Functions and mechanisms of cytosolic phospholipase A_(2)in central nervous system trauma

Central nervous system(CNS)trauma,including traumatic brain injury and spinal cord injury,has a high rate of disability and mortality,and effective treatment is currently lacking.Previous studies have revealed that neural inflammation plays a vital role in CNS trauma.As the initial enzyme in neuroinflammation,cytosolic phospholipase A_(2)(cPLA2)can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids andω3-polyunsaturated fatty acid dominated by arachidonic acid,thereby inducing secondary injuries.Although there is substantial fresh knowledge pertaining to cPLA2,in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to amelio rate the clinical res ults after CNS trauma are still insufficient.The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma,highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically,neuroinflammation,lysosome membrane functions,and autophagy activity,that damage the CNS after trauma.Moreover,we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway,and we explored how those agents might be utilized as treatments to improve the results following CNS trauma.This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

The Use of Lipoprotein-Associated Phospholipase A2 in a Chinese Population to Predict Cardiovascular Events

Objective To explore associations between lipoprotein-associated phospholipase A2(Lp-PLA2)and the risk of cardiovascular events in a Chinese population,with a long-term follow-up.Methods A random sample of 2,031 participants(73.6%males,mean age=60.4 years)was derived from the Asymptomatic Polyvascular Abnormalities Community study(APAC)from 2010 to 2011.Serum Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay(ELISA).The composite endpoint was a combination of first-ever stroke,myocardial infarction(MI)or all-cause death.Lp-PLA2 associations with outcomes were assessed using Cox models.Results The median Lp-PLA2 level was 141.0 ng/m L.Over a median follow-up of 9.1 years,we identified 389 events(19.2%),including 137 stroke incidents,43 MIs,and 244 all-cause deaths.Using multivariate Cox regression,when compared with the lowest Lp-PLA2 quartile,the hazard ratios with95%confidence intervals for developing composite endpoints,stroke,major adverse cardiovascular events,and all-cause death were 1.77(1.24–2.54),1.92(1.03–3.60),1.69(1.003–2.84),and 1.94(1.18–3.18)in the highest quartile,respectively.Composite endpoints in 145(28.6%)patients occurred in the highest quartile where Lp-PLA2(159.0 ng/m L)was much lower than the American Association of Clinical Endocrinologists recommended cut-off point,200 ng/m L.Conclusion Higher Lp-PLA2 levels were associated with an increased risk of cardiovascular event/death in a middle-aged Chinese population.The Lp-PLA2 cut-off point may be lower in the Chinese population when predicting cardiovascular events.

Destabilization of acrosome and elastase influence mediate the release of secretory phospholipase A2 from human spermatozoa

Aim： To determine the cellular distribution of secretory phospholipase A2 （sPLA2） in dependence on the acrosomal state and under the action of elastase released under inflammatory processes from leukocytes. Methods： Acrosome reaction of spermatozoa was triggered by calcimycin. Human leukocyte elastase was used to simulate inflammatory conditions. To visualize the distribution of sPLA2 and to determine the acrosomal state, immunofluorescence techniques and lectin binding combined with confocal laser scanning fluorescence microscopy and flow cytometry were used. Results： Although sPLA2 was detected at the acrosome and tail regions in intact spermatozoa, it disappeared from the head region after triggering the acrosome reaction. This release of sPLA2 was associated with enhanced binding of annexin V-fluoroscein isothiocyanate （FITC） to spermatozoa surfaces, intercalation of ethidium-homodimer I, and binding of FITC-labelled concanavalin A at the acrosomal region. Spermatozoa from healthy subjects treated with elastase were characterized by release of sPLA2, disturbance of acrosome structure, and loss of vitality. Conclusion： The ability of spermatozoa to release secretory phospholipase A2 is related to the acrosomal state. Premature destabi- lization of the acrosome and loss of sPLA2 can occur during silent inflammations in the male genital tract. The distribution pattern of sPLA2 in intact spermatozoa might be an additional parameter for evaluating sperm quality.

Oxidized phospholipids and lipoprotein-associated phospholipase A_2 as important determinants of Lp(a) functionality and pathophysiological role

Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.

