Phospholipase A2 Activity Research Articles

Redox signaling regulation in human spermatozoa: a primary role of peroxiredoxins.

Reactive oxygen species (ROS) play a dual role in mammalian spermatozoa. At high levels, they are detrimental to sperm function since they can promote oxidative stress that produces oxidation of protein, lipids, and sperm DNA. This oxidative damage is associated with male infertility. On the other hand, when ROS are produced at low levels, they participate in the redox signaling necessary for sperm capacitation. Capacitation-associated ROS are produced by the sperm oxidase, whose identity is still elusive, located in the plasma membrane of the spermatozoon. ROS, such as superoxide anion, hydrogen peroxide, nitric oxide, and peroxynitrite, activate protein kinases and inactivate protein phosphatases with the net increase of specific phosphorylation events. Peroxiredoxins (PRDXs), antioxidant enzymes that fight against oxidative stress, regulate redox signaling during capacitation. Among them, PRDX6, which possesses peroxidase and calcium-independent phospholipase A2 (iPLA2) activities, is the primary regulator of redox signaling and the antioxidant response in human spermatozoa. The lysophosphatidic acid signaling is essential to maintain sperm viability by activating the phosphatidylinositol 3-kinase/protein kinase (PI3K/AKT) pathway, and it is regulated by PRDX6 iPLA2, protein kinase C (PKC), and receptor-type protein tyrosine kinase. The understanding of redox signaling is crucial to pave the way for novel diagnostic tools and treatments of male infertility.

A genus-wide study on venom proteome variation and phospholipase A2 inhibition in Asian lance-headed pit vipers (genus: Trimeresurus)

High molecular weight proteins are present abundantly in viper venoms. The amino acid sequence can be highly variable though, contributing to the structure and function diversity of snake venom protein. This, however, remains unresolved in many species. The study investigated the venom protein variability in a distinct clade of Asian pit vipers (Trimeresurus species) through comparative proteomics, applying gel electrophoresis (SDS-PAGE), liquid chromatography-tandem mass spectrometry (LCMS/MS), and bioinformatic approaches. The proteomes revealed a number of conserved protein families, within each are variably expressed protein paralogs that are unrelated to the snake phylogeny and geographic origin. The expression levels of two major enzymes, i.e., snake venom serine proteinase and metalloproteinase, correlate weakly with procoagulant and hemorrhagic activities, implying co-expression of other functionally versatile toxins in the venom. The phospholipase A2 (PLA2) abundance correlates strongly with its enzymatic activity, and a unique phenotype was discovered in two species expressing extremely little PLA2. The commercial mono-specific antivenom effectively neutralized the venoms' procoagulant and hemorrhagic effects but failed to inhibit the PLA2 activities. Instead, the PLA2 activities of all venoms were effectively inhibited by the small molecule inhibitor varespladib, suggesting its potential to be repurposed as a highly potent adjuvant therapeutic in snakebite envenoming.

Venom variation and ontogenetic changes in the Crotalus molossus complex: Insights into composition, activities, and antivenom neutralization.

The Crotalus molossus complex consists of five to seven phylogenetically related lineages of black-tailed rattlesnakes widely distributed in Mexico. While previous studies have noted venom variation within specific lineages of the Crotalus molossus complex, a comprehensive characterization of interspecific and ontogenetic venom variations, their functional implications, and the neutralizing ability of the Mexican antivenom against these variants remains largely unexamined. Herein, using two proteomic approaches for five lineages (C. basiliscus, C. m. molossus, C. m. nigrescens, C. m. oaxacus, and C. ornatus) of the C. molossus complex we characterized the number of toxins and their relative abundance in the venom of individuals of varying sizes. All five lineages undergo ontogenetic venom composition shifts associated with snake length. However, the pattern of ontogenetic shifts varied among lineages. In some lineages, these shifts led to significant differences in proteolytic, phospholipase A2, and fibrinogenolytic activities. Venom in smaller C. basiliscus, C. m. nigrescens, and C. m. oaxacus individuals had lower LD50 values (more lethal) in mice. Whereas the venom lethality of C. m. nigrescens (both juvenile and adult) and C. m. oaxacus (adult) was several times higher in a mammalian (mouse) model than in a reptilian (iguana) model. Antivipmyn® showed different neutralizing potencies toward venom pools. Overall, our results indicated that even among closely related rattlesnake lineages, venom phenotypes may vary greatly, impacting their function and the efficacy of antivenom neutralization.

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, using Xenopus oocyte maturation as a well-established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPRβ. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPRβ, resulting in the production of lipid messengers that are G-protein coupled receptor agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity.

