Phospholipase A2 Activity Research Articles

Proteomic and functional analyses of Lachesis acrochorda snake venom from the Valle del Cauca Department of Colombia

Lachesis acrochorda envenomation has a lethality rate of approximately 90%. Despite its high lethality, little is known about its local and systemic effects and its relationship with its protein content. Thus, to increase knowledge of L. acrochorda snake venom from the Southwestern ecoregion of Colombia, we developed a proteomic analysis using a "bottom-up shotgun proteomic profiling" approach. Besides, we evaluated toxinological properties and compared the effects with the Bothrops asper snake venom activities. The RP-HPLC profile showed similarities with the L. acrochorda snake venom from the Northwestern ecoregion of Colombia. However, the results displayed differences in the protein families identified, probably due to the proteomic identification strategy. The in vitro and in vivo tests showed a L. acrochorda snake venom with Phospholipase A2 and metalloproteinase activities related to myotoxic, edematic, and hemorrhagic effects. Nevertheless, the L. acrochorda snake venom displayed a low lethality despite a large amount of inoculated venom. This investigation's results will help us improve the knowledge about the relationship between the clinical manifestations of L. acrochorda envenomation and the venom protein content.

Evaluation of the properties of Bungarus caeruleus venom and checking the efficacy of antivenom used in Bangladesh for its bite treatment.

As a disaster-prone country with unique geographical features, snake biting is a major public health concern in Bangladesh. The primary reasons of mortality from snakebite include late presentation to the hospital, low efficacy of antivenom, and a lack of adequate management facilities. Because snake venom characteristics vary depending on geographical location, antivenom should be manufactured from snakes native to the region in which it would be administered. Bungarus caeruleus is a highly venomous snake contributing to the major snakebite issue in Bangladesh. Therefore, the neutralization efficacy of the antivenom against B. caeruleus venom was evaluated in the current study along with the characterization of venom. For biological characterization of venom, RP-HPLC and SDS-PAGE profiling, hemolytic activity, hemorrhagic activity, phospholipases A2 (PLA2) activity, edema inducing activity and histopathological observations were carried out following standard protocol. LD50 of the venom was calculated along with neutralization potency of Incepta antivenom through probit analysis. Results showed that venom possesses phospholipase A2 activity, hemolytic activity and edema inducing activity while hemorrhagic activity was absent in the skin of envenomed mice. Histopathological alterations including necrosis, congestion and infiltrations were observed in envenomed mice organs after hematoxylin and eosin staining. Neutralization study showed that Incepta polyvalent antivenom could neutralize (potency 0.53mg/ml) the lethal effect in in vitro study on mice. Further investigation on snakebite epidemiology and clinical observations of the envenomed patients will help in combating the snakebite problem more efficiently.

Lipoprotein-Associated Phospholipase A2 Activity as Potential Biomarker of Vascular Dementia.

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer's disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (n = 136), other dementia subtypes (n = 45), and cognitively normal controls (n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06-5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

Deficiency of Vitamin E and Selenium Enhances Calcium-Independent Phospholipase A2 Activity in Rat Lung and Liver

Conditions promoting oxidative stress, which is implicated in many diseases, activate phospholipases A2, a family of enzymes central to phospholipid metabolism and signal transduction. Little is known about isozyme specificity with respect to this activation process. Accordingly, a dietary deficiency model known to induce oxidative stress was used to investigate phospholipase A2 isozyme activity in rat tissues. Long-Evans hooded rats were fed purified diets for 6 wk with or without the addition of vitamin E and selenium in a 2 ՠ2 factorial design. Phospholipase A2 activity was assessed in lung, liver, kidney and heart cytosol and microsomes in the presence (5 mmol/L CaCl2) or absence (5 mmol/L EGTA) of calcium with dipalmitoylphosphatidylcholine at pH 6.5. Lung phospholipase A2 activity was also assessed with 1-stearoyl-2-arachidonoylphosphatidylcholine as substrate at pH 8.5. Organ samples from rats deficient in both nutrients showed two- to tenfold higher calcium-independent phospholipase A2 activity in lung cytosol and microsomes, and in liver cytosol compared with samples from control and single nutrient-deficient rats. In contrast, the calcium-dependent activity was affected only slightly. The malondialdehyde concentration of the organs was measured and the pattern obtained mirrored that of enhanced phospholipase A2 activity for lung but not for liver. The enhanced phospholipase A2 activity in the lung cytosol and microsomes from rats deficient in both nutrients was partially blocked by p-bromophenacylbromide, further enhanced by dithiothreitol and unaffected by treatment with diisopropylfluorophosphate. These results suggest that deficiency of both vitamin E and selenium activates and/or induces unique calcium-independent forms of phospholipase A2 markedly in rat lung, and to a lesser extent in liver.

