Lipoxygenase Pathway Research Articles

Transfection of 12/15-lipoxygenase effectively alleviates inflammatory responses during experimental acute pancreatitis

BACKGROUND Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined. AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats. METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels. RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15 -transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP. CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.

Cysteinyl Leukotrienes in Allergic Inflammation.

The cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, are potent lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway. These mediators produce both inflammation and bronchoconstriction through three distinct G protein-coupled receptors (GPCRs)-CysLT1, CysLT2, and OXGR1 (also known as CysLT3 or GPR99). While CysLT-mediated functions in the effector phase of allergic inflammation and asthma have been established for some time, recent work has demonstrated novel roles for these mediators and their receptors in the induction and amplification of type 2 inflammation. Additionally, in vitro studies and murine models have uncovered diverse regulatory mechanisms that restrain or amplify CysLT receptor activation and CysLT receptor function. This review provides an overview of CysLT biosynthesis and its regulation, the molecular and functional pharmacology of CysLT receptors, and an overview of the established and emerging roles of CysLTs in asthma, aspirin-exacerbated respiratory disease, and type 2 inflammation.

Dynamic Change of Volatile Fatty Acid Derivatives (VFADs) and Their Related Genes Analysis during Innovative Black Tea Processing

Volatile fatty acid derivatives (VFADs) play a significant role in contributing to flowery–fruity flavor black tea. Innovative black tea is typically crafted from aroma-intensive tea cultivars, such as Jinmudan, using defined production methodologies. In this study, the during-processing tea leaves of innovative black tea were applied as materials, and we selected a total of 45 VFADs, comprising 11 derived aldehydes, nine derived alcohols, and 25 derived esters. Furthermore, the dynamic variations of these VFADs were uncovered. Transcriptome analysis was performed to identify genes involved in the LOX (lipoxygenase) pathway, resulting in the identification of 17 CsLOX genes, one hydrogen peroxide lyase (CsHPL) gene, 11 alcohol dehydrogenases (CsADH) genes, 11 genes as acyl CoA oxidase (CsACOX) genes, and three allene oxide synthase (CsAOS) genes. Additionally, the expression levels of these genes were measured, indicating that the processing treatments of innovative black tea, particularly turn-over and fermentation, had a stimulation effect on most genes. Finally, qRT-PCR verification and correlation analysis were conducted to explain the relationship between VFADs and candidate genes. This study aims to provide a reference for illuminating the formation mechanisms of aroma compounds in innovative black tea, thereby inspiring the optimization of innovative processing techniques and enhancing the overall quality of black tea.

Regulatory mechanism of methyl jasmonate and methyl dihydrojasmonate in enhancing aroma in 'Cabernet Gernischt' via the lipoxygenase pathway.

The present study explored the effects of pre-harvest methyl jasmonates spraying on the volatiles of 'Cabernet Gernischt' grapes through the lipoxygenase pathway. Headspace solid-phase microextraction combined with gas chromatography-mass spectrometry and an enzyme-linked immunosorbent assay were utilized to analyze volatile metabolites and key enzyme activities following methyl jasmonates application. Total RNA extraction and cDNA library construction were followed by transcriptome sequencing. The application of 0.1 mmol L-1 methyl jasmonate and 5 mmol L-1 methyl dihydrojasmonate significantly increased the levels of C6 compounds in 'Cabernet Gernischt' berries, and also enhanced the utilization of unsaturated fatty acids as precursors in the lipoxygenase-hydroperoxides lyase pathway. The up-regulated expression of VvADH1, VvADH2, VvHPL and VvLOX2S genes led to modulations in enzyme activity, thereby enhancing the berries's aromatic profile. There was a significant correlation between linoleic and linolenic acids (i.e. the precursors of the lipoxygenase pathway) and the activities and metabolites of key enzymes. The optimal concentration of methyl jasmonates treatment favorably influences the accumulation of green leaf volatiles in 'Cabernet Gernischt' grape. © 2024 Society of Chemical Industry.

