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Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

Pseudomonas aeruginosa is regarded as the most opportunistic pathogen. It can induce ferroptosis in humans. It secretes a unique lipoxygenase (LOX) isoform, pLoxA that can oxidize polyenoic fatty acids. Unlike other lipoxygenases, pLoxA can oxygenate membrane phospholipids like phosphatidylethanolamine, leading to hemolysis of red blood cells (RBC). This functional overlap with human 15-LOX that uses the same substrate has provided a bottleneck to the discovery of pLoxA-specific inhibitors and there is an immediate need to find pLoxA specific drugs. The active site of pLoxA is much larger than LOX enzymes, reflecting its ability to accommodate bulky substrates, such as phospholipids. The molecular docking of two experimentally established inhibitors and the further molecular dynamics simulations provided possible key residues in the active site of pLoxA. Our study found that this region is essentially hydrophobic including His 377 and His 382 that are placed to the non-heme iron atom and help to stabilize the inhibitors in the binding site along with hydrophobic residues contribute well toward ligand interactions that involve Phe 415, Ile 416 and Leu 424. MD simulations showed that interactions with those residues were dynamic in nature. Main contribution to binding stability arose via π-π stacking, π-cation, and alkyl interactions. Graphical Abstract

Key messageLipoxygenases mediate important biological processes. Through comparative genomics, domain-scan analysis, sequence analysis, phylogenetic analysis, homology modelling and transcriptional analysis the lipoxygenase gene family of pepper (Capsicum annuum) has been identified.Lipoxygenases (LOXs) are non-heme, iron-containing dioxygenases playing a pivotal role in diverse biological processes in plants, including defence and development. Here, we exploited the recent sequencing of the pepper genome to investigate the LOX gene family in pepper. Two LOX classes are recognized, the 9- and 13-LOXs that oxygenate lipids at the 9th and 13th carbon atom, respectively. Using two main in-silico approaches, we identified a total of eight LOXs in pepper. Phylogenetic analysis classified four LOXs (CaLOX1, CaLOX3, CaLOX4 and CaLOX5) as 9-LOXs and four (CaLOX2, CaLOX6, CaLOX7 and CaLOX8) as 13-LOXs. Furthermore, sequence similarity/identity and subcellular localization analysis strengthen the classification predicted by phylogenetic analysis. Pivotal amino acids together with all domains and motifs are highly conserved in all pepper LOXs. Expression of 13-LOXs appeared to be more dynamic compared to 9-LOXs both in response to exogenous JA application and to thrips feeding. Bioinformatic and expression analyses predict the putative functions of two 13-LOXs, CaLOX6 and CaLOX7, in the biosynthesis of Green Leaf Volatiles, involved in indirect defence. The data are discussed in the context of LOX families in solanaceous plants and plants of other families.

Free radicals and inflammation have pivotal role in various degenerative diseases like cancer, rheumatoid arthritis, diabetes, cardiovascular and neurodegenerative disorders. Pyrazoles possess a wide range of biological activities such as antifungal, antituberculosis, antimicrobial, antiviral, anti-inflammatory, anti-convulsant, anticancer etc. In this present study a series of dibenzalacetones and the corresponding pyrazole hybrids were designed through bioisosterism, synthesized and biologically evaluated to highlight the importance of the extended conjugated system and substitution to the anti-inflammatory and antioxidant activity. The synthesis of dibenzalacetones was achieved via Claisen-Schmidt reaction. The dihydro-pyrazoles were synthesized from the substituted dibenzacetones and phenylhydrazines, hydrazine and semicarbazide under microwave irradiation optimizing reaction conditions. The synthesized compounds were spectroscopically characterized and evaluated for their anti-lipid peroxidation (AAPH) activity, their interaction with the free radical DPPH and the inhibition of soybean LOX. The novel derivatives were studied in terms of their physicochemical properties. Many of the dihydro-pyrazoles showed potent antioxidant properties and significant inhibition of soybean lipoxygenase as a result of their physicochemical features. Compounds 4a and 4b presented the most potent anti-lipid peroxidation abilities (98% and 97%), whereas compounds 2d and 2e have proved to be the most potent lipoxygenase inhibitors with IC50 values 2.5 μM and 0.35 μM. Moreover, docking studies with soybean lipoxygenase highlight the interactions of the novel derivatives with the enzyme.

