How To Raise Metabolism

Old School Body Hacks

Created by a famous celebrity trainer and nutritionist, this program offers a great deal of information so you can get over the bad symptoms that come with age. John Rowley is known for using old-school techniques which employ the basic strategies that celebrities and bodybuilders to look younger by the day. His methods and secrets that have helped him and other clients who struggle with age have transformed the way that John and many people's looks and ways they felt. Their metabolism went up and their health was back to the way they were when they were younger just by using his 5 principles and 37 old school hacks to shed off layers of fat and gain alean muscular sculpted body. This program works for people who have struggled with diets and different programs that have done nothing to them, but this set of workout techniques have completely changed the way their body clock functions since it employs scientifically backed up techniques that study the way the body functions. The product includes a set of E-books that can be downloaded easily and instantly once you make a successful purchase and it will help you achieve the body you always dreamt of and improve your health. Read more here...

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Caffeine and cerebral energy metabolism

The effects of methylxanthines on cerebral metabolic rates for glucose (LCM-Rglcs) described in the present review have been explored by means of the quantitative autoradiographic 14C 2-deoxyglucose method of Sokoloff et al.,12 which allows the simultaneous visualization of functional activity in discrete areas of the brain of conscious animals. This technique permits the identification of neuronal pathways affected by a pharmacological agent and is very useful for relating behavioral effects to the central action of a drug.

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....

Antiepileptic Drugs Vagus Nerve Stimulation And Brain Energy Metabolism

Reduced cerebral glucose metabolism occurs not only with CR but also with the use of several common antiepileptic drugs, e.g., phenobarbital, primidone, phenytoin, carbamazepine, vigabatrin, and valproate (108-112). The combination of carba-mazepine and valproate causes a reduction in the cerebral metabolic rate of glucose even greater than when that recorded either drug is used alone (109). Decreased nutri ent intake and body weight loss are associated with the antiepileptic action of zon-isamide and topiramate (113-115), suggesting a mechanism that involves alterations in brain energy metabolism. The inclusion of active body weight controls in clinical trials with these drugs could test this hypothesis. Furosemide and similar diuretics that have anticonvulsant potential inhibit glucose uptake and glycolysis and thus may also alter energy homeostasis (116,117). Vagus nerve stimulation (VNS) is a novel therapy that reduces seizure frequency in patients with refractory seizures (9)....

NAA in Neuronal Energy Metabolism

The first report that NAA might be involved in brain metabolism was by Buniatian and coworkers in 1965.18 The idea that NAA is involved in energy metabolism in the nervous system is based on a number of facts, including that 1) NAA is synthesized by aspartate N-acetyltransferase in neuronal mitochondria19,20, 2) traumatic brain injury causes rapid and partially reversible decreases in NAA concentrations,21-23 3) inhibition of mitochondrial respiration results in the simultaneous decrease of NAA production, ATP production and oxygen consumption in isolated brain mitochondria,24 and 4) NAA levels in the striatum of rats and primates were significantly decreased after the animals were treated with a mitochondrial toxin (3-ntiroproprionate).25 Recently, Madhavarao and coworkers proposed a model whereby NAA is associated with neuronal energy production (see Namboodiri et al. and Madhavarao and Namboodiri, this volume). In this model, aspartate aminotransferase, the enzyme that synthesizes...

Energy Metabolism

The advent of new imaging technologies has allowed the analysis of brain energy metabolism. A number of studies have now documented that glucose PPARy plays critical roles in energy metabolism due to its direct effects on mitochondrial function and ultimately ATP production. Mitochondria may be key players in cerebral hypometabolism observed in AD, as this organelle plays critical roles in both energy metabolism as well as neuronal apoptosis. In the diseased brain, the numbers of neuronal mitochondria are greatly reduced and those remaining have very distinct morphological changes in their size and the number or cristae they contain. These morphological changes are seen mainly in neurons that have lost their dendritic arborization 99 . Therefore, therapeutic strategies that aim at maintaining mitochondrial integrity are of importance.

What Are the Key Strategies in Obtaining Optimal Results When Instituting the KD

KD initation by fasting What is the advantage of initiating the KD with a brief fasting period What does that fasting period achieve other than to increase the rate of ketosis And, to challenge the existing lore, does the KD really establish a starvation -like metabolic state

Functions Of Copper And Regulation Of Copper Metabolism

Most of the copper transporters and chaperones already described, that have been cloned and investigated so far, are listed in Table 3, along with a brief summary of what occurs when they are defective or knocked out (if this is known). For most of these, more detailed descriptions of their functions have already been provided. The fact that copper is an essential element, however, is not because of its carriers and transporters but because of specific copper-dependent enzymes (and perhaps also other factors) that are crucial for life and for human metabolism and function. A list of the known copper-containing enzymes proteins in humans and mammals is given in Table 4, along with brief descriptions of their functions. This is in addition to the list of plasma copper constituents given in Table 2. Ceruloplasmin is included in Tables 2-4, because it plays a variety of roles in addition to that of delivering copper via the blood. Further descriptions of the most interesting aspects of...

NAA as Acetate Carrier for Myelin Lipid Synthesis

It is important to state that the acetate-lipid synthesis hypothesis does not address the presence of the extraordinarily high levels of NAA in adult neurons. A theory that pertains directly to the high concentrations of NAA in the neurons of adult animals posits that NAA is intimately involved in neuronal energy metabolism.

Does PET Hypoxia Imaging Detect Hypoxia and Regions of Radiation Resistance in Human Cancers

Regardless of the correlation between PET-based hypoxia imaging and other approaches for hypoxia detection, the most important question is whether hypoxia imaging can detect regions of radiation resistance in human cancers for radiation targeting or treatment modification. Because it is impossible, in most situations, to determine the exact focus of recurrence within the tumor at the time of relapse, most studies use local relapse, locoregional relapse, or progression-free survival as surrogate endpoints. A recent critical review of FMISO-PET provides a useful clinical summary of the prognostic role of this tracer in more than 300 patients imaged throughout the world 26 . The largest published study to date, correlating treatment outcomes with hypoxia imaging, is that of Rajendran et al. 27 , who performed pretreatment FMISO-PET in 73 HNC patients treated in a nonuniform manner. The investigators found that the FMISO tumor-to-blood ratio (T BR) was an independent prognostic factor for...

Centralautonomic Connections

There probably are no purely autonomic or somatic centers of integration extensive overlap occurs somatic responses always are accompanied by visceral responses, and vice versa. Auto-nomic reflexes can be elicited at the level of the spinal cord and are manifested by sweating, blood pressure alterations, vasomotor responses to temperature changes, and reflex emptying of the urinary bladder, rectum, and seminal vesicles. The hypothalamus and the STN are principal loci of integration of ANS functions, including regulation of body temperature, water balance, carbohydrate and fat metabolism, blood pressure, emotions, sleep, respiration, and reproduction. Signals are received through ascending spinobulbar pathways, the limbic system, neostriatum, cortex, and to a lesser extent other higher brain centers.

On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

It is well known that genetic and environmental factors interact to favor weight gain, changes which disrupt metabolism. The body fat stores are normally maintained within a narrow range by energy homeostasis. This process is controlled by the brain regions, such as hypothalamus, that control appetite and energy balance in addition to peripheral signaling systems that monitor energy stores. Glucose, free fatty acids, insulin and leptin are examples of the signaling molecules that activate the hypothalamus thereby controlling the metabolic rate and the desire to eat. Obesity does not simply arise from the passive accumulation of excess body weight but is an active adaptation to the elevation of body fat. Clearly, the genetic background of the individual contributes to the variation in the response to elevated body fat which helps to explain why some individuals are protected against weight gain while the majority is not despite the fact that they live in the same environment and eat...

Other Data Relevant To An Evaluation Of Carcinogenicity And Its Mechanisms

Tests of genetic and related effects are described in view of the relevance of gene mutation and chromosomal damage to carcinogenesis (Vainio et al., 1992 McGregor et al., 1999). The adequacy of the reporting of sample characterization is considered and, where necessary, commented upon with regard to complex mixtures, such comments are similar to those described for animal carcinogenicity tests on p. 18. The available data are interpreted critically by phylogenetic group according to the end-points detected, which may include DNA damage, gene mutation, sister chromatid exchange, micro-nucleus formation, chromosomal aberrations, aneuploidy and cell transformation. The concentrations employed are given, and mention is made of whether use of an exogenous metabolic system in vitro affected the test result. These data are given as listings of test systems, data and references. The data on genetic and related effects presented in the Monographs are also available in the form of genetic...

Patterns of Cerebral Activity Associated with Syndromes

The observation that each of the three syndromes is associated with a specific pattern of cognitive impairment suggests that each might be associated with a specific pattern of abnormal cerebral activity. This hypothesis might be tested employing a functional imaging technique such as positron emission tomography (PET), which provides images of regional cerebral blood flow (rCBF) or regional glucose metabolic rate (rCMRglu). Since rCBF and rCMRglu are tightly coupled to the level of local neuronal activity, these techniques provide images that reflect regional neural activity.

