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 peroxidat...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).展开更多
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 ne...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.展开更多
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 dest...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.展开更多
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 parti...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.展开更多
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 u...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.展开更多
Objective:To study characteristics of phospholipases C(PLCs),their importance for producing microorganisms us well us the potential of their use for industrial purposes.Methods:PLC from Bacillus cereus(B.cereus) D101 ...Objective:To study characteristics of phospholipases C(PLCs),their importance for producing microorganisms us well us the potential of their use for industrial purposes.Methods:PLC from Bacillus cereus(B.cereus) D101 was selected as an example of Gram-positive PLCs and PLC from Pseudomanas aeruginosa(P.aeruginosa) D183 of Gram-negative ones.Enzymes were partially purified by ammonium sulfate precipitation followed by membrane dialysis.Partially purified preparations were used to study effect of different factors on activities as well as in substrate specificity tests which were conducted using a turbidimetric assay method.Results:Maximum activity was at pH 7 and 8 and 40 ℃ for P.aeruginosa PLC,and pH 8-10 and 37 ℃ for B.cereus PLC.Both PLCs were inhibited by Pi at 5 mM or higher,whereas,PLC from B.cereus only was inhibited by EDTA.Activity of P.aeruginosa PLC was not affected by removing Zn^(2+) ions from reaction mixture or their replacement with Ca^(2+),Ba^(2+),Mg^(2+) or Mn^(2+)ions.Vis-a-vis,activity of B.cereus PLC was found to be metal ion dependent PLCs from both isolates were relatively thermostable and showed maximum affinity toward phosphatidylcholine.Sphingomyelin and phosphatidylethanolamine were not good substrates and phosphatidylinositol,phosphatidylserine,phosphatidylglycerol and cardiolipin could be considered nonsubstrates.Conclusions:Human body physiological conditions could favor activity of P.aeruginosa and B.cereus PLCs.These enzymes may participate in phosphate scavenging and virulence of producing isolates but not in autolysis.PLCs from both isolates are potential candidates for industrial use.展开更多
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 fatt...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.展开更多
Acute fulminant pancreatitis was produced in dogs by injection of autobile into the mainpancreatic duct.After injection the phospholipase A<sub>2</sub>（PLA<sub>2</sub>）activities in serum,lun...Acute fulminant pancreatitis was produced in dogs by injection of autobile into the mainpancreatic duct.After injection the phospholipase A<sub>2</sub>（PLA<sub>2</sub>）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 PLA<sub>2</sub> inhibitor,chloroquine,blocked the changes mentionedabove.This experiment suggests:1.PLA<sub>2</sub> activity in lung lymph fluid as well as in serum andBAL is elevated in acute hemorrhagic pancreatitis.2.Elevated PLA<sub>2</sub> activity may increase thepulmonary vascular permeability.3.PLA<sub>2</sub> is the major factor leading to pulmonary edema in acutehemorrhagic pancreatitis.4.Phagocytes contribute to the lung injury induced by PLA<sub>2</sub> to some ex-tent.展开更多
Objective To survey changes and the significance of phospholipase A2（PLA2） on brain tissue of SD rat in acute pancreatitis.Methods With retrograde injection of 3% taurocholate sodium into pancreatic and biliary duct...Objective To survey changes and the significance of phospholipase A2（PLA2） 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 PLA2 inhibitor-treated group of SAP.Serum amylases,PLA2 and PLA2 in brain tissue were measured and the brain tissue changes were observed.Results There were no significant difference in serum amylases, PLA2 and PLA2 in brain tissue between the sham-operation and the control groups;the levels of serum amylases,PLA2 and PLA2 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,PLA2 and PLA2 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 PLA2 might play an important role in brain tissue damages in severe acute pancreatitis.展开更多
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...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.展开更多
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 marker...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, Medical College of Wuhan Polytechnic University; Faculty of Human Anatomy and Histology & Embryology, 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 immunohistochemical 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.展开更多
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...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.展开更多
AIM: To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP).METHODS: A total of 64 rats were random...AIM: To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP).METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane.Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 (P＜0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and (P＜0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20) μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07) μg/L (P＜0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P＜0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred.CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.展开更多
Phospholipase D(PLD,EC 3.1.4.4) plays an important role in adaptive response of postharvest fruit to environment.In this study,a novel cDNA of PLDα was isolated with the strategy of in silico cloning in combination w...Phospholipase D(PLD,EC 3.1.4.4) plays an important role in adaptive response of postharvest fruit to environment.In this study,a novel cDNA of PLDα was isolated with the strategy of in silico cloning in combination with RT-PCR from peach(Prunus persica L.cv.Jiubao).The obtained PLDα gene contained a complete open reading frame encoding a 92-kDa protein of 810 amino acid residues,which possessed the characteristic C2 domain and two catalytic HKD motifs.The alignment analysis of the deduced peach PLDα protein with other known PLDα family proteins indicated that peach PLDα was conserved and highly homologous with strawberry PLDα.Semi-quantitative RT-PCR and Northern blot analysis indicated PLDα mRNA in peach fruits could be induced by low temperature.This work provided a scientific basis for further investigating the mechanism of postharvest fruit adaptation to low temperature.展开更多
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 cardi...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).展开更多
AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3 ) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS:...AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3 ) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine amino-transaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.展开更多
基金This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital,Fudan University.
文摘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).
基金supported by the National Natural Science Foundation of China,No.82072192(to KLZ)Public Welfare Technology Research Project of Zhejiang Province,No.LGF20H150003(to KLZ)+1 种基金the Natural Science Foundation of Zhejiang Province,Nos.LY17H060009 and Y21H060050(both to WFN)Wenzhou Science and Technology Bureau Foundation,No.Y20210438(to KLZ)。
文摘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.
