Phospholipase A2 Activity Research Articles

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.

Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders.

Neural membranes are composed of phospholipids, sphingolipids, cholesterol, and proteins. In response to cell stimulation or injury, the metabolism of lipids generates various lipid mediators, which perform many cellular functions. Thus, phospholipids release arachidonic acid or docosahexaenoic acid from the sn-2 position of the glycerol moiety by the action of phospholipases A2. Arachidonic acid is a precursor for prostaglandins, leukotrienes, thromboxane, and lipoxins. Among these mediators, prostaglandins, leukotrienes, and thromboxane produce neuroinflammation. In contrast, lipoxins produce anti-inflammatory and pro-resolving effects. Prostaglandins, leukotrienes, and thromboxane are also involved in cell proliferation, differentiation, blood clotting, and blood vessel permeability. In contrast, DHA-derived lipid mediators are called specialized pro-resolving lipid metabolites (SPMs). They include resolvins, protectins, and maresins. These mediators regulate immune function by producing anti-inflammatory, pro-resolving, and cell protective effects. Sphingolipid-derived metabolites are ceramide, ceramide1-phosphate, sphingosine, and sphingosine 1 phosphate. They regulate many cellular processes, including enzyme activities, cell migration and adhesion, inflammation, and immunity. Cholesterol is metabolized into hydroxycholesterols and 7-ketocholesterol, which not only disrupts membrane fluidity, but also promotes inflammation, oxidative stress, and apoptosis. These processes lead to cellular damage.

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 receptors agonists. Therefore, P4 drives meiosis by inducing an ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.

Characterization and proteomic analysis of plasma-derived small extracellular vesicles in locally advanced rectal cancer patients.

Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT. Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC. A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454-0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity. Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT.

Metabolic and genetic basis of liver damage in mechanical jaundice of non-tumor genesis in obstractive cholangitis or biliary pancreatitis

Aim. Establishment of versatile mechanisms behind liver damage in mechanical jaundice of non-tumor genesis combined with acute obstructive cholangitis or acute biliary pancreatitis.Materials and methods. In total, 64 cases of mechanical jaundice developed against the background of cholelithiasis were studied. Group 1 included 30 patients with mechanical jaundice combined with cholangitis; group 2 included 34 patients with acute biliary pancreatitis. Bile duct reconstruction was performed by an open method followed by standardized treatment. The intensity of membrane lipid peroxidation was determined by the level of diene conjugates, malonic dialdehyde, superoxide dismutase activity, and the activity of phospholipase A2. The severity of endotoxemia was estimated; a molecular-genetic test of the polymorphism of antioxidant system genes was performed.Results. The significance of the gene polymorphism of antioxidant enzymes in the formation of systemic alterative phenomena and severity of liver damage in mechanical jaundice complicated by cholangitis or acute pancreatitis was determined by allocation of patient subgroups depending on the presence of mutant allele T in the gene of superoxide dismutase SOD2 (C1147T). The groups of patients with the presence of such polymorphism, regardless of the combined diseases, demonstrated more pronounced and prolonged liver functional disorders and homeostasis disorders after restoration of biliary tract patency.Conclusion. The presence of mutant alleles of the SOD2 gene (C47T) in patients with non-tumor mechanical jaundice combined with acute cholangitis or pancreatitis is associated with an increase in the intensity of damage mechanisms at the systemic level, primarily with membrane lipid peroxidation, which correlates with the severity of liver damage (r = 0.834–0.967; p &lt; 0.05).

Lipoprotein-associated phospholipase A2 activity levels is associated with artery to artery embolism in symptomatic intracranial atherosclerotic disease

BackgroundLipoprotein-associated phospholipase A2 activity (Lp-PLA2-A) is a pivotal enzyme involved in the inflammatory process and atherosclerotic plaque vulnerability. This study aimed to investigate the potential of Lp-PLA2-A as a biomarker for reflecting artery-to-artery embolism (AAE), a critical mechanism with high risk of stroke recurrence in symptomatic intracranial atherosclerotic disease (sICAD). MethodsThe current analysis included a cohort of 1,908 patients with sICAD and baseline levels of Lp-PLA2-A from the Third China National Stroke Registry (CNSR-III). The baseline Lp-PLA2-A levels were quantified centrally using an automatic enzyme assay system. Diagnosis of sICAD was made by experienced stroke neurologists based on the presence of a cerebral infarction within the territory of a stenotic (>50 %) or occluded artery, or when clinical symptoms were consistent with the diagnosis. Infarct lesions affecting the cortex serve as imaging biomarkers for stroke mechanism involving AAE.The relationship between baseline Lp-PLA2-A quartile levels and the presence of cortical infarction was analyzed using multivariate logistic regression. ResultsCompared to patients in the first Lp-PLA2-A quartile, those in the second, third and fourth quartiles demonstrated a significantly higher proportion of AAE. The proportion of patients with cortical infarction increased with rising Lp-PLA2-A quartiles, observed at 39.3 %, 47.1 %, 47.4 %, and 50.7 % for the first, second, third and fourth quartiles respectively (P for trend=0.004). Compared with the first quartile, the odds ratios (ORs) were 1.38 (95 % CI = 1.06-1.79) for the second, 1.33 (95 % CI = 1.02-1.72) for the third quartile and 1.48 (95 % CI = 1.14-1.92) for the fourth quartile. The association between higher Lp-PLA2-A and increased proportion of cortical infarction was also present in the subgroups defined by age <65 years, male, and high-sensitivity C-reactive protein ≥2 mg/L. In sensitivity analyses, the positive correlation between Lp-PLA2-A levels and proportion of cortical infarction remained consistent. ConclusionsThis research highlights the significance of Lp-PLA2-A as a biomarker for reflecting stroke mechanism in sICAD. Additional studies are warranted to explore the potential of targeting Lp-PLA2-associated inflammatory pathways as a pivotal approach in arresting the advancement of intracranial atherosclerotic stenosis and reducing the incidence of embolic strokes.

