With the acceleration of aging society, delaying aging or promoting healthy aging has become a major demand for human health. 5-Lipoxygenase (5-LOX) is a key enzyme catalyzing arachidonic acid into leukotrienes (LTs), which is a potent mediator of the inflammatory response. Previous studies showed that abnormal activation of 5-LOX and overproduction of LTs are closely related to the occurrence and development of aging-related inflammatory diseases. Therefore, inhibiting 5-LOX activation is a possibly potential strategy for treating age-related diseases. In this paper, the latest research progress in 5-LOX activation, 5-LOX in mediating aging-related diseases and its small molecule inhibitors is briefly reviewed to provide scientific theoretical basis and new ideas for the prevention and treatment of aging-related inflammatory diseases.
Humans ; Arachidonate 5-Lipoxygenase ; Leukotrienes ; Arachidonic Acid ; Aging ; Lipoxygenase Inhibitors/pharmacology*

PURPOSE: The aim of this work was to investigate the beneficial effects of rhamnazin against inflammation, reactive oxygen species (ROS)/reactive nitrogen species (RNS), and anti-oxidative activity in murine macrophage RAW264.7 cells. METHODS: To examine the beneficial properties of rhamnazin on inflammation, ROS/ RNS, and anti-oxidative activity in the murine macrophage RAW264.7 cell model, several key markers, including COX and 5-LO activities, NO•, ONOO-, total reactive species formation, lipid peroxidation, •O₂ levels, and catalase activity were estimated. RESULTS: Results show that rhamnazin was protective against LPS-induced cytotoxicity in macrophage cells. The underlying action of rhamnazin might be through modulation of ROS/RNS and anti-oxidative activity through regulation of total reactive species production, lipid peroxidation, catalase activity, and •O₂, NO•, and ONOO• levels. In addition, rhamnazin down-regulated the activities of pro-inflammatory COX and 5-LO. CONCLUSION: The plausible action by which rhamnazin renders its protective effects in macrophage cells is likely due to its capability to regulate LPS-induced inflammation, ROS/ RNS, and anti-oxidative activity.
Arachidonate 5-Lipoxygenase ; Catalase ; Inflammation* ; Lipid Peroxidation ; Macrophages* ; Nitrogen ; Reactive Nitrogen Species ; Reactive Oxygen Species

Cysteinyl leukotrienes (cys-LTs) are potent mediators of inflammation derived from arachidonic acid through the 5-lipoxygenase/leukotriene C4 synthase pathway. The derivation of their chemical structures and identification of their pharmacologic properties predated the cloning of their classical receptors and the development of drugs that modify their synthesis and actions. Recent studies have revealed unanticipated insights into the regulation of cys-LT synthesis, the function of the cys-LTs in innate and adaptive immunity and human disease, and the identification of a new receptor for the cys-LTs. This review highlights these studies and summarizes their potential pathobiologic and therapeutic implications.
Adaptive Immunity ; Arachidonate 5-Lipoxygenase ; Arachidonic Acid ; Asthma ; Clone Cells ; Cloning, Organism ; Humans ; Inflammation Mediators ; Leukotrienes*

5-Lipoxygenase (5-LO) plays a pivotal role in the progression of atherosclerosis. Therefore, this study investigated the molecular mechanisms involved in 5-LO expression on monocytes induced by LPS. Stimulation of THP-1 monocytes with LPS (0~3 microg/ml) increased 5-LO promoter activity and 5-LO protein expression in a concentration-dependent manner. LPS-induced 5-LO expression was blocked by pharmacological inhibition of the Akt pathway, but not by inhibitors of MAPK pathways including the ERK, JNK, and p38 MAPK pathways. In line with these results, LPS increased the phosphorylation of Akt, suggesting a role for the Akt pathway in LPS-induced 5-LO expression. In a promoter activity assay conducted to identify transcription factors, both Sp1 and NF-kappaB were found to play central roles in 5-LO expression in LPS-treated monocytes. The LPS-enhanced activities of Sp1 and NF-kappaB were attenuated by an Akt inhibitor. Moreover, the LPS-enhanced phosphorylation of Akt was significantly attenuated in cells pretreated with an anti-TLR4 antibody. Taken together, 5-LO expression in LPS-stimulated monocytes is regulated at the transcriptional level via TLR4/Akt-mediated activations of Sp1 and NF-kappaB pathways in monocytes.
Arachidonate 5-Lipoxygenase ; Atherosclerosis ; Monocytes* ; NF-kappa B ; p38 Mitogen-Activated Protein Kinases ; Phosphorylation ; Transcription Factors