Tagetes erecta L. is a popular ornamental plant of the Asteraceae family, which is widely cultivated not only for its decorative use, but also for the extraction of lutein. Besides carotenoid representatives, which have been extensively studied, other important classes of secondary metabolites present in the plant, such as polyphenols, could exhibit important biological activities. The phytochemical analysis of a methanolic extract obtained from T. erecta inflorescences was achieved using liquid chromatography–mass spectrometry (LC-MS) techniques. The extract was further subjected to a multistep purification process, which allowed the separation of different fractions. The total extract and its fractions contain several polyphenolic compounds, such as hydroxybenzoic and hydroxycinnamic acid derivatives, flavonols (especially quercetagetin glycosides), and several aglycons (e.g., quercetin, patuletin). One of the fractions, containing mostly quercetagitrin, was subjected to two different antioxidant assays (metal chelating activity and lipoxygenase inhibition) and to in vitro cytotoxicity assessment. Generally, the biological assays showed promising results for the investigated fraction compared to the initial extract. Given the encouraging outcome of the in vitro assays, further purification and structural analysis of compounds from T. erecta extracts, as well as further in vivo investigations are justified.

Key messageThis report shows detailed characterization of LOX gene family in sorghum and provides new insight of sorghum LOX genes in genetic structure and their roles in plant response to infestation by sugarcane aphids.Lipoxygenases (LOXs) are monomeric, nonheme iron-containing dioxygenases that initiate the fatty acid oxidation pathway creating oxylipins and plant hormone jasmonate both have a key role in plant development and defense. To date, a comprehensive and systematic analysis of sorghum LOXs is still deficient. Thus, we performed a genome-wide analysis of the sorghum LOXs genome and identified nine LOXs genes. Detailed examination of protein sequences and phylogenetic analysis categorized the sorghum LOXs into two subclasses, 9-LOXs (SbLOX1, SbLOX3, SbLOX4, SbLOXm, and SbLOXo), 13-LOXs (SbLOX9, SbLOX5, and SbLOX2), and the unclassified SbLOX8. This classification was further supported by sequence similarity/identity matrix and subcellular localization analysis. The lipoxygenase domains, motifs, and vital amino acids were highly conserved in all sorghum LOX genes. In silico analysis of the promoter region of SbLOXs identified different hormones responsive cis-elements. Furthermore, to explore the roles of sorghum LOXs during sugarcane aphid feeding and exogenous MeJA application, expression analysis was conducted for all the eight LOXs in resistant (Tx2783) and susceptible (Tx7000) sorghum lines, respectively. As detailed in this report, the data generated from both genome-wide identification and expression analysis of lipoxygenase genes suggest the putative functions of two 13-LOXs (SbLOX9 and SbLOX5) and three 9-LOXs (SbLOX1, SbLOX3, and SbLOXo) in biosynthesis of jasmonic acid, green leaf volatiles and death acids, and all of them are involved in defense-related functions in plants. Furthermore, this report represents the first genome-wide analysis of the LOX gene family in sorghum, which will facilitate future studies to characterize the roles of each individual LOXs gene in aphid resistance and defense responses to other stresses.

The lipoxygenase ( LOX ) gene family is widely distributed in plants, and its activity is closely associated with seed viability and stress tolerance. In this study, we cloned the rice( Oryza sativa )lipoxygenase gene OsLOX1 , a key participant in the 13-lipoxygenase metabolic pathway. Our primary focus was to investigate its role in mediating responses to drought stress and seed germination in rice. Histochemical staining and qPCR analysis indicated that the expression level of OsLOX1 was relatively high in leaves and early germinating seeds. Our findings revealed that mutant lines with CRISPR/Cas9-induced knockout of OsLOX1 exhibited reduced tolerance to drought stress compared with the wild-type. This was accompanied by elevated levels of H 2 O 2 and malondialdehyde, and a decrease in the expression levels of genes associated with antioxidant enzymes. Furthermore, knockout of OsLOX1 reduced the longevity of rice seeds increased H 2 O 2 and MDA levels, and decreased the activities of the antioxidant enzymes superoxide dismutase and catalase, compared with the wild-type. These findings demonstrated that OsLOX1 positively regulated rice seed vigor and drought stress.

