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Glucose Uptake And Energy Metabolism

A-Lipoic acid has a number of actions in addition to its antioxidant properties. These include its effect on glucose uptake. We therefore evaluated glucose uptake, nerve energy metabolism, and the polyol pathway in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid at various doses (0, 10, 25, 50, and 100 mg kg). Duration of diabetes was 1 month, and a-lipoic acid was administered intraperitoneally 5 times during the final week of the experiment. Nerve glucose uptake was reduced to 60 , 37 and 30 of control values in the sciatic nerve, L5 DRG, and superior cervical ganglion, respectively, in EDN. a-Lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose but reversed the deficit in EDN, with a threshold between 10 and 25 mg kg. Endoneurial glucose, fructose, sorbitol, and myo-inositol were measured in sciatic nerve and L5 DRG. ATP, creatine phosphate, and lactate were measured in sciatic nerve and superior cervical ganglion....

Neuronal activation and energy metabolism

Another important metabolic aspect of neuronal cell function is the storage and timely release of neurotransmitters upon receipt of signals, functions which require intense membrane fatty acid synthesis and turnover. Insulin production exemplifies the importance of neuropeptides in regulating de novo fatty acid synthesis and turnover in differentiating islet beta cells as outlined later in this review. Glucagon-like peptide-l (GLP-1) is a powerful neuropeptide regulating beta cell de novo fatty acid synthesis and turnover with a primary effect of increasing glucose carbon channeling towards fatty acid synthesis, chain elongation and desaturation of the long chains. Further explorations of these unique metabolic effects of hormones acting in the brain, for example, GLP-1, improve the understanding of neuronal response and neurological and psychiatric diseases and lead to the discovery of new target sites for drug interactions with molecular mechanisms responsible for defective...

Cellular homeostasis and regulatory processes

The second type of mechanism is inherent in metabolic pathway design. Every enzyme in a pathway contributes to the control of the pathway's overall rate. This topic has attracted the attention of mathematical biologists and a well-established body of theory has resulted, throwing light on some otherwise puzzling experimental data. Curiously, many biochemists pay scant attention to this body of theory and maintain that only certain key enzymes, which are subject to feedback control (e.g. by the end product of the pathway), contribute to metabolic rate regulation. Key enzymes probably help to determine the balance between alternative pathways, but in general they contribute no more to the rate of a particular pathway than any other enzyme in that pathway.

Cortical Spreading Depression

The model of the cerebral metabolic response to activation developed by Magistretti and colleagues 51 envisages that glycolytic activity is predominantly in the astrocytic compartment (where almost all glycogen in the brain is held 52, 53 ), stimulated by an increase in extracellular glutamate during functional activation. It is further proposed that astrocytes deliver lactate to neurons, which, relying on lactate dehydrogenase activity in reverse, convert lactate to pyruvate. This pyruvate is then metabolised via the tricarboxylic acid cycle. Glucose transport across the blood brain barrier is highly efficient, to the extent that total unidirectional flux into the brain under non-activated conditions is approximately twice the rate of utilisation by glycolysis 54 . This, allied with the hyperaemic response to CSD discussed below, endows the cortex with its capacity to meet the challenges of activation. It is not appropriate to pursue further this important topic in this context, and...

Quantification Of Openness And Allometric Principles

Where k is roughly a constant for all species, equal to approximately 5.6 kJ g day, and m the metabolic rate per unit weight W. (for aquatic organisms) follow the same trends as the metabolic rate. This is of course not surprising, as excretion is strongly dependent on metabolism and the direct uptake dependent on the surface.

Intraoperative Cerebral Protection

The effort to identify appropriate means by which to provide specific neuroprotection beyond adequate cerebral perfusion and oxygenation during aneurysmal surgery has been the focus of a large body of experimental and clinical research (63). Barbiturates have been intensively studied in regard to their potential for intraoperative protection (64). These gamma-aminobutyric acid (GABA)-agonistic agents reduce the cerebral metabolic rate to 50 at minimal electrical brain activity (EEG burst suppression) and, subsequently, reduce CBF and ICP (reduction in blood volume). Barbiturates, such as thiopental, must be provided prior to temporary occlusion in order to exert their potential neuroprotective effects, and their application might be associated with significant arterial hypotension (65), which, in turn, might compromise cerebral perfusion in areas at risk for ischemia due to impaired autoregulation. The mechanism of neuroprotection is controversial and possibly relates to the...

Pharmacological Studies

Eating Disorders - Stress decreases food intake and weight gain and these effects are reproduced with centrally administered CRF (11). These effects are inhibited by antisauvigine-30 and CRF(9-41), which also alleviates the stress-like effects are also seen with the brain anorectic agent, CART (68, 73 - 74). In contrast, the small molecule CRFi antagonist 20 had no effect CRF induced decreases in body weight suggesting a role for CRF2 (73). Urocortin is a 30-fold selective CRF2 agonist whose effects on food intake can also be blocked by antisauvigine-30. Antisauvagine-30 had no effect on the associated changes in tissue weights and serum chemistry seen with central CRF administration implying that CRF2 mediates only the anorexic, not the metabolic effects, of CRF (71). Central administration of urocortin-ll has supported earlier observations in CRF1 knock out mice that intimated CRF2 activation may be only responsible for later stage (beyond 6 hours) suppression of food intake and not...

Mediterranean Diet Effects on Oxidative Stress

Oxidative stress markers commonly used, including nonspecific in vitro assays to determine the susceptibility of lipids to oxidation (i.e. lag time, thiobarbituric acid substances, malondialdehyde, oxygen radical absorbing capacity (ORAC) or assays that measure, in vivo, end-product of oxidative damage to lipids (e.g., breath ethane or urinary isoprostanes). Formation of these oxidation products is dependant on free radical activity (i.e. metabolic rate), substrate concentration (i.e. lipids), and antioxidant activity (both endogenous and dietary). Hence, alterations in dietary patterns can give important insight into the benefit or harm of nutrients when linked to subsequent changes in markers of oxidative stress.

Neuropeptide Y family modulators

A tricyclic derivative 38 (L-152804) has been studied in different rodent models of obesity 76,77 . This compound showed moderate Y5R binding affinity (mY5R 44 nM, rY5 K 31 nM, Ca2+ IC50 210 nM) and was claimed to have little off-target activity (no significant cross reactivity with 120 other binding assays and seven enzyme assays). Compound 38 decreased body-weight gain in DIO mice, reduced adipose tissue mass, and improved DIO-associated hyperinsulinemia. It was specifically reported that high and sustained ROs were required for activity. Compound 38 was inactive in Y5R KO mice. A patent application has claimed that 38 can prevent the decrease in metabolic rate and energy expenditure that can occur with food restriction and loss of body weight 78 . The carbamoyl derivative 39 has been previously disclosed in the patent application literature as a Y5R antagonist 79 . A new paper describes methods for quantifying 39 in human plasma and urine to support human pharmacokinetic studies 80...

General considerations

A recent paradigm shift has led to efforts by neuroimmunologists to acquire deeper insight into the neurodegenerative features of chronic neuroinflammation. Recently, proteolytic enzymes, cytokines, death ligands, such as TRAIL, oxidative products, such as 7-keto-cholesterol, and free radicals have been identified as potential contributors to neuronal damage (Zipp and Aktas, 2006). It has yet to be clarified what immune cells and what mechanisms initiate neurodegeneration in in vivo animal models and the human disease. In addition, inflammation may compromise energy metabolism and cause hypoxia and cytotoxicity, making neuroprotective drugs a likely candidate for future treatment strategies. The contribution of excitotoxicity was shown by Raine and coworkers, who influenced chronic neuronal damage in the EAE model via AMPA kainate receptor antagonists (Pitt et al., 2000). Unlike ischemic or traumatic models, in which dramatic metabolic failure leads to rapid irreversible

Medicinal Chemistry Efforts Reported Prior To 2009

More recently, a series of alkynyl thiazoles was reported, of which some analogs exemplified by 3 (ACC2 IC50 38 nM, ACC1 IC50 > 30,000 nM) showed high selectivity for ACC2 versus ACC1 28 . Sprague-Dawley rats dosed orally with 3 showed a dose-dependent reduction of malonyl-CoA in liver and muscle, indicating that inhibition of ACC2 alone may be sufficient to achieve a metabolic response. Extensive structure-activity relationship (SAR) studies around the phenyl and acetylene groups in this series have also been reported 29-31 . Additionally, gene expression analysis in animals treated with 3 suggested that the peroxisome proliferator-activated receptor a (PPARa) pathway was upregulated by ACC2 inhibition 32 . Although other compounds from the same group did not show PPARa activity, such an effect of 3 could potentially confound the interpretation of the pharmacology of its ACC inhibition.

Clinical Box 11 Why Doesnt Your Stomach Digest Itself

The situation with the carbonic acid buffer reaction Eq. (1.15) is complicated by the fact that this buffer system involves gaseous CO2, which is in abundant supply in the atmosphere and is also a main intracellu-lar product of energy metabolism. Both of these sources of CO2 impact the distribution of the components of the carbonic acid buffer system.