5-Lipoxygenase, one of lipoxygenase isozymes, is a well-studied oxidative metabolism enzyme. It widely exists in various human tissues and cells, participates in the oxidative metabolism of endogenous and exogenous chemicals, and produces a variety of metabolites, all of which contribute to the occurrence of human diseases, such as inflammation, asthma, atherosclerosis, and tumor and so on. The expression of 5-lipoxygenase is at low level in normal human tissues while at high level in abnormal tissues. 5-Lipoxygenase is closely related to many kinds of diseases in human ovary, brain, cardiovascular system, lung, liver, pancreas and other tissues. The abnormal expression of 5-lipoxygenase tends to promote the development of the disease.
Arachidonate 5-Lipoxygenase ; physiology ; Atherosclerosis ; enzymology ; Humans ; Inflammation ; enzymology ; Neoplasms ; enzymology

OBJECTIVETo investigate the effect of intracellular 5-lipoxygenase on oxidation of benzidine in HBE cells and to provide further evidence that lipoxygenase is an alternative pathway for the oxidation of xenobiotics mediated by cytochrome P450.

METHODSEnzyme system test: Soybean lipoxygenase (SLO), substrate (benzidine) and other components reacted in the enzyme system, followed by detection of the reaction products by spectrophotometry. In vitro test: After HBE cells were exposed to benzidine, the protein levels of 5-lipoxygenase in HBE cells were assessed by Western-blot, and the DNA damage by the single cell gel electrophoresis. At last, the effect of the specific inhibitor of 5-lipoxygenase (AA861) on 5-lipoxygenase protein expression and DNA damage in HBE cells were detected.

RESULTSSLO could catalyze the co-oxidation of benzidine to generate benzidine diimine in the presence of hydrogen peroxide. Under optimal condition, numax value of the oxidation of benzidine catalyzed by SLO was 1.42 nmol*min(-1) SLO, and the Km value of benzidine was 1.48 mmol/L. EGCG could inhibit the oxidation of benzidine by SLO. Benzidine could induce 5-lipoxygenase protein expression in HBE cells, but AA861 was invalid. Benzidine caused DNA damage in HBE cells, which could be significantly inhibited by AA861.

CONCLUSION5-LOX protein expression in HBE cells can be regulated by benzidine, which suggests that the co-oxidation of benzidine by 5-LOX could produce into electrophile that could covalently bind to DNA and induce DNA damage, which could be one of the mechanisms for carcinogenesis of BZD. 5-LOX inhibitor AA861 can inhibit this effect.

Arachidonate 5-Lipoxygenase ; metabolism ; Benzidines ; pharmacokinetics ; toxicity ; Cells, Cultured ; DNA Damage ; drug effects ; Epithelial Cells ; drug effects ; enzymology ; metabolism ; Humans

OBJECTIVETo determine whether 5-lipoxygenase (5-LOX) is involved in rotenone-induced injury in PC12 cells, which is a cell model of Parkinson disease.

METHODSAfter rotenone treatment for various durations, cell viability was determined by colorimetric MTT reduction assay, and 5-LOX translocation was detected by immunocytochemistry. The effect of 5-LOX inhibitor zileuton was also investigated.

RESULTRotenone (0.3-30 μmol/L) induced PC12 cell injury, and zileuton (3-100 μmol/L) attenuated this injury. Rotenone also time-and concentration-dependently induced 5-LOX translocation into the nuclear envelope, and zileuton (1-30 μmo/L) significantly inhibited rotenone-induced 5-LOX translocation.

CONCLUSION5-LOX is involved in rotenone-induced injury in PC12 cells, and 5-LOX inhibitor zileuton can reduce rotenone-induced 5-LOX activation and cell injury.

Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; physiology ; Cell Survival ; drug effects ; Hydroxyurea ; analogs & derivatives ; pharmacology ; Lipoxygenase Inhibitors ; pharmacology ; PC12 Cells ; Rats ; Rotenone ; pharmacology