2′-hydroxy-chalcones are naturally occurring compounds with a wide array of bioactivity. In an effort to delineate the structural features that favor antioxidant and lipoxygenase (LOX) inhibitory activity, the design, synthesis, and bioactivity profile of a series of 2′-hydroxy-chalcones bearing diverse substituents on rings A and B, are presented. Among all the synthesized derivatives, chalcone 4b, bearing two hydroxyl substituents on ring B, was found to possess the best combined activity (82.4% DPPH radical scavenging ability, 82.3% inhibition of lipid peroxidation, and satisfactory LOX inhibition value (IC50 = 70 μM). Chalcone 3c, possessing a methoxymethylene substituent on ring A, and three methoxy groups on ring B, exhibited the most promising LOX inhibitory activity (IC50 = 45 μM). A combination of in silico techniques were utilized in an effort to explore the crucial binding characteristics of the most active compound 3c and its analogue 3b, to LOX. A common H-bond interaction pattern, orienting the hydroxyl and carbonyl groups of the aromatic ring A towards Asp768 and Asn128, respectively, was observed. Regarding the analogue 3c, the bulky (-OMOM) group does not seem to participate in a direct binding, but it induces an orientation capable to form H-bonds between the methoxy groups of the aromatic ring B with Trp130 and Gly247.

Ultrasound-assisted extraction technology was utilized to extract total flavonoids from Chaenomeles speciosa (Sweet) Nakai, and response surface methodology was employed to optimize the extraction process. The anti-oxidant and lipoxygenase inhibitory activities were evaluated, along with an analysis of the type of inhibition. The results revealed that the optimal extraction conditions for total flavonoids from Chaenomeles speciosa (Sweet) Nakai were as follows: an ethanol concentration of 62%, a liquid-to-solid ratio of 15:1 mL/g, an ultrasonic temperature of 68°C, and an ultrasonic time of 40 min, resulting in a total flavonoid extraction rate of 10.18%. Antioxidant assays demonstrated that the Chaenomeles speciosa (Sweet) Nakai extract exhibited significant radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl radicals, 2,2’-azinobis (3-ethylbenzothiazoline-6-sulfonic acid ammonium salt) radicals, and hydroxyl radicals, with IC 50 values of 582 µg/mL, 538 µg/mL, and 1709 µg/mL, respectively. Furthermore, enzyme inhibition assays indicated that the Chaenomeles speciosa (Sweet) Nakai extract possesses notable inhibitory activity against lipoxygenase, with an IC 50 value of 2658 µg/mL. This inhibition is mediated through a mixed reversible inhibition mechanism.

Cinnamic acids have been identified as interesting compounds with antioxidant, anti-inflammatory and cytotoxic properties. In the present study, simple cinnamic acids were synthesized by Knoevenagel condensation reactions and evaluated for the above biological activities. Compound 4ii proved to be the most potent LOX inhibitor. Phenyl- substituted acids showed better inhibitory activity against soybean LOX, and it must be noted that compounds 4i and 3i with higher lipophilicity values resulted less active than compounds 2i and 1i. The compounds have shown very good activity in different antioxidant assays. The antitumor properties of these derivatives have been assessed by their 1/IC50 inhibitory values in the proliferation of HT-29, A-549, OAW-42, MDA-MB-231, HeLa and MRC-5 normal cell lines. The compounds presented low antitumor activity considering the IC50 values attained for the cell lines, with the exception of compound 4ii. Molecular docking studies were carried out on cinnamic acid derivative 4ii and were found to be in accordance with our experimental biological results.