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Dermato-endocrinology May 2009Tissue inflammation is a major component of the acne process. Leukotriene B(4) (LTB(4)) is considered to be a major player in the development of tissue inflammation....
Tissue inflammation is a major component of the acne process. Leukotriene B(4) (LTB(4)) is considered to be a major player in the development of tissue inflammation. Synthesis of LTB(4) is controlled by the enzyme 5-lipoxygenase. Since Zileuton blocks the activity of 5-lipoxygenase, experimental and clinical studies have been conducted to test mode of function, as well as efficacy and safety of this compound in the treatment of acne vulgaris. Human SZ95 sebocytes and inflammatory cells in vitro express the enzymes of the leukotriene pathway at mRNA and protein levels and enzymes involved in the biosynthesis of LTB(4) are activated in sebaceous glands of acne lesions. Pre-treatment of SZ95 sebocytes with Zileuton partially prevented short-term arachidonic acid-induced effects, such as induction of LTB(4), increase of neutral lipid content and stimulation of interlekin-6 release. Long-term treatment with Zileuton directly reduced the content of neutral lipids and interleukin-6 release from SZ95 seb ocytes. PPAR mRNA levels were not regulated by Zileuton. In a first pilot clinical study with 10 patients with papulopustular acne Zileuton 4 x 600 mg/d p.o. for 3 months decreased the acne severity index in a time-dependent manner being 41% of the initial score at week 12 (p < 0.05). This was mostly due to a decrease of the number of inflammatory lesions of 29% (p < 0.01). In addition, total sebum lipids significantly decreased (35%, p < 0.05) and the pro-inflammatory free fatty acids (22%) and lipoperoxides (26%) were markedly diminished in patients' sebum under treatment. The magnitude of clinical improvement strongly correlated with the reduction of total sebum lipids (p = 0.0009, r(2) = 0.81) and free fatty acids (p = 0.0003, r(2) = 0.82). In a further study, a 40-year-old female with mild disseminated sebaceous gland hyperplasia and seborrhea, responded with normalization of the casual skin surface lipids and similar reduction of facial sebum synthesis under treatment with Zileuton over 2weeks and-after a wash-out phase-low-dose isotretinoin (10 mg/2nd d) over 5 weeks. These data are in agreement with a phase II multicenter, clinical study in 101 patients with mild to moderate inflammatory facial acne conducted in the US, which showed a significant efficacy of Zileuton in a subset of patients with moderate acne, whereas those patients treated with Zileuton showed a significant mean decrease in inflammatory lesions compared to the placebo group. In all clinical studies, Zileuton was found to be safe and well tolerated.
PubMed: 20436887
DOI: 10.4161/derm.1.3.8368 -
Biomedicine & Pharmacotherapy =... Jun 2023Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis...
Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis and drug resistance. However, the functional role of 5-LOX in hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we analyzed the contribution of 5-LOX in HCC progression and investigated the potential of targeted therapy. Analysis of 86 resected HCC specimens and the clinical data of 362 cases of liver cancer from The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, showed that 5-LOX expression was associated with postoperative survival. The cancer proliferative and stem cell potential were correlated with the levels of 5-LOX in CD163(+) tumor-associated macrophages (TAMs). In an HCC mouse model, CD163(+) TAMs expressed 5-LOX and produced LTB4 and LTC/D/E4; the 5-LOX inhibitor, zileuton, suppressed HCC progression. LTB4 and LTC/D/E4 promoted cancer proliferation and stem cell capacity via phosphorylation of extracellular signal-regulated kinase 1/2 and stem cell-associated genes. Taken together, we identified a novel mechanism of HCC progression in which CD163(+) TAMs express 5-LOX and produce LTB4 and LTC/D/E4, thereby enhancing the proliferative and stem cell potential of HCC cells. Furthermore, inhibition of 5-LOX activity regulates HCC progression, suggesting it has potential as a new therapeutic target.
Topics: Mice; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Arachidonate 5-Lipoxygenase; Tumor-Associated Macrophages; Leukotriene B4
PubMed: 36966664
DOI: 10.1016/j.biopha.2023.114592 -
Anatolian Journal of Cardiology Apr 2017The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory...
OBJECTIVE
The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used.
METHODS
Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.
RESULTS
Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group.
CONCLUSION
5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors.
