Metabolic iteration,evolution and cognition in cellular proliferation

Summary A model for cellular proliferation is described according to which proliferation ensues when metabolism evolves towards commitment to DNA synthesis, and inhibition of proliferation occurs when enzymic interactions are iterated within a few metabolic pathways, another limiting factor being the supply of metabolites. The model successfully describes cellular growth and division as a cognitive process based on interaction within enzymic elements and the genome, and affords an explanation in these terms of some empirical phenomena which have previously been understood only as isolated observations.     

Detection of toxic metabolites in the hemolymph ofBeauveria bassiana infectedSpodoptera exigua larvae

Highly active metabolites have been detected in the hemolymph of the lepidopteranSpodoptera exigua infected with the mycopathogen,Beauveria bassiana. A combination of phenyl sepharose and CM ion exchange chromatography was utilized to extract the active metabolites from infected hemolymph samples. The active in vivo metabolites, having a molecular mass greater than 10 KDa, were thermolabile and were inactivated by proteinase K. These metabolites were characterized by their ability to disrupt metamorphosis, killing treated larvae at the wandering or pupal stage. Additionally, injection ofS. exigua larvae with active samples caused a reduction in the number of filopodial-producing hemocytes. The biological activities and biochemical properties suggest that novel compounds are produced duringB. bassiana mycosis.     

Minor nitrogenous sesquiterpenes from the marine spongeAxinella cannabina. A hypothesis for the biogenesis of the spiro-axane skeleton

Summary Three nitrogenous sesquiterpenoids (4–6), possessing an isocyanide, isothiocyanate or formylamino function, have been isolated from the marine spongeAxinella cannabina. The proposed structures were based on interpretation of spectral data including 2D-NMR techniques and chemical evidence. A plausible pathway for the biogenesis of these compounds and the co-occurring spiro-axane (1–3) metabolites is proposed.Work supported by C.N.R. (Progetto Finalizzato Chimica Fine e Secondaria and by MPI Italy.     

Metabolic iteration, evolution and cognition in cellular proliferation

A model for cellular proliferation is described according to which proliferation ensues when metabolism evolves towards commitment to DNA synthesis, and inhibition of proliferation occurs when enzymic interactions are iterated within a few metabolic pathways, another limiting factor being the supply of metabolites. The model successfully describes cellular growth and division as a 'cognitive process' based on interaction within enzymic elements and the genome, and affords an explanation in these terms of some empirical phenomena which have previously been understood only as isolated observations.     

The phytotoxins ofMycosphaerella fijiensis,the causative agent of Black Sigatoka disease of bananas and plantains

Black Sigatoka is the most costly to control disease of bananas and plantains in the world. Currently, a worldwide search is underway either to find or to produce cultivars that are disease-resistant or-tolerant. Phytotoxins isolated from the pathogen might facilitate the discovery of such cultivars. Several aromatic compounds from liquid cultures ofMycosphaerella fijiensis, the causal agent of Black Sigatoka disease of bananas and plantains, have been isolated. The most abundant and phytotoxic of these compounds is 2,4,8-trihydroxytetralone, which induces necrotic lesions at 5 g/5 l in less than 12 h on sensitive cultivars of bananas. This compound exhibits host-selectivity that mimics that of the pathogen. Other phytotoxins isolated from this fungus, in lesser amounts, were juglone, the novel compound 2-carboxy-3-hydroxycinnamic acid, isoochracinic acid and 4-hydroxyscytalone. Some of the phytotoxins isolated are melanin shunt pathway metabolites, which makes this fungus unique among plant pathogens.     

Novel metabolite of nitrazepam in the rabbit urine

Summary Two novel metabolites appearing mainly as conjugated form in the urine of rabbits fed nitrazepam have been isolated as deconjugated form. From the data of elemental and spectral analysis, the structure was confirmed as 2-amino-3-hydroxy-5-nitrobenzophenone (M-I) and 2-benzoyl-4-nitro-2-hydroxyacetanilide (M-II).     

Roquefortine and isofumigaclavine A,metabolites fromPenicillium roqueforti

Summary The structures of two metabolites fromPenicillium roqueforti, designated roquefortine and isofumigaclavine A, have been determined by chemical and spectroscopic studies.     

New tamjamine class alkaloids from the marine ascidianAtapozoa sp. and its nudibranch predators. Origin of the tambjamines inAtapozoa

Summary Two new tambjamine class alkaloids, possessing ichthyodeterrent properties, have been isolated from the organic extracts of the marine ascidianAtapozoa sp. and its nudibranch predators. The structure of the new metabolites were elucidated through interpretation of their physical and spectral data and by comparison with spectral data for related compounds. Microscopic examination ofAtapozoa considering the yellow color of the tambjamines suggested thatAtapozoa is capable of the de novo biosynthesis of these metabolites.     