Antivenom Activity of Solanum xanthocarpum Hydroethanolic Root Extract Targeting the Enzymes Present in Naja Snake Venom

Background: The work reported in this paper targets the ethnobotanical role of one of the traditional medicinal plant Solanum xanthocarpum, whose medicinal value was reported in Ayurveda. Traditionally Solanum xanthocarpum was used as the antidote for treatment of snake bites by different tribal community of India, to explore and scientifically validate these concept this work was planned. Methods: We have prepared the hydro ethanolic root extract (HERE) of Solanum xanthocarpum and investigated its pharmacological activity both in vitro and in vivo, targeting the enzymes present in Naja snake venom. We have used the wistar albino rat as the animal model in our study. Result: It was inferred by our study that Solanum xanthocarpum is safe for wistar albino rats upto 2000 mg/kg body weight. Phospholipase A2 (PLA2) and anti-fibrinogenolytic activity are significantly neutralized by Solanum xanthocarpum. Dose dependent inhibition of human red blood cell (HRBC) lysis was also observed. In the future, bioactive compounds from HERE could be isolated and standardized to act as an antidote to Naja venom.

PRDX6 Promotes Fatty Acid Oxidation via PLA2-Dependent PPARα Activation in Rats Fed High-Fat Diet.

Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally, which is defined as an excess accumulation of fat caused by the imbalance of lipogenesis and lipid catabolism. Recently, increasing evidence suggests that peroxiredoxin 6 (PRDX6) is involved in the pathogenesis and progression of NAFLD. However, little is known regarding its role in liver lipid catabolism. Results: We found that PRDX6 level was significantly increased in liver tissues after high-fat diet (HFD) treatment. PRDX6 knockout (KO) exacerbated HFD-induced hepatic steatosis. PRDX6 KO did not affect messenger RNA (mRNA) and protein levels of peroxisome proliferator-activated receptor alpha (PPARα). However, PRDX6 KO decreased the mRNA and protein levels of carnitine palmitoyltransferase-1alpha (CPT-1α) and acyl-CoA oxidase 1 (ACOX1), the target genes of PPARα. PRDX6 KO also did not activate AMP-activated protein kinase (AMPK)α/proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), the upstream signal of PPARα. However, PRDX6 KO reduces the levels of PPARα activators, the oxidized fatty acids (9- and 13-hydroxyoctadecadienoic acid) in HFD rats. More interestingly, PRDX6 promoted the production of oxidized fatty acids by hydrolyzing oxidized low-density lipoprotein (Ox-LDL), which depends on its phospholipase A2 (PLA2) activity. PRDX6 mutation on its PLA2 and its competitive phospholipase inhibitor inhibited the production of the oxidized fatty acids as well as the activation of PPARα. Furthermore, PRDX6 overexpression enhanced the transcriptional activation of PPARα. Innovation and Conclusion: This study elucidates for the first time the role of PLA2 enzyme activity of PRDX6 in fatty acid oxidation and reveals a novel mechanism of PRDX6 involved in liver steatosis. Antioxid. Redox Signal. 38, 1184-1200.

In-vitro and In-vivo Neutralization Activity of Methanol Extract of Adansonia digitata Fruit Pulp against Naja nigricollis Venom

Background: Adansonia digitata has been used as a traditional medicine to treat various diseases including snakebite envenomation. Objective: In this study, the protective and ameliorative potentials of crude methanol extract of Adansonia digitata fruit pulp against crude venom of Naja nigricollis in-vitro and in-vivo were investigated. Method: The dose-dependent inhibitory studies, pharmacological, histopathological and in vivo studies were conducted using standard methods. Result: The mean lethal dose of the crude methanolic extract of Adansonia digitata fruit pulp in Wistar rats was > 5,000 mg/kg, while Naja nigricollis venom was 0.89 mg/kg. The anti-lethality effective concentration of the fruit pulp on Naja nigricollis venom was 92.52 mg/ml. Treatment significantly (< 0.05) inhibited the activities of Naja nigricollis phospholipase A2 and dose-dependently reduced Naja nigricollis venom-induced paw oedema at 1-4 hours post-envenomation. In-vivo, treatment with 250 and 500 mg/kg of Adansonia digitata fruit pulp was protective against the clinical signs and mortality. Serum acetylcholinesterase activities were maintained in the group treated with normal saline and the ameliorative groups but decreased significantly (p < 0.05) in other groups. Brain acetylcholinesterase was high in all the groups by day 1 but was reduced with increasing dose by day 2 in the ameliorative groups only. Adansonia digitata fruit pulp also preserved the histoarchitecture of the brain, heart, liver and spleen from venom-induced pathologies. Conclusion: Crude methanolic extract of Adansonia digitata fruit pulp possesses good protective and ameliorative neutralization effects on Naja nigricollis venom and could be promising in the management of snakebite envenomation.

Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death.

Lipid droplets are fat storage organelles ubiquitously distributed across the eukaryotic kingdom. They have a central role in regulating lipid metabolism and undergo a dynamic turnover of biogenesis and breakdown to meet cellular requirements for fatty acids, including polyunsaturated fatty acids. Polyunsaturated fatty acids esterified in membrane phospholipids define membrane fluidity and can be released by the activity of phospholipases A2 to act as ligands for nuclear receptors or to be metabolized into a wide spectrum of lipid signaling mediators. Polyunsaturated fatty acids in membrane phospholipids are also highly susceptible to lipid peroxidation, which if left uncontrolled leads to ferroptotic cell death. On the one hand, lipid droplets act as antioxidant organelles that control polyunsaturated fatty acid storage in triglycerides in order to reduce membrane lipid peroxidation, preserve organelle function and prevent cell death, including ferroptosis. On the other hand, lipid droplet breakdown fine-tunes the delivery of polyunsaturated fatty acids into metabolic and signaling pathways, but unrestricted lipid droplet breakdown may also lead to the release of lethal levels of polyunsaturated fatty acids. Precise regulation of lipid droplet turnover is thus essential for polyunsaturated fatty acid distribution and cellular homeostasis. In this review, we focus on emerging aspects of lipid droplet-mediated regulation of polyunsaturated fatty acid trafficking, including the management of membrane lipid peroxidation, ferroptosis and lipid mediator signaling.

Plasma lipidomic profile of depressive symptoms: a longitudinal study in a large sample of community-dwelling American Indians in the strong heart study.

Dyslipidemia has been associated with depression, but individual lipid species associated with depression remain largely unknown. The temporal relationship between lipid metabolism and the development of depression also remains to be determined. We studied 3721 fasting plasma samples from 1978 American Indians attending two exams (2001-2003, 2006-2009, mean ~5.5 years apart) in the Strong Heart Family Study. Plasma lipids were repeatedly measured by untargeted liquid chromatography-mass spectrometry (LC-MS). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies for Depression (CES-D). Participants at risk for depression were defined as total CES-D score ≥16. Generalized estimating equation (GEE) was used to examine the associations of lipid species with incident or prevalent depression, adjusting for covariates. The associations between changes in lipids and changes in depressive symptoms were additionally adjusted for baseline lipids. We found that lower levels of sphingomyelins and glycerophospholipids and higher level of lysophospholipids were significantly associated with incident and/or prevalent depression. Changes in sphingomyelins, glycerophospholipids, acylcarnitines, fatty acids and triacylglycerols were associated with changes in depressive symptoms and other psychosomatic traits. We also identified differential lipid networks associated with risk of depression. The observed alterations in lipid metabolism may affect depression through increasing the activities of acid sphingomyelinase and phospholipase A2, disturbing neurotransmitters and membrane signaling, enhancing inflammation, oxidative stress, and lipid peroxidation, and/or affecting energy storage in lipid droplets or membrane formation. These findings illuminate the mechanisms through which dyslipidemia may contribute to depression and provide initial evidence for targeting lipid metabolism in developing preventive and therapeutic interventions for depression.

