The role of serum lipoxin A4 levels in the association between periodontal disease and metabolic syndrome

PURPOSE: An unresolved inflammatory state contributes to the pathogenesis of periodontal disease and metabolic syndrome (MetS). Therefore, the purpose of this study was to evaluate the role of lipoxin A4 (LXA4), a proresolving lipid mediator, in the association between periodontal disease and MetS. METHODS: Sixty-seven patients with MetS and 65 patients without MetS were included in the study. Sociodemographic information was obtained via a questionnaire, and detailed medical diagnoses were made. Periodontal parameters (plaque index [PI], gingival index [GI], probing pocket depth [PD], and clinical attachment level [CAL]) and metabolic parameters were measured, and serum LXA4 levels were determined. The associations among MetS, periodontal parameters, and serum LX levels were evaluated by adjusted multivariate linear regression analyses. RESULTS: Patients with MetS were older and had a higher body mass index than patients without MetS. Periodontal parameters (PI, GI, PD, and CAL) were higher in patients with MetS than in those without MetS. Serum LXA4 levels were higher in patients without MetS. Multivariate linear regression analysis indicated a positive association between MetS and periodontal parameters (PD and CAL). Negative associations were established between MetS and LXA4 levels, and between LXA4 and periodontal parameters (PI, PD, and CAL). CONCLUSIONS: The presence of higher values of periodontal parameters in patients with MetS and the negative relationship of LXA4 with MetS and periodontal disease may support the protective role of proresolving lipid mediators in the association between periodontal disease and MetS.

Research on protective function of aspirin-triggered lipoxins on acute kidney injury in mice / 中华实用儿科临床杂志

Objective To investigate the renoprotective effect of aspirin-triggered lipoxins(ATL)on kidney of mice with acute kidney injury(AKI).Methods Eighty-eight male specific pathogen-free(SPF)C57BL/6J mice were randomly divided into lipopolysaccharide(LPS)groups(including 2 h group,4 h group,8 h group,12 h group, 24 h group),ATL+LPS(including 2 h group,4 h group,8 h group,12 h group,24 h group)and normal control group according to random numble table,and each group had 8 mice.The mice in LPS groups were given LPS intraperitoneal injection to establish AKI animal models,while the mice in ATL+LPS groups were given ATL intraperitoneal injection 30 minutes before LPS intraperitoneal injection.The enzyme linked immunosorbent assay was used to test the serum creatinine(Scr),serum urea nitrogen(BUN),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and urine neutrophil gelatinase-associated lipocalin(NGAL),kidney injury molecule-1(KIM-1),cysteine-rich protein-61 (Cyr61)and netrin-1 levels of mice.Results The kidney tissue injury scores of mice of ATL+LPS group[4 h:(22.32 ± 1.04)scores,8 h:(31.11 ± 1.86)scores,12 h:(18.22 ± 0.92)scores,24 h:(20.87 ± 3.18)scores] were lower than those of LPS group at the corresponding time points[4 h:(35.47 ± 2.27)scores,8 h:(52.28 ± 2.82) scores,12 h:(54.99 ± 4.56)scores,24 h:(53.41 ± 4.76)scores],and the differences were statistically significant(all P<0.01).The values of Scr,BUN,TNF-α and IL-1β in ATL+LPS group[Scr 8 h:(143.07 ± 5.02)μmol/L, BUN 12 h:(33.07 ± 3.52)mmol/L,TNF-α 4 h:(196.33 ± 14.181)ng/L and 8 h:(221.77 ± 10.11)ng/L,IL-1β 4 h:(50.25 ± 2.67 ng/L)]were lower than those in LPS group at the corresponding time points[Scr 8 h:(227.43 ± 11.17)μmol/L,BUN 12 h:(59.68 ± 3.84)mmol/L,TNF-α 4 h:(267.87 ± 26.48)ng/L and 8 h:(334.78 ± 21.08)ng/L,IL-1β 4 h:(89.45 ± 5.87)ng/L],and the differences were statistically significant(all P<0.01). The urine NGAL[4 h:(56.76 ± 4.01)μg/L,8 h:(65.44 ± 7.81)μg/L],KIM-1[8 h:(78.19 ± 9.48)μg/L] and netrin-1[8 h:(40.12 ± 2.01)ng/L,12 h:(36.87 ± 2.87)ng/L]of mice in ATL+LPS group were lower than those in LPS group at the corresponding time points[NGAL 4 h:(168.77 ± 10.77)μg/L,8 h:(155.33 ± 8.26) μg/L;KIM-1 8 h:(124.73 ± 13.47)μg/L;netrin-1 8 h:(89.17 ± 2.74)ng/L,12 h:(81.11 ± 3.88)ng/L],and the differences were statistically significant(all P<0.01).Conclusions ATL can treat LPS-induced AKI and play a renoprotective role in the kidney.