Time-dependent changes of glial fibriliary acidic protein and cytosolic phospholipase A2 in hippocampal area of focal cerebral ischemia/reperfusion in rats

BACKGROUND： Interaction between astrocyte and neuron may two-dimensionally influence on ischemic injury; however, glial fibriliary acidic protein （GFAP） and cytosolic phospholipase A2 （cPLA2） are both important markers to reflect changes of astrocyte and neuron after cerebral ischemia, respectively. OBJECTIVE： To observe the changes of GFAP and positive cPLA2 cells in hippocampal area of model rats with focal cerebral ischemia in various phases of cerebral ischemia/reperfusion. DESIGN ： Randomized contrast observation SETTING： Department of Basic Medical Science of Human Anatomy and Histology ＆ Embryology, Medical College of Wuhan Polytechnic University; Faculty Medical College of Wuhan University. MATERIALS： The experiment was carried out in the Department of Basic Medical Science, Medical College of Wuhan Industry College from May to June 2004. A total of 28 healthy SD rats of either gender and weighing 200-250 g were provided by Animal Department of Medical College of Jianghan University. METHODS： All 28 rats were randomly divided into 7 groups, including sham operation group, 2-, 6-, 12-, 24- and 48-reperfusion groups, and triphenyltetrazolium chloride （TTC） group, with 4 in each group. Two hours after ischemia, ischemia/reperfusion models were established in left middle cerebral artery （MCA）; common carotid artery was ligated and line cork was inserted into it with the depth of （1.8±0.5） cm. Rats in sham operation group were inserted with the depth of 1.0 cm, and other operations were as the same as those in 2-hour ischemia/reperfusion groups. Models in TTC group were established as the same as those in 2-hour ischemia/24-hour reperfusion group, and they were used to evaluate the therapeutic effect. Changes of GFAP and cPLA2 in hippocampal area in various phases were detected with immunohisto- chemical method. MAIN OUTCOME MEASURES ： Changes of GFAP and positive cPLA2 cells in hippocampal area of rats with focal cerebral ischemia in various phases of ischemia/reperfusion. RESULTS： All 28 rats were involved in the final analysis without any loss. （1） Animal models successfully showed the effect of focal cerebral ischemia. （2） Changes of GFAP and cPLA2 in hippocampal area in various phases： Two hours after ischemia/reperfusion, changes of GFAP and cPLA2 were increased gradually, reached at peak at 24 hours, and decreased gradually. CONCLUSION ： Courses of GFAP and cPLA2 are changed at the onset of focal cerebral ischemia, and this suggests that both of them participate in injury or protection of brain tissue of focal cerebral ischemia.

SCREENING A CDNA LIBRARY FOR PHOSPHOLIPASE A2 CLONES USING BLOOD AGAR PLATES

A technique was developed for detecting venom phospholipase A2(PLA2) using serum and red blood cells. M1 and M2, two PLA2s isolated from Crotalus m.molossus (Northern black-tail rattlesnake), were used for preliminary development of the as say. Various combinations of human, sheep, rat, and mouse red blood cells (RBC) with human,rat,and mouse sera were tested on their effectiveness to detect PLA2.Complete hemolysis (b hemolysis) was evident in the plate with rat RBC mixed with mouse serum.No hemolysis was detected in plates containing human RBC and human serum. Human RBC mixed with mouse serum proved to be ideal, even though this combination displayed incomplete hemolysis(a hemolysis).Susceptible RBC, in conjunction with rat or mouse serum, are excellent indicators for the presence of PLA2.Mixtures of RBC and serum in combination with BB4(E. coli) cells,λbacteriophage,and IPTG on LB agar plates provide an excellent detection system for cDNA clones that express venonl PLA2. Hemolysis surrounding a plaque is identified as positive for PLA2.