Superoxide Radicals O2

Superoxide radicals and hydrogen peroxide are formed, for instance, in mitochondria as part of energy metabolism (Equation 4.5, see also Chapter 3). Here, the reduction of O2 to H2O formally requires four electrons. Complete reduction of O2 is not always achieved, though, and the remainder is reduced to O2 - and H2O2 (see Chapters 2 and 3).

Prediet Referral And Evaluation

Because most of our patients are referred from other centers, one of our major tasks is to ensure the validity of their histories and the completeness of prior evaluations. The laboratory studies we either obtain, or ensure that they were done accurately elsewhere, are listed in Table 1. The condition of children with underlying metabolic disorders or certain mitochondrial syndromes may be worsened by the KD (5). Children with pyru-vate carboxylase deficiency, fatty acid oxidation defects, and other syndromes in which energy metabolism is compromised could experience increased seizures on the diet and or metabolic decompensation, especially during periods of illness. For that reason, we ensure that all children have had a urine and plasma metabolic screen and a serum lactate prior to admission. Children become acidotic on the diet, and baseline acidosis may indicate a metabolic problem that might worsen with the diet. We have not seen the bruising on the ketogenic diet reported by...

Immune Activation In Major Depression

The status of the immune system in major depression has been extensively studied over the last ten years and there is now some evidence that the acute episode of this illness may be accompanied by immune activation acute phase response (Maes., 1993 Sluzewska et al., 1996b). The acute phase response (apr) is a response of the organism to disturbances of its homeostasis due to factors such as, infection, tissue injury, neoplastic growth or immunological disorders (Heinrich et al., 1990). Within this systemic reaction, that involves the endocrine, immunologic and metabolic system (Kushner and Mackiewicz., 1993), there are also behavioural changes, which are expressed as sickness behaviour, characterised by psychomotor retardation, sleep disturbances, anorexia, anergy, and lethargy (Kent et al., 1992).

Structure And Morphology

As more examples of mitochondria in different tissues were examined, distinguishing features soon became apparent. The matrix was not homogeneous and exhibited a fine granularity, and frequently there were distinct crystalline inclusions or small particles of high electron density. Their number could in some instances be shown to depend on the metabolic state of the tissue observed. The high electron density may be the result of a sequestration and storage of calcium. Other studies have suggested that the electron density is the consequence of the retention of osmium tetroxide by a phospholipoprotein that may bind calcium in vitro, but may not have such a role in vivo (Figure 3.3).

A Adrenergic Receptor Antagonists

Effects of a adrenergic antagonists may be predicted from the consequences of a receptor stimulation. The a1 adrenergic receptors mediate contraction of arterial and venous smooth muscle. The a2 receptors are involved in suppressing sympathetic outflow from the CNS, increasing vagal tone, facilitating platelet aggregation, inhibiting the release of NE and ACh from nerve endings, and regulating metabolic effects (e.g., suppression of insulin secretion and inhibition of lipolysis) and contraction of some arteries and veins.

Nuclear signaling pathways

Astrocytes are intimately involved in regulating energy metabolism in the CNS (Magistretti and Pellerin, 1999) and it has been suggested that the endogenous cannabinoid system plays a role in regulating astrocyte metabolic activity (reviewed by Guzman and Sanchez, 1999). Cannabinoid stimulation has certainly been linked to changes in metabolic activity in astrocytes but the majority of work to date has utilized plant-derived and synthetic cannabinoids which may not be indicative of the actions of the endocannabinoids in m two systems. In various astrocyte-related cell lines activation ofthe MAPK pathway has been described upon stimulation with

Weight Control and Regulation of Body

Non-institutionalized population, have been recently re-evaluated. Data have suggested that after controlling for energy intake and physical activity, contrary to common thought, an adequate calcium intake may actually be associated with a reduced likelihood of being in the highest quartile for adiposity.57 Zemel et al. reported an almost 80 difference in obesity rates between those Americans in the lowest quartile of dietary calcium intake versus those in the highest quartile.57 Several studies have reported an impact of supplemental dietary calcium on weight loss and have suggested that diets low in calories but high in calcium may provide some better protection against obesity. Experimental data in animals and in humans have also suggested a possible role of dietary calcium in regulating body fat, and an increase in lipolysis with a high-calcium low-fat diet, consistent with an increase in energy metabolism.58 61 Data from six observational studies and three controlled trials in...

Naa As A Marker For Neuronal Health

In support of this view, some evidence has been presented showing that NAA levels are restored when patients recovered clinically49. These observations bring up a central question in NAA research. Does NAA play a part in the functional recovery, or is it just a marker for the recovery of mitochondrial energy metabolism

Energy Supply And Storage

Adequate D-glucose transport from the circulating blood to the retina is essential for energy metabolism in the retina. Betz and Goldstein (10) were the first to report a carrier-mediated transport process for D-glucose at the inner BRB using isolated bovine retinal capillaries and they showed that 14C 3-O-methyl-D-glucose (3-OMG, an analog of D-glucose that cannot be metabolized) uptake was saturable and could be inhibited by substrates and inhibitors of facilitative D-glucose transporters (i.e., GLUT). Ennis et al. (13) obtained a Michaelis constant (Km) for the rat blood-to-retina transport of D-glucose of 7.81 mM using a modification of the RUI method. In 1992, Takata et al. (14) demonstrated the immunolocalization of GLUT1 (Slc2a1) in the retina and showed that GLUT1 is localized at both the luminal (blood) and abluminal (retinal) sides of the inner BRB, and at both the apical and basolateral sides of the outer BRB. The expression of GLUT1 at the abluminal membrane of the inner...

The Role of Insulin in Glucose Metabolism

The insulin receptor (IR) is an insulin-activated trans-membrane protein-tyrosine-kinase. Following insulin binding, the receptor undergoes activation by autophosphorylation and subsequently phosphorylates several endogenous proteins on tyrosine moieties. Tyrosyl phosphorylation is linked to a serine threonine phosphorylation state of key enzymatic systems controlling the glucose and fat metabolism. When insulin is removed, termination occurs at several levels, one of which is dephosphorylation of tyrosyl residues by endogenous protein phosphotyrosine phosphatases (PTPase).20

Project Title Combination Drug Therapy In Huntingtons Disease

Summary (provided by applicant) Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function, huntingtin (htt). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to pathogenic mechanisms of oxidative stress, mitochondrial dysfunction, apoptosis, energy metabolism defects, and subsequent excitotoxicity. We have identified a number of drug compounds that separately target these mechanisms and have shown that they significantly ameliorate the phenotype of HD transgenic mice. These compounds or their analogs are available for human use and represent the immediate pipeline of candidate neuroprotective agents for clinical trials in HD. We have shown that these drugs have great potential for combined use to...

Novel Approaches for Biochemical Assessment of LigandGPCR Interaction

A final technology that should be mentioned utilizes silicon-based sensor technology to detect perturbations in cellular metabolism (64). The metabolic rates of most cells are greatly enhanced as a consequence of cell activation, and the net result is an extrusion of protons to maintain intracellular pH. The Cytosensor microphysiometer (Molecular Devices, Palo Alto, CA) utilizes a light-addressable potentiometric sensor (LAPS) to measure the rate of extracellular acidification. The Cytosensor detects small alterations in the rate of proton extrusion by monitoring the pH of the immediate environment of the stimulated cell. This technology is low through-put and labor intensive in its current form. However, since the technology is not dependent on prior knowledge of the signaling characteristics of the receptor, it may represent a viable and important approach for screening ligands. This is particularly true for orphan GPCR for which the endogenous activating ligands have not been...

Source manufacture and analysis of major nutraceuticals

Most nutraceuticals are natural products, being derived roughly equally from plants and animals. Some are endogenous human metabolites, while others are common dietary constituents that appear in human metabolism, for example lycopene. A number of entities exist in higher plants, and are commercially extracted from them, although some are present in insufficient levels for commercial exploitation, such as methyl-sulfonylmethane (MSM) and dehydroepiandrosterone (DHEA), and consequently are produced commercially by chemical synthesis. Similarly, those of animal origin may be produced by chemical synthesis, such as carnitine, creatine and the carotenoids, but may also be produced by fermentation, such as coenzyme Q10 (Co Q10) and S-adenosyl methionine (SAMe). Soy isoflavones which occur naturally in the glycoside form are available as both glycosides and their aglycones, and are invariably complex mixtures, as are green tea extracts, grape seed proanthocyanidin extract (GSPE) and...

Early Studies Of Ketogenic Diet Efficacy

Wilder of the Mayo Clinic proposed manipulating the ratio of dietary fat to proteins plus carbohydrates in a variety of ratios from 2 1 to 3 1 as a method of creating ongoing ketonemia that could mimic the metabolic effects provided by lengthy starvation and dehydration (6).