Lipoxin A4 inhibits the invasion and migration of endometrial stromal cells by down-regulating NF-κB signaling-mediated autophagy / 中华妇产科杂志

Objective@#To investigate whether the suppressive effects of lipoxin A4 (LXA4) on endometriosis are mediated by the regulation of autophagic activity, and to further explore the actual molecular mechanism.@*Methods@#(1) Eutopic and ectopic endometria were obtained from 13 patients with endometriosis, and 10 eutopic endometria collected from non-endometriosis patients were used as control. The expression of the autophagy-related biochemical markers [microtubule-associated protein 1 light chain 3 (LC3) and p62] were detected by western blot. Levels of LXA4 in the biopsies were measured by ELISA. (2) Primary human endometrial stromal cells (ESC) were isolated and cultured in vitro from eutopic endometria of infertility patients with endometriosis. After treatment with exogenous LXA4 or autophagy inhibitor 3-methyladenine (3-MA) or autophagy inducer rapamycin, cell migration and invasion were evaluated by transwell assay, and autophagy was detected by western blot. (3) ESC were treated with LXA4, the gene expressions of nuclear factor kappa B (NF-κB) etc. were examined by quantitative real-time PCR, and the activation of NF-κB signaling was detected by western blot. (4) ESC were incubated with 10 μmol/L NF-κB inhibitor BAY11-7080, the autophagic activation was detected by western blot.@*Results@#(1) Autophagy-related marker, LC3-Ⅱ and LC3-Ⅱ/LC3-Ⅰ ratio, showed a significant up-regulation in ectopic lesions of endometriosis compared with eutopic endometria of affected or healthy women (all P<0.05) . However, the LXA4 level significantly decreased in ectopic tissue (P<0.05) . There was a significant negative correlation between LXA4 concentration and relative expression of LC3-Ⅱ in ectopic lesions (r= -0.780, P=0.002) . (2) 10 and 100 nmol/L exogenous LXA4 could significantly down-regulate the LC3-Ⅱ protein expression and up-regulate the p62 protein expression (all P<0.05) . LXA4 markedly inhibited the invasion and migration of ESC (P<0.05) ;while the reactivation of autophagy by rapamycin almost reversed the anti-invasion and anti-migration effects of LXA4. (3) After LXA4 treatment, the expression level of NF-κB gene significantly decreased (P<0.05) . Furthermore, the results of western blot analysis showed that the nuclear translocation of NF-κB p65 was markedly down-regulated under LXA4 treatment (P<0.05) . (4) The NF-κB inhibitor BAY11-7080 markedly suppressed the autophagic activation of LXA4 (P<0.05) .@*Conclusion@#LXA4 could inhibit the invasion and migration of ESC by down-regulating the NF-κB signaling-mediated autophagy.

Effect of Alox-15 Polymorphism on GCF Levels of Lipoxin-A4 in Chronic Periodontitis: A Preliminary Study

Lipoxins play an important role in periodontal resolution, hence, investigation of genetic polymorphism of lipoxin gene may provide important information on the role of lipoxins in periodontal disease pathogenesis. The aim of this study was to investigate a polymorphism of C-to-T substitution at position c.-292 in ALOX15 (reticulocyte-type 15 lipoxygenase 1) gene in patients with chronic periodontitis and to associate the polymorphism with gingival crevicular fluid (GCF) lipoxin A4 (LXA4) levels. Forty-five chronic periodontitis and 45 periodontally healthy patients were included in this case-control study. Plaque index, calculus index, sulcus bleeding index, full mouth probing depth (PD) and clinical attachment loss (CAL) were recorded. GCF and blood samples were collected. GCF was analyzed for LXA4 levels by enzyme linked immunosorbant assay. Genotyping of ALOX15 polymorphism was studied using PCR. Mean LXA4 was lower in periodontitis group compared to the periodontally healthy group. There was a negative correlation between CAL and LXA4. The CC genotype was higher in the study group than in the control group. In the study group, mean CAL was significantly lower among individuals with the CT genotype. Mean LXA4 was significantly lower in CC genotype (45.0±7.11 ng/mL) compared to CT genotype (50.81±5.81 ng/mL) among the patients with periodontitis. The results suggest that LXA4 and c.-292T allele are associated with periodontal health. Polymorphisms in the ALOX15 gene may influence periodontal disease pathogenesis. Hence, investigation of such polymorphisms could benefit the evaluation of lipoxins role in periodontal disease.

Resumo Lipoxinas desempenham um papel importante na recuperação periodonta, portanto, a investigação do polimorfismo genético do gene da lipoxina pode fornecer informações importantes sobre o papel das lipoxinas na patogênese da doença periodontal. O objetivo deste estudo foi investigar um polimorfismo de substituição C-to-T na posição c-292 no gene ALOX15 (reticulócito-tipo 15 lipoxigenase 1) em pacientes com periodontite crônica e associar o polimorfismo com a lipoxina A4 (LXA4) do fluido gengival crevicular (FGC). Quarenta e cinco pacientes com periodontite crônica e 45 pacientes periodonalmente saudáveis foram incluídos neste estudo caso-controle. Índice de placa, índice de cálculo, índice de sangramento do sulco, profundidade de sondagem (PS) da boca toda e perda de inserção clínica (PIC) foram registrados. Amostras do FGC e de sangue foram coletadas. O FGC foi analisado quanto aos níveis de LXA4 por ensaio imunoadsorvente ligado à enzima (ELISA). A genotipagem do polimorfismo ALOX15 foi estudada por PCR. A média de LXA4 foi menor no grupo de periodontite em comparação com o grupo periodontalmente saudável. Houve uma correlação negativa entre PIC e LXA4. O genótipo CC foi maior no grupo de estudo do que no grupo controle. No grupo de estudo, a média de PIC foi significativamente menor entre os indivíduos com o genótipo CT. A média de LXA4 foi significativamente menor no genótipo CC (45,0 ± 7,11 ng / mL) em comparação com o genótipo CT (50,81 ± 5,81 ng / mL) entre os pacientes com periodontite. Os resultados sugerem que o alelo LXA4 e o alelo c-292T estão associados à saúde periodontal. Polimorfismos no gene ALOX15 podem influenciar a patogênese da doença periodontal. Assim, a investigação de tais polimorfismos pode beneficiar a avaliação do papel das lipoxinas na doença periodontal.

