased by inhibiting LOX activity and autoxidation, and the former inhibitory effect was stronger than autoxidation, while it was corresponding increased through adding eLOX, of particular in the later stage of air-drying. Collectively, LOX could promote the flavor formation of the mackerel in the dry-cured processing, which could be applied in the flavor adjustment of aquatic products or some similar fields.

Glucocorticoids regulate lipid mediator networks by reciprocal modulation of 15-lipoxygenase isoforms affecting inflammation resolution.

Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.

Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets.

BACKGROUND: Platelets for transfusion are stored for 5 to 7 days. Previous studies have shown that HETE levels in the storage bag negatively correlate with platelet performance in vivo, suggesting that the dysregulation of bioactive lipid mediators may contribute to the storage lesion. In the current study, we sought to understand how genetic deletion and pharmacological inhibition of 12-LOX (12-lipoxygenase) affects platelets during storage and after transfusion. METHODS: Platelets from 12-LOX+/+ (wild-type [WT]) and 12-LOX-/- mice were stored for 24 and 48 hours and profiled using liquid chromatography-tandem mass spectrometry-multiple reaction monitoring or transfused into thrombocytopenic hIL4R (human interleukin 4 receptor)-transgenic mice. Platelet function was assessed by flow cytometry and in vivo thrombosis and hemostasis models. To test the role of the COX-1 (cyclooxygenase-1) pathway, donor mice were treated with acetylsalicylic acid. Human platelets were treated with the 12-LOX inhibitor, VLX-1005, or vehicle, stored, and transfused to NOD/SCID (nonobese diabetic/severe combined immunodeficiency) mice. RESULTS: Polyunsaturated fatty acids increased significantly in stored platelets from 12-LOX-/- mice, whereas oxylipin concentrations were significantly higher in WT platelets. After transfusion to thrombocytopenic mice, we observed significantly more baseline αIIbß3 integrin activation in 12-LOX-/- platelets than in WT platelets. Stored platelets from 12-LOX-/- mice occluded vessels significantly faster than stored WT platelets. In hemostasis models, significantly more stored 12-LOX-/- than WT platelets accumulated at the site of venous injury leading to reduced blood loss. Inhibition of COX-1 abrogated both increased integrin activation and thromboxane generation in stored 12-LOX-/- platelets, highlighting the critical role of this pathway for improved post-transfusion function. Consistent with our mouse studies, human platelets stored with VLX-1005, showed increased integrin activation compared with vehicle-treated platelets after transfusion. CONCLUSIONS: Deleting 12-LOX improves the post-transfusion function of stored murine platelets by increasing thromboxane generation through COX-1-dependent arachidonic acid metabolism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans.

Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs.

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

Effects of inhibition of 5-lipoxygenase and 12-lipoxygenase pathways on skeletal muscle fiber regeneration.

We investigated the effect of inhibition of 5-lipoxigenase (LOX) and 12-LOX pathways on the regeneration of skeletal muscle fibers after injury induced by a myotoxin (MTX) phospholipase A2 from snake venom in an in vivo experimental model. Gastrocnemius muscles of mice injected with MTX presented an increase in 5-LOX protein expression, while 12-LOX was found to be a constitutive protein of skeletal muscle. Animals that received oral treatments with 5-LOX inhibitor MK886 or 12-LOX inhibitor baicalein 30 min and 48 h after MTX-induced muscle injury showed a reduction in the inflammatory process characterized by a significant decrease of cell influx and injured fibers in the degenerative phase (6 and 24 h after injury). In the beginning of the regeneration process (3 days), mice that received MK886 showed fewer new basophilic fibers, suggesting fewer proliferative events and myogenic cell fusion. Furthermore, in the progression of tissue regeneration (14-21 days), the mice treated with 5-LOX inhibitor presented a lower quantity of central nucleus fibers and small-caliber fibers, culminating in a muscle that is more resistant to the stimulus of fatigue during muscle regeneration with a predominance of slow fibers. In contrast, animals early treated with the 12-LOX inhibitor presented functional fibers with higher diameters, less resistant to fatigue and predominance of fast heavy-chain myosin fibers as observed in control animals. These effects were accompanied by an earlier expression of myogenic factor MyoD. Our results suggest that both 5-LOX and 12-LOX pathways represent potential therapeutic targets for muscle regeneration. It appears that inhibition of the 5-LOX pathway represses only the degenerative process by reducing tissue inflammation levels. Meanwhile, inhibition of the 12-LOX pathway also favors the anticipation of maturation and earlier recovery of muscle fiber activity function after injury.

Arachidonate lipoxygenases 5 is a novel prognostic biomarker and correlates with high tumor immune infiltration in low-grade glioma.