基金Supported by FORICA(the FOundation for Advanced Research in Hypertension and Cardiovascular diseases,www.forica.it)
文摘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.
基金supported by the National Natural Science Foundation of China [Grant No. 81973112 and Grant No.9204930002]
文摘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.
基金supported by grants from Key Project of Tianjin Natural Science Foundation (Grant No.18JCZDJC35200)NSFC-FRQS program (Grant No.81661128009)+1 种基金The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (Grant No.2017KJ202)Scientific Research Foundation for Returned Scholars and Doctoral Program of Tianjin Medical University Cancer Institute and Hospital (Grant No.B1703)
文摘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.
文摘Objective:To study characteristics of phospholipases C(PLCs),their importance for producing microorganisms us well us the potential of their use for industrial purposes.Methods:PLC from Bacillus cereus(B.cereus) D101 was selected as an example of Gram-positive PLCs and PLC from Pseudomanas aeruginosa(P.aeruginosa) D183 of Gram-negative ones.Enzymes were partially purified by ammonium sulfate precipitation followed by membrane dialysis.Partially purified preparations were used to study effect of different factors on activities as well as in substrate specificity tests which were conducted using a turbidimetric assay method.Results:Maximum activity was at pH 7 and 8 and 40 ℃ for P.aeruginosa PLC,and pH 8-10 and 37 ℃ for B.cereus PLC.Both PLCs were inhibited by Pi at 5 mM or higher,whereas,PLC from B.cereus only was inhibited by EDTA.Activity of P.aeruginosa PLC was not affected by removing Zn^(2+) ions from reaction mixture or their replacement with Ca^(2+),Ba^(2+),Mg^(2+) or Mn^(2+)ions.Vis-a-vis,activity of B.cereus PLC was found to be metal ion dependent PLCs from both isolates were relatively thermostable and showed maximum affinity toward phosphatidylcholine.Sphingomyelin and phosphatidylethanolamine were not good substrates and phosphatidylinositol,phosphatidylserine,phosphatidylglycerol and cardiolipin could be considered nonsubstrates.Conclusions:Human body physiological conditions could favor activity of P.aeruginosa and B.cereus PLCs.These enzymes may participate in phosphate scavenging and virulence of producing isolates but not in autolysis.PLCs from both isolates are potential candidates for industrial use.
文摘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.
文摘Acute fulminant pancreatitis was produced in dogs by injection of autobile into the mainpancreatic duct.After injection the phospholipase A<sub>2</sub>（PLA<sub>2</sub>）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 PLA<sub>2</sub> inhibitor,chloroquine,blocked the changes mentionedabove.This experiment suggests:1.PLA<sub>2</sub> activity in lung lymph fluid as well as in serum andBAL is elevated in acute hemorrhagic pancreatitis.2.Elevated PLA<sub>2</sub> activity may increase thepulmonary vascular permeability.3.PLA<sub>2</sub> is the major factor leading to pulmonary edema in acutehemorrhagic pancreatitis.4.Phagocytes contribute to the lung injury induced by PLA<sub>2</sub> to some ex-tent.
文摘Objective To survey changes and the significance of phospholipase A2（PLA2） 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 PLA2 inhibitor-treated group of SAP.Serum amylases,PLA2 and PLA2 in brain tissue were measured and the brain tissue changes were observed.Results There were no significant difference in serum amylases, PLA2 and PLA2 in brain tissue between the sham-operation and the control groups;the levels of serum amylases,PLA2 and PLA2 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,PLA2 and PLA2 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 PLA2 might play an important role in brain tissue damages in severe acute pancreatitis.
文摘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.
文摘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, Medical College of Wuhan Polytechnic University; Faculty of Human Anatomy and Histology & Embryology, 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 immunohistochemical 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.
文摘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.
基金Supported by the Traditional Chinese Medicine Administration Bureau Foundation of Jiangsu Province,No.9965the Applied Basic Research Program of Science and Technology Commission Foundation of Jiangsu Province,No.BJ2000327
文摘AIM: To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP).METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane.Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 (P＜0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and (P＜0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20) μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07) μg/L (P＜0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P＜0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred.CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.
基金supported by China Post doctoral Science Foundation (20070420095)the National Natural Science Foundation of China (30571279,30871699,30901012)+1 种基金Innovative Foundation of Shanghai UniversitySystems Biology Research Foundation of Shanghai University
文摘Phospholipase D(PLD,EC 3.1.4.4) plays an important role in adaptive response of postharvest fruit to environment.In this study,a novel cDNA of PLDα was isolated with the strategy of in silico cloning in combination with RT-PCR from peach(Prunus persica L.cv.Jiubao).The obtained PLDα gene contained a complete open reading frame encoding a 92-kDa protein of 810 amino acid residues,which possessed the characteristic C2 domain and two catalytic HKD motifs.The alignment analysis of the deduced peach PLDα protein with other known PLDα family proteins indicated that peach PLDα was conserved and highly homologous with strawberry PLDα.Semi-quantitative RT-PCR and Northern blot analysis indicated PLDα mRNA in peach fruits could be induced by low temperature.This work provided a scientific basis for further investigating the mechanism of postharvest fruit adaptation to low temperature.
文摘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).
基金Supported by FIRST Università degli Studi di Milano 2007,2008 to Valenti L, Fargion SRicerca corrente Ospedale Maggiore Policlinico 2006 and 2008 to Valenti L, Fargion SCentro per lo Studio delle Malattie del Fegato e del Metabolismo
文摘AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3 ) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine amino-transaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.