A study on the protective mechanisms of lipoxin A4 for hyperoxia-induced pulmonary epithelial cells injury in mice / 中国新生儿科杂志

Objective To study the protective mechanisms of lipoxin A 4 ( LXA4 ) for hyperoxia-induced lung injury through modulation of let-7c/TGF-β1 signal pathway in mice.Method MLE-12 cells was transfected with let-7c mimic, mimic negative control ( NC) , let-7c inhibitor and inhibitor NC.The cells were assigned into hyperoxia group , LXA4 group, let-7c over-expression group, let-7c silence group, let-7c silence+LXA4 group, and all exposed to 85% oxygen.The mRNA level of the extracellular matrixα-smooth muscle actin (α-SMA) and collagen Ⅰ( COL-Ⅰ) , and the expression of related genes in TGF-β1 signaling pathway (Smad 2, Smad 3, Smad 4, TGF-βR1, TGF-βR2) were examined using qPCR.The protein expressions in TGF-β1 signaling pathway was examined using Western blot .Result The mRNA expressions of α-SMA, COL-Ⅰ, Smad 3, Smad 4, TGF-βR1 and TGF-βR2 in LXA4 group [(24.3 ±2.1), (14.6 ±0.2), (17.0 ±0.0), (14.9 ±0.1), (20.8 ±0.1), (9.0 ±0.0) ] and let-7c over-expression group [ ( 12.2 ±0.5 ) , ( 3.0 ±0.0 ) , ( 3.1 ±0.0 ) , ( 9.6 ±0.4 ) , ( 28.5 ±0.2 ) , ( 7.6 ± 0.1)] were decreased comparing with the hyperoxia group [(51.4 ±0.5), (32.0 ±0.1), (40.6 ±0.2), (16.3 ±0.1), (89.1 ±1.1), (19.3 ±0.2)].These expressions were increased in both let-7c silence group [(87.3 ±7.0), (38.5 ±0.3), (48.0 ±0.2), (56.5 ±0.2), (126.0 ±0.9), (33.1 ±1.0)] and let-7c silence +LXA4 group [(144.5 ±12.9), (86.3 ±3.0), (91.5 ±4.7), (86.5 ±3.3), (109.0 ±4.5), (45.6 ±1.6)].The protein levels of Smad 2, Smad 3, Smad 4, p-Smad 2, p-Smad 3 and TGF-βR1 of LXA4 group and let-7c over-expression group were decreased comparing with the hyperoxia group, while p-Smad 2, p-Smad 3 of let-7c silence+LXA4 group were increased(P<0.05).Conclusion LXA4 may play a protective role through let-7c /TGF-β1 signal pathway of lung epithelial cells for hyperoxia-induced lung injury in mice .

Effects of lipoxin A4 on human type Ⅱ alveolar epithelial cell wound repair, proliferation and apoptosis / 中华麻醉学杂志

Objective To evaluate the effects of lipoxin A4 (LXA4) on human type Ⅱ alveolar epithelial cell wound repair,proliferation and apoptosis.Methods Experiment Ⅰ Human type Ⅱ alveolar epithelial cells were inoculated in 24-well plates and divided into 4 groups (n=10 each) using a random number table:control group (group C),1 nmol/L LXA4 group (group L1),10 nmol/L LXA4 group (group L2) and 100 nmol/L LXA4 group (group L3).Cells were cultured in normal culture atmosphere in group C.Cells were incubated with 1,10 and 100 nmol/L LXA4 in L1,L2 and L3 groups,respectively.The scratch wound assay was performed at 36 h of culture or incubation.Cell proliferation was measured at 24 h of culture or incubation.Experiment Ⅱ Human type Ⅱ alveolar epithelial cells were inoculated in 96-well plates and divided into 5 groups using a random number table:control group (group C,n=10),Fas-ligand group (n =10),Fas-ligand+LXA4 group (n =10),Fas-ligand+TNF-α group (n =5) and Fas-ligand+TNF-α+LXA4 group (n=5).Cells were incubated with 100 ng/ml Fas-Ligand,100 ng/ml Fas-Ligand plus 100 nmol/L LXA4,100 ng/ml Fas-Ligand plus 100 ng/ml TNF-α,and 100 ng/ml Fas-Ligand plus 100 ng/ml TNF-α plus 100 nmol/L LXA4 in Fas-ligand,Fas-ligand+LXA4,Fas-ligand+TNF-α,and Fas-ligand +TNF-α+LXA4 groups,respectively.The cell viability was measured at 24 h of culture or incubation.Cell apoptosis was detected using the flow cytometry,and apoptosis rate was calculated in C,Fas-ligand and Fas-ligand+LXA4 groups.Results Experiment Ⅰ Compared with group C,the percentage of cell repair size and percentage of proliferation were significantly increased in L1,L2 and L3 groups (P＜0.05 or 0.01).Compared with group L1,the percentage of cell repair size and percentage of proliferation were significantly increased in group L3 (P＜ 0.01),and no significant change was found in the parameters mentioned above in group L2 (P＞0.05).Experiment Ⅱ Compared with group C,the cell viability was significantly decreased,and the apoptosis rate was increased in group Fas-ligand,the cell viability was significantly decreased in group Fas-ligand+TNF-α (P＜ 0.01),and no significant change was found in the cell viability or apoptosis rate in group Fas-ligand+LXA4 or in the cell viability in group Fas-ligand+TNF-α+LXA4 (P＞0.05).Compared with group Fas-ligand,the cell viability was significantly increased,and the apoptosis rate was decreased in group Fas-ligand+LXA4 (P＜ 0.05).The cell viability was significantly higher in group Fas-ligand +TNF-α + LXA4 than in group Fas-ligand +TNF-α (P ＜ 0.01).Conclusion LXA4 can promote human type Ⅱ alveolar epithelial cell wound repair and proliferation and inhibit the apoptosis.