The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, the details of its signal transduction cascade remain elusive. Here, using Xenopus oocyte maturation as a well-established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires mPRβ. This PLA2 activity bifurcates P4 signaling by inducing clathrin-dependent endocytosis of mPRβ, resulting in the production of lipid messengers that are G-protein coupled receptor agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.

Effect of Fibrates on Lipoprotein-associated Phospholipase A2 Mass and Activity: A Systematic Review and Meta-analysis of Controlled Clinical Trials.

In vascular tissue, macrophages and inflammatory cells produce the enzyme lipoprotein- associated phospholipase A2 (Lp-PLA2). Treatment with fibrates decreases Lp-PLA2 levels in individuals with obesity and metabolic syndrome; however, these findings have not been fully clarified. The goal of this study was to investigate the possible effects of fibrate therapy on Lp-PLA2 mass and activity through a meta-analysis of clinical trials. Web of Science, PubMed, Scopus, Google Scholar, and ClinicalTrials.gov databases were searched using MeSH terms and keywords. Randomized controlled trials (RCT) evaluating the effect of statins on Lp- PLA2 mass and/or activity were included in the meta-analysis. Quantitative data were analyzed using a random- effects model and the generic inverse variance method. The meta-analysis of 10 clinical trials indicated that fibrate treatment has no significant effect on Lp- PLA2 mass (fibrate vs. placebo/nothing = WMD: -3.29 ng/ml, 95% CI: -21.35, 14.78, p = 0.72; fibrate vs. active control = WMD: -1.08 ng/ml, 95% CI: -51.38, 49.22, p = 0.97); Lp-PLA2 activity (fibrate vs. active control = WMD: 0.84 nmol/ml/min, 95% CI: -0.17, 1.84, p = 0.10); HDL-LpPLA2 activity (fibrate vs. active control = WMD: 0.77 nmol/ml/min, 95% CI: -0.33, 1.88, p = 0.17); and secretory PLA2 (fibrate vs. active control = WMD: 0.37 ng/ml, 95% CI: -1.22, 1.97, p = 0.65). Also, the results of the sensitivity analysis were robust for all these parameters. In conclusion, fibrate therapy did not reduce the mass and activity of Lp-PLA2.

Comparative Analysis of the Enzymatic, Coagulant, and Neuromuscular Activities of Two Variants of Crotalus durissus ruruima Venom and Antivenom Efficacy.

Background: We compared the enzymatic, coagulant, and neuromuscular activities of two variants (yellow-CDRy and white-CDRw) of Crotalus durissus ruruima venom with a sample of C. d. terrificus (CDT) venom and examined their neutralization by antivenom against CDT venom. Methods: The venoms were screened for enzymatic and coagulant activities using standard assays, and electrophoretic profiles were compared by SDS-PAGE. Neutralization was assessed by preincubating venoms with crotalic antivenom and assaying the residual activity. Results: SDS-PAGE showed that the venoms had similar electrophoretic profiles, with the main bands being phospholipase A2 (PLA2), serine proteinases, L-amino acid oxidase (LAAO), and phosphodiesterase. CDRy venom had the highest proteolytic and LAAO activities, CDRw venom had greater PLA2 and esterolytic activities at the highest quantity tested, and CDT had greater PLA2 activity than CDRy. CDRw and CDT venoms had similar proteolytic and LAAO activities, and CDRy and CDT venoms had comparable esterolytic activity. None of the venoms altered the prothrombin time (PT), but all of them decreased the activated partial thromboplastin time (aPPT); this activity was neutralized by antivenom. The minimum coagulant dose potency was CDRw >> CDRy > CDT. All venoms had thrombin-like activity that was attenuated by antivenom. CDRy and CDRw venoms showed α-fibrinogenolytic activity. All venoms partially cleaved the β-chain. CDRy and CDT venoms caused neuromuscular facilitation (enhanced muscle contractions) followed by complete blockade, whereas CDRw venom caused only blockade. Antivenom neutralized the neuromuscular activity to varying degrees. Conclusions: These findings indicate that while CDR and CDT venoms share similarities, they also differ in some enzymatic and biological activities and in neutralization by antivenom. Some of these differences could influence the clinical manifestations of envenomation by C. d. ruruima and their neutralization by the currently used therapeutic antivenom.

Prospect of using ethnobotanicals to manage snakebites in a cost-effective manner: validating Senegalia mellifera extract's inhibitory potential on Naja nigricincta nigricincta (zebra cobra) venom.

