What is the CYP pathway for AA metabolism?
The third AA metabolizing pathway is the cytochrome P450 (CYP) pathway that was first described in 1980. The CYP family of enzymes contains numerous subclasses, 17 but for the metabolism of AA ω-hydroxylase and epoxygenase activity are the most important.
Can AA metabolism identify new targets for the treatment of DM?
Therefore, research in AA metabolism and its enzymatic pathways may identify novel targets for the treatment of DM and its associated co-morbidities.
What factors affect the rate and pathway of opioid metabolism?
The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease).
What do the epoxygenases metabolize AA to?
The PGHSs (COXs) metabolize AA to protanoids, prostacyclin, and thromboxane. The LOXs metabolize AA to leukotrienes and HETEs. The P450 epoxygenases metabolize AA to midchain HETEs and four EET regioisomers. All EETs are then further metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH
How is glutamine metabolism?
As previously described, glutamine is metabolized by mitochondrial enzymes into α-KG, which serves as an important intermediate in the TCA cycle for anaplerosis. Furthermore, enhanced production of α-KG causes other critical effects, such as stimulation of the signaling pathways that support cell growth.
How and why carbohydrate metabolism is altered in cancerous cells?
Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even in the aerobic state and the presence of functioning mitochondria.
What metabolic changes are characteristic of malignant tumors?
There are six distinctive characteristics that a cell acquires during its progression into malignancy: limitless replicative potential, sustained angiogenesis, avoidance of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals and tissue invasion and metastasis.
Which enzymes plays an important role in tumor metabolism?
Which of the following enzymes plays an important role in tumour metabolism? Sol. (b) Pyruvate Kinase M2. 8.
Which enzymes metabolize AA?
The COXs, which generate prostanoids, i.e., prostaglandins (PGs) and thromboxane A 2 (TXA 2 ), were the first enzymes reported to metabolize AA. This requires the release of the lipid from the plasma membrane by phospholipases and subsequent metabolism by the COX enzymes to PGG 2 and PGH 2.
What is the COX pathway?
The COX pathway is one of the major treatment targets in atherosclerotic and ischemic heart disease because it affects major pathophysiological features of these diseases, including platelet aggregation, vessel wall tension, and inflammatory processes in atherosclerotic lesions. 12 The anti-inflammatory and anti-thrombotic features of aspirin, the only known irreversible inhibitor of COX-1, are primarily related to the suppression of PG and TXA2 synthesis. 78, 79 Meta-analyses of randomized trials show that the use of aspirin lowers the risk of cardiovascular events by 15% and myocardial infarction (MI) by as much as 30%. 80 Beyond effects on platelets, it seems that the COX-1/TXA2 pathway contributes to vascular hypercontractility in atherosclerotic ApoE-deficient mice, targeting this pathway pharmacologically improves endothelial function. 81 Aspirin is the only known nonsteroidial anti-inflammatory drug (NSAID) with cardiovascular protective effects but despite its widespread and long-term use, some aspects of aspirin treatment warrant further investigation; such as the interaction between body weight and the effectiveness of aspirin to prevent cardiovascular events. 76 COX-2 expression increases with inflammation and although COX-2 inhibitors preserve left ventricular function and dimensions in murine models of MI, these compounds have been found to increase cardiovascular risk in multiple clinical studies. For example, a retrospective cohort study including over 300,000 individuals suggested that the use of two highly selective COX-2 inhibitors; valdecoxib and rofecoxib, was associated with a higher risk of stroke. 82 Also, rofecoxib and etoricoxib increased blood pressure, whereas other members of this class of compound, i.e., celecoxib, lumiracoxib, and valdecoxib appeared to have little effect on blood pressure. 83 Another retrospective cohort study of over 2000 individuals aged over 65 also indicated a higher combined risk of recurrent congestive HF and mortality in patients prescribed with refecoxib rather than celecoxib. 84 The reason for these negative cardiovascular effects seems to be related to inhibition of PGI2 production by the COX-2 expressed by the vascular endothelium exposed to “atheroprotective” laminar flow. 85, 86 The potent vasoconstrictor 20-HETE is also affected by COX-2 inhibition as it is at least partially inactivated by a COX-2-dependent metabolic step. 75, 87 Combined therapeutic approaches may get around some of these issues and a new class of drugs that blocks both the COX-1/2 and 5-LOX pathways, may prove to be an effective treatment option for cancer, inflammatory and CVDs, with fewer side effects. 88 The compound currently in the most advanced phase of clinical development (phase III) is licofelone, previously known as ML3000. 89 Licofelone, characterized as a FLAP inhibitor and also has a weak effect on microsomal prostaglandin E synthase-1 (mPGES-1), developed by Merckle and the partners Alfa Wassermann and Lacer, has reached clinical phase III for the treatment of knee osteoarthritis 90 with several studies successfully completed. Compared with other nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone showed improved gastric tolerability and lower incidences of ulcers in healthy volunteers. 91
What are epoxides of AA?
It is well established that the epoxides of AA generated by CYP enzymes possess biological activity and affect a wide spectrum of cellular and tissue responses as well as having effects on the cardiovascular system . Perhaps most work on the EETs has been performed on vessels and vascular cells and less is known about the actions of cardiac-specific CYP-derived EETs in heart physiology and pathophysiology (Fig. 2 ), compared with the cardiac expression of CYP subfamilies identified in mammalian species including CYP1A, CYP1B, CYP2A, CYP2B, CYP2D, CYP2E, CYP2J, CYP2R, CYP2S, CYP2U, CYP4A, CYP4B, CYP4F, and CYP11B. 139
What is ischemia cardiomyopathy?