Recent progress of lipoxins in inflammatory signal pathway / 中华实用儿科临床杂志

Lipoxins are metabolic products of arachidonic acid,which possess a wide spectrum of adjustment function for various inflammatory cell function and the expression of inflammatory related genes.It is known asstop signals or braking signals of inflammatory response,which can promote the regression of inflammation through regulating a variety of inflammatory signaling pathway.Now,the progress in the regulation of multiple signal pathways by lipoxins and its anti-inflammatory mechanism are reviewed.

The mechanism of lipoxin A4 intervention on the oxidative stress induced by uric acid in human umbilical vein endothelial cells / 中华风湿病学杂志

Objective To investigate the effect and mechanism of lipoxin A4 (LXA4) on uric acid (UA) induced oxidative stress of human umbilical vein endothelial cells (HUVECs).Methods The HUVECs was treated with uric acid to constructing the model of oxidative stress,and intervene the model with LXA4 and xylene based iodine (DPI),rotenone.Reactive oxygen species (ROS) of HUVEC were detected by a fluorescence probe 2',7'-dichlorofluorescin diacetate (DCFH-DA).The activity of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and p47phox protein was measured by Lucigenin enhanced chemiluminescence and Western blotting among control,uric acid (UA),LXA4 and UA +LXA4 groups,respectively.All the results were described by the relative expression of the control group,repeated measure variance analysis and least significant difference test (LSD) were used for statistical analysis.Results UA could stimulate HUVEC to generate ROS with different concentrations and times (F=7.286,F=4.532,P＜0.05).Compared with the control group(100±l 1),the ROS production of group with 80 mg/L UA (177±18),120 mg/L (226±29) and 160 mg/L (225±16) increased significantly (t=4.127,t=7.591,t=7.236,P＜0.05).Compare with baseline(100±8),the ROS production increased significantly (t=3.688,t=3.513,t=4.526,t=8.269,t=3.829,P＜ 0.05) at 3 h(143±16),6 h(140±17),12 h(183±20),24 h(240±29) and 48 h(160±22).LXA4 could inhibit ROS generation at different concentrations and times (F=4.008,F =4.497,P ＜0.05).Compared with LXA4 concentration of 0 nmol/L,the LXA4 concentrations of 10 nmol/L (162±16) and 100 nmol/L (132±15) could significantly inhibit ROS generation(t=3.712,t=4.083,P＜0.05).Compared with pretreatment (269±39),the ROS generation decreased significantly (t=6.373,t=6.426,t=7.125,t=6.981,P＜0.05).with LXA4 pretreated for 15 min (160±16),30 rain(158±21),1 h (136±13) and 2 h(140±13).Compared with the UA group(252±31),LXA4 and DPI could significantly inhibited ROS generation (145±29,154±27;t=6.356,t=5.853,P＜0.05),but Rot was not significantly intervented (241±32;t=1.027,P＞0.05).The NADPH oxidase activity in the UA group was significantly higher than that in the control group (144±16,100±13;t=3.659,P＜0.05),but the group of LXA4+ UA was significantly lower than that of the UA group (119±14;t=3.124,P＜0.05).The cytoplasmic expression of NADPH oxidase subunit p47phox of UA group was significantly lower than that in the control group (47±6,100±8;t=7.562,P＜0.05),but the LXA4+UA group was significantly increased compare with the UA group (83±6,t=5.386,P＜0.05).The cytomembrane expression of p47phox of UA group was significantly higher than that in the control group (328±36,100±4,t=12.817,P＜0.05),but the LXA4+UA group was significantly decreased compared with the UA group (183±30,t=5.129,P＜0.05).Conclusion LXA4 inhibits UA induced ROS production in HUVECs.This mechanism might be through inhibiting p47phox trafficing from cytoplasm to cytomembrane,results in inhibiting the activation of NADPH oxidase.