Lxr And Atherosclerosis

A series of investigations in mice, including bone marrow transplantion studies, have revealed the critical role LXR plays in the development of atherosclerosis 13,14 - Importantly, LXR-induced upregulation of the ABCA1 cholesterol transporter in the arterial macrophages of the atherosclerotic vessel wall is sufficient to attenuate lesion development in the mouse 15,16 - This direct effect on the vessel wall may be critical to the clinical effectiveness of LXR agonists developed for the treatment of atherosclerosis, since other metabolic effects of LXR activation in the liver may differ substantially between species-The discovery process for LXR agonists has been clouded by the worrying

Limited Growth Potential

Discussion of the metabolic pathways used during anaerobic growth can shed some light on the genetic mechanisms governing the reduced killing of slow-growing bacteria. P. aeruginosa, for instance, can utilize NO3_ and NO2_ for anaerobic respiration (Hassett et al. 2002). These processes are carried out by the sequential actions of the nar, nir, nor, and nos genetic loci, which reduce the nitrogenous substances to N2. P. aeruginosa tightly regulates these genes in order to prevent buildup of toxic intermediates in the pathway (such as the production of nitric oxide). In fact, altered regulation of these loci in mutants of the quorum sensing gene rhlR under anaerobic conditions leads to rapid cell death (Hassett et al. 2002). Consequently, drugs targeting quorum sensing or nitrogen utilization pathways may be efficacious in destroying tenacious biofilms. Intriguingly, treating mature P. aeruginosa biofilms under anaerobic conditions with a combination of NO3_ and either cipro-floxacin...

Why is the cell the fundamental unit of life

A single cell fits our characterisation. Indeed, we developed the characterisation by reference to single cells rather than multicellular organisms. But consider any part of a eukaryotic cell an isolated nucleus, a mitochondrion, the cell minus its nucleus, or any other permutation. None of these sub-cellular parts can be deemed living. Take away the mitochondria and you take away most of energy metabolism, so the cell cannot be supplied with ATP the internal state cannot be maintained. Take away the nucleus and you take away the genes and therefore the pattern of gene expression. Alternatively, consider a fragment of a prokaryote. The fragment can no longer co-ordinate its responses to stimuli, its pattern of gene expression and its internal state, and hence it is not alive. Therefore, although a cell can be alive, no portion of a cell can be. Deprive a cell of any significant part and the remnant is dead or dying. In other words, the cell is the smallest possible unit of life.

Adipocyte Dysfunction And Insulin Resistance

A second mechanism by which improvement in adipocyte function can improve insulin sensitivity is by altering the release of signaling molecules from fat (adipocytokines) that have metabolic effects in other tissues27-28. For example, it is well known that adipocytokines, such as leptin, tumor necrosis factor-a (TNF-a), resistin and adiponectin, have profound metabolic effects. It has been observed that PPARy

Endocannabinoid System

A recently characterized physiologic system that plays a major role in modulating energy metabolism is the endocannabinoid-CB1 receptor system (Figure 4.9)31'32. The discovery of this system represents a significant advance in understanding mechanisms contributing to the development of obesity and as such, provides targets for new pharmacological approaches to target abdominal obesity and its related metabolic

Inflammation and Immune Effector Heterogeneity in MS 231 T and B Lymphocytes

When inflammatory mediators, such as reactive oxygen and nitrogen species, are excessively liberated, they contribute to mitochondrial dysfunction and a state of histotoxic hypoxia 2 . Hypoxic brain damage leads to the destruction of glial cells and neurons in the lesions. If the hypoxia is incomplete, a cascade of events occurs to increase the resistance of the tissue to subsequent hypoxic damage and thus limit structural damage from the insult. This is referred to as hypoxic preconditioning 90 . One master switch in the induction of hypoxic preconditioning is the expression of hypoxia-inducible factors (HIFs) a and P 90 . They act as transcription factors to induce gene expression of downstream molecules involved in neuroprotection, vasomotor control, angiogenesis, cell growth, and energy metabolism 2 . These proteins render the tissue resistant to further hypoxia-induced injury.

Metabolism or storage

Figure 4.9 The EC system has effects that modulate whole-body energy metabolism. Specifically, the system acts as a major contributor to the energy balance by altering dietary intake. In addition, the system has effects on digestion, absorption, and metabolism of substrates. PYY, peptide YY GLP-1, glucagon-like protein-1 that 50 of these metabolic effects were independent from the weight loss, suggesting a systemic metabolic effect on CB1 receptors located in peripheral tissues40.

Leptin Leptin Resistance and the Metabolic Syndrome

The mechanisms for leptin resistance are under intensive investigation. Decreased availability of leptin in the hypothalamus, impaired peripheral leptin action, or both have been proposed as mechanisms of leptin resistance during aging 111 . Scarpace et al. 112 described a metabolic response typical of leptin resistance following both central and peripheral leptin infusion in older rats. Following central leptin infusion, NPY mRNA levels did not significantly change in older rats compared to young rats 112 . STAT3 phosphorylation was found to be significantly diminished with age 112 . These data indicate that there may be two components to leptin resistance with aging, peripheral, and hypothalamic. Further research is clearly necessary to extend these interesting animal model findings to humans.

Excitotoxicity and Ionic Imbalance

Ischemic stroke results in impaired cellular energy metabolism and failure of energy-dependent processes such as the sodium-potassium ATPase. Loss of energy stores results in ionic imbalance, neurotrans-mitter release, and inhibition of the reuptake of excitatory neurotransmitters such as glutamate. Glutamate binding to ionotropic N-methyl-D-aspartate (NMDA) and acid (AMPA) receptors promotes excessive calcium influx that triggers a wide array of downstream phospholipases and proteases, which in turn degrade membranes and proteins essential for cellular integrity. In experimental models of stroke, extracellular glutamate levels increase in the micro-dialysate 2, 3 , and glutamate receptor blockade attenuates stroke lesion volumes. NMDA receptor antagonists prevent the expansion of stroke lesions in part by blocking spontaneous and spreading depolarizations of neurons and glia (cortical spreading depression) 4 . More recently, activation of the metabotropic subfamily of receptors has...

Temperature And Brain Injury

Hyperthermia in the immediate poststroke period is common and is associated with increased morbidity and mortality (47-51). Ironically, ischemic brain temperature tends to be higher than core body temperature (52). Hyperthermia might contribute to increased cerebral injury through several different mechanisms. First, temperature is the major determinant of the brain's metabolic rate of oxygen consumption (CMRO2). For every degree centigrade above normothermia (36.8 C), CMRO2 increases by approximately 5 to 10 conversely, for every degree centigrade below normothermia, the CMRO2 decreases by approximately 5 to 10 (53-55). Hyperthermia is also associated with increased inflammation and an increased release of excitotoxic amino acids conversely, hypothermia reduces the release of excitotoxic amino acids ( 56-60 ).

Lactate Dehydrogenase

Major pathway of energy metabolism in mature red blood cells and reticulocytes. G6P, glu-cose-6-phosphate F6P, fructose-6-phosphate F-l,6-diP, fructose-1,6-diphosphate DHAP, dihydroxy-acetone phosphate GA3P, glyceraldehyde-3-phosphate 1,3 DPG, 1,3-diphosphoglycerate 2,3 DPG, 2,3-diphosphoglycerate 3PG, 3-phosphoglycerate 2PG, 2-phosphoglycerate PEP, phosphoenolpyru-vate 6PG, 6-phosphoglycerate GSH, reduced glutathione GSSG, oxidized glutathione ATP, adenosine triphosphate ADP, adenosine diphosphate NAD, nicotinamide adenine dinucleotide NADH, reduced nicotinamide adenine dinucleotide NADP, nicotinamide adenine dinucleotide phosphate NADPH, reduced nicotinamide adenine dinucleotide phosphate ATPase, adenosine triphosphatase Pi, inorganic phosphate.

Developmental pathways to obesity

Given that infant and child mortality is highest as a result of developmentally mediated undernutrition during the earliest stages of the lifecycle, natural selection operating at this age may have had an important influence on the evolution of human metabolism. It is notable, for instance, that the challenge of surviving recurrent infections shares similarities with Neel's vision of a feast-famine scenario, and might be expected to favor the rise of similar metabolic-disease predisposing genes. In this sense, early life might be likened to an ontogenetic bottleneck through which any adult metabolic traits must first pass (17). Although all humans experience this age of heightened energetic vulnerability, there is much variation in the environments that individuals experience, which determines whether they will be forced to rely on such contingencies as brain sparing, lipolysis, or rapid replenishment of body fat. There is now considerable experimental evidence that one's early...

Phospholipid Metabolism

There is general agreement that glucose and cholinergic agents accelerate phospholipid turnover in islet cells. Meanwhile other secretagogues, including CCK8, that amplify insulin secretion have also been found to increase metabolism of phospholipids (Zawalich et al., 1987).

Key Points Intracranial And Cerebrovascular Disease y

In the normal brain cerebral blood flow varies directly with the cerebral metabolic rate. Inhalational agents are said to uncouple this relationship in that they decrease the cerebral metabolic rate while concurrently dilating cerebral blood vessels and increasing cerebral blood flow.

