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Abstract Background In mouse models of atherosclerosis, knockout of the PLA2G2A gene has been shown to reduce the volume of atherosclerotic plaques. Clinical trials have demonstrated the potential of using the sPLA2 inhibitor Varespladib in combination with statins to reduce lipid levels. However, this approach has not yielded the expected results in reducing the risk of cardiovascular events. Therefore, it is necessary to further investigate the mechanisms of PLA2G2A. Methods Single-cell transcriptome data from two sets of carotid plaques, combined with clinical patient information. were used to describe the expression characteristics of PLA2G2A in carotid plaques at different stages. In order to explore the mechanisms of PLA2G2A, we conducted enrichment analysis, cell–cell communication analysis and single-cell regulatory network inference and clustering analyses. We validated the above findings at the cellular level. Results Our findings indicate that PLA2G2A is primarily expressed in vascular fibroblasts and shows significant cell interactions with macrophages in the early-stage, especially in complement and inflammation-related pathways. We also found that serum sPLA2 levels have stronger diagnostic value in patients with mild carotid artery stenosis. Subsequent comparisons of single-cell transcriptomic data from early and late-stage carotid artery plaques corroborated these findings and predicted transcription factors that might regulate the progression of early carotid atherosclerosis (CA) and the expression of PLA2G2A. Conclusions Our study discovered and validated that PLA2G2A is highly expressed by vascular fibroblasts and promotes plaque progression through the activation of macrophage complement and coagulation cascade pathways in the early-stage of CA.

Background Hypertension is a common chronic non-communicable disease in clinical practice, and its prevalence is on the rise globally due to population aging and changes in human lifestyles. Prolonged high blood pressure can lead to damage to various target organs such as the heart, brain, kidneys, and retina, severely threatening human health and being a major cause of global disease burden. The left ventricle, as the primary target of end-organ damage, its structural changes are also the pathological basis for the development of many cardiovascular diseases. Objective This study aims to explore the relationship between the atherogenic index of plasma (AIP) and serum lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and left ventricular hypertrophy (LVH) in patients with primary hypertension. Methods A total of 167 patients with primary hypertension who visited the Department of Cardiovascular Medicine at the Second Affiliated Hospital of Zhengzhou University from October 2021 to June 2023 were enrolled in this study. Baseline data of the patients were collected, and fasting venous blood biochemical markers were measured. Echocardiograms were conducted within 24 hours of admission to calculate left ventricular mass (LVM) and left ventricular mass index (LVMI). Patients were divided into non-left ventricular hypertrophy (NLVH) group (87 patients) and LVH group (80 patients) based on LVMI. Pearson correlation test and Spearman rank correlation analysis were used to investigate the correlation between serum Lp-PLA2 level, AIP and echocardiographic parameters. Multivariate Logistic regression analysis was used to explore the influencing factors of LVH in hypertensive patients. Receiver operating characteristic (ROC) curve was plotted to explore the diagnostic value of serum Lp-PLA2 level and AIP in hypertensive patients with LVH, and the area under ROC curve (AUC) was calculated. Results Patients in the LVH group had higher age, duration of hypertension, levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), left ventricular posterior wall thickness (LVWPT), interventricular septal thickness (IVST), left ventricular end-diastolic diameter (LVEDd), left atrial end-systolic diameter (LAESd), Lp-PLA2 levels, AIP, LVM, and LVMI compared to the NLVH group (P

Lipoprotein-associated phospholipase A2(Lp-PLA2) is a protein composed of 441 amino acids, which can promote the aggregation of inflammatory cells to the inflammatory response site and the release of inflammatory factors. It can promote the synthesis of matrix metalloproteinases, increase the number of foam cells and extra cellular matrix in atherosclerotic plaque, attenuate plaque fiber cap and prone to rupture, thus promote the onset of acute coronary syndrome(ACS). Therefore, the determination and regulation of Lp-PLA2 levels in patients with ACS are clinically significant.

The widespread geographical distribution of Russell’s vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA2 inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA2 fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell’s viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100–300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom.

AbstractObjective The aim of this study was to investigate diagnosis of lipoprotein-associated phospholipase A2 (Lp-PLA2) in early diabetic nephropathy (DN).Methods A total of 342 type 2 diabetes mellitus (T2DM) patients hospitalized in department of metabolism and nephrology in our hospital from January 2019 to December 2019 were randomly selected. Patients were divided into three groups via urine albumin level: diabetes mellitus (DM) group, simple diabetes group (114 patients, urinary albumin creatinine ratio (UACR) 300mg/g). Eighty healthy adults were examined at the same time. Lp-PLA2, fasting blood glucose (FBG), creatinine (Cr), triglyceride (TG), total cholesterol (TCHOL), high-density lipoprotein (HDL), low-density lipoprotein (LDL), haemoglobin A1c (HbA1c), blood urea nitrogen/creatinine (BUN/Cr), estimated glomerular filtration rate (eGFR), 24-h urine protein, albumin and creatinine of all subjects were detected and compared. Pearson’s correlation analysis and multiple ordered logistic regression were used to investigate the correlation between serum Lp-PLA2 level and DN. The possibility of Lp-PLA2 in the diagnosis of early DN was studied by using the subject working curve.Results Lp-PLA2 level in DN1 and DN2 groups was significantly higher than that in DM group, with statistical difference (p

Snakes contain three types of phospholipase A2 (PLA2)-inhibitory proteins in their blood, PLIα, β, and γ, which protect them from their own venom, PLA2. PLIβ is the snake ortholog of leucine-rich α2 glycoprotein (LRG). Since autologous cytochrome c (Cyt c) serves as an endogenous ligand for LRG, in this study, we purified snake LRGs from various snake serum samples using Cyt c affinity chromatography. All purified snake LRGs were found to be dimers linked by disulfide bonds. Laticauda semifasciata and Naja kaouthia LRGs showed no inhibitory activity against L. semifasciata PLA2 and weak inhibitory activity against Gloydius brevicauda basic PLA2. Elaphe climacophora PLIβ had weaker inhibitory activity against G. brevicauda basic PLA2 than G. brevicauda and Elaphe quadrivirgata PLIs, which are abundant in blood and known to neutralize G. brevicauda basic PLA2. Protobothrops flavoviridis LRG showed no inhibitory activity against basic venom PLA2, PL-X, or G. brevicauda basic PLA2. Binding analysis of P. flavoviridis LRG using surface plasmon resonance showed very strong binding to snake Cyt c, followed by that to horse Cyt c, weak binding to yeast Cyt c, and no binding to P. flavoviridis PL-X or BPI/II. We also deduced the amino acid sequences of L. semifasciata and P. flavoviridis LRG by means of cDNA sequencing and compared them with those of other known sequences of PLIs and LRGs. This study concluded that snake LRG can potentially inhibit basic PLA2, but, whether it actually functions as a PLA2-inhibitory protein, PLIβ, depends on the snake.