Changes of serum levels of myeloperoxidase and lipoxin A 4 in patients with coronary heart disease and its significance / 心血管康复医学杂志

Objective:To observe changes of serum levels of myeloperoxidase (MPO) and lipoxin A4 (LXA4) in pa‐tients with coronary heart disease (CHD) and explore its clinical significance .Methods :A total of 120 CHD patients treated in our hospital from Jun 2013 to Sep 2014 were selected as CHD group ,another 40 healthy subjects were re‐garded as normal control group .According to CHD type ,patients were divided into stable angina pectoris (SAP) group (n=36) ,unstable angina pectoris (UAP) group (n=46) and myocardial infarction (MI) group (n=38) .Ac‐cording to plaque nature assessed by CT value ,patients were divided into calcified plaque group (n= 27) ,mixed plaque group (n=31) and non-calcified plaque group (n=62) .Levels of MPO and LXA4 and ratio of MPO/LXA4 were compared among all groups .Results:Compared with normal control group ,there were significant rise in MPO level [ (167.2 ± 20.4) U/L vs .(218.3 ± 32.5) U/L] and MPO/LXA4 [ (0.78 ± 0.08) vs .(1.34 ± 0.27)] ,and sig‐nificant reduction in LXA4 level [ (214.6 ± 31.3) nmol/L vs .(162.4 ± 22.4) nmol/L] in CHD group ,P<0.05 or<0.01 .Compared with SAP group ,there were significant rise in MPO level [ (180.4 ± 21.6) U/L vs .(230.3 ± 32.5) U/L vs .(238.6 ± 44.7) U/L] and MPO/LXA4 [ (0.97 ± 0.11) vs .(1.37 ± 0.23) vs .(1.62 ± 0.25)] ,and significant reduction in LXA4 level [ (184.7 ± 23.7) nmol/L vs .(156.3 ± 21.2) nmol/L vs .(148.4 ± 19.6) nmol/L] in UAP group and MI group ,and MPO/LXA4 of MI group was significantly higher than that of UAP group , P<0.05 or < 0.01 . Compared with calcified plaque group and mixed plaque group , there were significant rise in MPO level [(196.3 ± 27.2) U/L vs .(211.2 ± 24.6) U/L vs .(231.6 ± 26.5) U/L] and MPO/LXA4 [(1.13 ± 0.14) vs .(1.26 ± 0.16) vs .(1.51 ± 0.21)] ,and significant reduction in LXA4 level [ (174.3 ± 23.4) nmol/L vs .(167.4 ± 21.2) nmol/L vs .(154.6 ± 19.2) nmol/L] in calcified plaque group ,and MPO/LXA4 of mixed plaque group was significantly higher than that of calcified plaque group , P<0.05 or <0.01 .Conclusion:There exist significant ab‐normal levels of MPO and LXA4 in CHD patients ,ratio of MPO/LXA4 is more helpful for determining disease se‐verity and stability of atherosclerotic plaque .

Progress on lipoxins in kidney diseases / 国际儿科学杂志

Lipoxins possess a wide spectrum of adjustment function for various inflammatory cell functioning and the expression of inflammatory related genes,also progressing the inflammatory response by means of various cell.Lipoxins play an important role in the pathogenesis and clinical treatment of kidney diseases.

Mediators of Resolution in Inflammation: Exploring Avenues.

Timely resolution of an acute inflammatory response is essential for healthy tissues. Specialized chemical mediators derived from essential fatty acids are identified that actively promote resolution of inflammation via novel pro-resolving and anti-inflammatory cascades. In this review, we summarize potent role of the lipoxins ,resolvins along with other chemical mediators that are enzymatically generated and identified in the resolving inflammatory exudates.

The expression of HO-1,RvD1 and LXA4 in cases with ulcerative colitis / 中国医师杂志

Objective In this study,the change of HO-1,RvD1,LXA4 and IL-6 in the patient with ulcerative colitis (UC)was investigated.Effects on the pathogenesis of ulcerative colitis were dis-cussed.Methods The distribution of HO-1 proteins in the colonic tissues in 60 cases of UC and 30 cases of normal control group were detected by SABC immunohistochemistry and perfusion catheter manometer. The slides were then analyzed with an Image Analyzing system to obtain the density of stained proteins.The levels of RvD1,LXA4 and IL-6 in serum by using enzyme linked immunosorbent assay(ELISA).Results The expression of HO-1 in patients with active UC was higher than that in normal group and remission of UC.The levels of RvD1,LXA4 and IL-6 in patients with active UC were significantly higher than that in normal group and remission of UC.The levels of HO-1,RvD1,LXA4 in patients with active UC were posi-tively correlated with IL-6.The levels of HO-1,RvD1,LXA4 in patients with normal group and remission of UC had no relevance with IL-6.Conclusions The expression of HO-1,RvD and LXA4 in activity of the UC may plays an important role in the pathogenesis of gastrointestinal motility disorders such as UC.

Lipoxin A4 protects diabetic rats against focal cerebral ischemia-reperfusion by downregulating tumor necrosis factor-α and nuclear factor-κB / 国际脑血管病杂志