Alcohol Abuse And Cardiovascular Disease

Although there is considerable evidence that moderate drinking protects against mortality and morbidity from coronary heart disease 21,22 , heavy consumption is shown to have deleterious cardiovascular effects. It exerts its adverse effects by increasing the risks of cardiomyopathy, hypertension, and stroke 23 , Chronic ethanol consumption has been linked to the prevalence of hypertension, which contributes to an increased incidence of stroke. Heavy drinkers have alO mmHg higher systolic blood pressure than non-drinkers even though the relationship may differ between men and women 24 , Stroke is a leading cause of death and morbidity. Alcohol may increase the risk of stroke through various mechanisms that include hypertension, hypercoagulable states, cardiac arrhythmias, and cerebral blood flow reductions 25 , Hypertension, including borderline hypertension, is probably the most important stroke risk factor based on degree of risk and prevalence. Furthermore, cardiac morbidity,...

Anesthesia and the cholinergic system implications from sleep research

More recent studies have focused on the later-odorsal and pedunculopontine tegmental nuclei (LDT PPT) as important regions in the CNS where cholinergic transmission is altered during loss of consciousness. These midbrain nuclei contain choli-nergic neurones that project to the medial pontine reticular formation and thalamus, and it has been shown that their energy metabolism is altered in phase with the sleep awake cycle (Lydic et al., 1991a). Microdialysis studies have demonstrated that REM sleep is accompanied by an increase in ACh release in the medial pontine reticular formation (Lydic et al., 1991b). Injection of carbachol, a muscarinic agonist, into the medial pontine reticular formation produces REM-like sleep (Baghdoyan et al., 1993).

H pylori Functional Genomics

Information about H. pylori energy metabolism and biosynthetic pathways was also gained from the genome sequence, including identification of the membrane-embedded F0 and catalytic Fj components of ATP synthase, dehydrogenases, menaquinone, cytochromes, and a terminal oxidase for respiration-coupled oxidative phosphorylation. Fumarate reductase, which may play a role in anaerobic and or aerobic respiration, as well as superoxide dismutase, catalase, and two peroxidases, presumably to detoxify oxygen species, are also present. Nonetheless, the genetic basis of microaerophily remains incompletely understood. Genes encoding enzymes for nitrogen assimilation, the tricar-boxylic acid cycle, and nucleotide metabolism have also been identified, and a metabolic model has been constructed from genomic information that provides an in silico network of almost 400 H. pylori enzymatic and transport reactions (70). More recently, a global transposon mutagenesis approach has been used to identify...

Comparative Genomics and Virulence

The majority of these orthologs encode proteins involved in housekeeping functions, including transcription, translation, energy metabolism, and biosynthetic processes. All three organisms possess a small genome, similar coding capability, and a relatively low number of copies of ribosomal RNA genes. The high degree of homology among their genome contents is consistent with their similar morphology and growth requirements (Table 1). It has been proposed that these three organisms, along with W. succinogenes, are derived from a common ancestor with a larger genome, and have been subject to reductive evolution leading to reduced genome sizes (84). Subsequent to diverging from the common ancestor, each organism has acquired distinct genome features that contribute to their individual lifestyle and physiology. There are 544, 810, and 585 species-specific genes for H. pylori, H. hepaticus, and C. jejuni, respectively (84). In addition, a total of 109 H....

Sequence Of Events During Reperfusion

Because of rheological factors and cellular swelling that restricts capillary diameter, restoration of CBF after complete cerebral ischemia initially requires higher perfusion pressure than that anticipated from a CBF autoregulatory curve. Thus, the low cerebral perfusion pressures typically attained during chest compressions with cardiopulmonary resuscitation are generally inadequate for restoring cerebral energy metabolism (13,14). Moreover, delaying the onset resuscitation after cardiac arrest from 0 min to 1.5, 3, 6, and 12 min progressively worsens the level of CBF attained at low reperfusion pressures (15). Once cardiac function is restored, arterial pressure may transiently increase above normal levels because of the persistent action of endogenously released and exogenously administered vasopressors during resuscitation. It has been argued that brief hypertension after resuscitation may be beneficial for the brain by washing out the poorly deform-able leukocytes and...

Reactive Oxygen Species

Iron can be mobilized by the action of superoxide on ferritin (98) and by the action of lactic acid on bicarbonate bridges on transferrin (99). Iron can catalyze hydroxyl radical formation by the Fenton reaction and participate in other free radical reactions (100 ) . A role for iron-induced injury is implicated by a mobilization of iron from its storage proteins and a beneficial effect of the iron chelator deferoxamine in sustaining energy metabolism after severe acidotic ischemia (101,102).

Apoptotic Pathways Cell Morphology

Apoptosis represents an actively regulated form of cell death, whereas necrosis is considered to represent a passive form of cell death secondary to the loss of energy metabolism. Because energy metabolism usually recovers initially after reperfusion, but can decline hours later depending on ischemic duration, the role of apoptotic and necrotic mechanisms can be interrelated temporally in a complex fashion. With complete or near-complete global cerebral ischemia, most neurons that die have a necrotic appearance. Neurons that display classic apop-totic morphology are uncommon (124), unless the blood flow reduction is moderate or brief (125 ) . Apoptotic morphology is more common in models of hypoxia-ischemia in immature rodents (126). This age-dependent pattern probably reflects the increased expression of many of the apoptosis-regulatory proteins in immature brain, which normally undergo increased baseline apoptosis (127) . However, the lack of pure apoptotic morphology in mature...

Malnutrition vs cachexia

Malnutrition, in conditions such as kwashiorkor and pyloric stenosis, results from inadequate intake of nutrients despite a good appetite, and manifests as weight loss associated with protective metabolic responses such as decreased basic metabolic rate and preservation of lean body mass at the expense of fat mass. Cachexia differs from malnutrition in several key ways. First, despite the fact that the cachexic person is starving, he or she is anorexic. Second, in normal starvation the metabolic rate decreases as a protective mechanism. This protective reduction in metabolic rate is not observed in cachexia. Resting energy expenditure is high in patients with cachexia from renal failure (9,10). Third, in simple starvation fats are preferentially lost and there is preservation of lean body mass. In cachexia, lean tissues are wasted and fat stores are relatively underutilized (11). Finally, the abnormalities in malnutrition can usually be overcome simply by supplying more food or...

Leptin and ghrelin in cachexia

Leptin is secreted by adipocytes and regulates adiposity and metabolic rate by reducing food intake and increasing energy expenditure. Leptin is also a member of the IL-6 superfamily of cytokines. Experimental elevation of leptin within the physiological range produces weight loss and relative anorexia. Leptin secretion is increased by both central and systemic immunological challenge and has been proposed as a potential mediator of inflammation-induced anorexia. The mechanism of how leptin expression and secretion is enhanced during inflammation is complex, but there is evidence for mediation by both IL-1 and TNF-a. Conversely, leptin induces production and release of IL-1 in the brains of normal rats and the release of both IL-1P and TNF-a from mouse macrophages. Collectively, these observations suggest a complex interplay between leptin and other cytokines in the regulation of metabolism and appetite during acute and chronic illness (49).

Nondiabetic endocrine disease i

Hypoventilation may be a feature of hypothyroidism. The ventilatory responses to both hypoxia and hypercarbia are significantly impaired, making the hypothyroid patient sensitive to drugs that cause respiratory depression. Hypothyroidism also decreases the hepatic and renal clearance of drugs. In addition, patients are prone to hypothermia because of lowered metabolic rate and consequent lowered heat production. Treatment consists of supplementation with exogenous thyroid hormones, most frequently levothyroxine (T4), because its long half-life, 6 to 7 days, results in a more constant serum level. Levothyroxine is available for intravenous use with the intravenous dose being one half the oral dose. The principal risk with treatment is in patients with coronary artery disease (CAD). An increase in the basal metabolic rate may result in myocardial ischemia. A suggested thyroid supplementation protocol for hypothyroid patients is summarized below In hyperthyroidism the metabolic rate of...

Neuropeptides in cachexia

A current hypothesis of cachexia in chronic illness is that cytokines released during cancer, CKD, or chronic inflammation act on the central nervous system to alter the release and function of a number of key neurotransmitters, thereby altering both appetite and metabolic rate (54,55). The melanocortin system is critical in mediating the effect of cytokines, such as leptin, on metabolism. There are distinct local counterparts of the pro-opiomelanocortin (POMC) cells agouti-related protein (AgRP) and neuropeptide Y (NPY) producing cells in the arcuate nucleus. Activation of POMC neurons by leptin triggers the release of a-melanocyte-stimulating hormone (a-MSH) from POMC axon terminals, which in turn activates the type 4 melanocortin receptor-4 (MC-4R), leading to suppressed food intake and increased energy expenditure. Simultaneously, leptin suppresses the activity of arcuate nucleus NPY AgRP neurons, which otherwise would antagonize the effect of a-MSH on MC-4Rs through the release...

Hypoglycemia and Brain Energetics

Glucose concentration in the brain normally has a linear relationship to blood concentrations (Gruetter et al. 1998 Gruetter 2003), with normal brain concentrations ranging from roughly 0.8 to 2.3 mM (Gruetter et al. 1998). However, brain glucose consumption outstrips transport capacity at reduced blood glucose concentrations, resulting in brain glucose concentrations approaching zero when blood glucose concentrations fall below 2 mM (Feise et al. 1977 Choi et al. 2001). Although glucose is a necessary fuel for brain energy metabolism, it is not the only fuel that can be utilized. The brain can also utilize ketone bodies, particularly during early development and during starvation (Robinson and Williamson 1980), but ketone bodies cannot fully substitute for glucose.

