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 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

OBJECTIVEIn order to explore the pathway of dealkylation of pesticides other than cytochrome P450 monocoxygenases, lipoxygenase (LOX)-mediated demethylation of aminocarb and some other pesticides were measured.

METHODFormaldehyde generated in the reaction was estimated by Nash reaction to express the rate of demethylation of pesticides mediated by soy lipoxygenase (SLO).

RESULTSN-demethylation of aminocarb mediated by SLO was found to depend on the incubation time, concentration of the enzyme, concentration of aminocarb and hydrogen peroxide. Under optimal conditions, Vmax value of 18 nmol of formaldehyde.min-1.nmol-1 of lipoxygenase was observed. The reaction exhibited Km values of 3.4 mmol/L for aminocarb and 235 mumol/L for hydrogen peroxide. A strong inhibition of the reaction by nordihydroguaiaretic acid, gossypol, and phenidone clearly implicated the lipoxygenase involvement as the protein catalyst. A significant decline in the formaldehyde accumulation in the presence of either reduced glutathione or dithiothreitol suggested generation of a free radical species as an initial oxidation intermediate during the demethylation of aminocarb by SLO. The inhibition of formaldehyde generation by butylated hydroxyanisole(BHT) and butylated hydroxy toluene(BHA) further supported this contention. In addition to aminocarb, seven other pesticides were also found to undergo N-demethylation, albeit at relatively low rates.

CONCLUSIONCertain pesticides may oxidatively undergo dealkylation via the lipoxygenase pathway in animals and plants.

Butylated Hydroxyanisole ; pharmacology ; Butylated Hydroxytoluene ; pharmacology ; Dealkylation ; Free Radicals ; Lipoxygenase ; physiology ; Pesticides ; metabolism ; Phenylcarbamates ; metabolism ; Soybeans ; enzymology

OBJECTIVETo determine 5-lipoxygenase (5-LOX) expression and the effect of zileuton, a selective 5-LOX inhibitor,on hippocampal neuron injury induced by global cerebral ischemia in rats.

METHODSGlobal cerebral ischemia was induced by bilateral common carotid artery occlusion combined with hypotension in rats. 5-LOX expression was detected by Western blot analyses and 5-LOX localization was visualized by immunohistochemistry and double immunofluorescence methods. The 5-LOX inhibitor zileuton (10, 30, 50 mg/kg) was orally administered for 3 d after ischemia.

RESULTSThe 5-LOX expression was increased in the ischemic hippocampus on d1-7 (peaked at d3), and 5-LOX protein was primarily localized in neurons and translocated to the nuclei in the hippocampal CA1 region after ischemia. The 5-LOX inhibitor zileuton (30, 50 mg/kg) reduced ischemia-induced hippocampal neurons death 3d after ischemia.

CONCLUSION5-LOX is involved in global cerebral ischemic damage in rats, and the 5-LOX inhibitor zileuton has a protective effect on neuronal damage in the rat hippocampus following global cerebral ischemia.

Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; physiology ; Brain Ischemia ; metabolism ; pathology ; CA1 Region, Hippocampal ; metabolism ; pathology ; Disease Models, Animal ; Hydroxyurea ; analogs & derivatives ; pharmacology ; Lipoxygenase Inhibitors ; pharmacology ; Male ; Neurons ; drug effects ; pathology ; Rats ; Rats, Sprague-Dawley

Apoptosis ; drug effects ; Arachidonate 12-Lipoxygenase ; analysis ; physiology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Enzyme Inhibitors ; pharmacology ; Flavanones ; pharmacology ; Humans ; Lipoxygenase Inhibitors ; Multiple Myeloma ; drug therapy ; pathology

OBJECTIVETo determine whether oxygen-glucose deprivation (OGD) induces C6 cell injury, and whether 5-lipoxygenase (5-LOX)/cysteinyl leukotriene (CysLT) pathway is involved in OGD-induced injury.

METHODSAfter OGD treatment and recovery for various durations, the viability of C6 cells was determined, and the effects of 5-LOX inhibitors and CysLT receptor antagonists were investigated. Intracellular distribution of 5-LOX protein was detected by immunocytochemistry, and the mRNA expressions of CysLT1 and CysLT2 receptors were detected by RT-PCR. The effect of leukotriene D(4) (LTD(4)) on C6 cells was also investigated.

RESULTOGD for 4-8 h followed by recovery for 24-72 h significantly induced C6 cell injury. Neither 5-LOX inhibitors nor CysLT receptor antagonists inhibited OGD-induced injury. OGD did not induce 5-LOX translocation into the nuclear membrane. C6 cells highly expressed CysLT(2) receptor, but the expression of CysLT1receptor was much weaker; the expression was not affected by OGD. In addition, LTD(4) did not affect C6 cells significantly.

CONCLUSIONOGD can induce C6 cell injury, but 5-LOX/CysLT pathway might be not involved in OGD-induced injury.

Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; Cell Hypoxia ; physiology ; Glioma ; pathology ; Glucose ; metabolism ; Rats ; Receptors, Leukotriene ; metabolism ; Signal Transduction ; physiology ; Tumor Cells, Cultured

Reactive oxygen species (ROS) performs a pivotal function as a signaling mediator in receptor-mediated signaling. However, the sources of ROS in this signaling have yet to be determined, but may include lipoxygenases (LOXs) and NADPH oxidase. The stimulation of lymphoid cells with TNF-alpha, IL-1beta, and LPS resulted in significant ROS production and NF-kappaB activation. Intriguingly, these responses were markedly abolished via treatment with the LOXs inhibitor nordihydroguaiaretic acid (NDGA). We further examined in vivo anti-inflammatory effects of NDGA in allergic airway inflammation. Both intraperitoneal and intravenous NDGA administration attenuated ovalbumin (OVA)-induced influx into the lungs of total leukocytes, as well as IL-4, IL-5, IL-13, and TNF-alpha levels. NDGA also significantly reduced serum levels of OVA-specific IgE and suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. The results of our histological studies and flow cytometric analyses showed that NDGA inhibits OVA-induced lung inflammation and the infiltration of CD11b+ macrophages into the lung. Collectively, our findings indicate that LOXs performs an essential function in pro-inflammatory signaling via the regulation of ROS regulation, and also that the inhibition of LOXs activity may have therapeutic potential with regard to the treatment of allergic airway inflammation.
Animals ; Antioxidants/metabolism ; Asthma/complications/metabolism/pathology/physiopathology ; Bronchial Hyperreactivity/drug therapy/pathology ; Bronchial Provocation Tests ; Bronchoalveolar Lavage Fluid/cytology ; Cells, Cultured ; Drug Evaluation, Preclinical ; Humans ; Inflammation/*etiology/metabolism ; Jurkat Cells ; Lipoxygenase/*physiology ; Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Lymphocytes/drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Nordihydroguaiaretic Acid/pharmacology/therapeutic use ; Reactive Oxygen Species/*adverse effects/*metabolism

BACKGROUND/AIMS: The unique role of enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it a therapeutic target for inflammatory bowel disease (IBD). The aim of this study was to evaluate the effects of B-98, a newly synthesized benzoxazole derivatives and a novel 5-LO inhibitor, in a mouse model of IBD induced by dextran sulfate sodium (DSS). METHODS: C57BL/6 mice were randomly assigned to four groups: normal control, DSS colitis (DSS+saline), low dose B-98 (DSS+B-98 20 mg/kg) and high dose B-98 (DSS+B-98 100 mg/kg). B-98 was administered with 3% DSS intraperitoneally. The severity of the colitis was assessed via the disease activity index (DAI), colon length, and histopathologic grading. The production of inflammatory cytokines interleukin (IL)-6 was determined by RT-PCR. Th cells were examined for the proportion of Th1 cell, Th2 cell, Th9 cell, Th17 cell and Treg cell using intracellular cytometry. RESULTS: The B-98 group showed lower DAI, less shortening of the colon length and lower histopathologic grading compared with the DSS colitis group (p<0.01). The expression of IL-6 in colonic tissue was significantly lower in the B-98 groups than the DSS colitis group (p<0.05). The cellular profiles revealed that the Th1, Th9 and Th17 cells were increased in the DSS colitis group compared to the B-98 group (p<0.05). CONCLUSIONS: Our results suggest that acute intestinal inflammation is reduced in the group treated with B-98 by Th1, Th9 and Th17 involved cellular immunity.
Acute Disease ; Animals ; Arachidonate 5-Lipoxygenase/chemistry/metabolism ; Benzoxazoles/chemistry/*pharmacology ; Colitis/chemically induced/pathology/*prevention & control ; Colon/drug effects/pathology/physiology ; Dextran Sulfate/toxicity ; Disease Models, Animal ; Forkhead Transcription Factors/metabolism ; Injections, Intraperitoneal ; Interleukin-6/genetics/metabolism ; Lipoxygenase Inhibitors/chemistry/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Severity of Illness Index ; T-Lymphocytes/classification/*drug effects/metabolism

There is persuasive epidemiological and experimental evidence that dietary polyphenols have anti-inflammatory activity. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) have long been used to combat inflammation. Recently, cyclooxygenase (COX) inhibitors have been developed and recommended for treatment of rheumatoid arthritis (RA) and osteoarthritis (OA). However, two COX inhibitors have been withdrawn from the market due to unexpected side effects. Because conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of many inflammatory diseases, there is an urgent need to find safer compounds and to develop mechanism-based approaches for the management of these diseases. Polyphenols are found in many dietary plant products, including fruits, vegetables, beverages, herbs, and spices. Several of these compounds have been found to inhibit the inflammation process as well as tumorigenesis in experimental animals; they can also exhibit potent biological properties. In addition, epidemiological studies have indicated that populations who consume foods rich in specific polyphenols have lower incidences of inflammatory disease. This paper provides an overview of the research approaches that can be used to unravel the biology and health effects of polyphenols. Polyphenols have diverse biological effects, however, this review will focus on some of the pivotal molecular targets that directly affect the inflammation process.
Phospholipases A/antagonists & inhibitors ; Phenols/*pharmacology ; Peroxisome Proliferator-Activated Receptors/drug effects/physiology ; NF-kappa B/metabolism ; Lipoxygenase Inhibitors/pharmacology ; Humans ; Flavonoids/*pharmacology ; Cytokines/biosynthesis ; Cyclooxygenase Inhibitors/pharmacology ; Arachidonic Acid/metabolism ; Anti-Inflammatory Agents/*pharmacology ; Animals