Cytochrome P450-derived eicosanoids: the neglected pathway in cancer

Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed

BK channels affect glucose homeostasis and cell viability of muring pancreatic beta cells

AIMS/HYPOTHESIS: Evidence is accumulating that Ca(2+)-regulated K(+) (K(Ca)) channels are important for beta cell function. We used BK channel knockout (BK-KO) mice to examine the role of these K(Ca) channels for glucose homeostasis, beta cell function and viability. METHODS: Glucose and insulin tolerance were tested with male wild-type and BK-KO mice. BK channels were detected by single-cell RT-PCR, cytosolic Ca(2+) concentration ([Ca(2+)](c)) by fura-2 fluorescence, and insulin secretion by radioimmunoassay. Electrophysiology was performed with the patch-clamp technique. Apoptosis was detected via caspase 3 or TUNEL assay. RESULTS: BK channels were expressed in murine pancreatic beta cells. BK-KO mice were normoglycaemic but displayed markedly impaired glucose tolerance. Genetic or pharmacological deletion of the BK channel reduced glucose-induced insulin secretion from isolated islets. BK-KO and BK channel inhibition (with iberiotoxin, 100 nmol/l) broadened action potentials and abolished the after-hyperpolarisation in glucose-stimulated beta cells. However, BK-KO did not affect action potential frequency, the plateau potential at which action potentials start or glucose-induced elevation of [Ca(2+)](c). BK-KO had no direct influence on exocytosis. Importantly, in BK-KO islet cells the fraction of apoptotic cells and the rate of cell death induced by oxidative stress (H(2)O(2), 10–100 μmol/l) were significantly increased compared with wild-type controls. Similar effects were obtained with iberiotoxin. Determination of H(2)O(2)-induced K(+) currents revealed that BK channels contribute to the hyperpolarising K(+) current activated under conditions of oxidative stress. CONCLUSIONS/INTERPRETATION: Ablation or inhibition of BK channels impairs glucose homeostasis and insulin secretion by interfering with beta cell stimulus–secretion coupling. In addition, BK channels are part of a defence mechanism against apoptosis and oxidative stress

Reactive oxygen species and cerebrovascular diseases

In the normal physiologic state, reactive oxygen species (ROS) generation is intentional and important for the functioning of cerebral and systemic circulations. Furthermore, emerging evidence indicates that cerebral arteries generate higher levels of ROS than arteries outside of the brain in the normal physiologic state. As such, it has been proposed that ROS may play a more prominent role in the physiologic regulation of cerebral arteries. There are numerous potential enzymatic sources of ROS in the cerebral vasculature; however, increasing evidence indicates that the family of NADPH oxidases is a major source. Aberrant redox signaling or oxidative stress in the cerebral circulation, usually as a result of excessive production of ROS and reactive nitrogen species (RNS), is a common feature in diverse models of cardiovascular risk factors (e.g., hypertension, hypercholesterolemia) and cerebrovascular disease. Furthermore, oxidative stress is now believed to be an underlying cause of cerebrovascular dysfunction and damage associated with these disease states. In this chapter, we summarize the effects and potential roles of ROS/RNS in modulating cerebral artery function in the normal physiologic state, with a particular focus on their roles in modulating cerebrovascular tone. Furthermore, we will highlight current evidence for the involvement of ROS/RNS in cerebrovascular dysfunction associated with cardiovascular risk factors, stroke, and Alzheimer's disease