Effects of caffeine on the noradrenergic and serotoninergic cell groupings and on the sleepwake cycle

Previous studies using high doses of caffeine, i.e., the acute injection of 10 mg kg caffeine or the continuous perfusion of methylxanthine at a rate of 0.30 mg kg min reported increases in energy metabolism in structures known to control the sleep-wake cycle, such as the mesencephalic reticular formation, locus coeruleus, and raphe nuclei.115-19 Our present data show that the serotoninergic cell groupings, the medial and dorsal raphe nuclei, as well as the noradrenergic cell grouping, the locus coeruleus, are very sensitive to caffeine. In these three structures, LCMRglcs increase at all doses of caffeine used (1 to 10 mg kg) and are already activated at the lowest one, 1 mg kg (Figure 3.2). These data correlate well with the known sensitivity of sleep functions to the absorption of caffeine.24 In the cat, 10 mg kg of caffeine produce an activation of the cortical EEG similar to the activity induced by the direct stimulation of the reticular formation, a structure which plays a...

ROS Generation with Aging and Exercise

The reason for the enhanced ROS production as organisms get older is not entirely clear, although several scenarios have been postulated. A major paradigm focuses on the finding that aged mitochondria have a lower level of cytochrome aa3 content in proportion to other electron carriers, posing a potential danger that electrons may be transferred out of sequence thereby forming 02* at the inner membrane (Nohl, 1986). Another hypothesis was based on the age-related increase in the hydrophilic property of the mitochondrial inner membrane wherein polyunsaturated fatty acids undergo an increasing rate of peroxidative modification with age (Chen and Yu, 1996). Pamplona et al, (1999) reported that the level of unsaturated fatty acid was lower in heart mitochondria from long-lived pigeon (maximal life span 35 years) than from rat (maximal life span 4 years), although the former has a similar body size and a higher metabolic rate. However, several recent studies indicate that Complex I is...

Growth Metabolism and the Stress Response

The hormones secreted by the thyroid thyroxine (T4) and triiodothyronine (T3) and adrenal (cortisol and adrenaline) tissues are identical in both fish and mammals. In fish, however, these tissues do not form discrete glands the thyroid is scattered around the ventral aorta, while adrenal tissue is dispersed within the kidney. This makes it very difficult to measure the changes induced in their structure by chemical pollutants. The hormones of the thyroid regulate general metabolic rate, growth and possibly embryonic development, while those of the adrenal are involved in the stress response, osmoregulation and carbohydrate metabolism. Growth in fish is continuous and does not cease at puberty as in mammals. Fish size is therefore not only dependent on secretion of growth hormone by the pituitary gland as in mammals, but on age and the rate of metabolic activity and energy utilisation as determined by both the thyroid and interrenal glands. Thyroid and adrenal activities are also...

Antioxidant Response and Adaptation to Exercise

It has long been recognized that in mammals and birds antioxidant enzyme activity in skeletal muscle is higher in the wild species compared to their domestic counterparts (Burge and Neil, 1916). Within the body, tissues that have a higher metabolic rate, such as liver, heart, and brain, or those chronically exposed to ROS, such as eye lens, have greater antioxidant protection than those with lower oxygen or ROS exposure (Halliwell and Gutteridge, 1989). Antioxidant enzyme activity and GSH content vary widely in different skeletal muscle fibers. The more aerobic type 1 muscle possesses greater antioxidant potential than type 2a and type 2b muscle (Ji et al., 1993). While these inter-species and inter-organ tissue differences in antioxidant potential may reflect long-term adaptation during evolution and development, relatively short periods of oxidative stress have also been shown to induce certain antioxidants (Halliwell and Gutteridge, 1989 Harris, 1992). In humans, a higher...

Allosteric Regulation of Receptor Protein Tyrosine Phosphatases by Oxidation

It should - in addition to kinases - be mentioned that phosphorylases also attach phosphate groups to alcohols present in biomolecules. Unlike kinases, phosphorylases usually use inorganic phosphate (and not ATP) as their substrate. Furthermore, phosphorylases are mostly involved in energy metabolism, for instance in breaking down glycogen, not in cellular signaling. Interestingly, the activity of certain phosphorylases (such as phosphorylase b) is controlled by phosphorylation (which converts phosphorylase b to the active form, phosphorylase a), for instance by a particular phosphorylase kinase, which in turn may itself be activated by phosphorylation (and Ca2 + ions). This example already illustrates the complicated structure of (phosphorylation) signaling networks present in the human cell.

Of Calcium Homeostasis In Acute

Several of the pathological hallmarks of HD can be mimicked via intrastria-tal injection of glutamate agonists including selective loss of spiny neurons of the striatum. Based on these findings it has been proposed that the disease may be due to a preexisting metabolic defect resulting in impaired mitochondrial energy metabolism perhaps exacerbated by age-related declines rendering striatum neurons more vulnerable to normal physiological levels of glutamate or related endogenous compounds. This has been termed ''slow excitotoxicity'' as opposed to what is believed to occur in the acute chronic sort of excitotoxicity associated with stroke, which is believed to involve excess extracellular levels of the excitatory amino acid as a result of increased release and decreased presynaptic uptake, e.g., 57-60. Administration of chronic low dosages of 3-nitroproprionic acid (3-NP), an inhibitor of succinate dehydrogenase and therefore of mitochondrial respiration at complex II of the electron...

Comprehensive Functional Model For

In neurons, and the steady-state levels maintained there, would reflect the metabolic state of neuronal mitochondria because of the direct coupling of NAA production to a-ketoglutarate formation from glutamate. By preferentially using the aspartate aminotransferase reaction instead of the glutamate dehydrogenase reaction to generate a-ketoglutarate, neuronal mitochondria would prevent ammonia production associated with the glutamate dehydrogenase reaction, and this might avoid additional metabolic stress on neurons. In this model, NAA synthesis is intimately associated with the proper functioning of neuronal energy metabolism via the aspartate aminotransferase reaction in neuronal mitochondria. Further, NAA synthesized in neuronal mitochondria is transferred to oligodendrocytes by an as yet unknown mechanism, where ASPA liberates the acetate moiety to be used for myelin lipid synthesis. This hypothesis emphasizes the metabolic

Mechanism of Action

Mitochondria are rod-shaped structures in all eucaryotic cells where oxidative phosphorylation, the citric acid (Krebs) cycle, and fatty acid oxidations happen. Thus the electron-transfer, energy-generation, and storage processes all occur in them. The structural organization of mitochondria consists of a double lipoprotein membrane system, with the outer membrane enclosing an inner membrane that in turn, by a number of invaginations, results in a series of compartments called cristae. Within these invaginations are the respiratory assemblies, or oxysomes, containing all the enzymes of the electron transport system in the same sequential order in which the reactions occur flavoproteins, coenzyme Q, cytochromes b, Ci, c, a, and a3. Ferrodoxins (iron and sulfur atom-containing proteins involved in redox reactions) are also in the cristae. The Krebs-cycle-associated enzymes, succinic, malic, and a-ketoglutaric dehydrogenase are also located here. Thus the mitochondria have all but one of...

Coupling between cerebral blood flow and metabolism

In most situations, cerebral blood flow and glucose utilization are closely coupled in all cerebral regions, so that modifications in cerebral activity elicit parallel changes in cerebral glucose utilization and blood flow.5,8,9,62 In general, changes in cerebral blood flow are the consequence of variations in cerebral energy metabolism.71011 Contrary to the majority of pharmacological agents to which man is frequently exposed, and as shown in Figure 3.5, caffeine has the property to induce cerebral hypoperfusion accompanied by a simultaneous increase in glucose utilization15-1952 in other words, caffeine resets the level of coupling between cerebral blood flow and energy metabolism. Methylxanthines thus seem to modify the regulating mechanism between cerebral blood flow and cerebral metabolism. Although this mechanism is not yet fully understood, adenosine, with which methylxanthines compete, is known to be one of the modulators of the regulation of the relationship of blood flow to...

Sufentanil In Selective Operations

Sufentanil is a favorable opioid for use in neurosurgical procedures. This is because increasing dosages of the opioid (5-10-20-40 and 80 g kg body weight) similar to other fentanyl analogues, induce a dose-dependent significant drop in cerebral perfusion (CBF) and cerebral oxygen consumption (CMRO2 Figure III-38). This close correlation between the reduction in cerebral oxygen consumption and cerebral perfusion is similar to isoflurane in patients undergoing carotid endarterectomy 124 . The beneficial effect of sufentanil on cerebral tissue is especially demonstrated by a reduction of white matter turgor in craniotomized patients under basic isoflurane N2O O2-relaxant anesthesia. Also, sufentanil given as a bolus (0.3 g kg body weight) and followed by an infusion (0.3 g kg h) with a stable arterial pCO2 of 28 mmHg, in comparison to a saline infusion, resulted in a lesser protrusion of cortical tissue, a lesser turgor of cortical cells and a lesser perfusion of cerebral vessels....

