Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts

Gu, Jiali; Liu, Yaxia; Wen, Yeong-Ray; Natarajan, Rama; Lanting, Linda; Nadler, Jerry L.

doi:10.1002/1097-4652(200103)186:3<357::aid-jcp1034>3.0.co;2-e

Cited by 27 publications

(17 citation statements)

References 37 publications

(37 reference statements)

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“…It has been demonstrated that DEHP increased the generation of reactive oxygen species (ROS), with a concomitant decrease in the concentration of glutathione [22]. 12-LOX activation can regulate the oxidation process by generating superoxide [19,43,47]. These findings suggest that the 12-LOX expression activated by DEHP might contribute to ROS generation resulting in germ cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

Kim

Ishizuka

Kazusaka

et al. 2004

The Journal of Veterinary Medical Science

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ABSTRACT. Di-(2-ethylhexyl) phthalate (DEHP), a peroxisome proliferator-activated receptor α (PPARα) ligand, alters the lipid composition of rat testis, yet the mechanism is unclear. In this study, we investigated the effect of DEHP on the synthesis and metabolism of arachidonic acid (AA), a precursor of eicosanoids, in the testis of prepubertal rats. DEHP (100 and 1,000 mg/kg, 5 days) admini stration caused a significant reduction in activity of cytosolic phospholipase A 2 (cPLA 2 ), the rate-limiting enzyme in the AA and eicosanoid synthesis pathways. DEHP increased the expression of 12-lipoxygenase (12-LOX) in rat testis, whereas cyclooxygenase-2 (COX-2) expr ession was not altered. Cytochrome P450 4A1 (CYP4A1), a product of a PPARα-regulated gene, was markedly increased in the testis by DEHP administration. Taken together, DEHP suppresses cPLA 2 activity and induces the AA metabolizing enzymes such as 12-LOX and CYP4A1, resulting in the reduction of AA level. These data suggest that altered AA metabolic cascades may be related to the decrease of testosterone concentration in DEHP-induced testicular atrophy. KEY WORDS: arachidonic acid, cytosolic phospholipase A 2 , di-(2-ethylhexyl) phthalate, 12-lipoxygenase, testis.J. Vet. Med. Sci. 66(9): 1119-1124, 2004 The exposure of animals to phthalate esters can result in a significant perturbation of normal lipid metabolism in liver, heart, testis, adrenal gland and brain [4]. The plasticizer, di-(2-ethylhexyl) phthalate (DEHP), is a widespread environmental chemical due to its common use in the production of plastic medical devices and food packaging. On the exposure to phthalates for the human, certain populations may be exposed to much higher levels. The range of DEHP concentrations in medical devises are 3.1-650 mg/L [49]. Patients undergoing hemodialysis or blood transfusion received as much as 0.5-360 mg or 14-600 mg of DEHP via plastic medical devices, respectively [17,23]. Ingestion of DEHP, a peroxisome proliferator-activated receptor α (PPARα) ligand, by rats resulted in the increase of non-esterified fatty acids and phospholipids and changes in lipid composition in the testis [36]. Actually, altered lipid metabolism in the testis is frequently associated with testicular atrophy [11].Peroxisomes are ubiquitous eukaryotic organelles that play a key role in regulating lipid homeostasis in mammals. A peroxisome proliferator induces a broad spectrum of responses such as cell proliferation, decreased apoptosis, altered estradiol levels, increased metabolism of fatty acids and eicosanoids and carcinogenesis in the rodent liver [12]. DEHP activates many genes involved in lipid metabolism including fatty acyl-CoA oxidase, 3-ketoacyl-CoA thiolase and cytochrome P450 4A1 (CYP4A1) through PPAR in the liver [3]. Although DEHP is a well-known reproductive toxicant, the mechanism of its toxicity on lipid metabolism in the testis is still unclear.Phospholipase A 2 represents a large superfamily of enzymes that catalyze the hydrolysis of phospholipids at the sn-2 positio...

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Section: Discussionmentioning

confidence: 99%

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

Kim

Ishizuka

Kazusaka

et al. 2004

The Journal of Veterinary Medical Science

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“…Using immature cortical neurons and HT cells, it has been shown that a decrease in [GSH]i triggers the activation of neuronal 12-Lox, which leads to the production of peroxides, the influx of Ca 2+ , and ultimately to cell death (Li et al, 1997;Tan et al, 2001). The 12-Lox metabolite 12-HPETE proved to be capable of causing cell death (Gu et al, 2001). Inhibition of 12-Lox protected cortical neurons from b-amyloid induced toxicity (Lebeau et al, 2001).…”

Section: Neuroprotective Effects Of Tocotrienolmentioning

confidence: 99%

Tocotrienols in health and disease: The other half of the natural vitamin E family

Sen

Khanna

Roy

2007

Molecular Aspects of Medicine

298

203

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Tocochromanols encompass a group of compounds with vitamin E activity essential for human nutrition. Structurally, natural vitamin E includes eight chemically distinct molecules: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Symptoms caused by alpha-tocopherol deficiency can be alleviated by tocotrienols. Thus, tocotrienols may be viewed as being members of the natural vitamin E family not only structurally but also functionally. Palm oil and rice bran oil represent two major nutritional sources of natural tocotrienol. Taken orally, tocotrienols are bioavailable to all vital organs. The tocotrienol forms of natural vitamin E possesses powerful hypocholesterolemic, anti-cancer and neuroprotective properties that are often not exhibited by tocopherols. Oral tocotrienol protects against stroke-associated brain damage in vivo. Disappointments with outcomes-based clinical studies testing the efficacy of alpha-tocopherol need to be handled with caution and prudence recognizing the untapped opportunities offered by the other forms of natural vitamin E. Although tocotrienols represent half of the natural vitamin E family, work on tocotrienols account for roughly 1% of the total literature on vitamin E. The current state of knowledge warrants strategic investment into investigating the lesser known forms of vitamin E.

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“…Deletion of 12/15-LO reduces atherogenesis in ApoE-knockout mice [99]. This study initiated a number of investigations on the proatherogenic function of 12-LO and its products [100][101][102][103]. The human isoenzyme 15-LO type 1 (15-LO-1) appears to be a human analog of murine 12/15-LO and is considered to contribute to the formation of oxidized lipids in atherosclerotic lesions.…”

Section: Enzymes Of the Eicosanoid Cascadementioning

confidence: 99%

Macrophage Differentiation to Foam Cells

Shashkin¹,

Dragulev²,

Ley³

2005

CPD

246

159

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Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL-and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARα and PPARγ agonists, such as thiazolidinediones and fibrates, and PPARδ agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.

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Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts

Cited by 27 publications

References 37 publications

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

Alterations of Activities of Cytosolic Phospholipase A2 and Arachidonic Acid-Metabolizing Enzymes in Di-(2-Ethylhexyl)Phthalate-Induced Testicular Atrophy

Tocotrienols in health and disease: The other half of the natural vitamin E family

Macrophage Differentiation to Foam Cells

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