Phytochemical composition and potential anti-inflammatory and antioxidant mechanisms of leaf extracts of Sida linifolia L. (Malvaceae)

IntroductionThe classes of phytocompounds and in vitro anti-inflammatory and antioxidant potentials of crude aqueous extract (CAE) and ethanol extract (CEE) of Sida linifolia L. leaves were studied. MethodsThe assayed in vitro anti-inflammatory parameters were phospholipase A2 activity, platelet aggregation, albumin denaturation, membrane stabilization, protease inhibition, and heat-induced membrane hemolysis using the human red blood cells (HRBCs) method. Also, antioxidant properties of extracts were determined using reducing power assay, nitric oxide assay, total antioxidant capacity assay, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The anti-inflammatory study used aspirin and prednisolone as reference drugs, while the antioxidant assay deployed butylated hydroxytoluene (BHT), gallic acid, and ascorbic acid as standard drugs. All parameters were determined following conventional procedures. Results and discussionPhytochemical screening of both extracts showed varying amounts of tannins, saponins, flavonoids, steroids, cyanogenic compounds, glycoside, alkaloids, phenolics, and terpenoids. At various concentrations (0.2–1.0 mg/ml), the CAE and CEE exhibited significantly (P < 0.05) high % anti-inflammatory activities similar to the standard drugs (aspirin/prednisolone), and these correlated positively with concentration. However, CAE exhibited better anti-inflammatory activities than CEE across all the parameters assayed. The in vitro antioxidant study revealed that both extracts demonstrated good antioxidant activities, which increased with concentrations. The ranges of IC50 values (in mg/ml) for CAE (0.64–0.92) and CEE (0.51–0.62) showed that CEE possesses more antioxidant potential compared with CAE; however, both extracts were less potent compared with gallic acid (0.47), ascorbic acid (0.32–0.50), and BHT (0.30). ConclusionsThis study suggests that Sida linifolia leaf extracts are rich in some classes of biologically active phytocompounds and exhibit good anti-inflammatory and antioxidant activities.

Montane Rattlesnakes in México: Venoms of Crotalus tancitarensis and Related Species within the Crotalus intermedius Group.

The Crotalus intermedius group is a clade of rattlesnakes consisting of several species adapted to a high elevation habitat, primarily in México. Crotalus tancitarensis was previously classified as C. intermedius, until individuals occurring on Cerro Tancítaro in Michoacán, México, were reevaluated and classified as a new species (C. tancitarensis) based on scale pattern and geographic location. This study aimed to characterize the venom of C. tancitarensis and compare the venom profile to those of other species within the Crotalus intermedius group using gel electrophoresis, biochemical assays, reverse-phase high performance liquid chromatography, mass spectrometry, and lethal toxicity (LD50) assays. Results show that the venom profiles of species within the Crotalus intermedius group are similar, but with distinct differences in phospholipase A2 (PLA2), metalloproteinase PI (SVMP PI), and kallikrein-like serine proteinase (SVSP) activity and relative abundance. Proteomic analysis indicated that the highland forms produce venoms with 50-60 protein isoforms and a composition typical of type I rattlesnake venoms (abundant SVMPs, lack of presynaptic PLA2-based neurotoxins), as well as a diversity of typical Crotalus venom components such as serine proteinases, PLA2s, C-type lectins, and less abundant toxins (LAAOs, CRiSPs, etc.). The overall venom profile of C. tancitarensis appears most similar to C. transversus, which is consistent with a previous mitochondrial DNA analysis of the Crotalus intermedius group. These rattlesnakes of the Mexican highlands represent a radiation of high elevation specialists, and in spite of divergence of species in these Sky Island habitats, venom composition of species analyzed here has remained relatively conserved. The majority of protein family isoforms are conserved in all members of the clade, and as seen in other more broadly distributed rattlesnake species, differences in their venoms are largely due to relative concentrations of specific components.

Platelet aggregation inhibitors from Bothrops alternatus snake venom

Snake venoms are a complex mixture of proteins and peptides that can activate/inhibit platelet aggregation. Bothrops alternatus venom include three main families: metalloproteinases (SVMPs), serinoproteinases (SVSPs) and phospholipases A2 (PLA2s), among other minor components. In this work, we used inhibitor cocktails (containing Na2-EDTA, PMSF and/or pBPB) to investigate the effect of these three families and of baltergin (a PIII SVMP) on platelet aggregation by a turbidmetric method using a microplate reader. Cocktails 1 (active SVMPs) and 2 (active PLA2s) significantly reduced aggregation induced by ristocetin and collagen and by collagen and thrombin, respectively. Cocktail 3 (active SVSPs) showed a mild activation of aggregation, indicating the content of thrombin-like enzymes (TLEs) in this venom is low. Cocktail 4 (active minor components) displayed inhibitory effect with all agonists assayed (ristocetin, ADP, collagen and thrombin) but at higher IC50 values. Baltergin exhibited inhibitory effect when the catalytic domain was active for ristocetin-stimulated platelet aggregation and showed a non-enzymatic mechanism of inhibition when collagen was used as agonist. It was not able to disaggregate platelet thrombus. We conclude that B. alternatus venom is a source of natural inhibitors of platelet aggregation due to the action of SVMPs and PLA2s. Other minor components such as C-type lectins likely contribute to the antiplatelet effect. The interest in knowing the action of venom components on platelet function lies both in the understanding of the pathophysiology of snake bite envenomation and in their biotechnological application.