Neuroprotection In Ischemia

Another promising neuroprotective perspective is the use of hypothermia. Several studies have previously documented the neuroprotective effects of mild hypothermia, which may completely abrogate the ischemic changes.126-129 Similarly to multipotent agents, hypothermia appears to convey protection by acting via several mechanisms.129 Furthermore, a combination of hypothermia with putative cerebro-protective drugs shows synergistic effects as compared to either drug therapy or hypothermia alone.130 Postulated mechanisms of action of hypothermia include lowering excitatory amino acid secretion and downregulation of glutamate receptors,131,132 diminished production of ROS and reduced consumption of tissue antioxidants,133,134 and reduced inflammatory response.135,136 Other postulated mechanisms include a non-specific lowering of cerebral metabolic rate,137 and changes in cerebral bloodflow.138

Redox Balance and Aging ROS and NO

Despite similarities with the ROS cascade, aging appears to have the opposite effect on NO metabolism. Both NOS expression and NO production decline with age (Richmonds et al., 1999). These changes predict NO signaling and NO -mediated processes have only a minor role in the oxidant induced muscle dysfunction of aged individuals. However, other studies indicate NO may contribute to contractile dysfunction. Several researchers have shown that NO modifications accumulate in selective proteins of aged muscle. NO modifies proteins through an interaction with tyrosine residues to yield nitrotyrosine. In aged rats, the number of nitrotyrosines found in the type 2 sarcoplasmic reticulum Ca-ATPase (SERCA2a) is increased. This nitrosylation is associated with significant inactivation of SERCA2a Ca2+ uptake (Viner et al., 1999). This inactivation could contribute to contractile dysfunction through changes in Ca2+ regulation. In addition, the metabolic enzymes, p-enolase and a-fructose aldolase...

Relevance of Side Chain Degradation In Vivo

Taken together, our knowledge of the mechanism of vitamin E metabolism has increased tremendously during the last few years. These studies further demonstrate the unique and preferential role played by a-tocopherol. Different metabolic rates certainly will influence biopotency and bioequivalence of individual forms of vitamin E. The possibility that CYP, i.e., drug or xenobiotic metabolizing enzymes, are involved in the degradation of vitamin E opens the possibility of an interference of vitamin E with the drug metabolism that should be investigated thoroughly in view of the large dosages of vitamin E taken for self-supplementation.

Carnitine in human pain

Particular examination has been made into the effect of carnitine on the pain associated with human immunodeficiency virus (HIV). Infection with HIV can be complicated by a painful symmetrical neuropathy the pain of which can be lessened by parenteral and oral car-nitine. More commonly the treatments for HIV can lead to a significant neuropathy and neuropathic pain. Nucleoside analog reverse transcriptase inhibitors (NRTIs) disrupt mitochondrial DNA synthesis impairing energy metabolism and are widely used in the management of patients with HIV. Their use is also complicated by an antiretroviral toxic neuropathy. Studies have shown that long-term carnitine treatment produces symptomatic improvement in most patients with neuropathic pain while allowing the continued use of the antiretroviral medication. Furthermore, significant adverse effects of carnitine treatment are rare. In one study skin biopsies were taken before and during long-term carnitine treatment with...

Project Title Ubiquinone And Mitochondrial Oxidative Disorders Of Agin

In addition, a decline of aerobic energy metabolism in the affected tissue is often associated with the progression of these neurodegenerative diseases. A decline in aerobic metabolism has been observed in aging tissues. Ubiquinone(coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form(ubiqionol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo and for which there exists enzymic mechanisms which can regenerate it from its oxidized product formed in the course of its antioxidant function. Tissue ubiqionone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism they increase...

Oxidative Stress and the Mechanisms of Apoptosis

APAF-1 and activates caspase-3, initiating apoptosis 136 . Thus, at the beginning of apoptosis, cytochrome c is released to the cytosol prior to caspase-3 activation 138 . Anti-apoptotic proteins such as those of the Bcl-2 family, stabilize the pores and inhibit apoptosis 139,140 . Adenine nucleotides play a role in apoptosis, in the living cells and tissues 141, 142 . Today, it is believed that the complexes of mitochondrial proteins that participate in important mitochondrial cellular processes (such as opening of the MPT pore), are proteins of the inner mitochondrial membrane containing very important thiols that can easily be oxidized by oxidants and perox-ynitrite 9, 143 . In MPT pore, ANT is a significant protein which is affected by oxidants and peroxynitrite 23, 144, 145 . During oxidative stimulus, the complex VDAC-ANT-CyP-D forms and triggers the opening of the mitochondrial permeability transition pore leading to a subsequent release of pro-apoptotic proteins (e.g....

Alternative technologies to identify ligands for orphan receptors

The therapeutic value of the discovery is lacking, thereby making this a much more challenging task. Arena Pharmaceuticals have been using this approach exclusively to identify lead compounds for orphan receptors (Behan and Chalmers 2001). They have, as expected, identified chemical leads for a number of receptors and have examples in a number of different therapeutic areas. Their most advanced discoveries are small molecule modulators of the human 18F orphan GPCR, for the potential treatment of metabolic diseases and obesity. Preliminary experiments of the 18F GPCR modulators in animal models have shown that acute administration of these compounds leads to a reduction in food intake, a decrease in body weight and an increase in fat metabolism (Investigational Drugs Database (IDdb)).

Metabolic PET Studies

Metabolic studies use 18FDG to measure regional glucose metabolism. 18FDG, like all 18F compounds, has the advantage of a relatively long half-life (110 minutes). This allows the synthesis to be performed in one location, the subject injection in another location, and the scanning in yet another location. In fact, one can have a subject doing a particular task in a location remote from the PET scanner and inject 18FDG, which will be trapped in brain regions according to the local metabolic rate. This has an obvious advantage in situations in which placing the subject in the scanner would alter the conditions of the task. For example, 18FDG is used commonly in sleep studies. The main disadvantage is that the long half-life results in effectively no temporal resolution. This offers a time-averaged snapshot of a particular brain state, and the state is averaged over 20-60 minutes. Figure 10-1 shows functional localization of an epileptic focus in the right temporal lobe during...

Axonal Injury Is The Major Determinant Of Permanent Neurologic Disability In Multiple Sclerosis

The mechanism of axonal damage remains to be elucidated, and we can only speculate on the possibilities. Some of the possible mechanisms are summarized here. First, since the extent of axonal damage in active MS lesions is proportional to the degree of inflammatory activity within the lesion, axonal injury could be a direct result of inflammation per se (Figure 2). Substances such as free radicals, proteolytic enzymes, oxidative products and cytokines produced by activated immune and glial cells are potential mediators of such damage16. Oxidative damage to mitochondrial DNA and impaired activity of mitochondrial enzyme complexes in MS lesions indicate that inflammation can affect energy metabolism, ATP synthesis, and viability of affected cells17. Recently, data indicating that cytotoxic CD8+ T cells can mediate axonal transection in active MS lesions

Principles and Role in Psychopharmacology

Blood circulation and energy metabolism are closely linked to neuronal synaptic activity in the brain - an observation first suggested by nineteenth century researchers. fMRI, and specifically BOLD contrast fMRI (BOLD fMRI), is a modern neuroimaging technique that exploits the fact that such processes, particularly blood flow and blood oxygenation, are regionally coupled to changes in neuronal activity levels.

Photosynthesomes metabonucleons

Protein biosynthesis, protein folding and DNA metabolism along with Calvin cycle enzymes, solicit for the explanations concerning the organization of whole chloroplast metabolic system. The sequential enzymes of a metabolic pathway may be tightly and orderly packed to form a set of connections on the surface of thylakoid membranes. The peripheral components in these complexes may associate with enzymes of different metabolic pathways, resulting in large supramolecular structures performing all the linked functions in chloroplasts including photosynthesis, DNA and protein synthesis as well as fatty acid synthesis. The term metabolon would be inappropriate to describe these structures because it defines that only enzymes of one pathway are assembled 75,76 . A term Metabonucleon had been proposed to describe the putative superstructures along the thyla-koid membranes (K.H. S ss, personal communication, 2002). In the following, we describe the concept of structure and function of...

Analysis of Mutant Mice Selectively Lacking M3 mAChRs in Pancreatic b Cells

In vitro studies demonstrated that muscarinic agonist-stimulated PI hydrolysis was greatly enhanced in islets obtained from p-M3-Tg mice, as compared to those prepared from WT littermates (Gautam et al. 2006b). In keeping with this finding, Oxo-M-induced stimulation of glucose-dependent insulin secretion was significantly greater in islets obtained from p-M3-Tg mice (Gautam et al. 2006b). In vivo studies showed that p-M3-Tg mice displayed significantly reduced blood glucose levels (by 30-40 ), associated with a 3-fold increase in serum insulin levels. Moreover, the transgenic mice exhibited greatly improved glucose tolerance, most likely due to enhanced glucose-induced insulin release in vivo (Gautam et al. 2006b). Finally, Gautam et al. (2006b) demonstrated that p-M3-Tg mice were protected against the detrimental metabolic effects associated with the chronic consumption of an energy-rich, high-fat diet, such as hyperglycemia and glucose intolerance (Fig. 1). mice that were homozygous...