Lselectin as a signal transducing molecule

Simon et al. 138 reported that activation of L-selectin through antibody cross-linking enhanced the adhesive properties of neutrophils to LPS-treated HUVECs and that this adhesive interaction required the p2 integrin, Mac-1. Cross-linking of L-selectin on lymphocytes with the anti-L-selectin mAb MEL-14 induces homo-typic lymphocyte adhesion by a lymphocyte LFA-1-independent mechanism 139 . Furthermore, activation of L-selectin using the LAM1-116 mAb that binds to the lectin domain of L-selectin enhances the expression of pj and p2 integrin activation epitopes and results in the rapid homotypic adhesion of leukocytes 7 . This L-selectin-induced adhesion required energy metabolism, an intact cytoskeleton, and kinase function. Importantly, the binding of many other L-selectin mAbs to regions of the molecule other than the lectin domain did not trigger activation. In addition, activation of L-selectin through GlyCAM-1 binding results in increased integrin-mediated adhesion 8, 140 . Taken...

Hypothermia for Ischemic Stroke

Early clinical data have shown promise for induced hypothermia for the treatment of acute ischemic stroke. Hypothermia acts by decreasing the cerebral metabolic rate, stabilizing cell membranes, preserving the integrity of the BBB, reducing the release of destructive enzymes, reducing the inflammatory response, and decreasing the release of excitotoxic neurotransmitters, such as glutamate and dopamine. Early treatment with hypothermia may reduce total infarct volume, and may prevent the

Mechanisms Of Hypothermic Neuroprotection

The most attractive feature of induced hypothermia as a neuroprotective strategy is that its neuroprotective action appears to operate via multiple mechanisms. Hypothermia has been shown to alter metabolic rate (4) by decreasing cellular metabolism, thus retarding high-energy phosphate depletion and facilitating postischemic glucose utilization (5). Hypothermia attenuates the cytotoxic cascade by suppressing elevations of intracellular calcium, thereby inhibiting the release of excitotoxic amino acids and reducing intracellular acidosis (6-9).

Fatty Acid Ethyl Esters

A decreased capacity to produce metabolic energy was observed in many investigations 30-35 , It was noted that ethanol increases basal metabolic rates and oxygen consumption 35 , Changes in phosphate 02 and respiratory control ratios was also demonstrated with ethanol intake 30,36-38 , In addition, mitochondrial cristae disruption, swelling, and existence of dense inclusion bodies was detected in laboratory animals receiving chronic ethanol intake 26,39-41 , The toxic metabolite acetylaldehyde does not appear to cause these results for reasons discussed above. However, recent research on FAEEs may help elucidate the mechanism for ethanol's effect on the sarcolemma, SR, and cellular respiration.

Pathways Influenced by Mitochondrial ROS and Oxidized Lipids

Reactive oxygen species and possibly oxidized lipids, as described above, may have a central role in numerous mitochondria-related signaling pathways. Growth factors, inflammation-related factors, and reactive oxygen species can induce the production of ROS by mitochondria and the mechanisms described above, which in turn, induces subsequent steps in signaling pathways. These pathways induce responses which promote either cellular protection or cell death. Several cellular signaling pathways, which may be involved, include those activated by the vasoac-tive agents such as transforming growth factor (TGF)- beta ,90 epidermal growth factor (EGF),91 angiotensin II,92 and tumor necrosis factor (TNF)- alpha .19,93,94 These pathways induce the production of ROS, which acts in the transactivation of growth factor receptors. The transactivated receptors induce protection against oxidative stress.95 The downstream ROS-activated pathways may involve the MAPK proteins, which includes several...

Advances in Technologies for the Discovery and Characterization of Ion Channel Modulators Focus on Potassium Channels

At a basic research level, much more information is now available concerning the localization and function of many K+ channels. Information is also becoming available concerning the roles of p-subunits and other non-pore forming channel proteins. Currently, relatively little is publicly known about the effects of these accessory proteins and p-subunits on the pharmacology of particular K* channels. An exception is the Katp channels, K* channels which couple the metabolic state of the cell to its excitability via the suppression of channel opening by ATP. It is now

Measuring the Angiogenic Process

Tissues that are normally avascular, such as articular cartilage, have evolved the ability to survive with a very low metabolic rate. Cartilage depends on the blood flowing through adjacent structures for its nutritional support. Cartilage normally impedes its vascular invasion by its generation of antiangiogenic factors and a matrix environment that is hostile to vascular growth despite its normally low oxygen tensions 12-14 .

Can Stable Isotope Methods Provide New Insights Into Open Questions In Brain Metabolic Regulation And Neurological

These results indicate that a selective signaling mechanism was responsible for the differentiation-inducing metabolic effects of this hormone, being a peroxisome proliferator activated receptor-related (PPAR-related) nuclear signaling mechanism, which is a strong candidate for this action. This metabolic effect on glucose metabolic network induced by GLP-1 is totally different from the effect reported for the anticancer drug imatinib (Gleevec), which acts through a mechanism involving tyrosine kinase inhibition. In this case, the effect on glucose metabolism was on glycolysis whereas fatty acid metabolism was unaffected 71 . In light of these results it could be expected that SIDMAP characterization of GLP-1 effects on neuronal cells can aid in the identification of the signaling cascades and metabolic adaptations involved in the GLP-1 neuroprotective effect.

Transmethylation Reactions

A second cluster of methyl group acceptors are involved with energy metabolism (Fig. 1). Trimethyllysine is used to make carnitine which transports fatty acids into mitochondria for the production of ATP and acetyl CoA via beta oxidation. Creatine can accept phosphate from ATP when it is present in excess and provides a reservoir of high energy phosphate in muscle cells to maintain activity when energy demands exceed the amount of ATP that can be provided by the glucose in muscle. This maintains muscle activity as cellular metabolism adjusts to draw on glycogen for additional ATP and mobilize glucose from the liver. Epinephrine is a hormone that enables the cell to respond to stress by increasing glycogen utilization. In addition, it modulates the flow of fatty acids to and from cells (Montgomery et al., 1990).

Late Subarachnoid Hemorrhage Postclipping Vasospasm

Once the aneurysm has been secured by clipping or coiling, BP management is directed to optimizing CBF in the setting of vasospasm. In the presence of large artery vasospasm, autoregulation is impaired in the majority of patients (31,32). Yundt et al. (25) used positron-emission tomography to study CBV in response to global or regional reductions in CPP and found that in patients with aneurysmal SAH without vasospasm, CBF, cerebral metabolic rate of oxygen (CMRO2), and CBV were reduced with normal oxygen extraction fraction. In patients with arteriographic vasospasm, CBF and CBV were decreased, with minimal change in CMRO2 and with increased oxygen extraction fraction. This pattern is consistent with misery perfusion and suggests that parenchymal vessels distal to arteries with vasospasm are not capable of normal autoregulatory vasodilation (25). More practically, cerebral autoregulation can be assessed clinically with tests, such as the cuff deflation test (33) and transient...

FDGPET study of the bilateral subthalamic nucleus stimulation effects on the regional cerebral metabolism in advanced

The aim of the study was to evaluate the changes in regional cerebral metabolic rate of glucose (rCMRGlu) induced by bilateral subthalamic nucleurs (STN) stimulation in advanced Parkinson's disease (PD). Stimulation of the subthalamic nucleus (STN), especially bilateral stimulation, may improve all cardinal motor signs of the Parkinson's disease (PD), and has become an effective treatment option in advanced medically intractable PD patients. However, the underlying mechanisms are still poorly understood. To elucidate the functional anatomic substrate involved in the clinical effect of STN stimulation, we investigated the changes in regional cerebral metabolic rate of glucose (rCMRGlu) with 18F-fluoro-deoxyglucose (FDG) PET examinations in PD patients under clinically effective bilateral STN stimulation.

Adverse Effects of Systemic Glucocorticoid Therapy

As all nucleated cells in the body have a common GC receptor, all are potentially affected by GC therapy and thus susceptible to the development of untoward effects. These effects can occur immediately (i.e., metabolic effects) or can develop insidiously over several months to years (i.e., osteoporosis and cataracts). In addition, some adverse effects are limited to children (growth suppression) while others appear to require interaction with other drugs (nonsteroidal anti-inflammatory agents and peptic ulcer disease). Most adverse effects occur in a dose-dependent and duration-of-treatment manner, although this has not been uniformly noted. Table 3 lists many of the common adverse effects associated with chronic GC use. 6. Metabolic effects

Magnetic Resonance Spectroscopy

Since NAA is a marker of neuronal integrity, proton MRS provides a noninvasive means of quantifying neuronal loss or damage in vivo. Ch and other lipids are markers of altered neuronal membrane synthesis. Cr is a possible marker of defective energy metabolism. Typically, individual metabolic ratios obtained from peak areas of the spectrum are used as input to the statistical analysis. Because total Cr concentration is relatively resistant to change, Cr is often used as an internal standard to which the concentrations of other metabolites are normalized.