Dual COX/ 5-LOX inhibitory potential and antioxidant activities by extracts isolated from Melia Azedarach L. leaves

This study was aimed at evaluating the dual cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX) enzyme inhibition and antioxidant activity of the crude extract (CE) and various solvent fractions from Melia azedarach leaves. Multiple solvents were used to fractionate the 80% ethanolic extract of the leaves, which was then examined for enzyme inhibitory effectiveness against COX and 5-LOX enzymes. All fractions and CE were examined for antioxidant activity, and phenolic acids and flavonoids were identified using Reverse-Phase High-Performance Liquid Chromatography (RP-HPLC). The ethyl acetate fraction (EaF) had the greatest COX/5-LOX inhibitory impact among tested fractions.In vitro, COX activity studies showed that EaF and butanol fraction (BF) possess a higher COX-2 selectivity index than Indomethacin. Besides, the EaF exhibited the highest reduction potential among the control and the CE when tested for antioxidant activities. These findings support the traditional use of Melia azedarachas an anti-inflammatory drug, as the plant inhibited both COX/5-LOX and COX-2 with high selectivity.1.Introduction The most frequent chemical species that cause oxidative damage in the body are reactive oxygen species (ROS) like peroxides, superoxide, singlet oxygen, hydroxyl radical, hydrogen peroxides, and so on. These species produced in the body can cause various cardiovascular and other chronic diseases [1-3], neurodegenerative diseases [4,5], and inflammatory diseases [6,7]. Different inflammatory diseases are linked to oxidative stress (an imbalance between ROS and their removal by protective mechanisms such as antioxidants) [7-9]. Inflammatory mediators such as prostaglandins produced by the arachidonic acid pathway need to be reduced and inhibited as they mainly cause inflammation, pain, and fever in the body [10]. Currently, the symptomatic treatment of inflammation is mainly done by non-steroidal anti-inflammatory drugs (NSAIDs). However, the traditional NSAIDs used in COX reduction are non-selective, lead to gastrointestinal side effects, heart strokes and renal failure. On the other hand, the currently used selective COX-2 inhibitors like ‘coxibs' are reported for cardiovascular side effects [11]. In addition to COX-2, the increased level of leukotriene from the 5-LOX enzyme can result in bronchospasm [11]. In this regard, medicinal preparations that inhibit both Cyclooxygenase (COX-2) and 5-Lipoxygenase (5-LOX) pathways are superior to commonly used NSAIDs since they could produce a synergetic effect to achieve optimal anti-inflammatory activities [10,11]. This can be done by blocking the production of both leukotrienes and prostaglandins. Hence, indeed, there is a need for new, effective, and safe anti-inflammatory drugs with dual COX-2/5-LOX inhibition capacities, which may obliterate the side effects caused by the inhibition of COX-2 alone [12,13]. Melia azedarachL. (known commonly as “Chinaberry, bead tree, Bakain and Persian lilac") is a deciduous tree belonging to the Meliaceae family that is native to tropical Asia and Australia but has now spread throughout the world. [14-16]. The antioxidantand anti-inflammatory potential of Melia azedarachL. from various regions werereported by other groups [14,15, 17-21]. The plant with different species and some species of different cultivars markedly differin their phenolics, flavonoids and antioxidant activities [18,20]. The antioxidant and anti-inflammatory activities of plant extracts are closely linked to phytoconstituents like total phenolics and flavonoids [22-25]. There is no scientific report on the anti-inflammatory action and antioxidant potential of Taiwanese-originMelia azedarach. Therefore, the purpose of the current study is to investigate the dual COX-2 and 5-LOX inhibitor potential, antioxidant potential, quantification of key flavonoids and phenolic acids, as well as total phenolic and flavonoid content of Melia azedarach.