Measurements Of Brain Metabolites During Ketosis In

Pan et al. used 31P spectroscopic imaging at 4.1T to demonstrate an elevated ratio of PCr to inorganic phosphorus in patients on the KD and concluded that there was improvement of energy metabolism with use of the diet (14). Seven patients with intractable epilepsy (four with Lennox-Gastaut syndrome, one with absence seizures, one with primary generalized tonic-clonic seizures, and one with partial complex seizures) were studied before and after institution of the KD. Coronal *H anatomic imaging was performed to provide a correlate to the 31P data. Ratios of PCr to ATP were measured at baseline and compared with those obtained after the KD. These showed a small but significant increase from 0.61 0.08 to 0.69 0.08 (p 0.05). The ratio of PCr to inorganic phosphorus also changed from 2.45 0.27 at baseline to 2.99 0.44 during the diet (p 0.05). The authors made several assumptions to calculate the potential gain in energy by these changes (1) that the creatine kinase reactions stayed at...

How Are Brain Metabolism And Epilepsy Related

Is deficient energy metabolism an important mechanism causing intractable seizures in other patients Certainly, seizures themselves exert a great metabolic demand on the brain. One might expect epileptogenic focal structural lesions to be hypermetabolic, but it is well known that the exact opposite is found hypometabolic neocortical areas revealed on PET scan are associated with focal epileptogenic lesions causing intractable partial epilepsy. Careful coregistration of implanted electrodes in children with intractable epilepsy has recently revealed that the most active ictal regions are those lying within border-zone areas, not within the hypometabolic areas themselves (18). Indeed, a frequent finding during electrocorticography is slow-wave activity with reduced complexity over the lesion, with a surround of interictal epileptiform discharges in the border between the lesion and the normal brain. Is the adjacent tissue hypometabolic on PET because the cerebral energy demands in that...

Integration in Plant Respiration

Carbon oxidation in respiratory pathways (glycolysis, oxidative pentose phosphate pathway, tricarboxylic acid (TCA) cycle) is coupled to reduction ofpyridine nucleotides. An important route by which the reducing equivalents are subsequently oxidized is through the mitochondrial electron transport chain (ETC). Here, electron transport to O, is coupled (through the generation of proton motive force) to the synthesis of ATP from ADP and inorganic phosphate (Pi) by the process of oxidative phosphorylation (Siedow and Day, 2000). Because carbon metabolism and electron transport are coupled processes, there must be mechanisms to integrate them such as to accommodate for changes in the supply of, or demand for, carbon, reducing power and ATP by cell metabolism. The need for integration may be particularly important in plants, where another organelle (the chloroplast) is intimately involved in energy metabolism and where respiration plays a major role in both catabolic and anabolic processes....

Possible Relationship Of Metabolic Changes To Anticonvulsant Effect

Previous investigators have speculated that the ketogenic diet improves overall brain metabolism and that this might be the basis for the antiepileptic effect. Certainly the diet appears to favorably influence energy charge of the brain in selected groups of subjects (65,66). An outstanding issue is whether the improvement in overall energy metabolism is the cause or the consequence of reduced seizure frequency. It also has been postulated that the diet imposes a mild cerebral acidosis that diminishes the responsiveness of brain NMDA receptors, although efforts to document an accumulation of brain H+ have yielded a negative result (67,68).

Fuel Sensors 421 Fatty Acids

Sion of many genes encoding enzymes of intermediary metabolism (Fig. 2). This results in changes in cellular concentrations of such enzymes and, therefore, changes in the flow of fatty acids, glucose, and amino acids through the hepatocyte. For example, when PPARa is activated in the mouse liver by starvation, it causes an increase in fatty acid oxidation, an increase in ketogenesis, a decrease in glucose oxidation, and a decrease in amino acid transamination and deamination (11) (Fig. 2). In addition, blood levels of insulin and glucocorticoids alter the expression of the PPARa gene, hence the concentration of PPARa protein available for fatty acid activation (12). It can be seen, therefore, that activation of PPARa by a variety of blood-borne dietary signals results in an integrated metabolic response through reprogramming expression of genes encoding enzymes of hepatocyte intermediary metabolism. Three such genes regulated by PPARa, in human hepatocyte-derived cell lines, encode...

Contributing To Oxidative Stress In Ad

Not only at the site of trauma but in distant brain structures including the hippocampus (147). Similarly, cerebral ischemia is known to induce oxidative stress in neurons in and surrounding the ischemic focus (148). It is therefore not too surprising that head trauma and ischemia can combine with age-related increases in oxidative stress and impaired energy metabolism to accelerate the processes of amyloid deposition and neuronal degeneration that underlie AD. The beneficial effect of education is likely the result of the following mechanism. Increased brain use (i.e., activity in neuronal circuits involved in learning and memory) results in increased neurotrophic factor production. Increased levels of neuro-trophic factors promote neuronal growth and plasticity, and suppress age-related increases in levels of oxidative stress (149). This ''use-it-or-lose-it'' phenomenon is consistent with many different observations in both the human population and experimental animals.

Exercise and Brain Imaging Related to Physical and Mental Health

In the scope of applying PET to health promotion science, we have performed imaging studies in subjects during various forms of exercise such as running and bicycle riding. We have scanned not only the brain 11, 15 but also the skeletal 15, 16 and cardiac muscles 17 . By conducting whole-body scanning, we can obtain a whole-body map of energy metabolism in the living human body 16 (Fig. 3). Regional cerebral metabolic changes induced by exercise have been examined in animals with an autoradiography technique using 14C deoxyglucose ( 14C 2-DG) as a tracer, because it did not require the simultaneous scanning of subjects during exercise 18, 19 . These studies provided the first functional indices of brain activity with respect to exercise. Using this technique, Sharp 20 demonstrated a regional increase in glucose uptake in the cerebellar vermis of swimming rats. Human studies were later conducted by Herholz and coworkers 21 in the late 1980s, first using a 133Xe clearance method for...

The role of protein in human health

Proteins, unlike fatty acids and carbohydrates, are not stored in the body, but they are deaminated followed by the oxidation of carbon skeleton through the pathways of glucose or fat metabolism, or they are stored in the form of glycogen or fat. It depends on the specific amino acid and the energy balance at the time. Nitrogen waste is excreted in urine as either urea or ammonia. Considering the body need of proteins for sustaining the essential physiological functions, diet low in protein could be deficient in many important vitamins and minerals in comparison to protein-rich diet. During fasting and starvation, muscle provides a source of amino acids. The balance between protein synthesis and resolution is closely regulated (Becker and Smith, 2006). FAO WHO (De Onis et al, 1993) defines malnutrition as ''the cellular imbalance between the supply of nutrients and energy and the body's demand for them to ensure growth, maintenance, and specific functions.'' In the world, especially...

Thyroid Functions and Drugs Affecting Them

The thyroid gland, a 20 g tissue structure on the upper segment of the trachea, controls essential physiological function by its ability to make, store, and secrete two thyroid hormones. These functions include regulation of growth and general development, primarily by controlling DNA transcription and therefore protein synthesis. This in turn results in various enzymatic activities. Deficiencies in thyroid hormones have catastrophic effects in early life, the extremes of which can be manifested in cretinism by dwarfism and severe mental retardation. Another action is referred to as the calorigenic effect. This is evidenced by the increase in basal metabolic rates in organs such as the kidneys, heart, and liver, as well as in skeletal muscles. Valid mechanisms by which these effects can be satisfactorily explained have been elusive. Thermal regulation should be included in this area, as shown by the fact that thyroid secretions can be stimulated by a decrease in temperature.

Anandamide transport

As a putative neurotransmitter (e.g., in the brain) anandamide has many unusual features. One of them is that it is not stored in synaptic vesicles. Instead it is synthesized upon stimulation and is immediately released. The most important mechanism for the inactivation of anandamide is (re)uptake and fast metabolism to arachidonic acid and ethanolamine.

Deficiency Of Striatal Glutathione In

Zeevalk et al. (85) have shown that glutathione is an important neuroprotec-tant for midbrain neurons during situations when energy metabolism is impaired. Andersen et al. (86) have shown that a reduction in glutathione level by buthio-nine sulfoximine resulted in the same type of nigrostriatal degeneration that occurs during the aging process. Grasbon-Frodl et al. (87) have shown that treatment with lazaroid, which inhibits lipid peroxidation, prevents death of cultured rat embryonic mesencephalic neurons following glutathione depletion. Zucker et al. (88) showed that the treatment of fibroblasts with BSO caused efficient depletion of intracellular reduced glutathione that was followed by substantial cell death. Based on the induction of membrane blobbing, chromatin condensation, and DNA strand breaks, cell death was characterized as apoptosis. Apoptosis after glutathione depletion seemed to be induced by endogenous reactive oxygen species (ROS), as it was antagonized by the...