Despite the informative value of ultrasound examination of atherosclerotic vascular lesions, predicting­ the plaque vulnerabili­ty remains difficult. Circulating blood biomarkers could provide additional criteria that would allow better determination of the risk of recurrent stroke. The aim of our study was to estimate the level of C-reactive protein (CRP), low-density lipoproteins (LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) in the blood of patients in the early recovery period of atherothrombotic stroke depending on the density of atherosclerotic plaque according to duplex scanning of cerebral vessels. Clinical and laboratory analysis of 69 men and 61 women aged (60.42 ± 7.40) years in the early recovery period of atherothrombotic stroke was conducted. Depending on the structure of the atherosclerotic plaque the examinees were divided into two groups with stable (n = 80) and unstable (n = 50) atherosclerotic layers. The blood lipid spectrum was examined on a biochemical analyzer Screen master, the level of CRP was determined with a diagnostic kit and that of Lp-PLA2 by ELISA. Significantly higher levels of LDL, CRP and Lp-PLA2 were observed in patients with unstable atherosclerotic plaque compared to patients with stable atherosclerotic plaque in the early recovery period of atherothrombotic stroke. The increased level of LDL, CRP, and Lp-PLA2 in patients with cerebral atherosclerosis can be considered as an indicator of the vulnerability of atherosclerotic plaques, prone to rupture, and as a prognostic marker of repeated acute ischemic events.

Methicillin-resistant Staphylococcus aureus (MRSA) has been classified as a high priority pathogen by the World Health Organization underlining the high demand for new therapeutics to treat infections. Human group IIA-secreted phospholipase A2 (hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, including S. aureus. To determine hGIIA-resistance mechanisms of MRSA, we screened the Nebraska Transposon Mutant Library using a sublethal concentration of recombinant hGIIA. We identified and confirmed the role of lspA, encoding the lipoprotein signal peptidase LspA, as a new hGIIA resistance gene in both in vitro assays and an infection model in hGIIA-transgenic mice. Increased susceptibility of the lspA mutant was associated with enhanced activity of hGIIA on the cell membrane. Moreover, lspA deletion increased susceptibility to daptomycin, a last-resort antibiotic to treat MRSA infections. MRSA wild type could be sensitized to hGIIA and daptomycin killing through exposure to LspA-specific inhibitors globomycin and myxovirescin A1. Analysis of >26,000 S. aureus genomes showed that LspA is highly sequence-conserved, suggesting universal application of LspA inhibition. The role of LspA in hGIIA resistance was not restricted to MRSA since Streptococcus mutans and Enterococcus faecalis were also more hGIIA-susceptible after lspA deletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological interference with LspA may disarm Gram-positive pathogens, including MRSA, to enhance clearance by innate host defense molecules and clinically applied antibiotics.

Among the various natural compounds used in alternative and Oriental medicine, toxins isolated from different organisms have had their application for many years, and Apis mellifera venom has been studied the most extensively. Numerous studies dealing with the positive assets of bee venom (BV) indicated its beneficial properties. The usage of bee products to prevent the occurrence of diseases and for their treatment is often referred to as apitherapy and is based mainly on the experience of the traditional system of medical practice in diverse ethnic communities. Today, a large number of studies are focused on the antitumor effects of BV, which are mainly attributed to its basic polypeptide melittin (MEL). Previous studies have indicated that BV and its major constituent MEL cause a strong toxic effect on different cancer cells, such as liver, lung, bladder, kidney, prostate, breast, and leukemia cells, while a less pronounced effect was observed in normal non-target cells. Their proposed mechanisms of action, such as the effect on proliferation and growth inhibition, cell cycle alterations, and induction of cell death through several cancer cell death mechanisms, are associated with the activation of phospholipase A2 (PLA2), caspases, and matrix metalloproteinases that destroy cancer cells. Numerous cellular effects of BV and MEL need to be elucidated on the molecular level, while the key issue has to do with the trigger of the apoptotic cascade. Apoptosis could be either a consequence of the plasmatic membrane fenestration or the result of the direct interaction of the BV components with pro-apoptotic and anti-apoptotic factors. The interaction of BV peptides and enzymes with the plasma membrane is a crucial step in the whole process. However, before its possible application as a remedy, it is crucial to identify the correct route of exposure and dosage of BV and MEL for potential therapeutic use as well as potential side effects on normal cells and tissues to avoid any possible adverse event.

Viper venom phospholipase A2 enzymes (vvPLA2s) and phospholipase A2-like (PLA2-like) proteins are two of the principal toxins in viper venom that are responsible for the severe myotoxic and neurotoxic effects caused by snakebite envenoming, among other pathologies. As snakebite envenoming is the deadliest neglected tropical disease, a complete understanding of these proteins’ properties and their mechanisms of action is urgently needed. Therefore, we created a database comprising information on the holo-form, cofactor-bound 3D structure of 217 vvPLA2 and PLA2-like proteins in their physiologic environment, as well as 79 membrane-bound viper species from 24 genera, which we have made available to the scientific community to accelerate the development of new anti-snakebite drugs. In addition, the analysis of the sequenced, 3D structure of the database proteins reveals essential aspects of the anatomy of the proteins, their toxicity mechanisms, and the conserved binding site areas that may anchor universal interspecific inhibitors. Moreover, it pinpoints hypotheses for the molecular origin of the myotoxicity of the PLA2-like proteins. Altogether, this study provides an understanding of the diversity of these toxins and how they are conserved, and it indicates how to develop broad, interspecies, efficient small-molecule inhibitors to target the toxin’s many mechanisms of action.