Objective: To investigate the prognostic value of arachidonate lipoxygenases 5 (ALOX5) expression and methylation, and explore the immune functions of arachidonate lipoxygenases 5 expression in low-grade glioma (LGG). Materials and Methods: Using efficient bioinformatics approaches, the differential expression of arachidonate lipoxygenases 5 and the association of its expression with clinicopathological characteristics were evaluated. Then, we analyzed the prognostic significance of arachidonate lipoxygenases 5 expression and its methylation level followed by immune cell infiltration analysis. The functional enrichment analysis was conducted to determine the possible regulatory pathways of arachidonate lipoxygenases 5 in low-grade glioma. Finally, the drug sensitivity analysis was performed to explore the correlation between arachidonate lipoxygenases 5 expression and chemotherapeutic drugs. Results: arachidonate lipoxygenases 5 mRNA expression was increased in low-grade glioma and its expression had a notable relation with age and subtype (p < 0.05). The elevated mRNA level of arachidonate lipoxygenases 5 could independently predict the disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI) (p < 0.05). Besides, arachidonate lipoxygenases 5 expression was negatively correlated with its methylation level and the arachidonate lipoxygenases 5 hypomethylation led to a worse prognosis (p < 0.05). The arachidonate lipoxygenases 5 expression also showed a positive connection with immune cells, while low-grade glioma patients with higher immune cell infiltration had poor survival probability (p < 0.05). Further, arachidonate lipoxygenases 5 might be involved in immune- and inflammation-related pathways. Importantly, arachidonate lipoxygenases 5 expression was negatively related to drug sensitivity. Conclusion: arachidonate lipoxygenases 5 might be a promising biomarker, and it probably occupies a vital role in immune cell infiltration in low-grade glioma.

Allosteric Activation of 15-Lipoxygenase-1 by Boswellic Acid Induces the Lipid Mediator Class Switch to Promote Resolution of Inflammation.

Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are unexplored. It was shown that 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca2+ - and phosphorylation-independent, with modest induction of 5-LOX products. AKBA docks into a groove between the catalytic and regulatory domains of 15-LOX-1 interacting with R98; replacement of R98 by alanine abolishes AKBA-induced 15-LOX product formation in HEK293 cells. In zymosan-induced murine peritonitis, AKBA strikingly elevates SPM levels and promotes inflammation resolution. Together, targeted allosteric modulation of LOX activities governs SPM formation and offers new concepts for inflammation resolution pharmacotherapy.

Insights into the interaction of cyclooxygenase and lipoxygenase with natural compound 3,4',5,7-Tetrahydroxyflavone based on multi-spectroscopic and metabolomics.

Hypoxia induce right ventricular dysfunction in human heart, but the molecular mechanism remains limited. As known, cyclooxygenases (COX) and lipoxygenases (LOX) play a key role in the cardiovascular system under hypoxia. 3,4',5,7-Tetrahydroxyflavone (THF), which widely exists in a variety of plants and vegetables, is famous for good ability to relieve cardiac injury, but the mechanism remains to be further understood. In this study, we firstly estimated the preventive role of THF against hypoxia-induced right ventricular dysfunction. Metabolomics analysis showed there were differential metabolites involved in above process, which helped us to screen the crucial regulated enzymes of these metabolites. Molecular docking and multi-spectroscopic revealed the molecular mechanism of interaction between THF and COX/LOX. Results suggested that THF bound to COX/LOX through static quenching and these bindings were driven by hydrogen bonds. After binding with THF, the secondary structure of COX/LOX was changed. In general, this study indicated that THF inhibited COX/LOX by spontaneously forming complexes with them.

Protectins: Their biosynthesis, metabolism and structure-functions.

Several lipoxygenase enzymes and cyclooxygenase-2 stereoselectively convert the polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and n-3 docosapentaenoic acid into numerous oxygenated products. Biosynthetic pathway studies have shown, during the resolution phase of acute inflammation, that distinct families of endogenous products are formed. These products were named specialized pro-resolving mediators, given their specialized functions in the inflammation-resolution circuit, enhancing the return of inflamed and injured tissue to homeostasis. The lipoxins, resolvins, protectins and maresins, together with the sulfido-conjugates of the resolvins, protectins and maresins, constitute the four individual families of these local mediators. When administrated in vivo in a wide range of human disease models, the specialized pro-resolving mediators display potent bioactions. The detailed and individual biosynthetic steps constituting the biochemical pathways, the metabolism, recent reports on structure-function studies and pharmacodynamic data of the protectins, are presented herein. Emphasis is on the structure-function results on the recent members of the sulfido conjugated protectins and further metabolism of protectin D1. Moreover, the members of the individual families of specialized pro-resolving mediators and their biosynthetic precursor are presented. Today 43 specialized pro-resolving mediators possessing pro-resolution and anti-inflammatory bioactions are reported and confirmed, constituting a basis for resolution pharmacology. This emerging biomedical field provides a new approach for drug discovery, that is also discussed.

Roles of hydroxyeicosatetraenoic acids in diabetes (HETEs and diabetes).