Fasting And The Ketogenic Diet

Using the water-only diet of Conklin, Lennox and coworkers demonstrated an impressive management of epilepsy in patients having as many as five seizures per day (16,19). Seizure incidence actually increased over the first few days of the fast but decreased dramatically after 3 d (Fig. 1). This result is interesting because generally cerebral energy metabolism does not shift from glucose to ketone utilization before approx 3-4 d (20). Seizure control through fasting was also associated with reduced Although clinically effective, fasting is impractical for the long-term management of seizures. Consequently, the high-fat, low-carbohydrate ketogenic diet (KD) was developed to mimic the physiological effects of fasting, i.e., resulting in ketosis, without severe food restriction or starvation (16,21-23). The KD is effective in managing intractable seizures in children and may also be effective in managing seizures in adults (17,24-26). The KD is also effective in reducing epileptogenesis...

Caffeine and cognition

Which subjects received a single, timed-release dose (600 mg) of caffeine. The caffeine mimicked the benefits of sleep. Sleep-deprived subjects taking the caffeine performed the same on tests of vigilance and alertness as those who received a normal night's sleep.95 96 Caffeine has also been shown to increase the metabolic rates of sleep-deprived subjects to their predeprived levels.97 A number of other studies have also shown that caffeine improves vigilance performance98-100 on both auditory98-104 and visual88,104 tasks. Conversely, decrements in performance have been attributed to low levels of arousal,100 while higher levels improve performance on sustained attention tasks.14,15,105,106

Mode of Anti Inflammatory Actions of Aspirin

Among the multiple pharmacological actions of aspirin, most of the attention has been focused on its analgesic anti-inflammatory effects. This was also the reason why the substance was originally developed and clinically introduced (Section 1.1.3). Originally, it was thought that the anti-inflammatory action of aspirin (and salicylate) might result from its effects on cellular energy metabolism, that is, uncoupling of oxidative phosphorylation. This hypothesis, although attractive, was rejected 333 (Section 2.2.3). Future research was focused to more specific actions of salicylates on cells of interest. This included white cells, their numerous activation and secretion products, and the vascular

Blood Glucose Predicts Blood POHB Levels and Seizure Susceptibility in EL Mice

We next analyzed our data by using both simple linear regression and multiple logistic regression to determine if blood glucose levels were predictive of blood P-OHB levels and seizure susceptibility. These statistical analyses included mice considered to be outliers, i.e., mice that experienced CR but showed no changes in body weight, plasma glucose, or P-OHB levels (41). One outlier was found in the juvenile CR group and three outliers were found in the adult CR groups (two in the 15 CR group and one in the 30 CR group). The outliers were considered to be nonrestricted for caloric intake and similar to the mice in the AL-fed groups. These findings also emphasize that differences exist among inbred mice for food intake and energy metabolism (71). Hence, the efficacy of CR as an anticonvulsant therapy must be associated with reductions of blood glucose and body weight.

Oxidative Stresslnducible Genes

Is being downregulated by the oxidative stress developed during the reperfusion of ischemic myocardium (Maulik et al., 1998d). Ebselen, a glutathione peroxidase mimic, can preserve Bcl-2 by eliminating oxidative stress in the postischemic-reperfused myocardium. Our laboratory has also documented that a sequential upregulation of energy metabolism genes is induced by ischemia (Moraru et al., 1994). The central role of mitochondria is oxidative ATP synthesis, which leads to the deprivation of oxygen, thus triggering the stimulus to synthesize some of the mitochondrial genes (ATPase 6, ATPase 8, ATPase Fla) that are associated with preconditioning, ultimately leading to myocardial adaptation. Both '02 and -OH have been implicated in the induction of the expression of heme oxygenase. The fact that the expression of heme oxygenase can be induced directly by oxygen-derived free radicals (Maines and Kappas, 1997) or by the depletion of glutathione (Ewing and Maines, 1993) raises the...

Changes in mtROS Production Without Altering the Electron Transport Chain

The Uncoupling for Survival theory describes the effect of uncoupling proteins on longevity. According to this theory, the higher the metabolic rate the greater the longevity 79 , at least within a species. This hypothesis is supported by two facts first, uncoupling proteins decreases mtROS production 80 and second, dietary restriction increases UCP3 concentration in skeletal muscle 81 . Furthermore, mtROS production is also regulated by the proton leak in the internal mitochondrial membrane 82 . This is a quite interesting mechanism because it explains the reduction in mtROS production without alteration in the oxygen consumed by mitochondria, which is the exact mechanism proposed to occur in calory-restricted animals 53 .

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.

Pharmacokinetics And Disposition

Paroxetine is well absorbed from the alimentary tract, and absorption is not affected by the presence or absence of food (Kaye et al. 1989). Being a highly lipophilic compound, paroxetine is readily distributed into peripheral tissues and exhibits a high volume of distribution, ranging from 3.1 to 28 L kg (Kaye et al. 1989). Once absorbed, paroxetine is reportedly 95 bound to serum proteins (Kaye et al. 1989), though we have observed protein binding of 85 in our studies (M. J. Owens and C. B. Nemeroff, unpublished observations, June 1997). Oral bioavailability is affected by extensive first-pass metabolism, which is carried out by a high-affinity, low-capacity hepatic enzyme system (Lane 1996). With serial dosing, bioavailability increases as this metabolic system becomes saturated and a larger proportion of parent compound enters the systemic circulation (Kaye et al. 1989). Steady-state concentrations of paroxetine, following oral dosing, exhibit wide intersubject variability...

Biochemical Mechanisms of SConjugate Cytotoxicity

The mitochondria are the primary subcellular targets for S-conjugate-induced cytotoxicity in freshly isolated renal proximal tubular cells. For example, cellular respiration and ATP content were markedly reduced by and S-(l ,2-dichIorovinyl)-L-cysteine (Lash and Anders, 1987). The disruption of mitochondrial energy metabolism may contribute to glutathione depletion, reduced organic anion and cation transport, and the elevation in cytosolic Ca2+ concentrations due to impaired function of the Ca2 + -ATPases of the plasma membrane and the endoplasmatic reticulum (Jones et at., 1986 Wallin et al., 1987). All of these processes require energy in the form of ATP.

Ketone Bodies and the KD

Despite decades of clinical experience with the KD, the mechanisms underlying its anticonvulsant actions remain poorly understood. Among the numerous mechanistic hypotheses advanced to explain the anticonvulsant activity of the KD (64) are the following (1) changes in brain pH, e.g., acidosis, which would favor neuronal inhibition through proton-sensitive ion channels (65) (2) direct inhibitory actions of fatty acids, i.e., PUFAs (66) (3) changes in energy metabolism, reflected in part by ketone body production and metabolism (67-69) and (4) neurotransmitter alterations (70-73). Because of the striking ketosis associated with the KD and the ease with which BHB can be measured, much of the attention in this field has focused on the role of ketone bodies as mediators. However, direct evidence for a specific mechanism involving ketones has not emerged.

How are Mitochondrial ROS Regulated During Dietary Restriction

Initially, it was proposed that dietary restriction reduced the metabolic rate, and that it was this decrease that was responsible for the reduction in mtROS production. However, different studies demonstrated that such a simple relationship does not exist. It has been shown that dietary restriction does not alter metabolic rate 253, 254 . Although mitochondrial oxygen consumption could initially be reduced 254, 255 , after several weeks of dietary restriction there was no difference between the ad iibitum-fed and dietary restricted animals 53 .

Gene Expression in Sedentary Aged Animals

It may seem intuitive that compared with physically active animals, sedentary animals would in general, have lower gene expressions, perhaps due to less mechanical or metabolic stimulation. Interestingly, Bronikowski et al. (2002) reported that microarray analyses showed sedentary animals had a greater number of gene expressions compared with physically active animals. They reported a general decrease in the number of deleterious age-related gene expressions in the exercise group compared with the sedentary group. In the physically active group, fewer genes involved in inflammatory response, stress response, signal transduction, and energy metabolism were significantly altered with age compared to the sedentary population. This suggests that compared with sedentary animals, physically active animals experienced more stability and less cell damage over time. Bronikowski et al. (2002) found inflammatory and stress response genes were the most affected by age within the sedentary group....

Project Title Thyroidal Regulation Of Cardiac Sodiumpotassium Atpase Expression And Energetics

Summary Na+, K+-activated adenosine triphosphatase (Na, K-ATPase) is a ubiquitous energy transducing integral plasma membrane protein whose activity is of critical importance to the normal function of virtually all animal cells. In the heart the enzyme represents the cellular receptor for digitalis glycosides and its abundance and activity is significantly stimulated by the action of thyroid hormone (T3). The stimulatory effect of T3 on energy metabolism of the heart in vivo is a consequence of the direct actions of the hormone on cardiac myocytes as well as the increase in cardiac contractile work (cardiac output. in response to enhanced energy demand by other tissues. It has also been noted that the heart in hyperthyroid humans and animals manifests a reduction in functional reserve and maximal work capacity that is associated with a marked reduction in myocardial creatine-phosphocreatine pool. Such hearts are hence prone to fail if stimulated to work at or near maximal levels. The...