Phospholipases A2 (PLA2s) are a large family of snake toxins manifesting diverse biological effects, which are not always related to phospholipolytic activity. Snake venom PLA2s (svPLA2s) are extracellular proteins with a molecular mass of 13–14 kDa. They are present in venoms in the form of monomers, dimers, and larger oligomers. The cardiovascular system is one of the multiple svPLA2 targets in prey organisms. The results obtained previously on the cardiovascular effects of monomeric svPLA2s were inconsistent, while the data on the dimeric svPLA2 crotoxin from the rattlesnake Crotalus durissus terrificus showed that it significantly reduced the contractile force of guinea pig hearts. Here, we studied the effects of the heterodimeric svPLA2 HDP-1 from the viper Vipera nikolskii on papillary muscle (PM) contractility and the tension of the aortic rings (ARs). HDP-1 is structurally different from crotoxin, and over a wide range of concentrations, it produced a long-term, stable, positive inotropic effect in PMs, which did not turn into contractures at the concentrations studied. This also distinguishes HDP-1 from the monomeric svPLA2s, which at high concentrations inhibited cardiac function. HDP-1, when acting on ARs preconstricted with 10 μM phenylephrine, induced a vasorelaxant effect, similar to some other svPLA2s. These are the first indications of the cardiac and vascular effects of true vipers’ heterodimeric svPLA2s.

Aim:This study aimed to compare the serum phospholipase A2, neutrophil/lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV) levels of patients who presented to our emergency department due to scorpion stings and to determine a laboratory parameter that could assist in clinical grading.Materials and Methods:Sixty-three patients presenting to the emergency department due to scorpion stings and 33 volunteers presenting for other reasons between May and October 2018 were included in the study. The serum phospholipase A2, NRL, RDW and MPV levels of the patients were determined and compared with the control group.Results:In the evaluation performed in the patient group, the mean serum leukocyte and serum lymphocytes were higher and the RDW mean was statistically significantly lower compared to the control group, (p=0.001, 0.003, and 0.004, respectively). There was no significant difference between the patient and control groups in terms of the serum MPV, platelet and serum phospholipase levels (p>0.05). When the patients’ serum MPV values were compared according to their clinical grade, a statistically significant correlation was found (rho: - 0.432, p

Viruses are known to infect most types of organisms. In humans, they can cause several diseases that range from mild to severe. Although many antiviral therapies have been developed, viral infections continue to be a leading cause of morbidity and mortality worldwide. Therefore, the discovery of new and effective antiviral agents is desperately needed. Animal venoms are a rich source of bioactive molecules found in natural goods that have been used since ancient times in alternative medicine to treat a variety of human diseases. Recently, and with the onset of the COVID-19 pandemic, scientists have regained their interest in the possible use of natural products, such as bee venom (BV), as a potential antiviral agent to treat viral infections. BV is known to exert many therapeutic activities such as anti-proliferative, anti-bacterial, and anti-inflammatory effects. However, there is limited discussion of the antiviral activity of BV in the literature. Therefore, this review aims to highlight the antiviral properties of BV and its two primary constituents, melittin (MEL) and phospholipase A2 (PLA2), against a variety of enveloped and non-enveloped viruses. Finally, the innovative strategies used to reduce the toxicity of BV and its two compounds for the development of new antiviral treatments are also considered.

Abstract Background Secretory phospholipase A2 group IIA (sPLA2-IIA) is an independent risk factor for cardiovascular disease, but its role on high-density lipoprotein cholesterol (HDL-C) level has not been clarified. The aim of the present study was to explore the association between circulating sPLA2-IIA and HDL-C, and to evaluate if sPLA2-IIA enhances cholesterol efflux capacity through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ), liver X receptor α (LXR-α), and ATP-binding cassette A1 (ABCA1). Methods 131 patients with coronary artery disease were enrolled. The plasma level of sPLA2-IIA was tested with enzyme-linked immunosorbent assay kit, and serum lipids were assessed by biochemical analyzer. Human monocyte-macrophage cell line THP-1 was co-incubated with sPLA2-IIA in the presence/absence of selective PPAR-γ antagonist GW9662 in vitro. Real-time PCR and Western-blot were employed to measure the mRNA and protein expressions of PPAR-γ, LXR-α, and ABCA1, respectively. The cholesterol efflux was evaluated by using an assay kit. Results In subjects, circulating level of sPLA2-IIA was positively related with that of HDL-C (r = 0.196, p = 0.024). The plasma level of sPLA2-IIA was significantly higher in the high HDL-C (≥ 1.04 mmol/L) group (7477.828 pg/mL) than that in low HDL-C (

Abstract Background Most medicinal plants presently employed in traditional medicine are used without scientific evidence, thereby suggesting a need to explore efficient and reliable investigations of their potential. We, therefore, conducted the present study to ascertain the efficacy of flavonoid-rich extract of Peltophorum pterocarpum sterm-bark in the treatment and management of inflammatory disorders as employed in folk medicine. Materials and methods Flavonoid-rich extract of Peltophorum pterocarpum sterm-bark and a total of fifty-five (55) Wistar rats were used for this study. Eighteen (18) mice were used for toxicity testing, and the phytochemical analysis was done using the Trease and Evans method, while the acute toxicity was done using Lorke’s method. In vivo anti-inflammatory study was done using the egg albumin-induced paw oedema method, while the in vitro anti-inflammatory studies were performed for the extract using phospholipase A2 inhibition and calcium chloride-induced platelet aggregation assays. Results The phytochemical analysis revealed that the extract of Peltophorum pterocarpum sterm-bark contains tannins, terpenoids, steroids, phenols, alkaloids, flavonoids, glycosides, and saponins ranging from 0.307 ± 0.02 to 1279.567 ± 149.868. The acute toxicity test of the extract showed no toxicity up to 5000 mg/kg body weight. In the systemic oedema of the rat paw, scalar doses of the extract significantly (p

For over a century, polyclonal antibodies have been used to treat snakebite envenoming and are still considered by the WHO as the only scientifically validated treatment for snakebites. Nevertheless, moderate innovations have been introduced to this immunotherapy. New strategies and approaches to understanding how antibodies recognize and neutralize snake toxins represent a challenge for next-generation antivenoms. The neurotoxic activity of Micrurus venom is mainly due to two distinct protein families, three-finger toxins (3FTx) and phospholipases A2 (PLA2). Structural conservation among protein family members may represent an opportunity to generate neutralizing monoclonal antibodies (mAbs) against family-conserved epitopes. In this work, we sought to produce a set of monoclonal antibodies against the most toxic components of M. altirostris venom. To this end, the crude venom was fractionated, and its major toxic proteins were identified and used to generate a panel of five mAbs. The specificity of these mAbs was characterized by ELISA and antivenomics approaches. Two of the generated mAbs recognized PLA2 epitopes. They inhibited PLA2 catalytic activity and showed paraspecific neutralization against the myotoxicity from the lethal effect of Micrurus and Naja venoms’ PLA2s. Epitope conservation among venom PLA2 molecules suggests the possibility of generating pan-PLA2 neutralizing antibodies.

