paricalcitol With regard to participation of the

With regard to participation of the 12S-lipoxygenase in diabetes mellitus, inconsistent results have been obtained. Earlier studies demonstrated that the leukocyte-type 12S-lipoxygenase is specifically expressed in pancreatic b-cells and is involved in regulating glucose-stimulated insulin secretion [120]. Hepoxilins, metabolites of 12-lipoxygenase pathway, cause the release of insulin in the circulation when administered intra-arterially to the anesthetized rat [121]. 12S-lipoxygenase knockout mice are highly resistant to streptozotocin-induced diabetes as compared with control mice and have higher serum insulin levels [122]. Clinical studies on diabetes mellitus patients have shown that 12S-HETE is increased early in the diabetic process [123]. In contrast, decreased 12-lipoxygenase activity is reported in platelets of patients with non-insulin-dependent diabetes mellitus [124]. As for the glucagon secretion, we demonstrated the presence of leukocyte-type 12S-lipoxygenase in α-cells of rat pancreatic islets [27]. It was shown earlier that 12-HETE increased glucagon release from isolated pancreatic islets [125], and the overexpression of the leukocyte-type 12S-lipoxygenase stimulates glucagon secretion in an α-like cell line, αTC clone 6 [27]. Based on this information, the 12S-lipoxygenase appears to participate in the regulation of insulin and/or glucagon secretion from pancreatic islets. Platelet-type 12S-lipoxygenase mRNA is increased in prostate cancer tissues, and the expression level is correlated with the clinical stage of the disease [126], [127]. Moreover, human prostate adenocarcinoma cells stably expressing the platelet-type 12S-lipoxygenase form larger tumors when injected subcutaneously into athymic nude mice [128]. In Dunning rat prostatic carcinoma cells, thrombin causes rapid pseudopod detachment and shortening via a cascade involving 12S- and/or 15S-HETE [129]. In patients with breast cancer, cancer-involved tissue sections show a much higher level of leukocyte-type 12S-lipoxygenase mRNA than corresponding normal sections [130]. When the estrogen-dependent, linoleic acid-unresponsive MCF-7 human breast cancer cell line was transfected with 12-lipoxygenase cDNA, the transfectant grew in vitro in the absence of estrogen, and its growth was stimulated by linoleic paricalcitol [131]. Rapid growth of the 12-lipoxygenase gene-transfected MCF-7 breast cancer cells was also shown in athymic nude mice, and the role of this enzyme has been suggested to involve endothelial cell angiogenic responses [132]. There is a report that 12-HETE formation is significantly lower in carcinoma tissues from human uterine cervix, suggesting an anti-carcinogenic action of the 12-lipoxygenase [133]. Treatment of rat Walker 256 carcinosarcoma cells with lipoxygenase inhibitors or 12-lipoxygenase-specific antisense oligonucleotide induced apoptotic cell death [134], [135]. It has also been shown that treatment of a human gastric cancer cell line with a 12-lipoxygenase inhibitor significantly inhibits cell proliferation and that apoptosis is induced by blockade of the 12-lipoxygenase pathway [136]. Related to this finding, sodium butyrate treatment induced rat intestinal epithelial cells to undergo differentiation and apoptosis, and induction of 12-lipoxygenase has been suggested to be involved in this process [137]. Using immature cortical neurons and a clonal nerve cell line, it has been shown that glutathione depletion triggers the activation of 12-lipoxygenase that, in turn, leads to nerve cell death [138]. These reports suggest that the 12-lipoxygenase pathway plays an important role in regulating cell growth and apoptosis. The 12S-lipoxygenase appears to be associated with blood vessel disorders and with inflammatory processes. It has been reported that platelet 12S-HETE production is enhanced in the spontaneously hypertensive rat [139], [140]. In accord with this finding, 12S-HETE levels and platelet 12S-lipoxygenase protein are increased in patients with essential hypertension [141]. Plasma and urinary 12-HETE levels are increased in patients with sickle-cell disease, and this 12-lipoxygenase metabolite could potentially play a role in sickle-red-cell-endothelial adherence [142]. There is a marked upregulation of 12-lipoxygenase mRNA in rat carotid arteries injured by a balloon catheter, and the upregulation occurs mainly in vascular smooth muscle and inflammatory cells [143]. It has also been demonstrated that platelet-type 12S-lipoxygenase mRNA is present in cultured human rheumatoid arthritis type B synoviocytes and that IL-1β and TNF-α increases 12-HETE production in these cells [144]. In connection with these findings, conditioned medium from primary rat lung macrophages or J774 monocytic cells has been found to induce interstitial collagenase-3 gene expression, and the effect is dependent on the combination of TNF-α and 12-lipoxygenase-derived arachidonic acid metabolites [145].