Relation of phospholipase A2-Ⅴ and indoxam to hippocampal neuronal death

BACKGROUND: Ⅴ secretory phospholipase A2 (sPLA2-Ⅴ) is abundant in many mammal tissues. However, it remains unknown whether sPLA2-Ⅴ causes biological or pathological response in central nervous system. OBJECTIVE: To observe the effect of phospholipase A2-Ⅴ (PLA2-Ⅴ) and its inhibitor (indoxam) on hippocampal neuron survival. DESIGN: A repetitive measurement. SETTING: The Animal Center of South Carolina University. MATERIALS: Sprague-Dawley pregnancy day-7, 14, 21 female rats were selected; Reagents: sPLA2- Ⅴ and indoxam were obtained from the Dennis Research Laboratories METHODS: The experiment was finished at the animal center in South Carolina University from January to December, 2004. 0, 12.5, 25, 50 and 100 μg/L sPLA2-Ⅴ were added to neuron with none-MgCl2 Eagle’s medium at 37 ℃, then changed to normal neuron culture medium after 3 hours. 1, 2.5, 5 and 10 μmol/L indoxam was added at 6 hours after 100 μg/L sPLA2-Ⅴwas put to Day-21 SD rat hippocampal embryonic neurons with none-MgCl2 Eagle’s medium at 37 ℃. After 3 hours in the inhibition experiment, it was changed to normal neuron culture medium. The embryonic hippocampal neurons were primarily cultured, and the neuron survival ratio was detected with morphological method. MAIN OUTCOME MEASURES: Survival ratio of hippocampal neurons. RESULTS: ① Effects of sPLA2-Ⅴon neuron survival: When sPLA2-Ⅴ was 0, 12.5, 25, 50 and 100 μg/L, the neuron survival ratios in embryonic neurons of day-7 SD rats were (95.3±1.1)%, (81.4±3.1)%, (74.2±2.2)%, (62.4±1.7)% and (48.9±1.6)%, those in embryonic neurons of day-14 rats were (93.2±1.4)%, (74.3±1.9)%, (68.1±1.7)%, (56.1±1.4)% and (42.5±1.1)%, and those in embryonic neurons of day-21 rats were (91.2±1.2)%, (69.4±2.1)%, (60.3±2.2)%, (49.1±1.2)% and (35.5±1.9)%. There were significant differences among different concentrations (P < 0.05). ② Effects of indoxam on neuron survival: In case of sPLA2-Ⅴ 100 μg/L, the neuron survival ratios were (58.65±1.4)%, (69.34±1.1)%, (82.11±1.2)% and (95.28±0.9)% when indoxam was 1, 2.5, 5 and 10 μmol/L, respectively. There were significant differences among different concentrations (P < 0.05). CONCLUSION: ① The of neuronal death ratio is in a concentration-dependent manner with sPLA2-Ⅴ, and increases as the embryonic aging. ② Indoxam inhibits the proapoptotic effect of sPLA2-Ⅴ.

Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications

Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2(Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro-atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the LpPLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed.

Cytosolic phospholipase A2α modulates cell-matrix adhesion via the FAK/paxillin pathway in hepatocellular carcinoma

Objective: To explore the effect of cytosolic phospholipase A2α(cPLA2α) on hepatocellular carcinoma(HCC) cell adhesion and the underlying mechanisms.Methods: Cell adhesion, detachment, and hanging-drop assays were utilized to examine the effect of cPLA2α on the cell-matrix and cell-cell adhesion. Downstream substrates and effectors of cPLA2α were screened via a phospho-antibody microarray.Associated signaling pathways were identified by the functional annotation tool DAVID. Candidate proteins were verified using Western blot and colocalization was investigated via immunofluorescence. Western blot and immunohistochemistry were used to detect protein expression in HCC tissues. Prognosis evaluation was conducted using Kaplan-Meier and Cox-proportional hazards regression analyses.Results: Our findings showed that cPLA2α knockdown decreases cell-matrix adhesion but increases cell-cell adhesion in HepG2 cells. Microarray analysis revealed that phosphorylation of multiple proteins at specific sites were regulated by cPLA2α. These phosphorylated proteins were involved in various biological processes. In addition, our results indicated that the focal adhesion pathway was highly enriched in the cPLA2α-relevant signaling pathway. Furthermore, cPLA2α was found to elevate phosphorylation levels of FAK and paxillin, two crucial components of focal adhesion. Moreover, localization of p-FAK to focal adhesions in the plasma membrane was significantly reduced with the downregulation of cPLA2α. Clinically, cPLA2α expression was positively correlated with p-FAK levels. Additionally, high expression of both cPLA2α and p-FAK predicted the worst prognoses for HCC patients.Conclusions: Our study indicated that cPLA2α may promote cell-matrix adhesion via the FAK/paxillin pathway, which partly explains the malignant cPLA2α phenotype seen in HCC.

Role of Calcium-Independent Phospholipase A2 V IA in Mediating Neurological Disorder and Cancer

Calcium-independent phospholipase A_2(iPLA_2) belongs to the group VI family of phospholipase superfamily(PLA_2) that catalyses the hydrolysis of glycerophospholipids at the sn-2 ester bond,producing unesterified fatty acids and 2-lysophospholipids.Research interests on iPLA_2 have not been as significant as those on secretary PLA_2 and cytosolic PLA_2.However,more efforts have been made recently on understanding the expression,regulation and biological function of iPLA_2.iPLA_2 plays important roles in several biological processes,including signal transduction,phospholipid remodelling,eicosanoid formation,cell proliferation,cell differentiation and apoptosis.Modulation of iPLA_2activity can have prominent effects on cellular metabolism,central nervous system and cardiovascular functions.Thus,dysregulation iPLA_2 can play a vital role in the pathogenesis of several diseases.The aim of this review is to provide the current understanding of the structure,function and regulation of group VI iPLA_2 and highlight its potential mechanisms of action in mediating several neurological disorders and cancer.

