Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Peptide activity scanning identified NAP (NAPVSIPQ) as a small active fragment of ADNP that provides neuroprotection at very low concentrations. In cell culture, NAP has demonstrated protection against toxicity associated with the beta-amyloid peptide, N-methyl-D-aspartate, electrical blockade, the envelope protein of the AIDS virus, dopamine, H2O2, nutrient starvation and zinc overload. NAP has also provided neuroprotection in animal models of apolipoprotein E deficiency, cholinergic toxicity, closed head injury, stroke, middle aged anxiety and cognitive dysfunction. NAP binds to tubulin and facilitates microtubule assembly leading to enhanced cellular survival that is associated with fundamental cytoskeletal elements. A liquid-chromatography, mass spectrometry assay demonstrated that NAP reaches the brain after either intravenous or intranasal administration. In a battery of toxicological tests including repeated dose toxicity in rats and dogs, cardiopulmonary tests in dogs, and functional behavioral assays in rats, no adverse side effects were observed with NAP concentrations that were approximately 500-fold higher than the biologically active dose. A Phase Ia clinical trial in the US assessed the tolerability and pharmacokinetics of intranasal administration of NAP in sequential ascending doses. The results supported the safety and tolerability of a single dose of NAP administered at up to 15 mg intranasally. Furthermore, dosing was recently completed for a second Phase I clinical trial in healthy adults and elderly volunteers with an intravenous formulation of NAP. NAP is poised for further clinical development targeting several indications, including Alzheimer's disease.
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PMID:NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP). 1661 35

The 5'-adenosine monophosphate-activated protein kinase (AMPK) is a metabolic and stress sensor that has been functionally conserved throughout eukaryotic evolution. Activation of the AMPK system by various physiological or pathological stimuli that deplete cellular energy levels promotes activation of energy restorative processes and inhibits energy consumptive processes. AMPK has a prominent role not only as a peripheral sensor of energy balance, but also in the CNS as a multifunctional metabolic sensor. Recent work suggests that AMPK plays an important role in maintaining whole body energy balance by coordinating feeding behaviour through the hypothalamus in conjunction with peripheral energy expenditure. In addition, brain AMPK is activated by energy-poor conditions induced by hypoxia, starvation, and ischaemic stroke. Under these conditions, AMPK is activated as a protective response in an attempt to restore cellular homeostasis. However in vivo, it appears that the overall consequence of activation of AMPK is more complex than previously imagined, in that over-activation may be deleterious rather than neuroprotective. This review discusses recent findings that support the role of AMPK in brain as a multidimensional energy sensor and the consequences of its activation or inhibition under physiological and pathological states.
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PMID:Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain. 1669 Jul 4

For much of the 20th century, the accumulation of a considerable amount of information about the processes of aging did not reveal the underlying mechanisms. Toward the end of that century, the biological basis for aging became very much clearer. It became apparent that the best strategy for animals' survival was to develop to an adult, but not to invest resources in maintaining the body, or soma, indefinitely. In their natural environment, animals do not survive environmental hazards (predators, disease, starvation, and drought) to reach a long life span. There is thus a trade-off between the investment of resources in reproduction, and the survival time of the soma. At a stroke, this solves the problem of different rates of aging in different species, because those that develop and reproduce fast also have short life spans, and those that develop and reproduce slowly have long life spans. This difference is due to actual resources invested in the maintenance of the adult soma. There is now much evidence that long-lived mammals have much more efficient maintenance mechanisms than short-lived mammals. Thus, aging can be defined as the eventual failure of maintenance. It also became apparent that many different maintenance mechanisms exist, and that these depend on very many genes and a considerable investment in metabolic resources. Most individual theories of aging revolve around the failure of a given maintenance system, but as there are many of these, it is likely that most of the important theories have some degree of truth. A broad interpretation of the different degenerative changes during senescence should therefore be adopted, with the major conclusion that aging is multicausal. It is also evident that the evolved design of many components of complex animals is incompatible with indefinite survival. We can therefore conclude that this evolved design is intrinsically related to the fact of aging. This in turn means that aging cannot be reversed, although it may be modulated, as, for example, by calorie restriction.
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PMID:Aging is no longer an unsolved problem in biology. 1680 64