Micrurus dumerilii is a coral snake of clinic interest in Colombia. Its venom is mainly composed of phospholipases A2 being MdumPLA2 the most abundant protein. Nevertheless, Micrurus species produce a low quantity of venom, which makes it difficult to produce anticoral antivenoms. Therefore, in this work, we present the recombinant expression of MdumPLA2 to evaluate its biological activities and its immunogenic potential to produce antivenoms. For this, a genetic construct rMdumPLA2 was cloned into the pET28a vector and expressed heterologously in bacteria. His-rMdumPLA2 was extracted from inclusion bodies, refolded in vitro, and isolated using affinity and RP-HPLC chromatography. His-rMdumPLA2 was shown to have phospholipase A2 activity, a weak anticoagulant effect, and induced myonecrosis and edema. The anti-His-rMdumPLA2 antibodies produced in rabbits recognized native PLA2, the complete venom of M. dumerilii, and a phospholipase from another species of the Micrurus genus. Antibodies neutralized 100% of the in vitro phospholipase activity of the recombinant toxin and a moderate percentage of the myotoxic activity of M. dumerilii venom in mice. These results indicate that His-rMdumPLA2 could be used as an immunogen to improve anticoral antivenoms development. This work is the first report of an M. dumerilii functional recombinant PLA2.

Increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of snake venoms. However, the complexity of animal venoms and the extreme synergy of the venom components during envenomation calls for critical review and analysis. The epithelium is a primary target for injected viper venom’s toxic substances, and therefore, is a focus in modern toxinology. We used the Vero epithelial cell line as a model to compare the actions of a crude Macrovipera lebetina obtusa (Levantine viper) venom with the actions of the same venom with two key enzymatic components inhibited (specifically, phospholipase A2 (PLA2) and metalloproteinases) in the bioenergetic cellular response, i.e., oxygen uptake and reactive oxygen species generation. In addition to the rate of free-radical oxidation and lipid peroxidation, we measured real-time mitochondrial respiration (based on the oxygen consumption rate) and glycolysis (based on the extracellular acidification rate) using a Seahorse analyzer. Our data show that viper venom drives an increase in both glycolysis and respiration in Vero cells, while the blockage of PLA2 or/and metalloproteinases affects only the rates of the oxidative phosphorylation. PLA2-blocking in venom also increases cytotoxic activity and the overproduction of reactive oxygen species. These data show that certain components of the venom may have a different effect within the venom cocktail other than the purified enzymes due to the synergy of the venom components.

Reports of bite from Protobothrops mucrosquamatus (Pmu) are frequent in Taiwan, and its wide-spread distribution and diverse habitats drove us to investigate its envenoming effects and relevant venom variations. We used reversed-phase high-performance liquid chromatography and mass spectrometry to analyze 163 Pmu venom samples collected from northern and southeastern Taiwan. Twenty-two major protein fractions were separated and analyzed, and their contents were determined semi-quantitatively. The results showed that despite the trivial differences in the protein family, there is an existing variation in acidic phospholipases A2s, serine proteinases, metalloproteinases, C-type lectin-like proteins, and other less abundant components in the Pmu venoms. Moreover, clinical manifestations of 209 Pmu envenomed patients hospitalized in northern or southeastern Taiwan revealed significant differences in local symptoms, such as ecchymosis and blistering. The mechanism of these local effects and possibly relevant venom components were examined. Further analysis showed that certain venom components with inter-population variation might work alone or synergistically with others to aggravate the local effects. Therefore, our findings of the venom variation may help one to improve antivenom production and better understand and manage Pmu bites.

Background: Conventional serum markers are routinely recommended to assess heart health. However, many new biochemical markers like lipoprotein-associated phospholipase A2 (Lp-PLA2) has been studied as an efficient cardiac risk marker. Our report is an attempt to present correlation between traditional lipid markers and Lp-PLA2 in a pan-India cohort. Materials and Methods: The study cohort included a total of 10347 pan-Indians including 5945 males and 4402 females respectively. The serum lipid parameters estimated include triglycerides, LDL- and HDL-cholesterol as well as total cholesterol by the technology of photometry. Results: The frequency of high Lp-PLA2 detected in our study was 6.4% and the frequency between males at 9.3% and females at 2.5% was detected to be significant at p

The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (Mpro) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of COVID-19 has shown that lipids and lipid metabolizing enzymes are critically involved in the severity of the infection. The purpose of the present study was to identify an inhibitor able to simultaneously inhibit both SARS-CoV-2 Mpro and phospholipase A2 (PLA2), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA2 inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA2, GK241, may also weakly inhibit SARS-CoV-2 Mpro. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 Mpro. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA2 and SARS-CoV-2 Mpro inhibitors.

While the survival rate has increased due to treatments for breast cancer, the quality of life has decreased because of the side effects of chemotherapy. Various toxins are being developed as alternative breast cancer treatments, and bee venom is drawing attention as one of them. We analyzed the effect of bee venom and its components on breast cancer cells and reviewed the mechanism underlying the anticancer effects of bee venom. Data up to March 2022 were searched from PubMed, EMBASE, OASIS, KISS, and Science Direct online databases, and studies that met the inclusion criteria were reviewed. Among 612 studies, 11 were selected for this research. Diverse drugs were administered, including crude bee venom, melittin, phospholipase A2, and their complexes. All drugs reduced the number of breast cancer cells in proportion to the dose and time. The mechanisms of anticancer effects included cytotoxicity, apoptosis, cell targeting, gene expression regulation, and cell lysis. Summarily, bee venom and its components exert anticancer effects on human breast cancer cells. Depending on the mechanisms of anticancer effects, side effects are expected to be reduced by using various vehicles. Bee venom and its components have the potential to prevent and treat breast cancer in the future.