Amelioration of chilling injury in ‘Guifei’ mango fruit by melatonin is associated with regulation of lipid metabolic enzymes and remodeling of lipidome

The susceptibility of harvested mango fruit to chilling injury (CI) restricts quality preservation. Cell membranes are recognized as primary sites of damage in fruits in response to cold stress, and the maintenance of membrane integrity and function is conducive to alleviating fruit CI. This study aimed to investigate the effects of melatonin (MT), an important bioactive molecule, on cold tolerance in relation to membrane lipid homeostasis in ‘Guifei’ mango fruit during refrigeration. The results showed that application of 0.5 mmol L−1 MT to mango fruit reduced the CI index, discoloration, relative electrolyte leakage (REL) and malondialdehyde (MDA) content while maintaining a higher Fv/Fm value. Reduced activities of phospholipase D (PLD), phospholipase C (PLC) and lipoxygenase (LOX) but increased phospholipase A2 (PLA2) activity were observed in MT-treated fruit compared to control fruit. Furthermore, lipidomic analysis revealed changes in molecular species profiles of various classes of lipids (phospholipids, lysophospholipids, sphingolipids and glycerides) in response to MT. These results indicate that MT could trigger remodeling of lipid molecules by regulating membrane lipid metabolism, which would be conducive to maintaining membrane structure and activating downstream signaling pathways, contributing to improved cold tolerance in mango fruit.

Preimplantation apoptotic endometrial caspase-3–mediated phospholipase A2 activation: a potential component in programming uterine receptivity

To examine the activation and consequence of uterine apoptotic caspase-3 action on day 1 post coitus (dpc) in the pregnant mouse. Previously we have demonstrated that pregnant uterine caspase-3 activation from mid to late gestation isolated to the myometrial compartment is largely non-apoptotic and controls uterine quiescence. We have also previously demonstrated that apoptotic caspase-3 activation, isolated to the endometrial compartment at term regulated endometrial prostaglandin synthesis METHODS: Uteri were isolated from pseudo pregnant (PsP) and non-ligated controls (GD), unilateral (UL) and bilateral ligated (BL) uterine horn mouse models at 1, 3 and 6 dpc. Uteri were examined for apoptotic indices, such as caspase-3 activation and TUNEL staining. Immunohistochemical analysis identified the site of uterine apoptotic caspase-3 activation. The truncated form of phospholipase A2 (tiPLA2) was examined as a measure of apoptotic caspase-3 mediated iPLA2 activation. We have identified the site and impact of uterine apoptotic caspase-3 activation utilizing uteri isolated from non-pregnant control animals at estrous and diestrous and control pregnant mice at 1-19 dpc. Our analysis determined that apoptotic caspase-3 and iPLA2 activation were limited to the endometrial compartments of the control and unilateral ligated uteri on 1dpc and were not found in the pseudo pregnant or bilateral ligated uterine horn or on 3 or 6 dpc in the control and unilateral ligated uteri. In this study we determined that uterine caspase-3 activation on 1 dpc, which is endometrial and apoptotic in nature, may play a potential role in regulating the previously reported pre-implantation surge in endometrial PGE2 synthesis through apoptotic caspase-3 mediated iPLA2 activation. Our data indicates that the presence of a conceptus on 1 dpc likely triggers an increase in endometrial apoptotic caspase-3 mediated iPLA2 activation. iPLA2 when activated causes the hydrolysis of fatty acids resulting in arachidonic acid release and production of PGE2, which in early pregnancy has been demonstrated to act in a leutoprotective manner, prolonging progesterone synthesis and promoting uterine receptivity.