Host Cell Signaling Pathways Modulated In Response

Several lines of evidence suggest that A. actinomycetemcomitans infection and subsequent internalization is associated with activation ofhost cell signaling pathways. An active metabolic state and novel protein synthesis by both A. actinomycetemcomitans and the epithelial cell are required for invasion (Sreenivasan et al., 1993). In addition, entry is associated with an elevation of intracellular Ca2+ levels (Fives-Taylor et al., 1996), a process associated with

Multiple System Atrophy

18FDG PET measures regional cerebral glucose metabolism (rCMRGlc), reflecting primarily the function of nerve terminal synaptic vesicles. The metabolic rate in a given region, therefore, reflects the activity of afferent projections to and interneurons in a region rather than that of its efferent projections. It is currently not possible to decide whether increases in rCMRGlc detected with PET represent excitatory or inhibitory activity (5).

Chronic Systemic Inflammation

Adiponectin is one of the most abundant gene products in adipose tissue. In contrast with many of the other adipokines, the levels of which rise in obesity, plasma adiponectin levels are decreased in obesity, and levels increase following weight loss. The predominant metabolic effects of adiponectin are in the liver and in skeletal muscle and include increased glucose uptake, inhibition of gluconeogenesis, and increased fatty acid oxidation (37). Adiponectin also has anti-inflammatory properties. Pertaining to asthma, adiponectin inhibits proliferation and migration of cultured vascular smooth muscle cells induced by mitogens (38). It will be important to determine whether adiponectin has similar effects on airway smooth muscles (ASM), especially because both the AdipoR1 and AdipoR2 receptors are expressed in cultured human ASM cells. In this context, it should be noted that increased ASM mass is a feature of human asthma, and modeling studies have shown that increased muscle mass...

Exercise and weight loss

Pharmacotherapy to reduce body weight has also demonstrated a concurrent improvement in biochemical marking of cardiometabolic risk. Sibutramine, a weight loss agent that speeds satiety and increases basal metabolic rate by inhibiting uptake of the neu-rotransmitters noradrenaline and serotonin, was tested in a randomized placebo-controlled trial of 1002 obese patients over 44 weeks. Over this period, an improvement in lipid profile concurrent with sibutramine's weight loss effects was demonstrated (Figure 8.4)7.

Multiple Endocrine Neoplasia Type

The bilobate thyroid gland is located on the anterior surface of the trachea at the junction of the larynx and secretes a number of hormones essential for growth and development. Each lobe has many hollow spherical clusters (follicles) that are circumscribed by a single layer of cells. Parafollicular cells (C cells) occupy the spaces between follicles. The follicular cells synthesize and secrete several hormones, including thyroxine and triiodothyronine, which regulate metabolic rate and maintain the responsiveness of the cardiovascular system to nerve impulses. The parafollicular cells manufacture and release calcitonin, which regulates the concentration of calcium ions in the blood and other body fluids. Calcitonin decreases calcium ion concentrations, stimulates the production of bone, reduces the absorption of Ca2+ by the intestine, and stimulates the excretion of Ca2+ by the kidneys.

Female Sex Steroid Hormones

The association between obesity and asthma has been particularly strong in adult women and postpubertal girls, suggesting that female sex hormones may be contributing to the increased risk of asthma in obesity (5,28,41). Aromatase, the enzyme responsible for converting androgens to estrogens, is found in adipose tissue. Therefore, it is reasonable to hypothesize that obesity increases estrogen and is associated with early menarche (42), and the risk of developing asthma is particularly strong in girls with early menarche (25). The two different estrogen receptors (ERs), ERa and ER , are expressed in adipose tissue. In general, estrogen leads to an increase in basal metabolic rate as well as increased ambulatory activity and decreased activity of lipoprotein lipase in laboratory animals. Mice genetically deficient in ERa, as well as those lacking in aromatase, are obese however, oophorectomized ERa mice have much less fat than intact ERa mice, suggesting that the estrogen signaling...

Laboratory Findings in CR Nonhuman Primates

The characteristics of CR monkeys are summarized in Table 2 72 and Fig. 12A-C 73 . CR monkeys weigh less 74 and have less total and abdominal obesity than controls 75 . In addition, CR reduces body temperature and induces a transient reduction in metabolic rate 76 . Young male CR monkeys also exhibit delayed sexual and skeletal maturation 72, 74 . In addition, several lines of evidence suggest that CR improves the disease risk in rhesus monkeys 72 . CR monkeys have reduced blood glucose and insulin levels and improved insulin sensitivity 75 . CR also reduces blood pressure and lowers the serum triglyceride and cholesterol levels 77 . In

Streptozotocin Diabetic

Plasma glucose is markedly elevated and insulin action on skeletal muscle glucose transport activity is substantially reduced in the streptozotocin-diabetic rat, possibly as a result of reduced muscle GLUT4 protein levels (25). Acutely, lipoic acid can cause a marked lowering of plasma glucose in these diabetic animals (25). Chronically, a 10-day treatment period of these diabetic animals with lipoic acid also results in a significant lowering of plasma glucose levels and causes profound increases in both skeletal muscle GLUT4 protein levels and insulin-stimulated glucose transport activity (25). Collectively, these results provide evidence that the beneficial metabolic effects of lipoic acid in this severely hyperglycemic diabetic animal model may be associated with an improvement in the oxidant antioxidant status of the animal.

Predictors of Alzheimers disease

Heterozygotes, in the absence of cognitive alterations during two years. Reiman et al. (2001) estimated that 50-150 cognitively normal s4 heterozygotes would probably be a sufficient number of subjects for testing the outcome of a preventive AD therapy. Cerebral metabolic rates and genetic factors may provide a means for preclinical AD detection and importantly assist in the evaluation of the efficiency of preventive drug treatments in the future.

What Information Is Provided by Imaging

Metabolism is the second general area that can be assessed by noninvasive imaging. This category includes the evaluation of organ function. Examples include noninvasive imaging to assess heart perfusion under stress, gastric emptying, ventilation perfusion of the lung, renal and liver function, and blood flow to the brain. Metabolite imaging is a further example, since magnetic resonance spectroscopy (MRS) techniques now detect altered metabolites in disease processes. Another aspect of metabolism that can be assessed is energy utilization. The increased metabolic rate of cancerous tissue relative to normal tissue can be imaged using radioactive probes that accumulate in areas of higher metabolic activity. These studies are accomplished by administration of a radioactive drug the increased uptake of the radioactive drug in the cancerous lesion is imaged with gamma-ray detection instruments. In a similar manner, the glucose or fatty acid metabolism in myocardium can be evaluated...

Applications of Arrays to Neurological Disorders

Mutant HTT has been found to bind to other polyglutamine containing proteins, including transcription factors 79 , and forms aggregates, with sequestration of other cellular proteins. Thus, the proposed mechanism of action for mutant HTT is through aberrant protein-protein interactions, particularly involving transcriptional dysregulation, as demonstrated by the human and mouse microarray studies 71, 72, 74 . This subsequent disruption of transcription is thought to underlie the apparent involvement of oxidative stress, mitochondrial dysfunction, apoptosis, energy metabolism disturbances, and excitotoxicity in neuronal cell death. Amyloid precursor protein (APP) is alternatively spliced to express several isoforms 100 , of which APP695 is preferentially expressed in neuronal tissue 101 . APP is cleaved first by -secretase, and then by 7-secretase to form -amyloid-40 and -amyloid-42. It is these -amyloid isoforms that aggregate in AD. PSEN1 has been demonstrated to be involved in the...

Positron Emission Tomography

Positron-emission tomography (PET) measures thresholds for penumbra and infarction, quantifying cerebral metabolic rate of oxygen (CMRO2) and CBF. PET using novel radioligands to visualize postischemic neurons, has been tested in living primates, and can be used to evaluate neuronal cell loss in postischemic patients. 18F-labeled fluoromisonidazole PET imaging of brain accurately documents the temporal and spatial progression of the penumbra, whereas uC-flumazenil PET imaging distinguishes irreversibly damaged brain tissue from penumbral tissue early after acute ischemic stroke (AIS). Multimodality imaging makes use of a combination of imaging methods, such as micro-PET and MR.

Energy expenditure in cachexia

The underlying mechanism of increased resting metabolic rate may involve the increased activity of mitochondrial uncoupling proteins (UCPs). These proteins translocate protons across the inner mitochondrial membrane in a process not coupled to phos-phorylation of ADP, so that energy is lost as heat. The principal UCPs are UCP1, which is found only in brown adipose tissue, and UCP3, which is found in both brown adipose tissue and skeletal muscle. Brown adipose tissue was found in the periadrenal tissues in 80 of cancer patients, compared with 13 of age-matched controls (15). In mice bearing the cachexia-inducing MAC16 adenocarcinoma, UCP1 mRNA levels in brown adipose tissue and UCP3 mRNA levels in skeletal muscles were increased (16). UCP3 mRNA levels were significantly higher in skeletal muscles of cancer patients with weight loss than in those who had not lost weight and in patients without cancer (17). The increase in UCP expression in cancer patients would increase energy...

Pathological Anatomy of Glands What Happens When an Acorn Falls

The patient with hypothyroidism will tend to have an extremely low BMR (basal metabolic rate), an abnormally low body temperature, sleep frequently, and be mentally unresponsive and sluggish. The major cause of these symptoms, of course, is hyposecretion (or nearly absent) secretion of thyroxine into the bloodstream.