Phospholipase A_2 and Its Relationship with Acute Lung Injury in Acute Pancreatitis in Dogs

Acute fulminant pancreatitis was produced in dogs by injection of autobile into the mainpancreatic duct.After injection the phospholipase A2（PLA2）activities in serum,lung lymph andbronchoalveolar lavage fluid（BAL）were elevated significantly,lung lymph flow and pulmonarytransvascular potein clearance increased progressively,protein content and cell numbers in BAL inthe experimental animals were significantly higher than those in the control animals.Furthermore thelung index,wet to dry lung weight ratio,extravascular lung water to bloodless dry lung weight ra-tio,extravascuar lung water to bloodless dry lung weight ratio increased significantly as comparedto control animals.Pretreatment with PLA2 inhibitor,chloroquine,blocked the changes mentionedabove.This experiment suggests:1.PLA2 activity in lung lymph fluid as well as in serum andBAL is elevated in acute hemorrhagic pancreatitis.2.Elevated PLA2 activity may increase thepulmonary vascular permeability.3.PLA2 is the major factor leading to pulmonary edema in acutehemorrhagic pancreatitis.4.Phagocytes contribute to the lung injury induced by PLA2 to some ex-tent.

Phospholipase A_2 changes and its significance on brain tissue of rat in severe acute pancreatitis

Objective To survey changes and the significance of phospholipase A_2(PLA_2) on brain tissue of SD rat in acute pancreatitis.Methods With retrograde injection of 3% taurocholate sodium into pancreatic and biliary duct,rat model of severe acute pancreatitis(SAP) was made,and it included four groups: the control group,the sham-operation group, the SAP group and the PLA_2 inhibitor-treated group of SAP.Serum amylases,PLA_2 and PLA_2 in brain tissue were measured and the brain tissue changes were observed.Results There were no significant difference in serum amylases, PLA_2 and PLA_2 in brain tissue between the sham-operation and the control groups;the levels of serum amylases,PLA_2 and PLA_2 in brain tissue in the SAP group were higher than those in the control.In the SAP group expansion and hemorrhage of meninges,intracephalic arteriolar hyperemia,in meninges and cephalic-parenchyma infiltration of inflammatory cells and interval broaden were observed,significant differences were found between two groups.Compared with the SAP group,the level of serum amylase,PLA_2 and PLA_2 in brain tissue were reduced significantly in the treatment group of SAP.Pathological damages in the treatment group were significantly reduced when compared with the SAP group.Conclusion PLA_2 might play an important role in brain tissue damages in severe acute pancreatitis.

Effects of anisodamine on pulmonary α_1-adrenergic receptor and phospholipase A_2 in acute lung injury

Objective: To imastigate the effects of anisodamine on pulmonary α1- adrenergic receptor andphospholipase A, in acute lung injurg. Methods: Change of α1--adrenergic receptor (al AR ) in lung tissllesduring endotoxin--induced rat acute lung injury was measured with radioligand biding assay. The effects ofanisodamine on pulmonary α1--AR and phospholipase A2 (PLA2 ) were observed. Results: 1. 4 h after theendotoxin injection, there was a significant decrease in the maximal binding capacity of α1--AR by 34% ascompared with the control group. meanwhile elevated activity of PLA2 in rat lung and reduction of thephospholipids content of cell membrane was found. 2. Anisodamine could attenuate endotoxin--induced acutelung injury in rats. Conclusion: This effect might be related to anisodamine’s blockage of α1--AR andsuppression of PLA2, prevention of membranous phospholipids from degradation. and the reduction ofarachidonic acid release.

A mix & act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening

In the treatment of central nervous system disease,the blood-brain barrier(BBB)is a major obstruction to drug delivery that must be overcome.In this study,we propose a brain-targeted delivery strat-egy based on selective opening of the BBB.This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material;however,the BBB still maintains the ability to completely block molecules from passing through.Based on the screening of BBB opening and matrix delivery mate-rials,we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine li-posomes can efficiently carry drugs into the brain immediately.At an effective dose,this delivery system is safe,especially with its effect on the BBB being reversible.This mix&act delivery system has a simple structure and rapid preparation,making it a strong potential candidate for drug delivery across the BBB.

