OBJECTIVE: To explore the expression patterns, prognostic implications, and biological role of leukotriene B4 receptor (LTB4R) in patients with acute myeloid leukemia (AML). METHODS: We collected the data of mRNA expression levels and clinical information of patients with AML from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database for mRNA expression analyses, survival analyses, Cox regression analyses and correlation analyses using R studio to assess the expression patterns and prognostic value of LTB4R. The correlation of LTB4R expression levels with clinical characteristics of the patients were analyzed using UALCAN. The co-expressed genes LTB4R were screened from Linkedomics and subjected to functional enrichment analysis. A protein-protein interaction network was constructed using STRING. GSEA analyses of the differentially expressed genes (DEGs) were performed based on datasets from TCGA-LAML stratified by LTB4R expression level. We also collected peripheral blood mononuclear cells (PBMCs) from AML patients and healthy donors for examination of the mRNA expression levels of LTB4R and immune checkpoint genes using qRT-PCR. We also examined serum LTB4R protein levels in the patients using ELISA. RESULTS: The mRNA expression level of LTB4R was significantly increased in AML patients (4.898±1.220 vs 2.252±0.215, P < 0.001), and an elevated LTB4R expression level was correlated with a poor overall survival (OS) of the patients (P=0.004, HR=1.74). LTB4R was identified as an independent prognostic factor for OS (P=0.019, HR=1.66) and was associated with FAB subtypes, cytogenetic risk, karyotype abnormalities and NPM1 mutations. The co- expressed genes of LTB4R were enriched in the functional pathways closely associated with AML leukemogenesis, including neutrophil inflammation, lymphocyte activation, signal transduction, and metabolism. The DEGs were enriched in differentiation, activation of immune cells, and cytokine signaling. Examination of the clinical serum samples also demonstrated significantly increased expressions of LTB4R mRNA (P=0.044) and protein (P=0.008) in AML patients, and LTB4R mRNA expression was positively correlated with the expression of the immune checkpoint HAVCR2 (r= 0.466, P=0.040). CONCLUSION LTB4R can serve as a novel biomarker and independent prognostic indicator of AML and its expression patterns provide insights into the crosstalk of leukemogenesis signaling pathways involving tumor immunity and metabolism.
Humans ; Leukemia, Myeloid, Acute/metabolism* ; Leukocytes, Mononuclear/metabolism* ; Prognosis ; RNA, Messenger/metabolism* ; Receptors, Leukotriene B4/genetics*

OBJECTIVETo observe the effect of montelukast treatment on levels of serum leukotriene B4 and urinary leukotriene E4 in infants with bronchiolitis.

METHODSSeventy-five children who were diagnosed with bronchiolitis between June 2014 and December 2014 were randomly assigned into two groups, one with thirty-eight cases as the montelukast treatment group and another thirty-seven cases as the control group. All of the children were given routine medical treatment. The children in the montelukast treatment group were additionally given montelukast daily (4 mg once a day, for 7 days). The serum leukotriene B4 and urinary leukotriene E4 levels were measured using ELISA before and after treatment. The relationship between serum leukotriene B4 and urinary leukotriene E4 levels was analyzed by Peason correlation analysis.

RESULTSAfter 7 days of treatment, the serum leukotriene B4 and urinary leukotriene E4 levels in the montelukast treatment and control groups were significantly reduced compared with before treatment (P<0.05). The montelukast treatment group showed significantly lower serum leukotriene B4 and urinary leukotriene E4 levels than the control group (P<0.05). The remission time of cough, wheezing and lung wheezes and the length of hospital stay in the montelukast treatment group were significantly shortened compared with the control group (P<0.05). There was a positive correlation between serum leukotriene B4 and urinary leukotriene E4 levels (r=0.723, P<0.05).

CONCLUSIONSMontelukast has a reliable clinical curative efficacy for bronchiolitis in infants, possibly by decreasing serum leukotriene D4 and urinary leukotriene E4 levels.

Acetates ; therapeutic use ; Bronchiolitis ; drug therapy ; metabolism ; Humans ; Infant ; Leukotriene B4 ; blood ; Leukotriene E4 ; urine ; Quinolines ; therapeutic use

OBJECTIVETo observe the changing contents of leukotriene B4 ( LTB4 ), leukotriene C4 ( LTC4 ), and leukotriene D4 (LTD4 ) of lung tissue in asthmatic rats, and explore the effect of Shuanglong Capsule (SLC) on it.