Nature presents a wide range of biomolecules with pharmacological potential, including venomous animal proteins. Among the protein components from snake venoms, phospholipases (PLA2) are of great importance for the development of new anticancer compounds. Thus, we aimed to evaluate the PLA2 anticancer properties from Bothrops moojeni venom. The crude venom was purified through three chromatographic steps, monitored by enzymatic activity and SDS-PAGE (12%). The purified PLA2 denominated BmPLA2 had its molecular mass and N-terminal sequence identified by mass spectrometry and Edman degradation, respectively. BmPLA2 was assayed against human epithelial colorectal adenocarcinoma cells (Caco-2), human rhabdomyosarcoma cells (RD) and mucoepidermoid carcinoma of the lung (NCI-H292), using human fibroblast cells (MRC-5) and microglia cells (BV-2) as a cytotoxicity control. BmPLA2 presented 13,836 Da and a 24 amino acid-residue homologue with snake PLA2, which showed a 90% similarity with other Bothrops moojeni PLA2. BmPLA2 displayed an IC50 of 0.6 µM against Caco-2, and demonstrated a selectivity index of 1.85 (compared to MRC-5) and 6.33 (compared to BV-2), supporting its selectivity for cancer cells. In conclusion, we describe a new acidic phospholipase, which showed antitumor activity and is a potential candidate in the development of new biotechnological tools.

Venom is a dynamic trait that has contributed to the success of numerous organismal lineages. Predominantly composed of proteins, these complex cocktails are deployed for predation and/or self-defence. Many non-toxic physiological proteins have been convergently and recurrently recruited by venomous animals into their toxin arsenal. Phospholipase A2 (PLA2) is one such protein and features in the venoms of many organisms across the animal kingdom, including snakes of the families Elapidae and Viperidae. Understanding the evolutionary history of this superfamily would therefore provide insight into the origin and diversification of venom toxins and the evolution of novelty more broadly. The literature is replete with studies that have identified diversifying selection as the sole influence on PLA2 evolution. However, these studies have largely neglected the structural/functional constraints on PLA2s, and the ecology and evolutionary histories of the diverse snake lineages that produce them. By considering these crucial factors and employing evolutionary analyses integrated with a schema for the classification of PLA2s, we uncovered lineage-specific differences in selection regimes. Thus, our work provides novel insights into the evolution of this major snake venom toxin superfamily and underscores the importance of considering the influence of evolutionary and ecological contexts on molecular evolution.

β-Neurotoxins are secreted phospholipase A2 molecules that inhibit transmission in neuromuscular synapses by poisoning the motor neurons. These toxins specifically and rapidly internalise into the nerve endings of motor neurons. Ammodytoxin (Atx) is a prototype β-neurotoxin from the venom of the nose-horned viper (Vipera ammodytes ammodytes). Here, we studied the relevance of the enzymatic activity of Atx in cell internalisation and subsequent intracellular movement using transmission electron microscopy (TEM). We prepared a recombinant, enzymatically inactive mutant of Atx, Atx(D49S), labelled with gold nanoparticles (GNP), and incubated this with PC12 cells, to analyse its localisation by TEM. Atx(D49S)-GNP internalised into the cells. Inside the cells, Atx(D49S)-GNP was detected in different vesicle-like structures, cytosol, endoplasmic reticulum and mitochondria, where it was spotted in the intermembrane space and matrix. Co-localization of fluorescently labelled Atx(D49S) with mitochondria in PC12 cells by confocal fluorescence microscopy confirmed the reliability of results generated using Atx(D49S)-GNP and TEM and allowed us to conclude that the phospholipase activity of Atx is not obligatory for its cell internalisation and translocation into the mitochondrial intermembrane space and matrix.

In Colombia, the genus Micrurus includes 30 species, of which M. mipartitus and M. dumerilii are the most widely distributed. Micrurus causes less than 3% of the approximately 5000 cases of snakebite per year. The elapid envenomation caused by the snakes from the Micrurus genus, are characterized by the severity of their clinical manifestations, due to the venom neurotoxic components such as three-finger toxins (3FTx) and phospholipases (PLA2). The treatment for snakebites is the administration of specific antivenoms, however, some of them have limitations in their neutralizing ability. A strategy proposed to improve antivenoms is to produce antibodies against the main components of the venom. The aim of this work was to produce an antivenom, using an immunization protocol including the main 3FTx and PLA2 responsible for M. mipartitus lethality. The antibody titers were determined by ELISA in rabbits’ serum. The immunized animals elicited a response against toxins and whole venom. The Immunoglobulin G (IgGs) obtained were able to neutralize the lethal effect of their homologous toxins. A combination of antivenom from M. mipartitus with antitoxins improved their neutralizing ability. In the same way, a mixture of anti 3FTx and PLA2 protected the mice from a 1.5 median lethal dose (LD50) of M. mipartitus venom. The results showed that this might be a way to improve antibody titers specificity against the relevant toxins in M. mipartitus venom and indicated that there is a possibility to develop and use recombinant 3FTx and PLA2 toxins as immunogens to produce antivenoms. Additionally, this represents an alternative to reduce the amount of venom used in anti-coral antivenom production.