The Interactions Between Stress Lipid Profiles Cortisone HPA Axis and Inflammation Immunity

Abd el Mohsen et al. studied the changes in sex hormones and lipid profiles in adult female albino rats subjected to treatment with nicotine (N), immobilization stress (S), or a combination of the two (N + S). The researchers found that the changes in the lipid pattern could be attributed to the alterations occurring in corticosterol and female sex hormones, caused by N, S, or a combination of the two 107 . Further, Ricart-Jane et al. studied the metabolic response to acute and chronic stress following a model of immobilization in rats and evaluated the resulting circulating lipoprotein levels 108 . Both acute and chronic stress decreased the plasmatic triacylglycerol concentration, as reflected by the reduction in the number of VLDL particles. This may be caused by an increase in the metabolism of triacylglycerol, as suggested by the slightly higher amounts of circulating LDL 108 . Chronic stress, but not acute stress, significantly increased both the number and the estimated size of...

The Multiple Assay Tier Concept Of Viability Assays

The LDH assay, unlike its predecessors, continues today to be useful for measuring preservation-induced cytotoxicity. The concept behind this cytolysis assay is simply that if the cell membrane is compromised, then LDH will leak into the extracellular milieu where it can be measured. LDH has at least three advantages over alternative enzymes that could have been selected as candidate enzymes to be measured. First, LDH is a common enzyme in all cells and varies little with the metabolic state of the cell. Second, unlike many other cytoplasmic enzymes, LDH exists in a relatively high concentration and is stable. Third, LDH can be measured using a coupled enzymatic reaction. In this series LDH oxidizes lactate to pyruvate which, in turn, can be converted to form formazan via the trazolium salt, INT. While there are a number of variations on how this can be accomplished as revealed in several protocols, the end result is that the LDH is measured indirectly via a spectrophotometer that...

Interaction Between Venous Sinus Hypertension and CSF Pressure

Pressure increases the volume of the venous system proximal to the obstruction and reduces the compliance of the craniospinal axis. When venous sinus obstruction occurs, the high compliance cerebral venous system should increase in size and should be reflected in the observation of increased cerebral blood volume (CBV). In fact, Dandy 31 hypothesised that PTS was a result of increased CBV. Mathew et al. 113 calculated cerebral blood flow (CBF) and CBV before and after treatment using carotid injections of Xe133 and Tc99m. Both patients demonstrated increased CBV and this decreased towards normal when CSF pressure had been reduced. CBF was also slightly reduced in both cases prior to treatment and increased after CSF pressure reduction. Mathew et al. 113 stated that the cases provide evidence of venous engorgement. Raichle et al. 140 studied CBF, cerebral metabolic rate oxygen (CMRO2) and CBV using carotid injection of 15O-labelled water, oxyhaemoglobin and carboxyhaemoglobin. Compared...

Metabolic Pathway Activity

Intracellular Metabolism

Whatever the source of the stimulus, genetic or environmental, natural or artificial, one or more intracellular processes are required to produce a developmental response. As illustrated in Figure 9.1, the pathway between the stimulus to a cell and its response can include any or all of transcription, translation, post-transitional modification, and export, activation, and function of an enzyme or other protein. Directly or indirectly, all of these processes rely on energy metabolism to provide cellular energy in the form of ATP, reducing equivalents in the form of NADH and NADPH, and precursors for the synthesis of macromolecules. The energy metabolism of the early mammalian embryo can be studied indirectly by culture in varying concentrations and combinations of energy substrates. A more direct approach is to measure the disappearance of substrates from, and the release of metabolic products into, the medium. The breakdown or incorporation of radiolabeled substrates can be used to...

DNA Microarray Analysis of Bacterial Pathogens

Brospinal fluid (CSF), and bacteria attached to a pharyngeal epithelial cell (ECC) line in vitro. Gene expression levels at these three sites were compared with levels when S. pneumoniae was grown in semisynthetic casein liquid medium. Such in vivo studies are limited by the difficulties of obtaining sufficient quantities of pure and relatively intact bacterial RNA from infected tissues. Interestingly, the majority of the genes (92 in the blood, 85 in CSF, and 90 after ECC) were expressed in a similar fashion as growth in culture medium. However, distinct patterns of gene expression in each anatomical site can be identified. Amazingly, only eight genes showed similar alterations in gene expression during bacterial growth in blood, in CSF, or during ECC (25). Two of the eight genes encode pspA (26) and prtA (27) previously characterized as virulence factors, three involved in manganese acquisition and transport (psa operon), two in energy metabolism and one transporter. Orihuela et al....

Application of Microarrays to Neuropsychiatry Disorders

Subsequent studies demonstrated the involvement of dysfunctional mito-chondrial energy metabolism in SZ, with decreases in the mitochondrial malate shuttle system and the tricarboxylic acid (TCA) cycle 145 . In this study, comparison of these gene expression changes with those occurring in haloperidol treated monkeys identified malate dehydrogenase as increased following treatment, suggesting a direct therapeutic effect of the drug on mitochondrial metabolism. Mitochondrial involvement was further analyzed by Iwamoto, whose study included both Sz and BD cases 141 . Focusing on the expression of 676 mitochondrial-related genes, global downregulation was seen in genes, including those involved in mitochondrial cell respiration, the TCA cycle, and mitochondrial transcription and translation. A previous study demonstrated that decreases in energy metabolism genes correlated with brain tissue of low pH (correlating with prolonged agonal state), rather than with the psychiatric disorders BD...

Robert H Mak and Wai W Cheung

Cachexia is brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. This combination is found in a number of disorders including cancer, chronic kidney disease (CKD), AIDS, cystic fibrosis, chronic heart failure, rheumatoid arthritis, and Alzheimer's disease. Cachexia has a stronger correlation with survival than any other current measure of diseases such as AIDS, cancer, and CKD. The underlying mechanism of increased resting metabolic rate may involve the increased activity of mitochondrial uncoupling proteins. Chronic overproduction of cytokines, such as interleukin (IL)-ip, IL-6, and tumor necrosis factor-a, may lead to cachexia in various chronic illness models, through the nuclear factor-kB and ATP-ubiquitin-dependent proteolytic pathways. Inhibition of these cytokines in experimental models ameliorated cachexia. Cytokines may also act on the central nervous system to alter the release and function of...

Disease Biosimulation

The biosimulation of Topp et al. was the first to address the issue of longitudinal progression of type 2 diabetes. While their analysis is intriguing, the biosimulation did not include the interplay between glucose and fat metabolism and the overall state of energy balance, factors believed to play a significant role in the development of the disease. Since their model was aimed at long time scales and incorporated aggregate representations of physiological processes, it was not applicable to the simulation of short-term experimental protocols that are used to assess various diabetic defects. Hall et al. constructed a comprehensive and quantitative biosimulation of the major physiologic systems involved in human metabolism and the defects responsible for type 2 diabetes (47). The authors first simulated the normal processes of digestion, absorption, storage, and oxidation of carbohydrate, fat, and protein, as well as the hormonal regulation of these processes. To simulate type 2...

Medical Measures to Control Cerebral Edema

Barbiturates, including pentobarbital, have been evaluated in clinical studies of a variety of cerebral insults with ICP elevation, including traumatic brain injury, cerebral aneurysm rupture, and ischemic stroke. They are effective in reducing ICP by lowering the cerebral metabolic rate,66 and may have neuroprotective qualities by being free radical scavengers.67 Their use, however, is complicated by the side effects of hypotension and sedation, as well as an increased infection risk with prolonged use. The ability to follow the neurological exam is lost, and this is a vital tool in monitoring a patient's clinical status following a stroke. Hypotension may compound ischemia by reducing the CPP, thereby collapsing any collateral vessels that may have been feeding ischemic but not yet infarcted tissue, or by causing global ischemia in a patient with high ICP who is dependent upon a higher MAP to maintain their CPP. Thus, although there have been no randomized studies of barbiturates in...

P Michael Conn Series Editor

Weetman, 2008 Energy Metabolism and Obesity Research and Clinical Applications, edited by Patricia A. Donohoue, 2008 Polycystic Ovary Syndrome Current Controversies, from the Ovary to the Pancreas, edited by Andrea Dunaif, Jeffrey R. Chang, Stephen Franks, and Richard S. Legro, 2008 The Metabolic Syndrome Epidemiology, Clinical Treatment, and Underlying Mechanisms, edited by Barbara C. Hansen and George

Leptin and the Anorexia of the Elderly

Several cross-sectional and longitudinal studies have described a decline in food intake with aging in healthy elderly subjects 80-83 . This physiological decrease in food intake with age was defined as anorexia 80-83 . In the NHANES III an average decline in energy intake of about 1000 kcal day (men) and 500 kcal day (women) between the age of 20 and 75 years was described 84 . Aging was also associated with a decline in total energy expenditure that is accounted not only by a decline in physical activity but also by a decrease in resting metabolic rate 83 . When the decrease in energy intake is greater than the decrease in energy expenditure, involuntary weight loss may occur. Anorexia in the elderly and involuntary weight loss has been related to adverse outcomes, such as increased risk of sarcopenia, frailty, functional impairment, and mortality 80-83 . Anorexia has multiple causes including alterations in taste, flavor and palatability of food, increased gastrointestinal...