Localization and Some Physiological Roles of Esterases

Tetrachloroethylene Degradation Pathway

Most tissues have well-defined patterns of esterase activity. Thus, the ES1 synthesized in mouse liver constitutes the major esterase activity in murine plasma. It has been postulated that the ES2 present in the lymph plays an essential role in fat resorption 92 . Four esterases designated ES5, SEI, SEII, and SEIII are restricted to serum and have not been identified in other tissues. The content of ES6 is highest in organs with active fat metabolism, but is absent in serum and erythrocytes. ES7 is present in erythrocytes, lung, tongue, testis, and most other tissues but not in plasma and brain.

Tetrachloroethylene PERC

Two similar Monte Carlo investigations have been conducted to determine the relative importance of the various parameters in a PBPK model for PERC. One study by Bois et al. (1990) reported that kinetic parameters defining the metabolic rate were the most important model parameters when considering the precision and sensitivity of PBPK models for mice, rats, and humans (Bois et al. 1990). In a second

Effects of caffeine on the mesolimbic dopaminergic system and psychostimulant effects

Eiffel Tower Plans

Previous studies using high doses of caffeine, i.e., the acute injection of 10 mg kg caffeine or the continuous perfusion of methylxanthine at a rate of 0.30 mg kg min reported increases in energy metabolism in the ventral tegmental area, the nucleus accumbens, and the medial prefrontal cortex.115-19 However, none of them discriminated between the shell and the core part of the nucleus accumbens. Our recent studies show that the increase in LCMRglcs recorded in the structures of the mesolimbic dopaminergic system are of lower amplitude (Figure 3.3) than those recorded in the other brain regions studied (Figures 3.1 and 3.2). Moreover, the significant activation of functional activity appears only at quite high doses, 5 mg kg for the area of origin, the ventral tegmental area, and 10 mg kg for the two subdivisions D. Effects of chronic caffeine exposure on cerebral energy metabolism When the rats have been previously exposed to a daily injection of 10 mg kg of caffeine for two weeks,...

Mitochondrial Electron Transport Chain and Oxidative Stress in pd

Tmrm Rotenone And Hek293 Cells

Deficiencies in mitochondrial electron transport chain underlie defects in energy metabolism and have been implicated in the neurodegenerative process. A reduction in complex I activity in PD is thought to cause bioenergetic dysfunction with subsequent loss of DA-ergic neurons 105 . Experimental evidence also points the involvement of certain genes, such as SNCA, Parkin, DJ-1, PINK1, GSTO1, LRRK2, and HTRA2 that encode corresponding proteins, including a-synuclein, E3 ubiquitin-protein ligase (parkin), transcriptional co-activator DJ-1, phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK-1), glutathione S-transferase omega 1 (GSTO1), leucine-rich repeat kinase 2 (LRRK2), and serine protease (HTRA2), in the pathogenesis of PD (Table 4).

COXIndependent Actions on Cell Function

Aspirin and salicylate exhibit a broad spectrum of pharmacological actions on cell function 142 that is probably not completely elucidated yet. The transacetylation and nontransacetylation-related actions of aspirin are nonselective and nonspecific. Transacetylations may occur at any appropriate molecular site in any macromolecule, most notably plasma albumin and hemoglobin 102 as well as DNA 143 , whereas salicylic acid will accumulate inside cell membranes, including those of mitochondria, with subsequent alterations in cell signaling and energy metabolism. The modulation of enzymes of the cell energy metabolism and, most interestingly, heat-shock proteins and chaperones 146-148 , probably, is

Effects of caffeine on the nigrostriatal dopaminergic system and on locomotor activity

The stimulant effects of caffeine on LCMRglcs in the structures mediating locomotor activity have been shown previously at quite high doses of caffeine, i.e., after the acute injection of 10 mg kg caffeine or the continuous perfusion of the methylxanthine at a rate of 0.30 mg kg min. These studies all reported increases over control values in the rates of energy metabolism in the dopaminergic substantia nigra, both the pars reticulata and compacta and in structures of the extrapyramidal motor system (caudate nucleus, globus pallidus, sensorimotor and cerebellar cortex) as well as in numerous thalamic motor and sensory relay nuclei.15-19

Conclusion On Ketogenic Diet

We suggest that CR may underlie the anticonvulsant mechanism of the KD and that CR alone may be an effective antiepileptic diet therapy. Moreover, the anticonvulsant action of CR may operate through the combined effects of reducing blood glucose and elevating blood ketones, thereby modulating cerebral energy metabolism. Our preclinical findings in EL mice suggest that CR may be an effective dietary therapy for some human epilepsies because CR is easy to administer and is devoid of the adverse side effects associated with other antiepileptic therapies.

The Mitochondrial Free Radical Theory of Aging

This observation proves that longevity is concerned with the number of electrons that leak out of the mitochondrial electron transport chain and not with the amount of oxygen consumed. If the percent free radical leak is high, a given organism will not live for long, independent of the amount of oxygen consumed. In the past several years, various novel experimental approaches have confirmed data. For this instance, mitochondria of long-lived bats or humans leak fewer electrons than mitochondria of short-lived rodents 15, 16 . In summary, published data indicate that mitochondria from long-lived animals produce fewer mtROS, thus supporting Harman's theory. The low levels of damage generated in these species make it unnecessary to have high levels of antioxidants and allow for the combination of high metabolic rates with high longevity.

Inborn Errors of Metabolism

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of lactic acidemia and represent relatively common inborn errors of metabolism in children ( 200 cases described). PDH complex is a mitochondrial enzyme that catalyzes the irreversible oxidation of pyruvate to acetyl-Co A. PDH is the rate-limiting enzyme connecting glycolysis with the tricarboxylic acid cycle and oxidative phosphorylation. It therefore plays an important role in energy metabolism (51,52).

Perspectives For Pharmacogenetic Research Into Eating Disorders And Obesity

Sibutramine is a selective inhibitor of the presynaptical reuptake of serotonin and norepinephrine, leading to enhanced central serotonin and norepinephrine neurotransmission which is associated with decreased sensations of hunger and increased feeling of satiety besides, sibutramine leads to a slightly enhanced basal metabolic rate (Hansen et al., 1999). Sibutramine has the following side effects xerostomia, insomnia, obstipation and a mild increase of blood pressure and heart rate.

Inborn Errors of Metabolism in Which the KD Is Contraindicated

There are definitive contraindications to the use of the KD. These include defects in fat metabolism and disorders that require high carbohydrate contents. Failure to diagnose these disorders before starting the KD could result in significant morbidity and may be fatal. These contraindications should therefore be considered in every child before the KD treatment is started.

Perspectives On The Antiepileptic Mechanism Of Caloric Restriction

Ketogenic Diet For Seizures

We propose that CR inhibits seizure susceptibility by shifting brain energy metabolism from glucose to ketone bodies. A CR-induced reduction in glucose utilization and increase in ketone utilization will, on the one hand, reduce the glycolytic energy reserves related to seizure activity and, simultaneously, decrease neuronal excitability through ketone metabolism. This involves multiple metabolic changes that would ultimately shift the neural environment from excitation to inhibition. An outline of these changes (Fig. 8) was recently presented in relation to metabolic control theory for the management of epilepsy (11). tic activity, and seizures are associated with enhanced glycolysis (82-86). Brain lactate levels also increase significantly during seizure activity (87,88). The seizure-associated lactate increase reflects the rapid increase in glycolytic rate over the cerebral metabolic rate of oxygen, and the maximally activated pyruvate dehydrogenase is the rate-limiting step (81)....

HT Receptors Feeding Behavior and Body Weight in Rodents

5ht2c Receptor Alzheimer

Fig. 17.1 Functional divergence in 5-HT2C receptor pathway. Serotonin (5-HT) inhibits feeding-stimulatory NPY AgRP neurons through 5-HT1B receptor, while activating feeding-inhibitory POMC CART neurons through 5-HT2C receptors. The primary effect by 5-HT receptor on energy metabolism requires downstream activation of MC4R. A novel 5-HT2C receptor pathway that regulates physiologic gastrointestinal (GI) motility, requiring sympathetic activity and leading to inhibition of ghrelin but not MC4R. 5-HT indirect agonist-selective serotonin reuptake inhibitors activate both 5-HT2C receptor pathways, but not the 5-HT1B pathway, for the anorexia and GI motor effects produced. AgRP agouti-related peptide, CART cocaine- and amphetamine-regulated transcript, DVC dorsal vagal complex, IML intermediolateral nucleus of the spinal cord, NPY neuropeptide Y, POMC pro-opiomelanocortin, SNS sympathetic nervous system (Reproduced from Fujitsuka et al. 2009. With permission) Fig. 17.1 Functional divergence...