Background Snake venoms are the complex mixtures of different compounds manifesting a wide array of biological activities. The venoms of kraits (genus Bungarus, family Elapidae) induce mainly neurological symptoms; however, these venoms show a cytotoxicity against cancer cells as well. This study was conducted to identify in Bungarus fasciatus venom an active compound(s) exerting cytotoxic effects toward MCF7 human breast cancer cells and A549 human lung cancer cells. Methods The crude venom of B. fasciatus was separated by gel-filtration on Superdex HR 75 column and reversed phase HPLC on C18 column. The fractions obtained were screened for cytotoxic effect against MCF7, A549, and HK2 cell lines using colorimetric assay with the tetrazolium dye MTT- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The primary structure of active protein was established by ultra high resolution LC-MS/MS. The molecular mechanism of the isolated protein action on MCF7 cells was elucidated by flow cytometry. Results MTT cell viability assays of cancer cells incubated with fractions isolated from B. fasciatus venom revealed a protein with molecular mass of about 13 kDa possessing significant cytotoxicity. This protein manifested the dose and time dependent cytotoxicity for MCF7 and A549 cell lines while showed no toxic effect on human normal kidney HK2 cells. In MCF7, flow cytometry analysis revealed a decrease in the proportion of Ki-67 positive cells. As Ki-67 protein is a cellular marker for proliferation, its decline indicates the reduction in the proliferation of MCF7 cells treated with the protein. Flow cytometry analysis of MCF7 cells stained with propidium iodide and Annexin V conjugated with allophycocyanin showed that a probable mechanism of cell death is apoptosis. Mass spectrometric studies showed that the cytotoxic protein was phospholipase A2. The amino acid sequence of this enzyme earlier was deduced from cloned cDNA, and in this work it was isolated from the venom as a protein for the first time. It is also the first krait phospholipase A2 manifesting the cytotoxicity for cancer cells.

Background: Acute coronary syndrome (ACS) is closely related to unstable plaques and secondary thrombosis. The inflammatory cells in plaques and their inflammatory products may be the cause for plaque instability and ruptures. The study aimed to disclose the changes of inflammatory factors including serum intracellular adhesion molecule-1 (ICAM-1), chitinase-3-like protein 1 (YKL-40), and lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with ACS and its clinical significance. Methods: A total of 120 patients with coronary heart disease (CHD) were categorized into 2 groups: 69 with ACS and 51 with stable angina pectoris (SAP); 20 patients with chest pain and normal angiography served as a control group. The 120 patients with CHD were categorized into single-vessel disease group, double-vessel disease group, and three-vessel disease group based on the number of coronary artery stenosis. The severity of coronary artery stenosis was quantified based on coronary angiography using Gensini score. They were further divided into mild CHD group with its Gensini score 54 (n = 36). Serum levels of ICAM-1, YKL-40, and Lp-PLA2 of different groups were determined by enzyme-linked immunosorbent assay. Correlation between ICAM-1, YKL-40, Lp-PLA2, and Gensini score was analyzed. Results: The levels of serum inflammatory factors ICAM-1, YKL-40, and Lp-PLA2 were significantly higher in the ACS group than those in control group and SAP group (all P < 0.05); and compared with control group, no significant difference was observed in terms of the serum ICAM-1, YKL-40, and Lp-PLA2 levels in the SAP group (P > 0.05).The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, single-vessel disease group, double-vessel disease group, and three-vessel disease group (all P > 0.05). The levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not significantly different among control group, mild CHD group (Gensini score 54) (all P > 0.05). Nonparametric Spearman correlation analysis showed that the levels of serum ICAM-1, YKL-40, and Lp-PLA2 were not correlated with the Gensini score in CHD patients (r = 0.093, r = –0.149, and r = –0.085, all P > 0.05; respectively). Conclusions: The serum levels of ICAM-1, YKL-40, and Lp-PLA2 were correlated with different clinical types of CHD, but not well correlated the severity and extent of artery stenosis, suggesting that ICAM-1, YKL-40, and Lp-PLA2 might be involved in occurrence of instability of atherosclerotic plaque, and might reflect the severity of CHD mostly through reflecting the plaque stability.

Phospholipase A2 (PLA2) toxins are one of the main toxin families found in snake venom. PLA2 toxins are associated with various detrimental effects, including neurotoxicity, myotoxicity, hemostatic disturbances, nephrotoxicity, edema, and inflammation. Although Naja sumatrana venom contains substantial quantities of PLA2 components, there is limited information on the function and activities of PLA2 toxins from the venom. In this study, a secretory PLA2 from the venom of Malaysian N. sumatrana, subsequently named A2-EPTX-Nsm1a, was isolated, purified, and characterized. A2-EPTX-Nsm1a was purified using a mass spectrometry-guided approach and multiple chromatography steps. Based on LC-MSMS, A2-EPTX-Nsm1a was found to show high sequence similarity with PLA2 from venoms of other Naja species. The PLA2 activity of A2-EPTX-Nsm1 was inhibited by 4-BPB and EDTA. A2-EPTX-Nsm1a was significantly less cytotoxic in a neuroblastoma cell line (SH-SY5Y) compared to crude venom and did not show a concentration-dependent cytotoxic activity. To our knowledge, this is the first study that characterizes and investigates the cytotoxicity of an Asp49 PLA2 isolated from Malaysian N. sumatrana venom in a human neuroblastoma cell line.

Pseudomonas aeruginosa is an opportunistic, Gram-negative pathogen and an important cause of hospital acquired infections, especially in immunocompromised patients. Highly virulent P. aeruginosa strains use a type III secretion system (T3SS) to inject exoenzyme effectors directly into the cytoplasm of a target host cell. P. aeruginosa strains that express the T3SS effector, ExoU, associate with adverse outcomes in critically ill patients with pneumonia, owing to the ability of ExoU to rapidly damage host cell membranes and subvert the innate immune response to infection. Herein, we review the structure, function, regulation, and virulence characteristics of the T3SS effector ExoU, a highly cytotoxic phospholipase A2 enzyme.

Discriminating Polistes dominula and Vespula spp. venom allergy is of growing importance worldwide, as systemic reactions to either species’ sting can lead to severe outcomes. Administering the correct allergen-specific immunotherapy is therefore a prerequisite to ensure the safety and health of venom-allergic patients. Component-resolved diagnostics of Hymenoptera venom allergy might be improved by adding additional allergens to the diagnostic allergen panel. Therefore, three potential new allergens from P. dominula venom—immune responsive protein 30 (IRP30), vascular endothelial growth factor C (VEGF C) and phospholipase A2 (PLA2)—were cloned, recombinantly produced and biochemically characterized. Sera sIgE titers of Hymenoptera venom-allergic patients were measured in vitro to assess the allergenicity and potential cross-reactivity of the venom proteins. IRP30 and VEGF C were classified as minor allergens, as sensitization rates lay around 20–40%. About 50% of P. dominula venom-allergic patients had measurable sIgE titers directed against PLA2 from P. dominula venom. Interestingly, PLA2 was unable to activate basophils of allergic patients, questioning its role in the context of clinically relevant sensitization. Although the obtained results hint to a questionable benefit of the characterized P. dominula venom proteins for improved diagnosis of venom-allergic patients, they can contribute to a deeper understanding of the molecular mechanisms of Hymenoptera venoms and to the identification of factors that determine the allergenic potential of proteins.