Despite Naja nigricincta nigricincta being responsible for most snake envenomation in remote Namibian regions, an effective intervention against its venom remains undiscovered. This study aimed to scientifically validate Namibian folklore claims about Senegalia mellifera extract's efficacy against snake envenomation. In vitro assays were conducted to assess the inhibitory potential of S. mellifera stem bark extract on snake venom phospholipase A2 (svPLA2) activity from N. n. nigricincta venom. Gas chromatography-mass spectrometry (GC-MS) and molecular docking predicted phytochemicals responsible for inhibitory effects on venom proteins. The svPLA2 activity assay demonstrated significant inhibitory potential of the extract, reducing enzyme activity from 100% to as low as 66.99%. GC-MS analysis indicated an abundant presence of terpenes having antisnake venom activity. Molecular docking identified phytochemicals of S. mellifera capable of neutralizing prevalent cobra toxins, that is, stigmasterol acetate, beta-Sitosterol acetate, vitamin E, kaur-15-ene, squalene and 4,6-Cholestadien-3beta-ol. This plant extract cannot be considered as a discrete treatment against venom. It may serve as a transient remedy to impede the toxic effects or supplement the action of antivenoms. Future research should be aimed at finding other plants with greater antivenom potential to increase the prospect of using ethnobotanicals to manage snakebites in a cost-effective manner.

Baicalein antagonises Rhopilema esculentum toxin-induced oxidative stress and apoptosis by modulating ROS-MAPK-NF-κB and inhibiting PLA2 activity.

The toxicity of jellyfish Rhopilema esculentum (R. esculentum), an edible jellyfish that releases venom, has been controversial. The aim of this comprehensive study was to investigate the toxic effects of jellyfish tentacle extract (TE), which was evaluated in vivo and in vitro using ICR mice and RAW264.7 cells respectively. A library of natural compounds was screened for their ability to antagonize phospholipase A2 (PLA2) activity to identify potential protective agents and mechanisms. Of the 20 natural compounds evaluated, baicalein was found to have the strongest PLA2 antagonistic and cytoprotective effects. In vivo, experiments showed that TE at a dose of 7.02 mg/kg only resulted in a 50% survival rate in mice. However, pretreatment with 30 mg/kg baicalein significantly increased the survival rate to 75%, while also attenuating TE-induced cardiac and hepatic injuries, and ameliorating TE-induced elevations in LDH, CK-MB, and AST levels. In vitro studies found that baicalein reduced cellular ROS and MDA levels, increased the expression of CAT, SOD, and GSH/GSSG to enhance cellular antioxidant defenses against TE-induced oxidative stress, and also inhibited TE-induced upregulation of TNF-α, IL-6, IL-1β, and CXCL10. Importantly, baicalein was found to modulate dysregulated MAPK and NF-κB signaling pathways disrupted by TE. Taken together, these findings suggest that baicalein can antagonize R. esculentum toxin-induced oxidative stress and apoptosis by modulating ROS/MAPK/NF-κB, which provides a viable therapeutic strategy to control the deleterious effects of jellyfish stings and associated inflammation.

Ability of brazilian Bothrops-Lachesis-Crotalus antivenom in neutralizing some biological activities of Crotalus durissus ruruima rattlesnake venom.

We evaluated the efficacy of freeze-dried Bothrops-Lachesis-Crotalus antivenom and liquid Crotalus antivenoms to neutralize Crotalus durissus ruruima (Cdr) venom (Roraima, Brazil) comparing with C. d. terrificus (Cdt) venom. Lethal and phospholipase A2 activities were similar between both spp. Crotamine was negative and individual Cdr venoms induced hemorrhage in mice. It was lower coagulant than Cdt venom. Only Bothrops-Lachesis-Crotalus antivenom neutralized all biological activities evaluated, suggesting that it could be used in snakebites in this region.

Simplifying traditional approaches for accessible analysis of snake venom enzymes.

Snake venoms enzymes affect diverse physiological mechanisms leading to effects such as inflammation, edema, hemolysis, and blood clotting disorders. In this report, we describe modifications to classical assays for assessing the enzymatic activity of snake venom phospholipase A2 (PLA2) and phosphodiesterase (PDE), including the adaptation of the PDE assay to an agar plate. A final staining step, using Stains-all®, was added to the PLA2 activity assay on an egg yolk-containing agar plate. Moreover, PDE activity was successfully and qualitative assed using an agar plate-immobilized bis-p-nitrophenyl-phosphate. The modified methods introduced in this study improve accessibility for a broader spectrum of researchers, enabling venom-related investigations in any laboratory setting, with special relevance for regions where snakebites are most prevalent.