Mechanism of aroma formation in white tea treated with solar withering

Withering is a crucial process that determines the quality of white tea (WT). Solar withering (SW) is reported to contribute to the aroma quality of WT. However, the mechanism by which aroma is formed in WT subjected to SW remains unclear. In this study, through headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC–MS) and transcriptomics, we found that 13 key genes enriched in the mevalonic acid and methylerythritol phosphate pathways, such as those of 1-deoxy-D-xylulose-5-phosphate synthase and terpineol synthase, were significantly upregulated, promoting the accumulation of α-terpinolene, geraniol, and nerolidol, which imparted floral and fruity odors to WT subjected to SW. Additionally, the significant upregulation of lipoxygenases enriched in the lipoxygenase pathway promoting the accumulation of hexanol, 1-octen-3-ol, (E, Z)-3,6-nonadien-1-ol, and nonanal, which contributed to the green and fresh odor in WT subjected to SW. This study provided the first comprehensive insight into the effect mechanism of SW on aroma formation in WT.

ABIOTIC STRESS GENE 1 mediates aroma volatiles accumulation by activating MdLOX1a in apple.

Fruit aroma is an important organoleptic quality, which influences consumer preference and market competitiveness. Aroma compound synthesis pathways in plants have been widely identified, among the lipoxygenase pathway is crucial for fatty acid catabolism to form esters in apple. However, the regulatory mechanism of this pathway remains elusive. In this study, linear regression analysis and transgene verification revealed that the lipoxygenase MdLOX1a is involved in ester biosynthesis. Yeast one-hybrid library screening indicated that a protein, MdASG1 (ABIOTIC STRESS GENE 1), was a positive regulator of MdLOX1a and ester production based on yeast one-hybrid and dual-luciferase assays, as well as correlation analysis among eight different apple cultivars. Overexpression of MdASG1 in apple and tomato stimulated the lipoxygenase pathway and increased the fatty acid-derived volatile content, whereas the latter was decreased by MdASG1 silencing and CRISPR/Cas9 knockout. Furthermore, MdASG1 overexpression enhanced the salt-stress tolerance of tomato and apple 'Orin' calli accompanied by a higher content of fatty acid-derived volatiles compared to that of non-stressed transgenic tomato fruit, while MdASG1-Cas9 knockdown calli do not respond to salt stress and promote the biosynthesis of fatty acid-derived volatiles. Collectively, these findings indicate that MdASG1 activates MdLOX1a expression and participates in the lipoxygenase pathway, subsequently increasing the accumulation of aroma compounds, especially under moderate salt stress treatment. The results also provide insight into the theory for improving fruit aroma quality in adversity.

CX-5461 ameliorates disease in lupus-prone mice by triggering B-cell ferroptosis via p53-SLC7A11-ALOX12 pathway

CX-5461, a first-in-class compound, is widely recognized as a selective inhibitor of RNA polymerase I. Recently, it has been reported to possess novel immunosuppressive properties with significant therapeutic effects in transplantation immune rejection. However, the potential use of CX-5461 for Systemic Lupus Erythematosus (SLE) treatment remains unknown. In this study, we elucidated the mechanism underlying the therapeutic efficacy of CX-5461 in lupus. Our findings demonstrated that CX-5461 selectively targets B cells and effectively reduces the proportions of B cells, germinal center B cells, and plasma cells in MRL/MPJ-Faslpr and Resiquimod (R848)-induced lupus mice. Molecular studies revealed that CX-5461 modulates CD36-Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4)-mediated glycerolipid metabolism in B cells, triggering ferroptosis through the p53- Solute Carrier Family 7 Member 11 (SLC7A11)- Arachidonate 12-Lipoxygenase (ALOX12) pathway, thereby decreasing IgG and Anti-Double-Stranded Deoxyribonucleic Acid (dsDNA) antibody levels and attenuating lupus. Collectively, these results suggest that CX-5461 holds promise as an effective candidate for targeted therapy against lupus.