Acute kidney injury (AKI) following Eastern Russell’s viper (Daboia siamensis) envenoming is a significant symptom in systemically envenomed victims. A number of venom components have been identified as causing the nephrotoxicity which leads to AKI. However, the precise mechanism of nephrotoxicity caused by these toxins is still unclear. In the present study, we purified two proteins from D. siamensis venom, namely RvPLA2 and RvMP. Protein identification using LCMS/MS confirmed the identity of RvPLA2 to be snake venom phospholipase A2 (SVPLA2) from Thai D. siamensis venom, whereas RvMP exhibited the presence of a factor X activator with two subunits. In vitro and in vivo pharmacological studies demonstrated myotoxicity and histopathological changes of kidney, heart, and spleen. RvPLA2 (3–10 µg/mL) caused inhibition of direct twitches of the chick biventer cervicis muscle preparation. After administration of RvPLA2 or RvMP (300 µg/kg, i.p.) for 24 h, diffuse glomerular congestion and tubular injury with minor loss of brush border were detected in envenomed mice. RvPLA2 and RvMP (300 µg/kg; i.p.) also induced congestion and tissue inflammation of heart muscle as well as diffuse congestion of mouse spleen. This study showed the significant roles of PLA2 and SVMP in snake bite envenoming caused by Thai D. siamensis and their similarities with observed clinical manifestations in envenomed victims. This study also indicated that there is a need to reevaluate the current treatment strategies for Thai D. siamensis envenoming, given the potential for irreversible nephrotoxicity.

Objective To discuss the changes of serum lipoprotein phospholipase A2 (Lp ⁃ PLA2) and c ⁃ reactive protein (CRP) levels in atorvastat in treatment for the patients with periodontitis and hyperlipidemia. Methods 148 pa⁃ tients with periodontitis and hyperlipidemia were involved, and divided into basic group (foundation treatment, 82 cases) and statin group (foundation treatment plus 20 mg atorvastatin treatment, 66 cases). 40 healthy cases from the medical center health personnel were selected as the healthy group. Attachment levels (AL), bleeding index (BI), serum total cho⁃ lesterol (TC), triacylglycerol (TG), Lp ⁃ PLA2, and CRP levels were checked and compared before and after 6 months of treatment. Lp ⁃ PLA2 and CRP were checked by enzyme linked immunosorbent assay (ELISA), and their relationship were analyzed by the method of Pearson. Results When the disease group were compared with the healthy group, the statistics were as follows: AL（3.92 ± 0.51 mm vs 0.42 ± 0.06 mm）, BI（2.81 ± 0.48 vs 0.34 ± 0.05）, TC（5.27 ± 0.83 mmol/L vs 4.02 ± 0.62 mmol/L）, TG（2.67 ± 0.41 mmol/L vs 0.93 ± 0.17 mmol/L）, Lp⁃PLA2（243.57 ± 58.71 μg/L vs 132.24 ± 34.27 μg/L）, CRP（9.72 ± 3.27 μg/L vs 3.21 ± 0.87 μg/L）, and the statistics of disease group were significant⁃ ly higher than the healthy group with a significant difference (P < 0.05). When Statin group was compared with basis group, the statistics were as follows: AL（3.70 ± 0.10 mmvs 3.78 ± 0.11 mm）, BI（1.05 ± 0.28 vs 1.43 ± 0.32）, TC （3.82 ± 0.67 mmol/L vs 4.51 ± 0.71 mmol/L）, TG（1.30 ± 0.29 mmol/L vs 1.83 ± 0.34 mmol/L）, Lp⁃PLA2（157.43 ± 40.18 μg/L vs 199.43 ± 47.24 μg/L）, CRP（4.21 ± 3.02 μg/L vs 6.37 ± 3.28 μg/L）, and the statistics of statin group were lower than that in basis group with a significant difference (P < 0.05). Pearson analysis showed Lp⁃PLA2 and CRP levels were positively correlated (r = 0.672, P < 0.05). Conclusion It shows the changes of Lp⁃ PLA2 and CRP level were related with the clinical conditions of periodontitis combined with hyperlipidemia, and atorvastatin therapy can ef⁃ fectively reduce the body􀆳s blood lipid levels, and improve the treatment effects of periodontitis combined with hyperlip⁃ idemia.

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer's. Age remains the greatest risk factor for Alzheimer's and the prevalence of age-related late onset Alzheimer's is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer's risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer's and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.

Secretory phospholipase-IIA A2 (sPLA2-IIA) is expressed in a variety of cell types under inflammatory conditions. Its presence in the bronchoalveolar lavage (BAL) fluid of patients with acute respiratory distress syndrome (ARDS) is associated with the severity of the injury. Exosomal type extracellular vesicles, (EVs), are recognized to perform intercellular communication. They may alter the immune status of recipient target cells through cargo shuttling. In this work, we characterized the exosomal type EVs isolated from BAL fluid of patients with early and late ARDS as compared to control/non-ARDS patients, through morphological (confocal and electron microscopy) and biochemical (dynamic light scattering, qRT-PCR, immunoblotting) approaches. We provide evidence for the presence of an sPLA2-IIA-carrying EV pool that coprecipitates with exosomes in the BAL fluid of patients with ARDS. PLA2G2A mRNA was present in all the samples, although more prominently expressed in early ARDS. However, the protein was found only in EVs from early phase ARDS. Under both forms, sPLA2-IIA might be involved in inflammatory responses of recipient lung cells during ARDS. The perception of the association of sPLA2-IIA to the early diagnosis of ARDS or even with a mechanism of development and propagation of lung inflammation can help in the adoption of appropriate and innovative therapeutic strategies.