Hydroxyeicosatetraenoic acids (HETEs) are metabolites of arachidonate acid (AA) oxidized by lipoxygenases or cytochrome P450 enzymes (CYP450). Since lipoxygenases and CYP450 enzymes widely exist in different organs and tissues, HETEs play significant roles in normal physiological and pathophysiological conditions. Mounting evidence has shown that HETEs play roles in modulation of inflammation during diabetes development. And accumulating evidence suggests that in prediabetic conditions, HETEs have already impacted on adipose tissue, kidney, heart, and islet. In the current review, we focused on the role of specific HETEs, namely 5-HETE, 12-HETE, 15-HETE and 20-HETE in diabetes, and highlighted their effects in the development of diabetes and diabetes-related complications. In conclusion, elucidation of HETEs' impacts on different organs that contribute to the development of diabetes leads to identification of novel therapeutic modalities.

Managing SARS-CoV2 Infections Through Resolution of Inflammation by Eicosanoids: A Review.

Severe Corona Virus Disease is characterized by angiocentric inflammation of lungs and cytokine storm leading to potentially fatal multiple organ failure. Several studies have shown the high levels of pro-inflammatory cytokines, indicative of a poor prognosis in COVID-19. Eicosanoids play an important role in the induction of inflammation and cytokine production, while anti-inflammatory and pro-resolving properties of some eicosanoic acid derivatives enable inflamed tissues to return to homeostasis through the resolution of inflammation by aiding the clearance of cell debris and downregulation of pro-inflammatory stimulants. This review attempts to provide an overall insight on the eicosanoids synthesis and their role in the resolution of inflammation in the context of Corona Virus infection.

Periodontal Stem Cells Synthesize Maresin Conjugate in Tissue Regeneration 3.

Periodontal disease is a significant public health problem worldwide. Excess unresolved chronic inflammation destroys the periodontal tissues that surround and support the teeth, and efforts to control inflammation by removal of bacterial deposits on the teeth have limited long-term impact. Likewise, procedures aimed at regeneration of the periodontal tissues have shown limited success. Recent advances in stem cell research have shown promising novel prospects for the use of periodontal ligament stem cells (PDLSCs) in tissue regeneration; however, control of inflammation remains a barrier. Human PDLSCs have been shown to release specialized proresolving lipid mediators (SPMs) that modulate the immune response and promote resolution of inflammation, tissue repair, and regeneration. Studies on stem cell biology in periodontology have also been limited by the lack of a good large animal model. Herein, we describe PDLSC biology of the Yorkshire pig (pPDLSCs). pPDLSCs were isolated and characterized. Using lipid mediator profiling, we demonstrate for the first time that pPDLSCs biosynthesize cysteinyl-containing SPMs (cys-SPMs), specifically, maresin conjugates in tissue regeneration 3 (MCTR3) and its authentication using liquid chromatography/tandem mass spectrometry. The exogenous addition of the n-3 precursor docosahexaenoic acid enhances MCTR3 biosynthesis. Using immunocytochemistry, we show that pPDLSCs express 4 of the SPM biosynthetic pathway enzymes necessary for SPM biosynthesis, including 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase-1. In addition, we identified and quantified the cytokine/chemokine profile of pPDLSCs using a 13-plex immunology multiplex assay and found that the pretreatment of pPDLSCs with MCTR3 in an inflammatory environment reduced the production of acute and chronic proinflammatory cytokines/chemokines. Together, these results suggest that enhancing resolution of inflammation pathways and mediators may be a possible key early event in predictable periodontal regeneration.

Plasma Oxylipin Profile Discriminates Ethnicities in Subjects with Non-Alcoholic Steatohepatitis: An Exploratory Analysis.

Non-alcoholic fatty liver disease (NAFLD) is a common liver pathology that includes steatosis, or non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH). Without a clear pathophysiological mechanism, it affects Hispanics disproportionately compared to other ethnicities. Polyunsaturated fatty acids (PUFAs) and inflammatory lipid mediators including oxylipin (OXL) and endocannabinoid (eCB) are altered in NAFLD and thought to contribute to its pathogenesis. However, the existence of ethnicity-related differences is not clear. We employed targeted lipidomic profiling for plasma PUFAs, non-esterified OXLs and eCBs in White Hispanics (HIS, n = 10) and Caucasians (CAU, n = 8) with biopsy-confirmed NAFL, compared with healthy control subjects (HC; n = 14 HIS; n = 8 CAU). NAFLD was associated with diminished long chain PUFA in HIS, independent of histological severity. Differences in plasma OXLs and eCBs characterized ethnicities in NASH, with lower arachidonic acid derived OXLs observed in HIS. The secondary analysis comparing ethnicities within NASH (n = 12 HIS; n = 17 CAU), confirms these ethnicity-related differences and suggests lower lipoxygenase(s) and higher soluble epoxide hydrolase(s) activities in HIS compared to CAU. While causes are not clear, these lipidomic differences might be with implications for NAFLD severity and are worth further investigation. We provide preliminary data indicating ethnicity-specific lipidomic signature characterizes NASH which requires further validation.