This article, which is partly biographical and partly scientific, summarizes a life in academic medicine. It relates my progress from benchside to bedside and then to academic and research administration, and concludes with the teaching of human biology to college undergraduates. My experience as an intern (anno 1953) treating a youngster in diabetic ketoacidosis underscored our ignorance of the controls in human fuel metabolism. Circulating free fatty acids were then unknown, insulin could not be measured in biologic fluids, and beta-hydroxybutyric acid, which was difficult to measure, was considered by many a metabolic poison. The central role of insulin and the metabolism of free fatty acids, glycerol, glucose, lactate, and pyruvate, combined with indirect calorimetry, needed characterization in a near-steady state, namely prolonged starvation. This is the main topic of this chapter. Due to its use by brain, D-beta-hydroxybutyric acid not only has permitted man to survive prolonged starvation, but also may have therapeutic potential owing to its greater efficiency in providing cellular energy in ischemic states such as stroke, myocardial insufficiency, neonatal stress, genetic mitochondrial problems, and physical fatigue.
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PMID:Fuel metabolism in starvation. 1684 98

Homocysteine (Hcy) is a thiol-containing amino acid that is considered to be medically important because it is linked to the development of several life-threatening diseases in humans, including cardiovascular disease and stroke. It inhibits the growth of Escherichia coli when supplied in the growth medium. Growth inhibition is believed to arise as a result of partial starvation for isoleucine, which occurs because Hcy perturbs the biosynthesis of this amino acid. This study attempted to further elucidate the inhibitory mode of action of Hcy by examining the impact of exogenously supplied Hcy on the transcriptome. Using gene macroarrays the transcript levels corresponding to 68 genes were found to be reproducibly altered in the presence of 0.5 mM Hcy. Of these genes, the biggest functional groups affected were those involved in translation (25 genes) and in amino acid metabolism (19 genes). Genes involved in protection against oxidative stress were repressed in Hcy-treated cells and this correlated with a decrease in catalase activity. The gene showing the strongest induction by Hcy was cspA, which encodes the major cold-shock protein CspA. RT-PCR and reporter fusion experiments confirmed that cspA was induced by Hcy. Induction of cspA by Hcy was not caused by nutritional upshift, a stimulus known to induce CspA expression, nor was it dependent on the presence of a functional CspA protein. The induction of cspA by Hcy was suppressed when isoleucine was included in the growth medium. These data suggest that the induction of CspA expression in the presence of Hcy occurs because of a limitation for isoleucine. The possibility that Hcy-induced cspA expression is triggered by translational stalling that occurs when the cells are limited for isoleucine is discussed.
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PMID:Global effects of homocysteine on transcription in Escherichia coli: induction of the gene for the major cold-shock protein, CspA. 1684 89

Court Decision: 512 New York Supplement, 2d Series 622; 1986 Oct 27 (date of decision). The wife of a comatose stroke patient petitioned the New York Supreme Court, Nassau County, for an order authorizing removal of the nasogastric tube which was the patient's only source of nourishment. The Court appointed a guardian ad litem who opposed the petition because the patient, though in a vegetative state, was neither terminally ill nor brain dead. The Court heard testimony by relatives and a family friend that, prior to his illness, the patient had expressed a wish not to be kept alive solely by artificial means. The Court denied the petition on the grounds that the patient was not being kept alive by extraordinary means but was simply unable to care for himself due to his infirmities. In view of this distinction, the Court held that society's duty was to care for the patient rather than to induce his death by starvation.
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PMID:Vogel v. Forman. 1708 48

Biological evolution abides by an unbending rule obligating organisms to maintain energy equilibrium. Hypoxia reduces cellular energy supply and is thus thought to be deleterious. We report that cells have evolved pH-sensitive mechanisms to maintain energy equilibrium by lowering energy demand. We found that fermentation-induced acidosis allows hypoxic cells to maintain energy equilibrium and viability under hypoxia by restricting ribosomal biogenesis, the most energy-demanding cellular process. Acidosis triggers nucleolar condensation, decreases precursor rRNA synthesis, reduces the dynamic profile of the RNA polymerase I preinitiation factor UBF1 and its interaction with the promoter of rRNA genes (rDNA). These changes require the pH-dependent interaction of the statically detained von Hippel-Lindau tumor suppressor protein (VHL) with rDNA. This phenomenon is promoted by, but does not require, activation of the hypoxia-inducible factor (HIF), a transcription factor implicated in extracellular acidification, energy production and oxygen homeostasis. Abrogating this program by silencing VHL expression, competing rDNA-VHL interaction or preventing environmental acidification triggers energy starvation and cell death under hypoxia. Our data suggest that oxygen-starved cells maintain energy equilibrium by gauging the environmental concentration of H(+) to statically detain VHL to nucleolar rDNA and restrict ribosome production. These findings also provide an explanation for the protective effect of acidosis in ischemic settings such as development, stroke and cancer.
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PMID:Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia. 1710 17