Atherosclerosis is a chronic inflammatory disease caused by lipids and calcareous accumulations in the vascular wall due to an inflammatory reaction. Recent reports have demonstrated that regulatory T (Treg) cells have an important role as a new treatment for atherosclerosis. This study suggests that bee venom phospholipase A2 (bvPLA2) may be a potential therapeutic agent in atherosclerosis by inducing Treg cells. We examined the effects of bvPLA2 on atherosclerosis using ApoE-/- and ApoE-/-/Foxp3DTR mice. In this study, bvPLA2 increased Treg cells, followed by a decrease in lipid accumulation in the aorta and aortic valve and the formation of foam cells. Importantly, the effect of bvPLA2 was found to depend on Treg cells. This study suggests that bvPLA2 can be a potential therapeutic agent for atherosclerosis.

Bee venom phospholipase A2 is a lipolytic enzyme in bee venom that catalyzes hydrolysis of the sn-2 ester bond of membrane phospholipids to produce free fatty acid and lysophospholipids. Current evidence suggests that bee venom phospholipase A2 (bvPLA2) induces regulatory T cell expansion and attenuates several immune system-related diseases, including Alzheimer’s disease. The induction of Treg cells is directly mediated by binding to mannose receptors on dendritic cells. This interaction induces the PGE2-EP2 signaling pathway, which promotes Treg induction in CD4+ T cells. In this study, we investigated the effects of bvPLA2 treatment on the apoptotic signaling pathway in Treg populations. Flow cytometry was performed to identify early apoptotic cells. As a result, early apoptotic cells were dramatically decreased in bvPLA2-treated splenocytes, whereas rapamycin-treated cells showed levels of apoptotic cells similar to those of PBS-treated cells. Furthermore, bvPLA2 treatment increased expression of anti-apoptotic molecules including CTLA-4 and PD-1. The survival rate increased in bvPLA2-treated Tregs. Our findings indicate that bvPLA2-mediated modulation of apoptotic signaling is strongly associated with the Treg induction, which exhibits protective effects against various immune-related diseases. To our knowledge, this study is the first to demonstrate that bvPLA2 is the major bee venom (BV) compound capable of inducing Treg expansion through altering apoptotic signal.

The phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA2 activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA2s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA2s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.

Background: Pathogenesis of cardiovascular diseases (CVDs) may be indicated by lipoprotein-associated phospholipase A2 (Lp-PLA2), serving as an inflammatory biomarker. However, the general dietary predictors of Lp-PLA2 have not been investigated so far. The aim of the present study is to investigate the relationship between the serum levels of Lp-PLA2 and dietary patterns in adults with cardiovascular risk factors. Materials and Methods: Dietary patterns extracted using factor analysis and serum levels of Lp-PAL2 in 470 adults aged 40–70 years who participated in the 5th phase of the Tehran Lipid and Glucose Study (2011–2014) were determined. Associations between the dietary patterns and serum levels of Lp-PAL2 considering some confounder factors were evaluated. Results: The results showed that Western and semi-Mediterranean dietary patterns had significant effects on changes in Lp-PLA2 levels in univariate analyses. In multivariate analyses, after adjusting for age, sex, total cholesterol, low-density lipoprotein cholesterol, body mass index and physical activity, energy intake, hormone therapy for women, and taking blood lipid-lowering drugs as potential confounders, the Western dietary pattern remained a significant factor influencing the Lp-PLA2 level (β value: 1.65, 95% confidence interval: 1.12, 1.89; P < 0.05). Moreover, after adjustment for the mentioned confounder factors, the effect of the semi-Mediterranean dietary pattern on Lp-PLA2 disappeared. Conclusion: It can be concluded that the Western dietary pattern is associated with higher Lp-PLA2 levels. We recommend that adults eat less carbonated drinks, fast foods, salty snacks, mayonnaise, and organ meat to counteract increased serum Lp-PLA2 levels, which are directly associated with vascular inflammation and CVDs.

The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA2) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLA2s and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA2-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA2 activation, arachidonic acid, increases in intracellular Ca2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLA2s and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA2 and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom.

Natural products represent important sources for the discovery and design of novel drugs. Bee venom and its isolated components have been intensively studied with respect to their potential to counteract or ameliorate diverse human diseases. Despite extensive research and significant advances in recent years, multifactorial diseases such as cancer, rheumatoid arthritis and neurodegenerative diseases remain major healthcare issues at present. Although pure bee venom, apitoxin, is mostly described to mediate anti-inflammatory, anti-arthritic and neuroprotective effects, its primary component melittin may represent an anticancer therapeutic. In this review, we approach the possibilities and limitations of apitoxin and its components in the treatment of these multifactorial diseases. We further discuss the observed unspecific cytotoxicity of melittin that strongly restricts its therapeutic use and review interesting possibilities of a beneficial use by selectively targeting melittin to cancer cells.

Kaempferol, a phytochemical found in many edible plants, is known to alleviate diseases such as cancer, allergy, and inflammation. The objective of this study was to investigate whether kaempferol could reduce omega-6 and ovalbumin-mediated allergic reactions at lung and trachea in BALB/c mice. Mice were allocated into five groups: 1) control group (CON); 2) positive control group with orally administration of omega-6 (POS); 3) bovine serum albumin (BSA) sensitization group (with BSA injection and ovalbumin inhalation); 4) BSA+K10 group: BSA injection, 10 μg/g of kaempferol administration and ovalbumin inhalation; and 5) BSA+K20 group: BSA injection, 20 μg/g of kaempferol administration and ovalbumin inhalation. Results revealed that serum histamine level was the highest (p

Antioxidant, antimicrobial, anti-hyperglycaemic, anti-diabetic and anti-inflammatory effects of Allium cepa (A. cepa) have been previously shown. In this study, the effects of A. cepa aqueous-alcoholic extract on tracheal responsiveness, lung inflammatory cells and phospholipase A2 (PLA2) level in bronchoalveolar fluid (BALF) of asthmatic rats were examined. Wistar rats were randomly divided into control group (C), asthmatic group (A), asthmatic group (A) treated with A. cepa extract (AC, 0.175, 0.35, and 0.7 mg/mL) and dexamethasone (D, 1.25 μg/mL). The extract of A. cepa and dexamethasone were added to animal's drinking water during sensitization period. Tracheal responsiveness to methacholine and ovalbumin, lung inflammatory cells and PLA2 level in BALF were assessed. Tracheal responsiveness to methacholine and ovalbumin, PLA2 level, total and most differential WBC count were increased but lymphocytes was decreased in asthmatic animals compared to group C (p