METHODSSD rats were randomly divided into the nomal group, asthmatic model group, Dexamethasone group and the high, middle and low dose SLC groups. All rats except those in the normal group were sensitized by ovalbumin and challenged with the antigen, and the contents of LTB4, LTC4 and LTD4 in lung tissue of all the groups were measured by reverse phase-high performance liquid chromatography (RP-HPLC) and compared.

RESULTSThe levels of LTB4, LTC4, and LTD4 of asthmatic rats were significantly higher than those of rats in the normal group. Dexamethasone and SLC at the dose of 8. 27 g/kg or 4. 13 g/kg could significantly inhibit the production of leukotrienes of lung tissue in asthmatic rats (P <0.05).

CONCLUSIONSLC can significantly inhibit the formation of inflammatory medium LTs of lung tissue in asthmatic rats, it may be one of the key mechanisms of SLC in anti-asthma and anti-inflammatory action.

Animals ; Anti-Asthmatic Agents ; pharmacology ; Asthma ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Leukotriene B4 ; metabolism ; Leukotriene C4 ; metabolism ; Leukotriene D4 ; metabolism ; Leukotrienes ; metabolism ; Lung ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Tablets

OBJECTIVETo study the antalgic and antiphlogistic functions and mechanism of ronggudingtong (RGDT) plaster (traditional Chinese medicine).

METHODSThe painful models were established with hot plate test or acetic acid writhing and the inflammatory models were established with daubing dimethylbenzene on auricle or injecting formaldehyde in toe or synovial envelope to study the antalgic and antiphlogistic functions of RGDT Plaster. The total protein and leukotriene B4(LTB4) in inflammatory exudate were detected to investigate the antalgic and antiphlogistic mechanism of RGDT plaster. The mice were randomly divided into different groups (n = 11), on the basis of drug using, the indexes of pain threshold, swelling degree were observed. Sixty-six mice were used to establish gasbag synovitis model and randomly divided into normal control group,model control group, positive control group (Voltaren gel 0.8 mg/d)and low/medium/high dosage RGDT plaster treating groups(30 mg/d, 60 mg/d, 120 mg/d).

RESULTS30 mg/d, 60 mg/d,120 mg/d RGDT plaster could upgrade the pain thresholds, remit auricular and foot swelling (P < 0.05, P < 0.01), and degrade total protein and LTB4 in inflammatory exudates (P < 0.05, P < 0.01).

CONCLUSIONRGDT plaster has some antalgic and antiphlogistic functions, and one of the mechanisms is depressing synthesis of LTB4.

Analgesics ; pharmacology ; Animals ; Anti-Inflammatory Agents ; pharmacology ; Leukotriene B4 ; metabolism ; Medicine, Chinese Traditional ; Mice ; Pain ; drug therapy

OBJECTIVETo observe the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the unstable plaque of patients with acute coronary syndrome (ACS), and the impact of leukotriene B4 (LTB4) on the EMMPRIN expression in macrophages.

METHODSThe EMMPRIN expression was detected by immunohistochemistry in 11 unstable plaques from patients with ACS. Protein expression of EMMPRIN was evaluated by Western blot on macrophages differentiated from THP-1 which were stimulated with LTB4 in the absence or presence of LTB4 antagonist U75302. There are 8 study groups: 1-THP-1, 2-8-the macrophages derived from THP-1, 2-6-macrophages were stimulated by LTB4 (0, 10(-10), 10(-9), 10(-8) and 10(-7) mol/L) for 24 h, 7-8-the macrophages were pretreated by 10(-6) mol/L or 10(-7) mol/L U75302 2 h before the LTB4 (10(-7) mol/L) stimulation.

RESULTSAbundant EMMPRIN expression was detected in macrophages and smooth muscle cells of unstable plaques from ACS patients. As to the THP-1 derived macrophages, EMMPRIN expression was significantly upregulated in a concentration-dependent manner in LTB4 stimulated groups, which was significantly higher in group 3-6 than in the THP-1 group (group 1) and macrophages group (group 2) (all P < 0.05) and pretreatment with U75302 significantly reduced the LTB4 induced upregulation of EMMPRIN in a dose-dependent manner (P < 0.05).