Objective To investigate the protective effect of lipoxin A4 on diabetic rats with focal cerebral ischemia-reperfusion and its mechanisms.Methods Thirty-six adult male Sprague-Dawley rats were randomly divided into a sham operation group,a cerebral ischemia-reperfusion group,and a lipoxin A4 group (n=12 in each group).Diabetes was induced by repeated intraperitoneal injection of low-dose streptozotocin.A model of middle cerebral artery occlusion and reperfusion was induced by the intraluminal suture method.Five minutes after cerebral ischemia,lipoxin A4 0.03 nmol/5 μ1 was injected via intracerebroventricular in the lipoxin A4 group.The other groups were injected equal volume of saline.Two hours after ischemia,the suture was pulled out and reperfusion was achieved.Neurological deficit scores were performed at 24 hours.Then the rats were decapitated and their brains were taken out.2,3,5-triphenyl tetrazolium chloride (TTC) staining was used to detect infarct size.Western blotting was used to detect the expression of cortical tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB).Results The neurological deficit score showed that no neurological deficit was observed in the sham operation group (score 0).The neurological deficit score in the lipoxin A4 group was significantly lower than that in the cerebral ischemia-reperfusion group (2.20 ± 1.03 vs.3.20 ± 1.03; P ＜0.05).TTC staining showed that no infarct was observed in the sham operation group.The infarct size in the lipoxin A4 group was significantly lower than that in the cerebral ischemia-reperfusion group (27.52％ ± 5.71％ vs.55.45％ ± 9.29％ ; P ＜0.05).Western blotting showed that the expression levels of TNF-α in the sham operation,cerebral ischemiareperfusion,and lipoxin A4 groups were 0.64 ± 0.16,1.85 ± 0.52,and 1.40 ± 0.34,respectively.There were significant differences among the 3 groups (F =18.868,P ＜0.001).The expression level of TNF-α in the lipoxin A4 group was significantly lower than that in the cerebral ischemia-reperfusion group (P ＜0.05).The expression levels of NF-κB in the sham operation,cerebral ischemia-reperfusion and lipoxin A4 groups were 0.79 ±0.24,2.09 ± 0.47,and 1.27 ± 0.35,respectively.There were significant differences among the 3 groups (F =16.736,P ＜ 0.001).The expression level of NF-κB in the lipoxin A4 group was significantly lower than that in the cerebral ischemia-reperfusion group (P ＜0.05).Conclusions Lipoxin A4 has certain protective effect on focal cerebral ischemia-reperfusion injury in diabetic rats,its mechanism may be associated with the inhibition of the expression of TNF-α and NF-κB.

Protective role of lipoxins in digestive diseases / 中国病理生理杂志

Lipoxins, metabolites of arachidonic acid , are a strong“braking signal” towards inflammatory reac-tion.Due to their anti-inflammatory and pro-resolving properties , lipoxins have emerged to be the central targets in the re-search on inflammation .The present article reviews the research advances of synthesis , biological effects and the protective role of lipoxins in the diseases of liver , pancreas , stomach and colorectum , thus providing a novel approach for the treat-ment of digestive diseases .

Effect of lipoxin receptor agonist on human cytomegalovirus replication and proliferation / 中国组织工程研究

BACKGROUND:The anti-inflammation and protective effects of lipoxin have been verified in several immunity-related disease models. Preliminary studies of our research group have shown that, lipoxin receptor agonist BML-111 has negative regulation effects on the human cytomegalovirus (HCMV)-induced immunological injury. However, the effect of BML-111 on the HCMV replication remains unclear. OBJECTIVE:To observe the influence of lipoxin receptor agonist BML-111 on HCMV replication and proliferation in THP-1 macrophages and human embryonic lung fibroblasts. METHODS:THP-1 macrophages were infected by HCMV AD169 strain, and were divided into three groups:mock infection, HCMV infection, HCMV+BML-111. The final concentration of BML-111 was 100 nmol/L. cells in each group were col ected at 0, 1, 2, 4, 12, 36, 48 hours, the mRNA levels of IE86 and pp65 in the THP-1 macrophages were tested by RT-PCR method. Human embryonic lung fibroblasts were infected with HCMV (MOI=0.1), and were divided into two groups:HCMV infection and HCMV+BML-111. The patho-morphous changes of human embryonic lung fibroblasts were observed under light microscope, and the cellnumber was measured. The infective virus titer changes in human embryonic lung fibroblasts were examined by plaque assay. RESULTS AND CONCLUSION:After the macrophages were infected by HCMV, compared with the mock infection group, the mRNA levels of IE86 and pp65 in the HCMV group and HCMV+BML-111 group were increased significantly;compared with the HCMV infection group, the mRNA levels of IE86 and pp65 in the HCMV+BML-111 group were increased significantly in the early stage (within 4 hours) after infection, but the pp65 mRNA levels were decreased significantly in the medium and late stages (24-72 hours) after infection. After human embryonic lung fibroblasts were infected by HCMV, the degree of the patho-morphous in the HCMV+BML-111 group reached 100%2 days earlier than the of HCMV infection group. The infective virus titer reached the peak 2 days earlier than the HCMV infection group, but no significant difference was found between the two groups. BML-111 accelerates the replication of HCMV in the early stage of infection, but inhibits the expression of pp65 gene in the late stage. BML-111 has no impact on the proliferation of the infective HCMV titer in vitro.

Lipoxinas inducidas por la aspirina: una alternativa para modular los procesos proinflamatorios en la preeclampsia / Aspirin induced lipoxins: alternative to modulate proinflammatory processes in preeclampsia

La preeclampsia es un síndrome hipertensivo que se presenta a partir de la semana 20 de gestación. El objetivo de este trabajo es describir la producción y los mecanismos de acción de las lipoxinas inducidas por la aspirina y proponerlas como una alternativa adecuada para modular los procesos oxidativos característicos de la preeclampsia y los ciclos proinflamatorios que inician con la cascada de activación del factor nuclear-kappa B, y en consecuencia de sus productos. La preeclampsia se caracteriza por la producción de sustancias proinflamatorias, que inducen la activación de células endoteliales, directa o indirectamente, a través de la activación previa de los monocitos, los cuales pueden generar especies reactivas de oxígeno y expresar moléculas de adhesión que median la interacción con el endotelio, contribuyendo a su estado de disfunción, activación e inducción de la cascada de señalización del factor nuclear-kappa B. La aspirina por su parte, induce la producción de lipoxinas que inhiben la activación del factor nuclear-kappa B mediante el bloqueo de la proteína quinasa IkB, necesaria para desencadenar la activación de la vía canónica y no canónica de este factor nuclear.