Traumatic Brain Injury

Canavan Disease

Reduced NAA concentrations can reflect neuronal death, but this mechanism cannot account for the reversible decreases in NAA observed in multiple sclerosis 22 and stroke 23 , or the possible increases over time, post-injury, observed in our TBI sample 18 . Given Gasparovic's results, and the fact that our NAA analyses were undertaken in normal appearing tissue, it may well be the case that individual variation in metabolism, rather than loss of neurons, underlies the well-established relationship between NAA and concurrent and long term cognitive function. Consistent with this possibility, Positron Emission Tomography analysis has shown that NAA concentrations correlate with overall metabolic rate 24 , which is often reduced after TBI.

Regulation of mRNA Translation and Stability in Iron Metabolism Is there a Redox Switch

Due to its capacity to donate or accept electrons, iron was selected since the earliest times of natural evolution for redox reactions in living organisms. Thus, iron in heme, in iron-sulfur clusters or directly bound to proteins is a constituent of many essential proteins with functions in oxygen transport, energy metabolism, electron transfer, deoxynucleotide synthesis or detoxification. Its presence in the active sites of numerous enzymes implies that cells must have a sufficient pool of free iron available for protein

O Antianginal Agents And Vasodilators

Energy metabolism by heart tissue provides an adequate supply of high-energy phosphate compounds to replace the adenosine triphosphate (ATP) that is continually being consumed in contraction, ion exchange across membranes, and other energy-demanding processes. Because of the high turnover rate of ATP in heart muscle, a correspondingly high rate of ATP production in the mitochondria is required.

Mechanism Of Action And Resistance

Metronidazole is a prodrug that is activated by reduction of the nitro group by susceptible organisms. Unlike their aerobic counterparts, anaerobic and microaerophilic pathogens such as T. vaginalis, E. histolytica, and G. lamblia and anaerobic bacteria contain electron transport components that have a sufficiently negative redox potential to donate electrons to metronidazole. Electron transfer forms a highly reactive nitro radical anion that kills susceptible organisms by radical-mediated mechanisms that target DNA. Metronidazole is catalytically recycled loss of the active metabolite's electron regenerates the parent compound. Increasing levels of O2 inhibit metronidazole-induced cytotoxicity because O2 competes with metronidazole for electrons generated by energy metabolism. Thus, O2 can both decrease reductive activation of metronidazole and increase recycling of activated drug. In susceptible organisms, pyruvate decarboxylation, catalyzed by pyruvate ferredoxin oxidoreductase...

Integrative Risk Assessment

Once we understand the individual data or data sets, the next step is integration of data from various assays. For example, early data on liver microsomal stability can alert the team to look for possible metabolites and get their profile (see above reference to species differences in metabolism). The poster child for this scenario is terfenadine, which has an active metabolite, fexofenadine (a safe drug), while the parent compound is a potent hERG channel blocker 41 . A retrospective, integrated risk assessment of terfenadine based on present, routine in vitro profiling clearly alerts to hERG inhibition, but equally importantly also shows the predicted high metabolism of this compound. Early analysis of the predicted metabolites in the in vitro profiling assays would have pointed directly towards the development of the safer compound, fexofenadine (Table 3.3).

Development Of Tolerance During Longterm Use Of Opioids

Nerve Endings Opioid Receptors

Metabolic causes, whereby an increase in activity of specific liver enzymes result in an increase of metabolic degradation with a reduced concentration of the pharmacologically active compound. Due to the habituation of the organism to the opioid, an increased metabolic rate results in major degradation, which is mirrored in a loss of efficacy. Then the dose must be sequentially increased in order to achieve a continuous and sufficient analgesic effect.

Compounds Acting on Glucose Absorption

The short-term efficacy of guar on postprandial glucose lowering has been repeatedly shown (Jenkins et al., 1977a, 1978 Johnson and Gee, 1980 Schwartz et al., 1982). The acute effect of guar on carbohydrate and fat metabolism lasts at least 4h and may result in improved carbohydrate tolerance to subsequent guar-free meals (Jenkins et al., 1980). No effect of dietary fibres such as guar was noted if the supplementation was with guar powder (Williams et al., 1980). In 13 maturity-onset non-insulin-dependent diabetics, 10 g of guar failed to decrease significantly the postprandial rise in plasma glucose and insulin seen after a similar meal without supplementation. Only when guar was added to liquid meals or incorporated into foods such as bread, or if dietary fibres had their origin from readily available foods, could metabolic effects be easily identified.

Peroxisomal Proliferator Activated Receptors

Hyperplasia, and hepatic malignancies in rodents (reviewed in Lemberger et al., 1996a Schoonjans et al., 1996b). This class of compounds includes many industrial chemicals and herbicides as well as drugs used to treat hypercholesterolemia and other lipid abnormalities. Peroxisomal prolifera-tors potentially exert their short- and medium-term effects through two mechanisms Genomic effects are mediated by members of the peroxisomal proliferator activated receptor family (PPARs), while nongenomic effects may be mediated by alterations in cellular energy metabolism and by the generation of peroxisomal metabolic by-products. The mediators of long-term peroxisomal proliferator effects are less clear, although their stimulation of peroxisomal hydrogen peroxide production has been suggested to cause their genotoxic effects. 4. PPARs Regulate Fat Metabolism, Adipocyte Differentiation, and Macrophage Function

Peripheral indications

Mice lacking the p1 adrenoceptor fail to respond to the inotropic action of -adrenoceptor agonists, confirming the importance of this subtype in the control of cardiac contractility. However, maximal exercise capacity is not reduced (Rohrer etal. 1998). Mice lacking the p2-adrenoceptor have a normal response to exogenous -adrenoceptor agonists, and have even greater exercise capacity than wild-type mice. However, these animals become hypertensive during exercise and have a lower respiratory exchange ratio, suggesting influences of the p2-adrenoceptor on energy metabolism (Chruscinski etal. 1999). Mice lacking both p1- and -adrenoceptors have normalbasal cardiovascular parametres and normal exercise capacity, although the ability of exercise or the administration of exogenous agonists to increase heart rate is blunted (Rohrer et al. 1999). Mice lacking the p3-adrenoceptor show mild increases in body fat stores, and do not show metabolic responses to a selective p3-adrenoceptor agonists...

Brain Energetics and Metabolism

With both generalized and focal seizure activity, the brain's demand for energy increases markedly. Cerebral metabolic rate rises, as manifested by elevations in cerebral blood flow as well as oxygen and glucose utilization, which increase severalfold. Multiple energy metabolites increase, as summarized in Table 2 (31). Glucose is

In Cubo Crystallization


The lipidic matrix of choice is a bicontinuous cubic phase of monoacylglyc-erols (MAGs) and water. MAGs are an important intermediate in fat metabolism that adopts a remarkable variety of liquid crystal phases when dispersed in water this makes them an ideal matrix choice. In both the recent p2AR and A2a T4L fusion structures, the MAG used was monoolein, which was substantially supplemented with cholesterol. While cholesterol provides an active component required to stabilize proteins, the lipid also provides a large number

Stress Obesity and Metabolic Syndrome

So, can perceived stress and its biological correlate lead to metabolic disturbance The answer would seem to be yes, in that, stress be it social or work-related leads to an immediate activation of the sympatho-adrenal network which leads to an outpouring of norepinephrine and cortisol which in healthy non-obese individuals results in tachycardia, a reflex vasodilation and the disposal of glucose while the opposite metabolic effects are seen in obesity 54 . The origin of the stress can be work-related or otherwise, as suggested in a study by Chandola et al. 55 who found that such stress was associated with higher cortisol levels in the morning and was directly related to the future development of IHD.

Hepatocyte M3 mAChRs Are Not Critical for Maintaining Normal Blood Glucose Levels

Accumulating evidence suggests that the activity of efferent hepatic vagal nerves is critical for maintaining normal blood glucose homeostasis (Pocai et al. 2005a, b Lam et al. 2005 Wang et al. 2008). Li et al. (2009) therefore speculated that the metabolic effects observed after stimulation of efferent hepatic vagal nerves might be mediated by activation of mAChRs expressed by liver hepatocytes. The authors first demonstrated that the M3 mAChR is the only mAChR subtype expressed by mouse hepatocytes, consistent with data obtained with rat hepatocytes (Vatamaniuk et al. 2003). To examine the potential metabolic importance of this subpopulation of M3 mAChRs, Li et al. (2009) used Cre loxP technology to generate mutant mice that lacked M3 receptors only in hepatocytes (Hep-M3-KO mice). In addition, the authors also created transgenic mice that overexpressed M3 mAChRs selectively in hepatocytes (Hep-M3-Tg mice). Somewhat surprisingly, detailed phenotypic analysis of these mutant animals...

The Effect of Diet on Drug Metabolism

It is also obvious that the absence of ingested food, i.e., starvation, will have its particular influences, although these are localized more prominently in the liver, where the activities of drug-metabolizing enzymes are changed by the nutritional status. Thus, protein-rich nutrition generally increases the respective activities, whereas starvation decreases the metabolic rate.

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