BACKGROUND AND OBJECTIVES: A recent study has demonstrated a possible involvement of leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, while no significances were noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) for the key enzymes involved in arachidonate metabolism, and cysteinyl leukotriene receptor 1 (CYSLTR1) in a larger scale of Korean population with AIA. MATERIALS AND METHODS: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls (NC) were enrolled. Single base extension method was applied for genotyping of SNPs in 5-lipoxygenase (ALOX5, -1708G>A, 21C>T, 270G>A, 1728G>A), ALOX5 activating protein (FLAP, 218A>G), cyclooxygenase 2 (COX2, -162C>G, 10T>G, 228G>A), LTC4S (-444A>C), and CYSLTR1 (927T>C). Haplotype analyses for ALOX5 were performed as well. RESULTS: There were no significant differences in allele and genotype frequencies of the SNPs among the three groups (p>0.05). However, the frequency of ALOX5-ht1[G-C-G-A] containing genotype in the AIA group was significantly higher than those of the ATA group (p=0.01, OR =5.0, 95%CI=1.54-17.9) and the normal controls (p=0.03, OR=4.5, 95%CI=1.1-18.4) with a dominant model. CONCLUSION: These results suggest a lack of association between FLAP, COX2, LTC4S, and CYSLTR1 gene polymorphisms, and AIA phenotype in Korean population. However, a possible involvement of ALOX5-ht1[G-C-G-A] in AIA development was suggested.
Alleles ; Arachidonate 5-Lipoxygenase* ; Aspirin ; Asthma* ; Cyclooxygenase 2 ; Genotype ; Haplotypes* ; Humans ; Leukotriene C4 ; Metabolism ; Phenotype ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Receptors, Leukotriene

Curcumin is naturally occurring polyphenolic compound found in turmeric and has many pharmacological activities. The present study was undertaken to evaluate anti-allergic inflammatory activity of curcumin, and to investigate its inhibitory mechanisms in immunoglobulin E (IgE)/Ag-induced mouse bone marrow-derived mast cells (BMMCs) and in a mouse model of IgE/Ag-mediated passive systemic anaphylaxis (PSA). Curcumin inhibited cyclooxygenase-2 (COX-2) dependent prostaglandin D2 (PGD2) and 5-lipoxygenase (5-LO) dependent leukotriene C4 (LTC4) generation dose-dependently in BMMCs. To probe the mechanism involved, we assessed the effects of curcumin on the phosphorylation of Syk and its downstream signal molecules. Curcumin inhibited intracellular Ca2+ influx via phospholipase Cgamma1 (PLCgamma1) activation and the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappaB (NF-kappaB) pathway. Furthermore, the oral administration of curcumin significantly attenuated IgE/Ag-induced PSA, as determined by serum LTC4, PGD2, and histamine levels. Taken together, this study shows that curcumin offers a basis for drug development for the treatment of allergic inflammatory diseases.
Administration, Oral ; Anaphylaxis* ; Animals ; Arachidonate 5-Lipoxygenase ; Curcuma ; Curcumin* ; Cyclooxygenase 2 ; Histamine* ; Immunoglobulin E ; Immunoglobulins* ; Leukotriene C4 ; Mast Cells* ; Mice* ; Mitogen-Activated Protein Kinases ; Phospholipases ; Phosphorylation ; Prostaglandin D2

Curcumin is naturally occurring polyphenolic compound found in turmeric and has many pharmacological activities. The present study was undertaken to evaluate anti-allergic inflammatory activity of curcumin, and to investigate its inhibitory mechanisms in immunoglobulin E (IgE)/Ag-induced mouse bone marrow-derived mast cells (BMMCs) and in a mouse model of IgE/Ag-mediated passive systemic anaphylaxis (PSA). Curcumin inhibited cyclooxygenase-2 (COX-2) dependent prostaglandin D2 (PGD2) and 5-lipoxygenase (5-LO) dependent leukotriene C4 (LTC4) generation dose-dependently in BMMCs. To probe the mechanism involved, we assessed the effects of curcumin on the phosphorylation of Syk and its downstream signal molecules. Curcumin inhibited intracellular Ca2+ influx via phospholipase Cgamma1 (PLCgamma1) activation and the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappaB (NF-kappaB) pathway. Furthermore, the oral administration of curcumin significantly attenuated IgE/Ag-induced PSA, as determined by serum LTC4, PGD2, and histamine levels. Taken together, this study shows that curcumin offers a basis for drug development for the treatment of allergic inflammatory diseases.
Administration, Oral ; Anaphylaxis* ; Animals ; Arachidonate 5-Lipoxygenase ; Curcuma ; Curcumin* ; Cyclooxygenase 2 ; Histamine* ; Immunoglobulin E ; Immunoglobulins* ; Leukotriene C4 ; Mast Cells* ; Mice* ; Mitogen-Activated Protein Kinases ; Phospholipases ; Phosphorylation ; Prostaglandin D2