Preeclampsia is a hypertensive syndrome that occurs after the 20th weeks of gestation. The objective of this review was to describe the mechanisms of production and action of aspirin- triggered lipoxins in order to consider them as a suitable alternative to modulate oxidative processes, which are characteristic of preeclampsia and proinflammatory cycles starting with cascade activation of nuclear factor-kappa B, consequently of their products. Preeclampsia is characterized by the production of proinflammatory substances that induce directly or indirectly endothelial cell activation,, through prior activation of monocytes, which can generate reactive oxygen species and expression of adhesion molecules that mediate interacting with the endothelium, contributing to its dysfunction, activation and induction of signaling cascade nuclear factor-kappa B. Aspirin induces lipoxin, which inhibits the activation of nuclear factor-kappa B by blocking IkB protein kinase, necessary to trigger the activation of canonical and non-canonical pathway of this nuclear factor.

Effects of aspirin-triggered lipoxin A4 on lipopolysaccharide-induced acute lung injury in mice / 中华麻醉学杂志

Objective To evaluate the effects of aspirin-triggered lipoxin A4 (ATL) on lipopolysaccharide (LPS)-induced acute lung injury in mice.Methods Thirty male SPF BALB/C mice,aged 10-12 weeks,weighing 25-30 g,were randomly assigned into 3 groups (n =10 each):normal saline group (group NS),LPS group and ATL groups.ATL 0.1 ml was injected via the tail vein 1 h after intra-tracheal instillation of 3 mg/kg LPS in LPS group.In ATL group,ATL 0.2 mg/kg was injected via the tail vein 1 h after intra-tracheal instillation of 3 mg/kg LPS.At 24 h after instillation,the mice were sacrificed.Bronchoalveolar lavage fluid was collected for determination of the total cell count,proportion of the polymorphonuclear leukocytes,proportion of the mononuclear leukocytes,and concentrations of the total protein,TNF-αt,IL-6,monocyte chemoattractant protein-1 (MCP-1) and IL-10.Lungs were removed for determination of myeloperoxidase (MPO) activity,phosphorylation of p38 mitogenactivated protein kinase (p38 MAPK),c-Jun N-terminal kinase (JNK),and extracellular signal-regulated kinase 1/2 (ERK1/2) in lung tissues and for microscopic examination.The pathological changes of lungs were scored.Results Compared with NS group,the lung injury scores,total cell counts,proportion of polymorphonuclear leukocytes,and concentrations of TNF-α,IL-6 and MCP-1 were significantly increased,and the proportion of mononuclear leukocytes was decreased in LPS and ATL groups,and IL-10 concentrations were decreased,and the concentrations of the total protein,MPO activity,and phosphorylation of p38 MAPK,JNK and ERK1/2 were significantly increased in group LPS (P ＜ 0.05),and no significant change in the concentrations of the total protein,MPO activity,phosphorylation of p38 MAPK,JNK and ERK1/2 was found in group ATL (P ＞ 0.05).Compared with LPS group,the lung injury scores,total cell counts,proportion of polymorphonuclear leukocytes and the concentrations of the total protein,TNF-α,IL-6 and MCP-1 were significandy decreased,the proportion of mononuclear leukocytes and IL-10 concentration were increased,and MPO activity and phosphorylation of p38 MAPK and JNK were decreased (P ＜ 0.05),and no significant change in the phosphorylation of ERK1/2 was found in group ATL (P ＞ 0.05).Conclusion ATL can ameliorate LPS-induced acute lung injury by inhibiting activations of p38MAPK and JNK signal pathways in mice.

Effects of lipoxin A4 administered at different time points on connexin-43 expression during myocardial ischemia-reperfusion in rats / 中华麻醉学杂志

Objective To evaluate the effects of lipoxin A4 (LXA4) administered at different time points on the expression of connexin43 (Cx43) during myocardial ischemia-reperfusion (I/R) in rats.Methods Seventytwo healthy male Sprague-Dawley rats,weighing 200-250 g,wcre equally and randomly divided into 6 groups:groups sham operation Ⅰ (group S1) and Ⅱ (group S2),groups myocardial I/R Ⅰ (group Ⅰ/R1) and Ⅱ (group I/R2),and groups LXA4 administered before chest opening (group LX1) and at 30 min of reperfusion (group LX2).Myocardial I/R was produced by 30 min occlusion of left anterior descending branch (LAD) of coronary artery followed by 120 min reperfusion.LXA4 100μg/kg was injected via femoral veins before chest opening and at 30 min of reperfusion in groups LX1 and group LX2,respectively.While normal saline 2 ml/kg was injected via the femoral vein at the corresponding time points in the other four groups.In groups S1 and S2,LAD was only threaded,but not ligated.Blood samples were taken from the femoral vein before chest opening and at 120 min of reperfusion for measurement of serum IL-8,TNF-α and cardiac troponin Ⅰ (cTnI) concentrations.The rats were then sacrificed after blood samples were taken at 120 min of reperfusion and hearts were removed for determination of Cx43 protein (by immunohistochemical SP method) and Cx43 mRNA expression (by real-time quantitative PCR),SOD activity and MDA content in myocardial tissues.The development of arrhythmia was observed from occlusion of LAD to 120 min of reperfusion.Duration of ventricular tachycardia (VTd) and ventricular fibrillation (VFd) was recorded.Scores of ventricular arrhythmias were calculated.Results The expression of Cx43 protein and mRNA was significantly down-regulated,and scores of ventricular arrhythmias,VTd,serum IL-8,TNF-α and cTnI concentrations,SOD activity and MDA content were increased in groups I/R1 and LX1 as compared with group S1,and in groups I/R2 and LX2 as compared with group S2 (P ＜ 0.05).The expression of Cx43 protein and mRNA was significantly up-regulated,SOD activity was increased,and scores of ventricular arrhythmias,VTd,VFd,serum IL-8,TNF-α and cTnI concentrations,and MDA content were decreased in group LX1 as compared with group I/R1,and in group LX2 as compared with group I/R2(P ＜ 0.05).The expression of Cx43 protein and mRNA was significantly lower,scores of ventricular arrhythmias,VTd and SOD activity were higher,and the serum IL-8,TNF-α and cTnI concentrations and MDA content were lower in group LX2 than in group LX1 (P ＜ 0.05).Conclusion LXA4 administered before myocardial ischemia and at 30 min of reperfusion can up-regulate the expression of Cx43 and reverse remodeling of Cx43,thus reducing myocardial I/R-induced arrhythmia in rats,and LXA4 administered before ischemia can provide better efficacy.