Исследование влияния различных физиологически активных веществ на изменение липидного состава и фосфолипазной активности поврежденных соматических нервов

The changes in lipid composition and phospholipase activity in damaged somatic nerves were studied against the background of the action of potassium hyaluronate and insulin-like growth factor-1. It has been shown that nerve cutting is accompanied by an increase in phospholipase A2 activity, resulting in an accumulation of lysophospholipids and free fatty acids, as well as an increase in phosphatidylinositol levels and a decrease in diacylglycerol content, which is most likely due to inactivation of phosphoinositide-specific phospholipase C against the background of injury to the nerve conductor. The introduction of potassium hyaluronate and insulin-like growth factor-1 enhances the recovery processes in the injured nerve conductor, however, the mechanisms of their action remain different. According to the literature data and the results of our own research, the action of potassium hyaluronate and insulin-like growth factor-1 is realized as a result of the launch of signaling pathways associated with the regulation of the activity of enzymes from the phospholipase family. At the same time, our data on a decrease in the activity of phospholipase A2 and the absence of significant changes in the level of phosphatidylinositol and diacylglycerol indicate that potassium hyaluronate most likely exerts its effect through the PL A2-mediated pathway. In addition, it was shown that against the background of the action of IGF-1, an intensification of phosphoinositide metabolism is observed, which is explained by the activation of phosphoinositidespecific phospholipase C. According to the literature, the launch of the phospholipase C-mediated mechanism is accompanied by the formation of components of the phosphatidylinositol 3-kinase signaling pathway involved in stimulation of the expression of various transcription factors necessary for axonal regeneration and restoration of the functioning of injured nerve conductors.

Mechano-induced arachidonic acid metabolism promotes keratinocyte proliferation through cPLA2 activity regulation.

Mechano-induced keratinocyte hyperproliferation is reported to be associated with various skin diseases. Enhanced cell proliferation often requires the active metabolism of nutrients to produce energy. However, how keratinocytes adapt their cellular metabolism homeostasis to mechanical cues remains unclear. Here, we first found that mechanical stretched keratinocytes showed the accumulation of metabolic arachidonic acid by metabolomic analysis. Second, we found that mechanical stretch promoted keratinocyte proliferation through the activation of cytosolic calcium-dependent phospholipase A2 (cPLA2). Knockdown or inhibition of cPLA2 could reduce the release of arachidonic acid and inhibit the proliferation of stretched keratinocytes invitro and invivo. Third, by analyzing overlapping transcriptomes of stretched keratinocytes and arachidonic acid-stimulated keratinocytes, we identified the upregulation of hexokinase domain-containing protein 1 (HKDC1) expression, a novel gene involved in glucose metabolism, which was associated with arachidonic acid-induced keratinocyte proliferation during stretching. Our data reveal a metabolic regulation mechanism by which mechanical stretch induces keratinocyte proliferation, thereby coupling cellular metabolism to the mechanics of the cellular microenvironment. Strategies to change the metabolism process may lead to a new way to treat skin diseases that are related to biophysical forces.

Serum lipoprotein‐associated phospholipase A2 activity in Chinese patients with systemic lupus erythematosus

Serum lipoprotein‐associated phospholipase A2 activity in Chinese patients with systemic lupus erythematosus

Single cell nuclei transcriptomics of human brains identify a role for homeostatic microglia in cellular senescence in Alzheimer’s disease

AbstractBackgroundCellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer’s disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so‐called “senescence‐associated secretory phenotype” (SASP) characterized by increased secretion of pro‐inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.MethodIn this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models. Bulk (n = 632) and single‐cell nuclei transcriptomic profiling (n = 427) of the human dorsolateral prefrontal cortex (DLPFC) from the Religious Order Study/Memory Aging Project (ROSMAP). Lipidomic profiling was performed on a subset of 200 brains from the midfrontal cortex of ROS.ResultOur findings revealed upregulation of cellular senescence signatures in postmortem AD brain tissues across different cell types in comparison with controls. We identified a strong correlation between SASP and arachidonic acid (AA) metabolism (P<0.001) in bulk RNA. In single cell nuclei transcriptomics, AA Activation was strongly correlated with P2RY12 (homeostatic) microglia (P<0.0001), and was associated with worse performance on all cognitive domains (p<0.001) and AD neuropathology (P<0.001) as shown in the figure. Lipidomic analysis of postmortem brain tissues confirmed activation of AA derived eicosanoids. Pathway analysis implicated the activation of calcium dependent phospholipase A2 (cPLA2). Inhibiting cPLA2 by treatment with ASB14780 reduced senescence‐associated eicosanoids in APOE4 mouse models.ConclusionThis work implicates the sustained activation of homeostatic microglia as an underlying mechanism of cellular senescence in the AD brain.

Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome.

The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.

Effect of Statin Treatment on Lipoprotein-Associated Phospholipase A2 Mass and Activity: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials.

The goal of this meta-analysis was to establish whether statin treatment reduces Lp-PLA2 mass concentration and/or activity. PubMed, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases were searched using MESH terms and keywords. Randomized controlled trials (RCT) with either parallel or cross-over design examining the effect of statins on Lp-PLA2 mass and/or activity were included in meta-analysis. Out of 256 articles, 10 RCT were selected for meta-analysis. Statin therapy significantly reduced both Lp-PLA2 mass (WMD -44.46 ng/mL; 95%CI -59.01, -29.90; p < 0.001; I2 = 93%) and activity (WMD -39.37 nmol/min/mL; 95%CI -69.99, -8.75; p = 0.01; I2 = 100%). The sensitivity analysis was robust for Lp-PLA2 mass and was also positive for two studies concerning Lp-PLA2 activity. Statin therapy significantly reduced both Lp-PLA2 mass and activity.

Hydrolysis of phospholipid monolayers by phospholipase A2 revealed by heterodyne-detected sum frequency generation (HD-SFG) spectroscopy.

Phospholipase A2 (PLA2) catalyzes the hydrolysis of the sn-2 acyl ester linkage in phospholipid, producing lysophospholipid and fatty acid in the presence of Ca2+. The hydrolysis mediated by PLA2 has attracted much interest in various fields, such as pharmacy and biotechnology. It is recognized that PLA2 cannot hydrolyze phospholipid monolayers at high surface coverage. However, the origin of different PLA2 activities is not fully understood yet. The present study investigated the interaction between DPPC (16:0 PC) monolayer and PLA2 using heterodyne-detected sum frequency generation spectroscopy, which is interface-specific spectroscopy and highly sensitive to molecular symmetry based on a second-order nonlinear optical process. It was revealed that PLA2 adsorbs to the DPPC monolayer on the aqueous solution surface only when the surface coverage is low. The adsorption at the low surface coverage significantly changes the interfacial structures of PLA2 and the hydration, which are stabilized by the presence of Ca2+. Therefore, the restriction of the hydrolysis of phospholipid monolayers at high surface coverage can be rationalized by the inhabitation of the PLA2 adsorption. The present study deepens our molecular-level understanding of the hydrolysis of phospholipids by PLA2.

The Toxin Diversity, Cytotoxicity, and Enzymatic Activity of Cape Cobra (Naja nivea) Venom.

"True" cobras (genus Naja) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra (Naja nivea) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca2+ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca2+ release and NO synthesis were low. Phospholipase A2 activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species' venom.

The Synergistic and Opposing Roles of ω-Fatty Acid Hydroxylase (CYP4A11) and ω-1 Fatty Acid Hydroxylase (CYP2E1) in Chronic Liver Disease

Cytochrome P450 fatty acid hydroxylase consists of members of the CYP4 family that ω-hydroxylate fatty acids and the CYP2E1 that ω-1 hydroxylates fatty acids. Although ω and ω-1 hydroxylation of fatty acids have been thought to play a minor role in fatty acid metabolism (less than 20%), it plays a vital role in excess liver fatty acids overload seen in fasting, diabetes, metabolic disorder, and over-consumption of alcohol and high-fat diet. This pathway provides anabolic metabolites for gluconeogenesis, succinate, and acetate for lipogenesis. The CYP4A and CYP2E1 genes are activated in fasting and several metabolic disorders, suggesting a synergistic role in preventing fatty acid-induced lipotoxicity with the consequence of increased liver cholesterol and lipogenesis leading to increased Lipid Droplet (LD) deposition. During the progression of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), activation of Phospholipase A2 (PLA2) releases arachidonic acid that CYP4A11 and CYP2E1 P450s metabolize to produce 20-hydroxyeicosatetraenoic acid (20-HETE) and 19-HETE, respectively. These metabolites have opposing roles in the progression of MASLD and chronic liver disease (CLD). This report discusses the synergistic role of the CYP4A and CYP2E1 P450s in the metabolism of saturated and unsaturated fatty acids and their opposite physiological role in the metabolism of Arachidonic Acid (AA). We finally discuss the role of ethanol in disrupting the synergistic and opposing roles of the CYP4A and CYP2E1 genes in MASLD and CLD.