Comparative venom analysis between melanistic and normally coloured phenotypes of the common adder (Vipera berus).

Snake venom is an ecologically relevant functional trait directly linked with a snake's fitness and survival, facilitating predation and defence. Snake venom variation occurs at all taxonomic levels, but the study at the intraspecific level is still in its early stages. The common adder (Vipera berus) exhibits considerable variation in colour phenotypes across its distribution range. Melanistic (fully black) individuals are the subject of myths and fairytales, and in German folklore such 'hell adders' are considered more toxic than their normally coloured conspecifics despite any formal investigation. Here, we provide the first comparative analysis of venoms from melanistic and normally coloured common adders. Specifically, we compared the venom profiles by sodium dodecylsulfate polyacrylamide gel electrophoresis and reversed-phase high-performance liquid chromatography and tested the venoms' protease, phospholipase A2 and cytotoxic activities. Phospholipase A2 activity was similar in both phenotypes, whereas general protease activity was higher in the melanistic venom, which was also more cytotoxic at two concentrations (6.25 and 12.5 µg ml-1). These minor differences between the venoms of melanistic and normally coloured adders are unlikely to be of clinical relevance in the context of human envenomation. In light of our results, the claim that melanistic adders produce more toxic venom than their normally coloured conspecifics appears rooted entirely in folklore.

Proteogenomics-guided functional venomics resolves the toxin arsenal and activity of Deinagkistrodon acutus venom

Snakebite primarily impacts rural communities of Africa, Asia, and Latin America. The sharp-nosed viper (Deinagkistrodon acutus) is among the snakes of highest medical importance in Asia. Despite various studies on its venom using modern venomics techniques, a comprehensive understanding of composition and function of this species' venom remains lacking. We combined proteogenomics with extensive bioactivity profiling to present the first genome-level catalogue of D. acutus venom proteins and their exochemistry. Our analysis identified an unusually simple venom containing 45 components from 20 distinct protein families. Relative toxin abundances indicate that C-type lectin and C-type lectin-related protein (CTL), snake venom metalloproteinase (svMP), snake venom serine protease (svSP), and phospholipase A2 (PLA2) constitute 90 % of the venom. Bioassays targeting key aspects of viperid envenomation showed considerable concentration-dependent cytotoxicity, particularly in kidney and lung cells, and potent protease and PLA2 activity. Factor Xa and thrombin activities were minor, and no plasmin activity was observed. Effects on haemolysis, intracellular calcium (Ca2+) release, and nitric oxide (NO) synthesis were negligible. Our analysis provides the first holistic genome-based overview of the toxin arsenal of D. acutus, predicting the molecular and functional basis of its life-threatening effects, and opens novel avenues for treating envenomation by this highly dangerous snake.

Antinociceptive and Anti-Inflammatory Activities of Acetonic Extract from Bougainvillea x buttiana (var. Rose).

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory properties and its potential action mechanisms. Methods: Analgesic and anti-inflammatory activities were evaluated using three murine pain models and two acute inflammation models. In vitro, the ability of the extract to inhibit proteolytic activity and the activities of the enzymes phospholipase A2 (PLA2) and cyclooxygenase (COX) were evaluated. In silico analysis was performed to predict the physicochemical and Absorption, distribution, metabolism, and excretion (ADME) profiles of the compounds previously identified in BxbRAE-100%. Results: In vivo BxbRAE-100% decreased the nociceptive behaviors in the writhing model, the tail immersion, and the formalin test, suggesting that the extract has the potential to relieve pain at peripheral and central levels. Additionally, topical or oral BxbRAE-100% treatment reduced dose-dependent 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation and carrageenan-induced paw edema, respectively. In vitro, BxbRAE-100% significantly inhibited proteolytic activity and PLA2, COX-1 and COX-2 activities. In silico, the compounds previously identified in BxbRAE-100% met Lipinski's rule of five and showed adequate ADME properties. Conclusions: These results support the use of B. x buttiana in Traditional Mexican Medicine and highlight its potential for the development of new treatments for pain and inflammation.

Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Globoside Is an Essential Intracellular Factor Required for Parvovirus B19 Endosomal Escape.

Human parvovirus B19 (B19V), like most parvoviruses, possesses phospholipase A2 (PLA2) activity, which is thought to mediate endosomal escape by membrane disruption. Here, we challenge this model and find evidence for a mechanism of B19V entry mediated by the glycosphingolipid globoside without endosome disruption and retrograde transport to the Golgi. We show that B19V PLA2 activity requires specific calcium levels and pH conditions that are not optimal in endosomes. Accordingly, endosomal membrane integrity was maintained during B19V entry. Furthermore, endosomes remained intact when loaded with MS2 bacteriophage particles pseudotyped with multiple B19V PLA2 subunits, providing superior enzymatic potential compared to native B19V. In globoside knockout cells, incoming viruses are arrested in the endosomal compartment and the infection is blocked. Infection can be rescued by promoting endosomal leakage with polyethyleneimine (PEI), demonstrating the essential role of globoside in facilitating endosomal escape. Incoming virus colocalizes with Golgi markers and interfering with Golgi function blocks infection, suggesting that globoside-mediated entry involves the Golgi compartment, which provides conditions favorable for the lipolytic PLA2. Our study challenges the current model of B19V entry and identifies globoside as an essential intracellular receptor required for endosomal escape.

Tumoral Malignancy Decreases Coupled with Higher ROS and Lipid Peroxidation in HCT116 Colon Cancer Cells upon Loss of PRDX6.

Peroxiredoxin 6 (PRDX6) is an atypical member of the peroxiredoxin family that presents not only peroxidase but also phospholipase A2 and lysophosphatidylcholine acyl transferase activities able to act on lipid hydroperoxides of cell membranes. It has been associated with the proliferation and invasive capacity of different tumoral cells including colorectal cancer cells, although the effect of its removal in these cells has not been yet studied. Here, using CRISPR/Cas9 technology, we constructed an HCT116 colorectal cancer cell line knockout for PRDX6 to study whether the mechanisms described for other cancer cells in terms of proliferation, migration, and invasiveness also apply in this tumoral cell line. HCT116 cells lacking PRDX6 showed increased ROS and lipid peroxidation, a decrease in the antioxidant response regulator NRF2, mitochondrial dysfunction, and increased sensitivity to ferroptosis. All these alterations lead to a decrease in proliferation, migration, and invasiveness in these cells. Furthermore, the reduced migratory and invasive capacity of HCT116 cancer cells is consistent with the observed cadherin switch and decrease in pro-invasive proteins such as MMPs. Therefore, the mechanism behind the effects of loss of PRDX6 in HCT116 cells could differ from that in HepG2 cells which is coherent with the fact that the correlation of PRDX6 expression with patient survival is different in hepatocellular carcinomas. Nonetheless, our results point to this protein as a good therapeutic target also for colorectal cancer.

A PLA2 deletion mutant using CRISPR/Cas9 coupled to RNASeq reveals insect immune genes associated with eicosanoid signaling.

Eicosanoids mediate insect immune responses and synthesized by the catalytic activity of phospholipase A2 (PLA2). A uniquely encoded secretory PLA2 (sPLA2) is associated with immune responses of a lepidopteran insect, Spodoptera exigua. Its deletion mutant was generated using a CRISPR/Cas9 genome editing technology. Both wild and mutant lines were then immune-challenged, and the resulting transcripts were compared with their naïve transcripts by RNASeq using the Illumina-HiSeq platform. In total, 12,878 unigenes were further analyzed by differentially expressed gene tools. Over 69% of the expressed genes in S. exigua larvae are modulated in their expression levels by eicosanoids, recorded from CRISPR/Cas9 mutagenesis against an eicosanoid-synthetic gene, Se-sPLA2. Further, about 36% of the immune-associated genes are controlled by the eicosanoids in S. exigua. Indeed, the deletion mutant suffered significant immunosuppression in both cellular and humoral responses in response to bacterial challenge as well as severely reduced developmental and reproductive potentials.

Novel Plasma Biomarkers Associated with Future Peripheral Atherosclerotic Disease and Abdominal Aortic Aneurysm-Insights from Contemporary Prospective Studies from the Malmö Diet and Cancer Study.