Acetylsalicylic acid inhibition of the lipoxygenase pathway: Implications for HIV prevention

Background1.5 million new HIV infections occurred in 2021, suggesting new prevention methods are needed. Inflammation increases the risk for HIV acquisition by attracting HIV target cells to the female genital tract (FGT). In a pilot study, acetylsalicylic acid (ASA/Aspirin) decreased the proportion of FGT HIV target cells by 35 %. However, the mechanism remains unknown. MethodsWomen from Nairobi, Kenya took low-dose ASA (81 mg) daily for 6-weeks. Free oxylipins in the plasma were quantified by high-performance liquid chromatography-tandem mass spectroscopy. ResultsOxylipins from 9 fatty acid substrates were detected, with more than one analyte from 4 substrates reduced post-ASA. Summary analysis found ASA downregulated cyclooxygenase and lipoxygenase but not cytochrome P450 activity with a lower n-6/n-3 oxylipin profile, reflecting reduced inflammation post-ASA. ConclusionsInflammation is associated with increased lipoxygenase activity and HIV risk. Our data suggests ASA reduces inflammation through downregulation of oxylipins. Understanding how ASA reduces inflammation may lead to novel HIV prevention approaches.

Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.

Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.

Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.

Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene-induced diabetes of youth (MIDY) with samples from wild-type littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects with diabetes mellitus.

New Horizons in Diabetic Neuropathies: An Updated Review on their Pathology, Diagnosis, Mechanism, Screening Techniques, Pharmacological, and Future Approaches.

One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need. The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause. Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored. This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications.

Expression characteristics of lipid metabolism-related genes and correlative immune infiltration landscape in acute myocardial infarction

Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to “leukotriene production involved in inflammatory response”, “lipoxygenase pathway”, “metabolic pathways”, and “regulation of lipolysis in adipocytes” pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.

A Narrative Review of the Published Pre-Clinical Evaluations: Multiple Effects of Arachidonic Acid, its Metabolic Enzymes and Metabolites in Epilepsy.

Arachidonic acid (AA), an important polyunsaturated fatty acid in the brain, is hydrolyzed by a direct action of phospholipase A2(PLA2) or through the combined action of phospholipase C and diacylglycerol lipase, and released into the cytoplasm. Various derivatives of AA can be synthesized mainly through the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (P450) enzyme pathways. AA and its metabolic enzymes and metabolites play important roles in a variety of neurophysiological activities. The abnormal metabolites and their catalytic enzymes in the AA cascade are related to the pathogenesis of various central nervous system (CNS) diseases, including epilepsy. Here, we systematically reviewed literatures in PubMed about the latest randomized controlled trials, animal studies and clinical studies concerning the known features of AA, its metabolic enzymes and metabolites, and their roles in epilepsy. The exclusion criteria include non-original studies and articles not in English.

Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS-CoV-2 infection in a mouse model with human angiotensin-converting enzyme 2 (ACE2) expression. Mice were infected with SARS-CoV-2 and treated with either vehicle or the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). At day 5 post-infection, SARS-CoV-2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6-8 post-infection. SARS-CoV-2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral-induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS-CoV-2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.

Whole-cell one-pot biosynthesis of dodecanedioic acid from renewable linoleic acid

BackgroundDodecanedioic acid (DDA), a typical medium-chain dicarboxylic fatty acid with widespread applications, has a great synthetic value and a huge industrial market demand. Currently, a sustainable, eco-friendly and efficient process is desired for dodecanedioic acid production.ResultsHerein, a multi-enzymatic cascade was designed and constructed for the production of DDA from linoleic acid based on the lipoxygenase pathway in plants. The cascade is composed of lipoxygenase, hydroperoxide lyase, aldehyde dehydrogenase, and unidentified double-bond reductase in E. coli for the main cascade reactions, as well as NADH oxidase for cofactor recycling. The four component enzymes involved in the cascade were co-expressed in E. coli, together with the endogenous double-bond reductase of E. coli. After optimizing the reaction conditions of the rate-limiting step, 43.8 g L− 1 d− 1 of DDA was obtained by a whole-cell one-pot process starting from renewable linoleic acid.ConclusionsThrough engineering of the reaction system and co-expressing the component enzymes, a sustainable and eco-friendly DDA biosynthesis route was set up in E. coli, which afforded the highest space time yield for DDA production among the current artificial multi-enzymatic routes derived from the LOX-pathway, and the productivity achieved here ranks the second highest among the current research progress in DDA biosynthesis.Graphical