CONCLUSIONEMMPRIN expression is enhanced in macrophages and smooth muscle cells on unstable coronary artery plaques from ACS patients. LTB4 could stimulate EMMPRIN expression on THP-1 derived macrophages suggesting that LTB4 and EMMPRIN might be both involved in the formation and progression of unstable plaques, future studies are warranted to explore if LTB4 and EMMPRIN antagonists are effective or not for treating patients with ACS.

Acute Coronary Syndrome ; metabolism ; pathology ; Basigin ; metabolism ; Cell Line ; Humans ; Leukotriene B4 ; metabolism ; pharmacology ; Macrophages ; drug effects ; metabolism ; Myocytes, Smooth Muscle ; drug effects ; metabolism ; Plaque, Atherosclerotic ; metabolism

OBJECTIVETo study inhibitory the effects of Cryptoporus volvatus ferment substance(CVFS) on leukotriene production in vitro from neutrophils in rats.

METHODSNeutrophil aggregation was induced by intraperitoneal injection of glycogen in rats. After 16 h, intraperitoneal lavage fluid(PLF) was collected and neutrophils were removed. Neutrophils were stimulated by calcium ionophore A23187 in vitro to produce leukotriene B(4), C(4), D(4). The concentrations of leukotriene B(4), C(4) and D(4) were measured by reversed-phase high-performance liquid chromatography(HPLC).

RESULTCVFS at 0.25, 1, 4 mg x L(-1)decreased leukotriene B(4), C(4), D(4) release from neutrophils in a concentration-dependent manner. Inhibitory rate of CVFS 0.25, 1, 4 mg x L(-1 )on A23187-induced leukotriene B(4) production was 27.4%, 54.2% and 78.8%(P<0.05), respectively. Inhibitory rate of leukotriene C(4) production was 65.1%, 74.3 and 79.0%(P<0.05), respectively. Inhibitory rate of leukotriene D(4) production was 55.6%, 60.9% and 72.8%(P<0.05), respectively.

CONCLUSIONThe results suggest that suppression of leukotriene release may be a mechanism of the anti-inflammation and anti-asthma effects of CVFS.

Animals ; Anti-Asthmatic Agents ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Fermentation ; Leukotriene B4 ; secretion ; Leukotriene C4 ; secretion ; Leukotriene D4 ; secretion ; Male ; Neutrophils ; drug effects ; physiology ; Polyporaceae ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate antigen-induced changes of leukotriene B(4)(LTB(4))content and LTA(4)-hydrolase mRNA expression in lung tissue and cerebral cortex in sensitized rats.

METHODSThe contents of LTB(4) in lung tissue and cerebral cortex homogenates and LTA(4)-hydrolase mRNA expression after antigen challenge by aerosol were respectively detected by reverse-phase high performance liquid chromatography(RP-HPLC) and semi-quantitative RT-PCR.

RESULTThe LTB(4) levels in lung tissue and cerebral cortex homogenates in asthmatic rats were significantly higher than those in control (P%0.05), and LTA4-hydrolase mRNA expression was also increased in asthmatic group. Dexamethason(DXM, 0.5 mg/kg, i.p.) decreased the LTB(4) content and inhibited the LTA(4)-hydrolase mRNA expression significantly in asthmatic rats(P%0.05).

CONCLUSIONLTB(4) content and LTA(4)-hydrolase mRNA expression in cerebral cortex and lung tissue are increased in asthmatic rats, and there may exist neuroimmunological cross-talking between central nervous system and lung tissue in asthma.

Animals ; Asthma ; metabolism ; Cerebral Cortex ; chemistry ; metabolism ; Epoxide Hydrolases ; genetics ; Female ; Leukotriene B4 ; analysis ; Lung ; chemistry ; metabolism ; Male ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley

Endotoxic responses to bacterial lipopolysaccharide (LPS) are triggered by Toll-like receptor 4 (TLR4) and involve the production of inflammatory mediators, including interleukin-6 (IL-6), by macrophages. The detailed mechanism of IL-6 production by macrophages in response to LPS has remained unclear, however. We now show that LPS induces IL-6 synthesis in mouse peritoneal macrophages via the leukotriene B4 receptor BLT2. Our results suggest that TLR4-MyD88 signaling functions upstream of BLT2 and that the generation of reactive oxygen species (ROS) by NADPH oxidase 1 (Nox1) and consequent activation of the transcription factor nuclear factor (NF)-kappaB function downstream of BLT2 in this response. These results suggest that a TLR4-MyD88-BLT2-Nox1-ROS-NF-kappaB pathway contributes to the synthesis of IL-6 in LPS-stimulated mouse macrophages.
Animals ; Cell Line ; Interleukin-6/*biosynthesis ; Leukotriene B4/metabolism ; Ligands ; Lipopolysaccharides/immunology ; Macrophages/immunology/*metabolism ; Macrophages, Peritoneal/immunology/metabolism ; Mice ; Myeloid Differentiation Factor 88/*metabolism ; NADH, NADPH Oxidoreductases/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Leukotriene B4/*metabolism ; Signal Transduction

OBJECTIVE: In traditional medicine, Artemisia capillaris has been used for treatment of chronic diarrhea. Previously we found Artemisia capillaris had an effect on rats with TNBS-induced colitis. Eupatilin, a kind of flavonoids, may be a probable effective component. To evaluate the effect of a eupatilin derivative compound DA-6034 on the rat with TNBS-induced colitis, we perfomed this study. METHODS: Colitis was induced with 1ml of 50 mg/ml TNBS mixed with 60 % ethanol (vol/vol) in Sprague- Dawley rats. From the next day, 1ml methylcellulose, 1 mg/kg prednisolone, 0.3 or 3 mg/kg of DA-6017 and DA-6034 were administered through rectum once daily for 2 weeks. At 2days, 1week, and 2weeks later, we evaluated the effect by gross damage score (0-10) and measured myeloperoxidase, PGE2, and LTB4 from the damaged mucosa. RESULTS: The mean gross damage scores of prednisolone and 3 mg/kg of DA-6034 groups were significantly lower than that of a placebo group at 2weeks (0.8, 0.9 vs. 4.0, p<0.05). Myeloperoxidase activities also seemed to be lower in those effective groups but were not statistically significant. LTB4 levels were lower in prednisolone and, 0.3 and 3 mg/kg of DA-6034 groups than in a placebo group at 2weeks (7.91, 7.23, and 7.13 vs. 13.90 ng/mg protein, p<0.05). PGE2 levels were decreased in prednisolone and 0.3 mg/kg of DA-6034 groups at 2days. DA-6017 showed no effects. CONCLUSIONS: Eupatilin derivative compound, DA- 6034 was effective in rats with TNBS-induced colitis. In that LTB4 level is lowered with some decrease of PGE2 level, this agent probably has an inhibitory effect on arachidonic acid metabolism.
Animals ; Arachidonic Acid ; Artemisia ; Colitis* ; Diarrhea ; Dinoprostone ; Ethanol ; Flavonoids* ; Leukotriene B4 ; Medicine, Traditional ; Metabolism ; Methylcellulose ; Mucous Membrane ; Peroxidase ; Prednisolone ; Rats* ; Rectum

Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder with worldwide incidence of 0.4 per 100,000 people. It is characterized by the triad of congenital ichthyosis, spastic diplegia or quadriplegia, and mental retardation. Herein we report a 2-year-old male child with SLS, asthma, and recurrent pneumonia. SLS was confirmed by a molecular genetics study that revealed a deletion mutation in the ALDH3A2 gene. An ALDH3A2 gene mutation results in dysfunction of the microsomal enzyme fatty aldehyde dehydrogenase and impaired metabolism and accumulation of leukotriene B4, which is a key molecule and a pro-inflammatory mediator in developing allergic diseases, especially asthma. An increased level of leukotriene B4 has been reported in SLS patients. As far as we are aware, this is the first report of SLS associated with asthma and recurrent pneumonia. In conclusion, pediatricians should be aware of and evaluate patients with SLS for possible associated asthma and allergic disorders.
Aldehyde Dehydrogenase ; Asthma* ; Cerebral Palsy ; Child ; Child, Preschool ; Humans ; Ichthyosis ; Incidence ; Intellectual Disability ; Leukotriene B4 ; Male ; Metabolism ; Molecular Biology ; Neurocutaneous Syndromes ; Pneumonia* ; Quadriplegia ; Sequence Deletion ; Sjogren-Larsson Syndrome*