Topics: Animals; Arachidonate 5-Lipoxygenase; Disease Models, Animal; Hydroxyurea; Leukotriene Antagonists; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha
PubMed: 27849187
DOI: 10.14744/AnatolJCardiol.2016.7248 -
Polskie Archiwum Medycyny Wewnetrznej Mar 2010Antileukotriene medications that have been implemented into clinical practice of bronchial asthma and allergic rhinitis include specific leukotriene receptor antagonists... (Review)
Review
Antileukotriene medications that have been implemented into clinical practice of bronchial asthma and allergic rhinitis include specific leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast) and leukotriene biosynthesis inhibitors (zileuton). The current GINA (Global Initiative for Asthma) guidelines, the PRACTALL (Practicing Allergology) report on asthma treatment in children, and ARIA (Allergic Rhinitis and its Impact on Asthma) recommendations classify antileukotriene therapeutic agents as a group of drugs controlling the course of the disease. However, inhaled glucocorticosteroids still remain the first-line treatment in chronic asthma. According to current guidelines, antileukotriene drugs are recommended as alternative treatment to low-dose inhaled glucocorticosteroids in the second level of asthma severity and as complementary treatment to inhaled and/or oral glucocorticosteroids, starting from the third level of asthma severity. Recently, clinical efficacy of antileukotriene drugs has been suggested in the treatment of isolated allergic rhinitis, chronic cough in the course of asthma, as a sole symptom of the disease, and as the therapy for episodes of wheezing caused by viral infections.
Topics: Anti-Asthmatic Agents; Asthma; Humans; Leukotriene Antagonists; Severity of Illness Index; Treatment Outcome
PubMed: 20332717
DOI: No ID Found -
Frontiers in Pharmacology 20215-Lipoxygenase (5-LO) is the key enzyme in the formation of pro-inflammatory leukotrienes (LT) which play an important role in a number of inflammatory diseases....
5-Lipoxygenase (5-LO) is the key enzyme in the formation of pro-inflammatory leukotrienes (LT) which play an important role in a number of inflammatory diseases. Accordingly, 5-LO inhibitors are frequently used to study the role of 5-LO and LT in models of inflammation and cancer. Interestingly, the therapeutic efficacy of these inhibitors is highly variable. Here we show that the frequently used 5-LO inhibitors AA-861, BWA4C, C06, CJ-13,610 and the FDA approved compound zileuton as well as the pan-LO inhibitor nordihydroguaiaretic acid interfere with prostaglandin E (PGE) release into the supernatants of cytokine-stimulated (TNFα/IL-1β) HeLa cervix carcinoma, A549 lung cancer as well as HCA-7 colon carcinoma cells with similar potencies compared to their LT inhibitory activities (IC values ranging from 0.1-9.1 µM). In addition, AA-861, BWA4C, CJ-13,610 and zileuton concentration-dependently inhibited bacterial lipopolysaccharide triggered prostaglandin (PG) release into human whole blood. Western Blot analysis revealed that inhibition of expression of enzymes involved in PG synthesis was not part of the underlying mechanism. Also, liberation of arachidonic acid which is the substrate for PG synthesis as well as PGH and PGE formation were not impaired by the compounds. However, accumulation of intracellular PGE was found in the inhibitor treated HeLa cells suggesting inhibition of PG export as major mechanism. Further, experiments showed that the PG exporter ATP-binding cassette transporter multidrug resistance protein 4 (MRP-4) is targeted by the inhibitors and may be involved in the 5-LO inhibitor-mediated PGE inhibition. In conclusion, the pharmacological effects of a number of 5-LO inhibitors are compound-specific and involve the potent inhibition of PGE export. Results from experimental models on the role of 5-LO in inflammation and pain using 5-LO inhibitors may be misleading and their use as pharmacological tools in experimental models has to be revisited. In addition, 5-LO inhibitors may serve as new scaffolds for the development of potent prostaglandin export inhibitors.
PubMed: 35126121
DOI: 10.3389/fphar.2021.782584 -
International Journal of Molecular... Apr 2022M1 microglia induce neuroinflammation-related neuronal death in animal models of spontaneous subarachnoid haemorrhage. Zileuton is a 5-lipoxygenase inhibitor that...
M1 microglia induce neuroinflammation-related neuronal death in animal models of spontaneous subarachnoid haemorrhage. Zileuton is a 5-lipoxygenase inhibitor that reduces the levels of downstream pro-inflammatory cytokines. This study aimed to investigate whether zileuton inhibits microglial activation and describe its underlying mechanisms. BV-2 cells were exposed to 1 mg/mL haemolysate for 30 min, followed by treatment with different concentrations (5, 10, 15, or 20 μM) of zileuton for 24 h. The cells were then assessed for viability, polarisation, and protein expression levels. Haemolysate increases the viability of BV-2 cells and induces M1 polarisation. Subsequent exposure to high concentrations of zileuton decreased the viability of BV-2 cells, shifted the polarisation to the M2 phenotype, suppressed the expression of 5-lipoxygenase, decreased tumour necrosis factor α levels, and increased interleukin-10 levels. Furthermore, high concentrations of zileuton suppressed the expression of myeloid differentiation primary response protein 88 and reduced the phosphorylated-nuclear factor-kappa B (NF-kB)/NF-kB ratio. Therefore, phenotype reversal from M1 to M2 is a possible mechanism by which zileuton attenuates haemolysate-induced neuroinflammation after spontaneous subarachnoid haemorrhage.
Topics: Animals; Hydroxyurea; Lipopolysaccharides; Lipoxygenase Inhibitors; Microglia; Myeloid Differentiation Factor 88; NF-kappa B; Signal Transduction; Subarachnoid Hemorrhage
PubMed: 35563304
DOI: 10.3390/ijms23094910 -
The Journal of Experimental Medicine Nov 2017Leukotriene B (LTB), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this...