Ischemic cardiomyopathy is defined as CVD resulting from a period of low oxygen flow to the heart. 140 This could be due to a blockage resulting in limited blood flow, and consequently oxygen, to the heart. Reduced oxygen levels lead to a wide range of consequences for heart activity and morphology that are detrimental to proper function and homeostasis. 140 Overall, CYP-derived EETs in the heart has been shown to improve the outcomes of ischemia and/or ischemia/reperfusion injuries. 141, 142 This is relevant inasmuch as the expression of many CYP enzymes is increased by hypoxia, 143 while that of the sEH is decreased 144 —conditions that would favor EET stability and bioavailability.
What enzymes insert oxygen in AA?
The LOX enzymes insert molecular oxygen in AA and depending on its position, 4 hydroperoxyeicosatetraenoic acids (HPETEs; 5-, 8-, 12-, and 15-HPETE) are formed by the corresponding LOX enzymes, i.e., 5-LOX, 8-LOX, 12-LOX, and 15-LOX.
Does EET inhibit apoptosis?
21, 152, 156, 205 This protective action for EETs appears to be multifactorial and EETs likely inhibit apoptosis in the brain tissue. Brain tissue EET cell signaling antiapoptotic mechanisms involve increased Bcl2, ceramide inhibition, and decreased ROS. 156, 206 Indeed, we found that CYP2J2 overexpression increased EET productions, increases regional cerebral blood flow (rCBF) and microvascular density, decreased ROS production, decreased brain infarct size and apoptosis after ischemia, the effects of which were associated with increased activation of the PI3K/AKT and apoptosis-related protein in the ischemic brain. Liu et al. 207 found that exogenous administration of 14,15-EET or AUDA could suppress astrogliosis and glial scar formation, inhibit microglia activation and inflammatory response, promote angiogenesis, attenuate neuronal apoptosis and infarct volume, and further promote the behavioral function recovery after focal ischemia.
What is the role of arachidonic acid in the cell membrane?
Abstract. The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) ...
Which enzyme metabolizes arachidonic acid?
Lipoxygenase enzymes metabolise arachidonic acid to a group of noncyclised eicosanoids, the leukotrienes, some of which are also important inflammatory mediators. They are probably of particular importance in leucocyte-mediated aspects of chronic inflammation.
What is the role of arachidonic acid in the body?
The acute inflammatory process, arachidonic acid metabolism and the mode of action of anti-inflammatory drugs. Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells.
Do anti-inflammatory drugs inhibit lipoxygenase?
Currently available non-steroidal anti-inflammatory drugs, however, do not inhibit lipoxygenase activity. In the light of recent evidence, the inflammatory process is re-examined and the important emerging roles of both cyclo-oxygenase and lipoxygenase derived eicosanoids are explored.
Is arachidonic acid a fatty acid?
Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells . Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, the eicosanoids.
Abstract
Cancer cells usually show adaptations to their metabolism that facilitate their growth, invasiveness, and metastasis. Therefore, reprogramming the energy metabolism is one of the current key foci of cancer research and treatment.
Introduction
Epithelial ovarian cancer (EOC) is one of the most common causes of cancer death in women for two main reasons: its most frequent presentation occurs at an advanced-stage and its high recurrence rate [ 1 ]. Despite the use of chemotherapy and targeted therapy, the ovarian cancer mortality rate remains as high as 70% [ 2 ].
A general consideration of ovarian cancer metabolism regarding glycolysis and the oxidative phosphorylation pathway
The pathways and regulation of glycolysis and OXPHOS are depicted in Figure 1. Under normal physiological conditions, glycolysis consists of a multistep pathway of glucose breakdown, followed by the conversion of phosphoenolpyruvate (PEP) to pyruvate via the enzyme pyruvate kinase M1 (PKM1).
Metabolic changes in the epithelial ovarian cancer cell lines
Previous in vitro studies investigated metabolic changes in the EOC cells and compared them to normal ovarian epithelial cells ( Table 1 ). In addition, the metabolic alterations of EOC cells have been compared within a variety of histologic types and also the invasiveness levels in the cells.
Metabolic changes in epithelial ovarian cancer cells: clinical evidence
Clinical evidence from previous studies investigating metabolic changes in ovarian cancer tissues and serum samples from patients is listed in Table 2.
The effects of glycolytic interventions on epithelial ovarian cancer
The impact of glycolytic intervention on the different aspects of EOC, growth, invasion, migration, and apoptosis, has been investigated in in vitro and in vivo studies.
The comparative effects of glycolytic and OXPHOS interventions on epithelial ovarian cancer
When glycolytic and OXPHOS interventions were compared, all the in vitro studies showed that EOC cell growth, invasion and migration depend mainly on glycolysis rather than OXPHOS ( Table 5 ).
Diabetes
Diabetes is a condition that prevents the body from properly regulating blood glucose levels with insulin. The American Diabetes Association states that more than 34 million Americans had diabetes in 2018, which is around 11% of the population. The most common types of diabetes are:
Hemochromatosis
Hemochromatosis is a condition that affects how the body absorbs iron. It can result from a mutation in the HFE gene or excessive iron from a person’s diet or blood transfusions. The disease causes iron buildups that can lead to symptoms including:
Phenylketonuria (PKU)
PKU is where someone is born without the ability, or has a reduced ability, to produce phenylalanine hydroxylase. This is an enzyme that is important for processing amino acids. Metabolic processes use amino acids to build proteins, which are essential for bodily growth and development.
Mitochondrial disorders
Mitochondrial disorders are a group of conditions that prevent the mitochondria from producing enough energy for cells to function correctly. They usually result from a genetic mutation that passes through families.