Low back pain: justification of treatment standards (literature review)

Low back pain: justification of treatment standards (literature review)

The versatile CYP74 clan enzyme CYP440A19 from the European lancelet Branchiostoma lanceolatum biosynthesizes novel macrolactone, epoxydiene, and related oxylipins

The present work reports the detection and cloning of a new CYP74 clan gene of the European lancelet (Branchiostoma lanceolatum) and the biochemical characterization of the recombinant protein CYP440A19. CYP440A19 possessed epoxyalcohol synthase (EAS) activity towards the 13-hydroperoxides of linoleic and α-linolenic acids, which were converted into oxiranylcarbinols, i.e., (11S,12R,13S)-11-hydroxy-12,13-epoxy derivatives. The conversion of 9-hydroperoxides produced distinct products. Linoleic acid 9(S)-hydroperoxide (9-HPOD) was mainly converted into 9,14-diol (10E,12E)-9,14-dihydroxy-10,12-octadecadienoic acid and macrolactone 9(S),10(R)-epoxy-11(E)-octadecen-13(S)-olide. In addition, (8Z)-colneleic acid was formed. Brief incubations of the enzyme with 9-HPOD in a biphasic system of hexane–water enabled the isolation of the short-lived 9,10-epoxydiene (9S,10R,11E,13E)-9,10-epoxy-11,13-octadecadienoic acid. The structure and stereochemistry of the epoxyalcohols, macrolactone, (8Z)-colneleic acid (Me), and 9,10-epoxydiene (Me) were confirmed by 1H-NMR, 1H-1H-COSY, 1H-13C-HSQC, and 1H-13C-HMBC spectroscopy. Macrolactone and cis-9,10-epoxydiene are novel products. The 9-hydroperoxide of α-linolenic acid was mainly converted into macrolactone 9(S),10(R)-epoxy-11(E),15(Z)-octadecadiene-13(S)-olide and a minority of divinyl ethers, particularly (8Z)-colnelenic acid. The versatility of enzyme catalysis, as well as the diversity of CYP74s and other enzymes involved in oxylipin biosynthesis, demonstrates the complexity of the lipoxygenase pathway in lancelets.

Influences of Cluster Thinning on Fatty Acids and Green Leaf Volatiles in the Production of Cabernet Sauvignon Grapes and Wines in the Northwest of China.

Cluster thinning has been widely applied in yield management and its effect on green leaf volatiles (GLVs) in wines has seldom been studied. GLVs are important flavor compositions for grapes and wines. This work aimed to investigate the impact of cluster thinning on these volatiles and their precursors in grapes and wines. Severe cluster thinning (CT1) and medium cluster thinning (CT2) were performed on Cabernet Sauvignon (Vitis vinifera L.) vines in two sites (G-farm and Y-farm) from Xinjiang province in the Northwest of China. The impact of cluster thinning treatments on the accumulation of GLVs and their precursors, long chain fatty acids (LCFAs) of grape berries and C6 volatiles, in resulting wines was investigated. Multivariate analysis showed that cluster thinning treatments induced significant changes in fruit and wine composition in both farms. In Y-farm, medium cluster thinning (CT2) significantly increased the average cluster weight of harvested berries. Additionally, both cluster thinning treatments (CT1 and CT2) increased fatty acids in harvested berries and CT2 led to an increase in C6 esters and a decrease in C6 alcohols in the wines of Y-farm under the warmer and drier 2012 vintage. However, the effect of cluster thinning was likely negative in G-farm due to its wetter soil and excessive organic matter. The treatments may be applicable for local grape growers to improve viticultural practices for the more balanced vegetative and reproductive growth of Cabernet Sauvignon grapevines. This work also provided further knowledge on the regulation of fatty acids and the derived C6 volatiles through the lipoxygenase (LOX) pathway.

Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors

Selective inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15–25, 29–30 with IC50 values in the range of 5.6–82.3 nM in a cell-free assay of prostaglandin (PG)E2 formation. We also demonstrate that 20 (TG554, IC50 = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.