After stroke or traumatic damages, both necrotic and apoptotic neuronal death cause a loss of functions including memory, sensory perception, and motor skills. From the fact that necrosis has a nature to expand, while apoptosis to cease the cell death cascade in the brain, it is considered that the promising target for the rapid treatment for stroke is the necrosis. In this study, I introduce the discovery of prothymosin alpha (ProTalpha), which inhibits neuronal necrosis, and propose its potentiality of clinical use for stroke. First of all, it should be noted that ProTalpha inhibits the neuronal necrosis induced by serum-free starvation or ischemia-reperfusion stress, which causes a rapid internalization of GLUT1/4, leading a decrease in glucose uptake and cellular ATP levels. Underlying mechanisms are determined to be through an activation of Gi/o, phospholipase C and PKCbetaII. ProTalpha also causes apoptosis later through a similar mechanism. However, we found that ProTalpha-induced apoptosis is completely inhibited by the concomitant treatment with neurotrophins, which are up-regulated by ischemic stress in the brain. Of most importance is the finding that the systemic injection of ProTalpha completely inhibits the brain damages, motor dysfunction and learning memory defect induced by cerebral ischemia-reperfusion stress. As ProTalpha almost entirely prevents the focal ischemia-induced motor dysfunction 4 h after the start of ischemia, this protein seems to have a promising potentiality for clinical use.
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PMID:Prothymosin alpha plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke. 1817 98

Neurotrophins are critical for the survival of neurons during development and insufficient access to neurotrophins later in life may contribute to the loss of neurons in neurodegenerative disease, spinal cord injury, and stroke. The prolyl hydroxylase inhibitors ethyl 3,4-dihydroxybenzoic acid (DHB) and dimethyloxalylglycine (DMOG) were shown to inhibit cell death in a model of neurotrophin deprivation that involves depriving sympathetic neurons of nerve growth factor (NGF). Here we show that treatment with DMOG or DHB reverses the decline in 2-deoxyglucose uptake caused by NGF withdrawal and suppresses the NGF deprivation-induced accumulation of reactive oxygen species. Neither DMOG nor DHB prevented death when NGF deprivation was carried out under conditions of glucose starvation, and both compounds proved toxic to NGF-maintained neurons deprived of glucose, suggesting that their survival-promoting effects are mediated through the preservation of glucose metabolism. DHB and DMOG are well known activators of hypoxia-inducible factor (HIF), but whether activation of HIF underlies their survival-promoting effects is not known. Using gene disruption and RNA interference, we provide evidence that DMOG and, to a lesser extent, DHB require HIF-2alpha expression to inhibit NGF deprivation-induced death. Furthermore, suppressing basal HIF-2alpha expression, but not HIF-1alpha, in NGF-maintained neurons is sufficient to promote cell death. These results implicate HIF-2alpha in the neuroprotective mechanisms of prolyl hydroxylase inhibitors and in an endogenous cell survival pathway activated by NGF in developing neurons.
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PMID:Prolyl hydroxylase inhibitors depend on extracellular glucose and hypoxia-inducible factor (HIF)-2alpha to inhibit cell death caused by nerve growth factor (NGF) deprivation: evidence that HIF-2alpha has a role in NGF-promoted survival of sympathetic neurons. 1920 94

Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions including memory, sensory perception and motor skills. Since necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. Pure neuronal necrosis occurs when cortical neurons are cultured under serum-free and low-density conditions. Prothymosin alpha (ProTalpha) isolated from conditioned medium after serum-free culture was found to prevent necrosis by recovering the energy crisis due to endocytosed glucose transporters. At a later time point under the same starvation conditions, ProTalpha causes apoptosis, which in turn seems to inhibit the rapidly occurring necrosis by cleaving poly (ADP-ribose) polymerase, a major machinery involved in ATP consumption. Indeed, ProTalpha administered via systemic routes markedly inhibits the histological and functional damage induced by cerebral and retinal ischemia. Although ProTalpha also causes a cell death mode switch from necrosis to apoptosis in vivo, the induced apoptosis was found to be completely inhibited by endogenously occurring brain-derived neurotrophic factor or erythropoietin. Since forced downregulation of ProTalpha deteriorates the ischemic damage, it is evident that ProTalpha plays in vivo neuroprotective roles after ischemic events. Analyses in terms of the therapeutic time window and potency suggest that ProTalpha could be the prototypic compound to develop the medicine useful for treatment of stroke in clinics.
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PMID:Prothymosin alpha and cell death mode switch, a novel target for the prevention of cerebral ischemia-induced damage. 1950 Jun 18


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