Intracellular pH In Tumors

There have been attempts to determined the intracellular pH (pHj) with glass micro-electrodes with a diameter as small as 1 m, but the results of these studies were inconclusive. In the late 1970s, magnetic resonance spectroscopy (MRS) was introduced as a means to determine pH in tumors in situ, or in normal tissues in animals and humans. Since then, there has been a marked improvement in the MRS technique, and it is now widely used to determine the pHj, as well as the metabolic state of tumors. The use of MRS for assessing tumor pH is attractive, because it is noninvasive, can be used for deep-seated tumors, and it may provide information about spatial pH distribution.

George N Chaldakov Anton B Tonchev Nese Tuncel Pepa Atanassova and Luigi Aloe

Recently, the endocrine activity of adipose tissue cells has been intensively studied. In effect, a wide range of exported secretory proteins, dubbed adipokines, have been identified as constituents of the adipose proteome (adipokinome). Besides their effects on glucose and energy metabolism, adipokines are potent modulators of inflammation. This chapter provides a state-of-the-science review of adipokine-mediated paracrine signaling that may be implicated in the pathogenesis of inflammation-related diseases such as atherosclerosis, thyroid-associated ophthalmopathy, and breast cancer. We also point out a possible contribution of adipose tissue-associated mast cell secretory activity to the development of these diseases. Finally, we provide arguments for yin-yang (protective vs pathogenic) roles of adipokines in inflammation. This hypothesis may provide further novel drug targets for the development of adipopharmacology of inflammatory diseases.

Review shivering and nonshivering thermogenesis

Shivering is the spontaneous, asynchronous, random contraction of skeletal muscles in an effort to increase the basal metabolic rate. Shivering is modulated through the hypothalamus and can increase the body's production of heat by up to 300 in young, muscular individuals. It increases oxygen consumption and carbon dioxide production. This effect may be undesirable in the patient with coronary artery disease or pulmonary insufficiency.

Adiponectin as Insulin Sensitizing Hormone

The chronic effects of adiponectin on insulin sensitivity and energy metabolism were also investigated in adiponectin transgenic mice or adiponectin knockout (KO) mice. Scherer's group generated a transgenic mouse model with approximately threefold elevation of native adiponectin oligomers (19). The authors demonstrated that hyper-adiponectinemia significantly increased lipid clearance and lipoprotein lipase activity, and enhanced insulin-mediated suppression of hepatic glucose production, thereby improving insulin sensitivity. Kadowaki's group showed that transgenic overexpression of globular adiponectin in the genetic background of ob ob obese mice led to partial amelioration of insulin resistance, hyperinsulinemia, and hyperglycemia (20). Conflicting results have been obtained from adiponectin KO mice studies. Yamauchi et al. found no impact of adiponectin depletion on insulin sensitivity under either normal chow or after 7 mo of feeding with a high-fat diet (21). In contrast,...

Role Of Cerebral Blood Flow Changes

SPECT was also used to study the flow in the perihematoma region and showed decreased CBF that peaked at 24 hr and normalized as edema formed during the first 3 days after ICH the extent of edema correlated with the size of the initial deficit (51), suggesting that hypo-perfusion was present and was highest in the early hours following ICH (52,53). PET studies also reported perihematomal CBF reductions, mainly diffuse and in the ipsilateral hemisphere, without evidence of ischemia (54-56). Although evidence of hypoperfusion has been shown in the perihematoma area or in the ipsilateral hemisphere, it seems to be self-limited and without ischemia (50,52,57,58). The mechanism for transient hypoperfusion may be related to a hydrostatic mechanism with normalization of perfusion as elevated tissue pressure normalizes (49 ), or it may be due to a transient reduction in metabolic rate of oxygen, suggesting that flow changes may represent hypoactive tissue rather than ischemia (59 ). Upon...

Radiographic Indicators Of Progressing Stroke

Anatomia Cranio

MRI includes a variety of techniques that can be employed to predict outcome of progressing stroke and are described in detail in Chapter 18. Diffusion-weighted imaging (DWI) permits the in vivo measurement of the translational mobility of water in tissue and was first reported as a marker of acute ischemic brain injury in 1990 (13,14). The image intensity on DWI is dependent on the apparent diffusion coefficient (ADC), measuring the mobility of water molecules in tissue and the transverse relaxation time (T2) that might represent prior distortion of tissue architecture (T2 shine-through). In ischemic brain tissue, ADC values decline, leading to a region of hyperintensity on a gray-scale derived image. The ADC probably reflects the accumulation of intracellular water (cytotoxic edema) caused by disruption of energy metabolism and loss of ion homeostasis (15). These ADC changes do not occur uniformly throughout the ischemic lesion. Serial studies performed in experimental stroke models...

Peri Infarct Depolarisations PIDS

Fall in net ATP yield per mole glucose utilised from 38 to 2 moles. Glucose utilisation increases to compensate 101 this is possible despite presence of ischaemia, due to the remarkable effectiveness of the capillary glucose uptake transport mechanism. This concept is based on several lines of evidence. Hansen showed that following cardiac arrest in rats, delay before terminal ischaemic depolarisation was proportional to plasma glucose, indicating an inverse relationship between depolarisation rate (the dependent variable) and glucose availability in the brain 23 . In 1986, Nedergaard and Astrup showed in rats (MCAO) that hyperglycaemia reduced the frequency of PIDs (although a plasma level in excess of 30 mmol L was needed to achieve this) 102 . They also showed an increase in phosphorylation of 14C 2-deoxyglucose (an index of metabolic rate) that was related to frequency of PIDs, and predicted that with ischaemia accompanied by PIDs the brain free glucose pool would tend towards...

Role of il6 in insulin resistance

IL-6 is released from contracting skeletal muscle, causing the serum concentration to increase as much as 100-fold (54). IL-6 increases hepatic glucose production when administered to human subjects, and there is evidence to suggest that the release of IL-6 from exercising muscle mediates the early phase on exercise-induced hepatic glucose output. The fact that IL-6 opposes insulin action in the liver has led to speculation that its oversecretion may play a role in insulin resistance. In the liver, IL-6 causes release of NEFAs and is the primary stimulator of for production of acute phase proteins (55). Administration of IL-6 in healthy volunteers induced dose-dependent increases in blood glucose (56), probably by inducing resistance to insulin action. In vitro, IL-6 has been shown to impair insulin signaling by several distinct molecular mechanisms (57). Weight loss significantly decreases IL-6 levels in both adipose tissue and serum (58). Genetic studies have also demonstrated a...

Rat 2Vessel Occlusion

It is relatively easy to achieve reproducible insult severity across rat strains using the 2-VO approach, as the depth of ischemia is dependent on successful blood pressure reduction rather than surgical attenuation of collateral perfusion. Effective ischemia in some animals may require more severe hypotension than initially reported, with 30 mmHg identified as optimal in 2 independent evaluations (83,84). Increasing the halothane level has been suggested by several investigators as an alternative to hypovolemic hypotension (85-87), although this clearly also impacts metabolic rate (88-90). Another noninvasive approach to blood pressure reduction has been proposed, in which external suction is applied to pool blood in the lower body (91), which also avoids the need for heparin administration.

Metabolic Modulation

The modes of action of most prophylactic antianginal agents involve hemodynamic changes, such as a reduction in systemic vascular resistance, coronary vasodilatation, or negative inotropism, thus improving the imbalance in myocardial oxygen supply and demand. Recently it has become apparent that certain antianginal treatments exert a primarily metabolic action and have little or no effect on coronary hemodynamics. These drugs have considerable potential as adjunctive therapy for angina, particularly in patients refractory to standard therapies, and may be a primary therapeutic option in certain circumstances. They generally do not adversely affect blood pressure, pulse rate, or left ventricular systolic function, offering a significant advantage in patients in whom conventional agents may induce symptomatic hypotension, inappropriate bradycardia, or worsening heart failure. The purpose of this review is to draw attention to some of these metabolic agents, while at the same time...

Cerebral Blood Flow

Many investigators have studied the changes that occur in the cerebral hemodynamics during vasospasm, but results are conflicting, probably because of heterogeneous study populations, different treatments, and nonstandardized measurement techniques. A number of positron emission tomography studies have indicated that soon after SAH, prior to developing delayed cerebral metabolic rate of oxygen, and cerebral blood flow are decreased and cerebral blood volume (CBV) is increased (131-133). In patients who do develop arteriographic vasospasm, though, regional CBV is reduced in spite of an increase in regional oxygen extraction fraction, which is usually associated with compensatory distal arteriolar vasodilation and increases in regional CBV (134). A potential explanation for this finding could be spastic parenchymal vessels losing the ability to vasodilate in response to tissue hypoxia. This adds further evidence to support the theory of microvascular involvement in cerebral vasospasm.