Mechanistic Insights of Rutin against Metabolic Disorders

Rutin, a quercetin glycoside comes under the class flavonol. The aglycone part of rutin is known as quercetin. It is found in numerous fruits and plants, especially apricots, buckwheat, cherries, grapefruit, grapes, oranges, and plums. Rutin shows cardioprotective, neuroprotective, and nephroprotective effects mediated via its antioxidant mechanism. The neuroprotective effect of rutin is utilized in the treatment of Parkinson’s disease. It has been documented in the scientific literature that rutin improves obesity through brown fat activation, modulates DNA damage signaling in cancer cells, reduces inflammation by inhibiting eicosanoid biosynthesis, lipoxygenase, cyclooxygenase, and phospholipase A2 activities, enhances insulin release as well as decreases the expression of resistin along with increases the expression of PPAR γ in diabetic patients, increases total cholesterol, high-density lipoprotein and very low-density lipoprotein levels, whereas low-density lipoprotein level decreases resulting into antilipidemic activity, inhibits diabetic liver injury and diabetic cardiomyopathy. Repurposing of rutin was also done against SARS-CoV-2. Our study aims to survey the most recent progress with emphasis on how rutin adapts intracellular signaling cascades to treat different metabolic disorders. However, the precise cellular and molecular mechanisms of rutin are known and more clinical studies are required to provide a novel therapeutic approach for the treatment of metabolic disorders.

Changes in Lp-PLA 2 are associated with elevated alanine aminotransferase levels: A nested case-control study in a three-year prospective cohort

Background/Aim: Elevation in liver enzymes and hepatic fat may indicate a higher susceptibility to cardiovascular disease (CVD). This research sought to find anthropometric/biochemical variables significantly related to the alanine aminotransferase (ALT) increase in healthy populations. Methods: Nine hundred healthy subjects were included in a 3-year prospective cohort study. The initial screening revealed that 538 were found to be nondiabetic (fasting glucose &lt; 126 mg/dL) and had normal ALT levels. Among them, 79 individuals with slightly elevated ALT levels after three years were assigned to the elevated ALT group. Of the remaining 459 participants, 241 subjects matched to the increased ALT group were the control group. Results: After three years of follow-up, individuals with elevated ALT showed notably higher aspartate aminotransferase (AST), ALT, gamma-glutamyl-transferase (g-GT), high sensitivity C-reactive protein (hs-CRP), lipoprotein-associated phospholipase A2 (Lp-PLA2 ) activity, oxidised low-density lipoprotein (ox-LDL), urinary 8-epi-prostaglandin F2a (8-epi-PGF2a) levels and brachial-ankle pulse wave velocity (ba-PWV) in comparison to the control group. Changes (D) in ALT showed a positive correlation with D AST, D gammaGT, D hs-CRP, D Lp-PLA2 activity, D ox-LDL, D urinary 8-epi-PGF2a and D ba-PWV. Furthermore, a direct positive link was observed between the D Lp-PLA2 activity and D AST, D ox-LDL and D ba-PWV. Conclusion: Increased Lp-PLA2 activity and other CVD risk indicators were observed to have a pronounced association with elevated ALT levels. This mild ALT elevation could potentially contribute to chronic low-grade inflammation.

Prevalence of resistant hypertension and its relation with plasma lipoprotein-associated phospholipase A2

Background: A major modifiable risk factor for cardiovascular disease is hypertension. Resistant hypertension is observed to be associated with an increased likelihood of deleterious effects such as cardiovascular events, cerebrovascular accident, and renal dysfunction. The raised levels of inflammatory cytokines in the plasma like the C-reactive protein (CRP) have previously been observed to be significantly raised in hypertensive patients, but the overlying mechanisms corresponding to these processes remain unknown. Materials and Methods: In essence, this was an observational study with data collected from a population at a specific moment in the time to assess the relationships between the variables analyzed. A total of 200 individuals with arterial hypertension took part in the study. Fasting venous blood was obtained to evaluate plasma lipoprotein-related phospholipase A2 (Lp-PLA2) activity, and baseline data were collected. To diagnose RH, a 24-h ambulatory blood pressure management was done. Results: RH was observed among 100 patients and found to be predominant among males and older individuals, who were smokers and having hypertension for a longer period of time with higher Lp-PLA2 activity. More RH patients used calcium channel blockers and diuretics, while a fewer used angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and statins (P 0.05 for all comparisons). Conclusion: The plasma Lp-PLA2 activity beyond a certain threshold suggests a raised risk of RH, and the statins can help in reducing the RH incidence among persons with high Lp-PLA2 levels.

Functional mass spectrometry imaging maps phospholipase-A2 enzyme activity during osteoarthritis progression.