Research Advance of Chinese Medicine in Treating Atherosclerosis:Focus on Lipoprotein-Associated Phospholipase A2

As a serious cardiovascular disease,atherosclerosis(AS)causes chronic inflammation and oxidative stress in the body and poses a threat to human health.Lipoprotein-associated phospholipase A2(Lp-PLA2)is a member of the phospholipase A2(PLA2)family,and its elevated levels have been shown to contribute to AS.Lp-PLA2 is closely related to a variety of lipoproteins,and its role in promoting inflammatory responses and oxidative stress in AS is mainly achieved by hydrolyzing oxidized phosphatidylcholine(ox PC)to produce lysophosphatidylcholine(lyso PC).Moreover,macrophage apoptosis within plaque is promoted by localized Lp-PLA2 which also promotes plaque instability.This paper reviews those researches of Chinese medicine in treating AS via reducing Lp-PLA2 levels to guide future experimental studies and clinical applications related to AS.

High patatin like phospholipase domain containing 8 expression as a biomarker for poor prognosis of colorectal cancer

BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidation.However,the role of PNPLA8 in colorectal cancer(CRC)progression is unclear.AIM To explore the prognostic effects of PNPLA8 expression in CRC.METHODS A retrospective cohort containing 751 consecutive CRC patients was enrolled.PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores.CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off va-lues,which were calculated by X-tile software.The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis.The over-all survival(OS)rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.RESULTS PNPLA8 expression was significantly associated with distant metastases in our cohort(P=0.048).CRC patients with high PNPLA8 expression indicated poor OS(median OS=35.3,P=0.005).CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS.For patients with left-sided colon and rectal cancer,the survival curves of two PN-PLA8-expression groups showed statistically significant differences.Multivariate analysis also confirmed that high PNPLA8 expression was an independent prog-nostic factor for overall survival(hazard ratio HR=1.328,95%CI:1.016-1.734,P=0.038).

A secreted phospholipase A_(2) (BmsPLA_(2)) regulates melanization of immunity through BmDDC in the silkworm Bombyx mori

Insect immune-associated phospholipase A_(2) (PLA_(2)) is an important target of pathogen invasion. Melanization, an effective defense response, has significant correlations with other immune responses to coordinate immune attack against invaders. However, the effect of PLA_(2) on melanization has not yet been reported in insects or other arthropods. In this work, we cloned a PLA_(2) gene (BmsPLA_(2)), and its protein had characteristic features of secreted PLA_(2) (sPLA_(2)). After injection of bacteria, BmsPLA_(2) expression and sPLA_(2) activity in hemolymph significantly increased. BmsPLA_(2) fluorescence was transferred from the cytoplasm to the cell membranes of circulating hemocytes. These results indicated that BmsPLA_(2) was related to hemolymph immunity in silkworms. Interestingly, reducing BmsPLA_(2) by RNA interference decreased melanosis (melanistic hemocytes) levels in vivo and in vitro, while BmsPLA_(2) overexpression had the opposite effect. The larval survival and melanization rate in the hemocoel both slowed depending on the PLA_(2) inhibitor dosage. These results demonstrated that BmsPLA_(2) plays a role in melanization during the immune process of silkworms. Surprisingly, the level of BmDDC matched the degree of melanization in various observations. BmDDC expression showed a significant increase, with the peak occurring later than that of BmsPLA_(2) after injection of bacteria, implying that BmsPLA_(2) was activated prior to BmDDC. Moreover, the alteration of BmsPLA_(2) by RNA interference or overexpression led to altered BmDDC levels. These results suggested that BmsPLA_(2) regulates the melanization response in silkworms through BmDDC. Our study proposes a new regulatory mechanism of the melanization response and new directions for understanding the complex immune networks of insects.

Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury

Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers:A case report and review of literature

BACKGROUND Genetic factors of chronic intestinal ulcers are increasingly garnering attention.We present a case of chronic intestinal ulcers and bleeding associated with mu-tations of the activin A receptor type II-like 1(ACVRL1)and phospholipase A2 group IVA(PLA2G4A)genes and review the available relevant literature.CASE SUMMARY A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain,diarrhea,and dark stools.At the onset 6 years ago,the patient had received treatment at a local hospital for abdominal pain persisting for 7 d,under the diagnosis of diffuse peritonitis,acute gangrenous appendicitis with perforation,adhesive intestinal obstruction,and pelvic abscess.The surgical treat-ment included exploratory laparotomy,appendectomy,intestinal adhesiolysis,and pelvic abscess removal.The patient’s condition improved and he was dis-charged.However,the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge.On the basis of these features and results of subsequent colonoscopy,the clinical diagnosis was established as in-flammatory bowel disease(IBD).Accordingly,aminosalicylic acid,immunotherapy,and related symptomatic treatment were administered,but the symptoms of the patient did not improve significantly.Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes.ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation,respectively.This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes.Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms.CONCLUSION Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD.Orally administered Kangfuxin liquid may have therapeutic potential.