Summary

Cortical spreading depression is a non-physiological global depolarisation of neurones and astrocytes that can be initiated with varying degrees of difficulty in the normally perfused cerebral cortex in the experimental laboratory. Induction is typically with electrical stimulation, needling of the cerebral cortex, or superfusion of isotonic or more concentrated potassium chloride solution. The phenomenon propagates across the cerebral cortex at a rate of 2-5 mm per minute, and is accompanied by marked but transient increases in cerebral blood flow, in local tissue oxygen tension, and most probably in metabolic rate. Magistretti PJ, Sorg O, Yu N, Martin JL, Pellerin L (1993) Neurotrans-mitters regulate energy metabolism in astrocytes implications for the metabolic trafficking between neural cells. Dev Neurosci 15 306-312 Koizumi J (1974) Glycogen in the central nervous system. Prog Histochem Cytochem 6 1-37 131. Nilsson B, Ponten U (1977) Experimental head injury in the rat. Part 2...

Other Nucleotides

Cyclic adenosine monophosphate (cAMP) (see fig. 2.29b) is a nucleotide formed by the removal of both the second and third phosphate groups from ATP. In some cases, when a hormone or other chemical signal (first messenger) binds to a cell surface, it triggers an internal reaction that converts ATP to cAMP. The cAMP then acts as a second messenger to activate metabolic effects within the cell.

Hunger

We need to eat to live and for most people the feeling of hunger is a regular and very familiar occurrence. But the mechanisms that control hunger are a very complex mixture of the physiological and the psychological. There is the intake of necessary energy in the form of calories and there are fat deposits and general metabolic rate. There are also external, psychologically mediated factors such as the sight or the smell of a favourite food. This might well tempt us to eat even though we have recently eaten.

Mechanisms

Alpha-2 receptors suppress central sympathetic output, increase central vagal tone, facilitate platelet aggregation, and inhibit the release of norepinephrine and acetylcholine from nerve endings. These receptors also regulate metabolic effects through suppression of insulin secretion and inhibition of lipolysis in adipose cells. (ii) Disopyramide blocks sodium channels, prolongs repolarization and has negative inotropic effect. Concomitant disopyramide and ethanol administration had no effect on the total body clearance or halflife of disopyramide in a study ofhealthy volunteers 63 , The renal clearance of disopyramide significantly increased, possibly from ethanol-induced diuresis 63 , Chronic ethanol consumption may increase metabolism of disopyramide through enzyme induction.

Hhhhbbhhhh

ROS may interact with diminished neurotropic support, impaired energy metabolism, and ischemia in experimental DPN (neurotrophism). Oxidative stress induced by diabetes (45) would be particularly injurious to the PNS, which is particularly vulnerable to oxidative stress (46). Impaired neurotrophic support in diabetes (47) may be mediated by ROS (48). ROS contribute to inschemia-reperfusion injury (49). ROS-induced apoptosis may share similar cell death pathways with neurotrophic withdrawal (50,51), and neurotrophic may protect against ROS damage by inducing antioxidative defense mechanisms (52-54). Recent data suggest that antioxidant therapy may ameliorate some aspects of reduced neurotrophic support in experimental DPN (55).

The RNA world

The longer the RNA, the more fragile it is but a short RNA is relatively useless both as a repository of information and as an enzyme. Perhaps several short RNA molecules working together could have formed a replicating system, but assembly of a number of short RNAs in the same confined space would have been improbable. Third, RNA seems unable to catalyse many of the reactions crucial for energy metabolism. Fourth, as in the case of amino acid selection for protein manufacture, it is not clear how nucleotides with the correct handedness were selected for polymerisation. Fifth, there are major differences in the RNA replication mechanisms of archaea, bacteria and eukaryotes, suggesting that these mechanisms had no common ancestry. This throws doubt on the idea that all major branches of life arose from an RNA world. Finally, it is not clear how the proto-organisms of the RNA world were supposed to manage without membranes. There is no indication of internal state,...

Their Hormones

Along with the pancreas, perhaps the most-recognized endocrine gland is the thyroid (THIGH-royd) gland. The thyroid gland literally ''resembles'' (-oid) two large, oblong ''shields'' (thyr) -as from a pair of African warriors pressing hands under the chin (Figure 10.3). The thyroid gland busily extracts the element iodine from the bloodstream, then incorporates it into its most important hormone, thyroxine (thigh-RAHKS-in). Thyroxine stimulates mitosis (cell division) and protein synthesis, thereby promoting body growth and tissue repair. It also tends to raise the BMR or Basal (BAY-sal) Metabolic Rate. The BMR (Basal Metabolic Rate) is the rate at which the body cells operate when they are under ''resting'' or ''basal'' conditions. In general, this means the times when we are neither exercising nor digesting any food. Thus, because it speeds up the metabolism, thyroxine tends to raise body temperature, as well. The hypothalamus and pituitary body....

Excitotoxicity

To understand why some neurons die while nearby neurons are spared in a nonrandom manner, much research has focused on the pattern of excitatory and inhibitory receptors on particular neuronal populations. Anoxic depolarization results in the release of excitatory and inhibitory neu-rotransmitters. Impaired reuptake by energy-dependent mechanisms results in large increases in intrasynaptic and extrasynaptic concentrations of neurotransmitters. In the case of the primary excitatory neurotransmitter glutamate, reuptake largely depends on transporters in astrocytes and neurons that are driven by the high extracellular-to-intracellular Na+ gradient that is normally maintained by Na,K-ATPase. This gradient is lost during anoxic depolarization but can gradually recover during reperfusion (3). After some delay in the restoration of ATP production during reperfusion, extrasynaptic glutamate concentration measured by microdialysis is reduced (36). However, intrasynaptic glutamate concentration...

Calpain

Calpain is a Ca2+-dependent cysteine protease with multiple substrates, including caspases and the cytoskeletal protein fodrin. Increased calpain activity has been observed during the early hours of reperfusion after global ischemia in selectively vulnerable regions (58-60). A delayed increase in activity can also occur in hippocampus (59,61). In dendrites, calpain is associated with NMDA receptors whose activity can normally modulate cytoskeletal reorganization during synaptic plasticity (62). After ischemia, degradation of fodrin is ameliorated by NMDA receptor antagonists and calpain inhibition (58). Abnormalities in dendritic morphology and synaptic organization during reperfusion (63) might contribute to abnormal Ca2+ signaling and electrophysiologic function, at least temporarily, despite overall recovery of cellular energy metabolism. Calpain may play a role in (i) initially downregulating caspase-3 activity, (ii) later augmenting apoptotic signaling through actions on Bid and...

Respon

However, there is growing evidence that suggests that the role of TNF in MOF is not straightforward. In particular the reported levels of TNF and efficacy of antibodies against TNF are different in different models of lethal sepsis (B4). Systemic Escherichia coli infection induces high levels of circulating TNF, and antibodies to TNF inhibit the lethal consequences of infection. On the other hand, in compartmentalized infection, rat cecal ligation-induced peritonitis, no circulating or peritoneal TNF was detected and antibodies to TNF failed to inhibit lethal outcome. In another model, which used fecal material to infect the peritoneal cavity, circulating TNF levels were elevated but again antibodies failed to protect against lethal outcome (B4). Circulating TNF and IL-1 have been reliably detected only in the serum or plasma of individuals with severe acute sepsis. This may, however, be due to the presence of serum binding proteins masking lower levels of this...

Chemistry

Synthetic GCs are cortisone-based molecules that have undergone structural modifications designed to enhance their potencies and prolong their durations of action. Antiinflammatory GCs have a 17-hydroxyl group and methyl groups at carbons 18 and 19. Further modifications to the basic steroid structure have increased the anti-inflammatory while decreasing mineralocorticoid effects however, it has not been possible to separate the unwanted metabolic effects while retaining the desired anti-inflammatory properties of the synthetic GCs that are systemically administered.

Genetics

The possibility that genes known to be important in asthma may also be important in obesity is among the most interesting areas of research in this field. Because genes tend to be pleiotropic, it is biologically plausible that genes important in one complex trait could be important in another. Linkage analysis has identified several linkage peaks with chromosomal regions that are shared for obesity and asthma phenotypes (28). Chromosomal areas of 5q, 6p, 11q, and 12q all contain regions with loci common to both complex phenotypes. Chromosome 5q contains the -adrenergic receptor gene ADRB2 and the glucocorticoid receptor gene NR3C1. Furthermore, ADRB2 encodes a receptor that influences sympathetic nervous system activity, which is important in controlling both airway tone and metabolic rate. The glucocorticoid receptor is involved in modulating inflammation important in both diseases. Chromosome 6p, which contains the HLA gene cluster and TNF, influences the immune and inflammatory...

Conclusions

Energy metabolism and aging A lifelong study of Fischer 344 rats. Am J Physiol 1992 263 E448-E452. 35 McCarter RJ, McGee JR. Transient reduction of metabolic rate by food restriction. Am J Physiol 1989 257 E175-E179. 42 Duffy PH, Feuers RJ, Leakey JA, Nakamura K, Turturro A, Hart RW. Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat. Mech Ageing Dev 1989 48 117-133. 44 Higami Y, Pugh TD, Page GP, Allison DB, Prolla TA, Weindruch R. Adipose tissue energy metabolism Altered gene expression profile of mice subjected to long-term caloric restriction. FASE J 2004 18 415-417. 85 Overton JM, William TD, Chambers JB, Rashotte ME. Central leptin infusion attenuates the cardiovascular and metabolic effects of fasting in rats. Hypertension 2001 37 663-669.

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