Leukotriene B (LTB), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.
Topics: Animals; Arachidonate 5-Lipoxygenase; Benzopyrans; Carboxylic Acids; Cell Transplantation; Chemokines; Cytokines; Graft vs Host Disease; Hydroxyurea; Leukocytes; Leukotriene Antagonists; Leukotriene B4; Lipoxygenase Inhibitors; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy, Confocal; Transplantation, Homologous
PubMed: 28947611
DOI: 10.1084/jem.20170261 -
British Journal of Pharmacology Feb 20085-lipoxygenase (5-LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5-LO-product, cysteinyl-LT...
BACKGROUND AND PURPOSE
5-lipoxygenase (5-LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5-LO-product, cysteinyl-LT (Cys-LT), with a 5-LO inhibitor (zileuton) and a Cys-LT, receptor antagonist (montelukast), in the inflammatory response and tissue injury associated with spinal cord injury (SCI).
EXPERIMENTAL APPROACH
SCI was induced in mice by the application of vascular clips to the dura via a two-level T6 to T7 laminectomy for 1 min. Cord inflammation was assessed histologically and by measuring inflammatory mediators (ELISA) and apoptosis by annexin V, TUNEL, Fas ligand staining and Bax and Bcl-2 expression (immunohistochemistry and western blots). Motor function in hindlimbs was assessed by a locomotor rating scale, for 10 days after cord injury.
KEY RESULTS
SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) expression, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in injured tissue. Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury, neutrophil infiltration, TNF-alpha, COX-2 and pERK1/2 expression, PGE(2) and LTB(4) production, and apoptosis. In separate experiments, zileuton or montelukast significantly improved the recovery of limb function over 10 days.
CONCLUSIONS AND IMPLICATIONS
Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI. Our data underline the important role of 5-LO and Cys-LT in neurotrauma.
Topics: Acetates; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cyclooxygenase 2; Cyclopropanes; Cysteine; Dinoprostone; Disease Models, Animal; Gene Expression Regulation; Hydroxyurea; Inflammation; Leukotrienes; Lipoxygenase Inhibitors; Male; Mice; Neutrophil Infiltration; Quinolines; Recovery of Function; Spinal Cord Injuries; Sulfides; Tumor Necrosis Factor-alpha
PubMed: 18059327
DOI: 10.1038/sj.bjp.0707577 -
Biomedicine & Pharmacotherapy =... Jan 2022Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid...
Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.
Topics: Animals; Arachidonate 15-Lipoxygenase; Cell Line; Humans; Isoenzymes; Lipoxygenase Inhibitors; Mice; Sf9 Cells; Species Specificity
PubMed: 34801853
DOI: 10.1016/j.biopha.2021.112434 -
Alternative Therapies in Health and... Jul 2023Ferroptosis is a novel type of cell-death pattern characterized by iron-dependent, oxidative stress, and lipid peroxidation. Neurological pathology, especially in spinal...
CONTEXT
Ferroptosis is a novel type of cell-death pattern characterized by iron-dependent, oxidative stress, and lipid peroxidation. Neurological pathology, especially in spinal cord injury (SCI), may involve a trace amount of ferroptosis. However, it's uncertain whether zileuton (ZIL), a selective 5-lipoxygenase (5-LO) inhibitor, can inhibit ferroptosis in SCI.
OBJECTIVE
The study intended to investigate the etiology of neuronal ferroptosis and the ameliorative effects of ZIL against it for SCI mice.
DESIGN
The research team performed an animal study.
SETTING
The study took place at the Fourth Affiliated Hospital of Harbin Medical University in Harbin, China.
ANIMALS
The animals were adult, male, C57BL/6 mice, about 20 to 25 g in weight.
INTERVENTION
The research team: (1) stimulated HT22 cells, an immortalized mouse hippocampal neuronal cell line treated with erastin, and mice induced spinal cord trauma using a moderate hit, and (2) treated the cells and mice with ZIL.
OUTCOME MEASURES
The research team measured: (1) motor function, (2) neurological damage, (3) iron content, (4) lipid oxidation, and (5) neuroinflammation and glial response.
RESULTS
ZIL administration attenuated ferroptosis and lipid peroxidation in the HT22 cells. Moreover, ZIL mitigated the ferroptosis and inflammation in the injured spinal cords. Hence, ZIL can decrease neurological damage and improve recovery of motor function, indicating an ameliorative role for ZIL in SCI.
CONCLUSIONS
ZIL has anti-ferroptosis and anti-oxidative effects in neurons, which can contribute to recovery of motor function after induction of SCI. ZIL is a promising drug for inhibiting ferroptosis and protecting neurological functions after induction of SCI.
Topics: Mice; Male; Animals; Mice, Inbred C57BL; Spinal Cord Injuries; Neurons; Iron
PubMed: 37171943
DOI: No ID Found