Expression of lipoxin A4, leukotriene C4 and lipoxygenase-5 in severe preeclampsia / 中华围产医学杂志

Objective To investigate the expression and clinical significance of lipoxin A4,leukotrienc C4,lipoxygenase-5 in peripheral blood of pregnant women with different types of severe preeclampsia.Methods Forty-five singleton pregnant women who accepted antenatal care and delivered in First Affiliated Hospital of Wenzhou Medical College were enrolled in this study from December 2010 to June 2011.All objects were divided into normal pregnancy group (n=20),early onset severe preeclampsia group (n=10) and late onset severe preeclampsia group (n=15).Enzymelinked immunosorbent assay was used to detect lipoxin A4 and leukotriene C4 levels in peripheral blood.The level of lipoxygenase-5 mRNA in white blood cells was detected by real time fluorescence quantitative reverse transcription-polymerase chain reaction.The differences of lipoxin A4,leukotriene C4 and lipoxygenase-5 mRNA among groups were compared by analysis of variance and LSD-t test;and correlations among their expressions were analyzed by linear regression.Results Lipoxin A4 level in early and late onset severe preeclampsia group was (355.3±116.0) pg/ml and (389.7±117.5) pg/ml,which were both significantly lower than that in normal pregnancy group [(555.0±139.8) pg/ml] (t=-4.03 and-3.77,P＜0.05 respectively).The leukotriene C4 level in early and lateonset severe preeclampsia and normal pregnaney group was (591.3±185.5) pg/ml,(510.3±197.1) pg/ml and (496.9 ± 158.8) pg/ml,no statistical difference were found (F=0.889,P＞0.05) ; neither did the expression of lipoxygenase 5 mRNA,which was 4.2± 1.9 in normal pregnancy group,4.8 ± 2.0 in early onset severe preeclampsia group and 4.4 ± 1.2 in late onset severe preeclampsia group (F=0.311,P＞0.05).There was no correlation among the levels of lipoxin A4,leukotriene C4 and lipoxygenase-5 mRNA in each group (P ＞ 0.05).Conclusions Early and remarkable decreasing of lipoxin A4 level might contribute to the development of early onset severe preeclampsia.

Protective effect and mechanism of lipoxinA4 on oxidative injury in trophoblastic cells / 中华围产医学杂志

Objective To explore lipoxinA4 (LXA4) expression in maternal serum of pregnant women and the protective effect and mechanism of LXA4 on trophoblastic cells from oxidative injury. Methods Trophoblastic cells were randomized into six groups: Control group; Lipopolysaccharides (LPS) group, cells were stimulated by 10 μg/ml LPS for 24 h; Intervention group, cells stimulated by LPS were treated with 100 nmol/L LXA4 for 24 h; LXA4 group, cells were treated with 100 nmol/L LXA4 for 24 h; Antagonistic group, cells stimulated by LPS were treated with 100 nmol/L LXA4 plus 100 μmol/L N-tert-butoxycarbonyl-2-pyrrolidine (BOC-2) for 24 h; BOC-2 group, trophoblastic cells stimulated by LPS were treated with 100 μmol/L BOC-2 for 24 h. The serum concentration of LXA4 in normal group and preeclampsia group was detected by ELISA. The intracellular formation of reactive oxygen species (ROS) was detected by 2,7-dichlorofluorescein diacetate (DCFH-DA) as a fluorescent probe. SOD mRNA was analyzed by RT-PCR. SOD and Nrf2 protein expressions were analyzed by Western blot. The levels of SOD in trophoblastic cells were detected by using detection kit. Results (1) The serum concentration of LXA4 was significantly lower in preeclampsia group (165.53±18.89) pg/L than in the control [(545.67±30.91) pg/L, P0.05). Conclusions LXA4 can significantly reduce the oxidative stress of placental trophoblastic cells stimulated by LPS. LXA4 can bind to lipoxin receptors and activate Nrf2-ARE signaling pathway playing a protective effect. So LXA4 in pregnant women can affect the oxidative stress of placenta.