The potential utility of inflammatory and hemodynamic plasma biomarkers for the prediction of incident lower extremity arterial disease (LEAD), carotid artery stenosis (CAS), isolated atherosclerotic disease without concomitant abdominal aortic aneurysm (AAA), and isolated AAA without concomitant atherosclerotic disease has not yet been integrated in clinical practice. The main objective of this prospective study was to find predictive plasma biomarkers for cardiovascular disease and to evaluate differences in plasma biomarker profiles between asymptomatic and symptomatic CAS, as well as between isolated atherosclerotic disease and isolated AAA. Blood samples collected at baseline from participants in the prospective Malmö Diet and Cancer study (MDCS) cardiovascular cohort (n = 5550 middle-aged individuals; baseline 1991-1994) were used for plasma biomarker analysis. Validation of each incident cardiovascular diagnosis was performed by random sampling. Cox regression analysis was used to calculate hazard ratios (HRs) per one standard deviation increment of each respective log-transformed plasma biomarker with 95% confidence intervals (CI). Adjusted lipoprotein-associated phospholipase A2 (Lp-PLA2) activity (HR 1.33; CI 1.17-1.52) and mass (HR 1.20; CI 1.05-1.37), C-reactive protein (CRP) (HR 1.55; CI 1.36-1.76), copeptin (HR 1.46; CI 1.19-1.80), N-terminal pro-B-type natriuretic peptide (N-BNP) (HR 1.28; 1.11-1.48), and cystatin C (HR 1.19; 95% 1.10-1.29) were associated with incident symptomatic LEAD. Adjusted N-BNP (HR 1.59; CI 1.20-2.11), mid-regional proadrenomedullin (HR 1.40; CI 1.13-1.73), cystatin C (HR 1.21; CI 1.02-1.43), and CRP (HR 1.53; CI 1.13-1.73) were associated with incident symptomatic but not asymptomatic CAS. Adjusted HR was higher for Lp-PLA2 (mass) for incident isolated AAA compared to for isolated atherosclerotic disease. Plasma biomarker profile data support that subclinical vascular inflammation and cardiovascular stress seem to be relevant for the development of atherosclerotic disease and AAA.

Exploring predictive molecules of acute adverse events in response to volumetric‑modulated arc therapy for prostate cancer using urinary metabolites.

Volumetric-modulated arc therapy (VMAT) is a radiotherapy technique used to treat patients with localized prostate cancer, which is frequently associated with acute adverse events (AEs) that can affect subsequent treatment. Notably, the radiation dose of VMAT can be tailored to each patient. In the present study, a retrospective analysis was performed to predict acute AEs in response to a therapeutic high radiation dose rate based on urinary metabolomic molecules, which are easily collected as noninvasive biosamples. Urine samples from 11 patients with prostate cancer who were treated with VMAT (76 Gy/38 fractions) were collected. The study found that seven patients (~64%) exhibited genitourinary toxicity (Grade 1) and four patients had no AEs. A total of 630 urinary metabolites were then analyzed using a mass spectrometer (QTRAP6500+; AB SCIEX), and 234 relevant molecules for biological and clinical applications were extracted from the absolute quantified metabolite values using the MetaboINDICATOR tool. In the Grade 1 acute AE group, there was a significant negative correlation (rs=-0.297, P<0.05) between the number of VMAT fractions and total phospholipase A2 activity in the urine. Additionally, patients with Grade 1 AEs exhibited a decrease in PC aa C40:1, a phospholipid. These findings suggested that specific lipids found in urinary metabolites may serve as predictive biomarkers for acute AEs in response to external radiotherapy.

The Hepatoprotective Effect of Glycyrrhiza glabra Roots Extract Against Amiodarone Induced Hepatotoxicity in Male Rats

Amiodarone (AMD), a powerful antidysrhythmic medication, can cause hepatotoxicity when used long-term or in high doses. It affects both mitochondrial and lysosomal function because of its lipophilic nature and accumulation in tissues. It also has direct production of ROS. Glycyrrhiza glabra is one of the medicinal plants that have been commonly used for thousands of years. It possesses anti-ulcer, anti-inflammatory and antioxidant properties. In this study, the antihepatotoxic effect of Gg was evaluated against AMD liver toxicity in rats model, thirty rats were taken and divided evenly into five groups given daily doses by gastric gavage oral tube for 3 weeks as follows: the 1st group acted as a control group given D.W., and the 2nd group received AMD at a dose of 300mg/kg for 2 weeks. 3rd, 4th, and 5th groups were pretreated with Gg in doses of 200, 400, and 800 mg, respectively, for one week, then along with AMD for 2 weeks. Hepatic damage, revealed by histology and the increased activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum phospholipase A2 (PLA2) was decreased in the AMD group. Gg extract significantly reduced the elevated AST and ALT levels caused by AMD intoxication, rendering PLA2 to its normal level. It also enhanced liver superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels. Gg extract markedly reverses the increased serum TNF levels induced by AMD; therefore, it may be considered a good hepatoprotective agent.