Background: Enzymes are central components of many physiological processes, and changes in enzyme activity are linked to numerous disease states, including osteoarthritis (OA). Assessing changes in enzyme function can be challenging because of difficulties in separating affected tissue areas that result in the homogenisation of healthy and diseased cells. Direct correlation between spatially-resolved enzyme distribution(s) and diseased cells/tissues can thus lead to advances in our understanding of OA pathophysiology. Herein, we present a method that uses mass spectrometry imaging (MSI) to visualise the distribution of lipase enzymes and their downstream lipid products in fresh bone and cartilage tissue sections. Immunohistostaining of adjacent tissue sections was then used to identify OA cells/tissues, which were then statistically correlated with molecular-level images. Methods: MSI was used to image lipase enzymes, their substrates, and their metabolic products to validate enzymatic activity and correlate to OA regions determined by immunohistochemistry (IHC). Based on the modified Mankin score, six non-OA and OA patient-matched osteochondral samples were analysed by matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI). Due to the involvement of phospholipase A2 (PLA2) in inflammatory pathways, explant tissues were treated with IL-1β to mimic inflammation observed in OA. Bovine explant tissues were then subject to MSI methods to observe the spatial distribution of PLA2. Results: Compared with non-OA samples, OA samples showed an elevated level of multiple arachidonic acid (AA)-containing phospholipids (P < 0.001), in which the elevation in the surface and deep layer cartilage of OA tissues is correlated to elevated PLA2 activity (P < 0.001). Bovine explant tissues treated with IL-1β to mimic OA pathophysiology validated these results and displayed elevated PLA2 levels in OA mimic samples relative to the controls (P < 0.001). It was established that the PLA2G2A isoform specifically was responsible for PLA2 enzyme activity changes in OA tissues (P < 0.001). Conclusion: Our results present a reliable method for imaging enzyme dynamics in OA cartilage, which sets up the foundation for future spatial enzyme dynamics in the OA field. We demonstrated that OA patients exhibit increased expression of PLA2G2A at the superficial and deep cartilage zone that degrades cartilage differently at the spatial level. A tissue-specific PLA2G2A precision inhibition may be the potential target for OA.

Oxoeicosanoid signaling mediates early antimicrobial defense in zebrafish

5-oxoETE is a bioactive lipid derived from arachidonic acid generated when phospholipase A2 activation coincides with oxidative stress. Through its G protein-coupled receptor OXER1, pure 5-oxoETE is a potent leukocyte chemoattractant. Yet, its physiological function has remained elusive owing to the unusual OXER1 conservation pattern. OXER1 is conserved from fish to primates but not in rodents, precluding genetic loss-of-function studies in mouse. To determine its physiological role, we combine transcriptomic, lipidomic, and intravital imaging assays with genetic perturbations of the OXER1 ortholog hcar1-4 in zebrafish. Pseudomonas aeruginosa infection induces the synthesis of 5-oxoETE and its receptor, along with other inflammatory pathways. Hcar1-4 deletion attenuates neutrophil recruitment and decreases post-infection survival, which could be rescued by ectopic expression of hcar1-4 or human OXER1. By revealing 5-oxoETE as dominant lipid regulator of the early antimicrobial response in a non-rodent vertebrate, our work expands the current, rodent-centric view of early inflammation.

Anti-Oxidant and Pro-Oxidant Effects of Peroxiredoxin 6: A Potential Target in Respiratory Diseases.

Peroxiredoxin 6 (PRDX6) is widely distributed in several organs, especially the lungs. The role of PRDX6 in oxidative stress is controversial and even contradictory, as indicated by research conducted over the past 20 years. PRDX6 has anti-oxidant or pro-oxidant effects on oxidative stress in different diseases. It can even exhibit both anti-oxidant and pro-oxidant effects in the same disease. These findings are attributed to the fact that PRDX6 is a multifunctional enzyme. The peroxidase and phospholipase A2 activity of PRDX6 is closely related to its anti-oxidant and pro-oxidant effects, which leads to the conflicting regulatory effects of PRDX6 on oxidative stress in respiratory diseases. Moreover, PRDX6 interacts with multiple redox signaling pathways to interfere with cell proliferation and apoptosis. PRDX6 has become a new target in respiratory disease research due to its important regulatory role in oxidative stress. In this paper, the role of PRDX6 in oxidative stress in respiratory diseases and the research progress in targeting PRDX6 are reviewed.