Innate and intrinsic antiviral immunity in Drosophila

The fruit fly Drosophila melanogaster has been a valuable model to investigate the genetic mechanisms of innate immunity. Initially focused on the resistance to bacteria and fungi, these studies have been extended to include antiviral immunity over the last decade. Like all living organisms, insects are continually exposed to viruses and have developed efficient defense mechanisms. We review here our current understanding on antiviral host defense in fruit flies. A major antiviral defense in Drosophila is RNA interference, in particular the small interfering (si) RNA pathway. In addition, complex inducible responses and restriction factors contribute to the control of infections. Some of the genes involved in these pathways have been conserved through evolution, highlighting loci that may account for susceptibility to viral infections in humans. Other genes are not conserved and represent species-specific innovations.     

The emerging roles of ribosomal histidyl hydroxylases in cell biology,physiology and disease

Hydroxylation is a novel protein modification catalyzed by a family of oxygenases that depend on fundamental nutrients and metabolites for activity. Protein hydroxylases have been implicated in a variety of key cellular processes that play important roles in both normal homeostasis and pathogenesis. Here, in this review, we summarize the current literature on a highly conserved sub-family of oxygenases that catalyze protein histidyl hydroxylation. We discuss the evidence supporting the biochemical assignment of these emerging enzymes as ribosomal protein hydroxylases, and provide an overview of their role in immunology, bone development, and cancer.     

Identification of catecholamines and serotonin in the notochords of chick embryos]

The neurotransmitter amines, norepinephrine, dopamine and serotonine have been isolated from Chick notochords. Cholinergic agents produce important modifications in the amount of these amines and of one of their metabolites. The results demonstrate the presence, at a very early stage of development, between the second and the third day of incubation, of biogenic amines and cholinergic receptors.     

Ion and metabolite transport in the chloroplast of algae: lessons from land plants

Chloroplasts are endosymbiotic organelles and play crucial roles in energy supply and metabolism of eukaryotic photosynthetic organisms (algae and land plants). They harbor channels and transporters in the envelope and thylakoid membranes, mediating the exchange of ions and metabolites with the cytosol and the chloroplast stroma and between the different chloroplast subcompartments. In secondarily evolved algae, three or four envelope membranes surround the chloroplast, making more complex the exchange of ions and metabolites. Despite the importance of transport proteins for the optimal functioning of the chloroplast in algae, and that many land plant homologues have been predicted, experimental evidence and molecular characterization are missing in most cases. Here, we provide an overview of the current knowledge about ion and metabolite transport in the chloroplast from algae. The main aspects reviewed are localization and activity of the transport proteins from algae and/or of homologues from other organisms including land plants. Most chloroplast transporters were identified in the green alga Chlamydomonas reinhardtii, reside in the envelope and participate in carbon acquisition and metabolism. Only a few identified algal transporters are located in the thylakoid membrane and play role in ion transport. The presence of genes for putative transporters in green algae, red algae, diatoms, glaucophytes and cryptophytes is discussed, and roles in the chloroplast are suggested. A deep knowledge in this field is required because algae represent a potential source of biomass and valuable metabolites for industry, medicine and agriculture.     

The potential therapeutic role of statins in central nervous system autoimmune disorders

3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of mevalonate are also involved in posttranslational modification of specific proteins involved in cell proliferation and differentiation. Thus, statins have important biologic effects that may be independent of their cholesterol-reducing properties. Recent studies indicate that statins have antiinflammatory and neuroprotective properties which may be beneficial in the treatment of multiple sclerosis as well as other central nervous system (CNS) neurodegenerative diseases. This article will outline current experimental evidence that may suggest potential clinical benefits for patients with CNS autoimmune disorders. Ultimately, clinical trials will have to determine the safety and efficacy of statins in this patient population.Received 17 April 2003; received after revision 21 May 2003; accepted 22 May 2003     

The clinical potential of sphingolipid-based therapeutics

The era of sphingolipid-based therapeutics is upon us. A large body of work has been accumulating that demonstrates the distinct biological roles of sphingolipids in maintaining a homeostatic environment and in responding to environmental stimuli to regulate cellular processes. It is thus necessary to further investigate alterations in sphingolipid-metabolism in pathological conditions and, in turn, try to exploit altered sphingolipid-metabolizing enzymes and their metabolites as therapeutic targets. This review will examine how advances in the fields of drug delivery, drug discovery, synthetic chemistry, enzyme replacement therapy, immunobiology, infectious disease and nanotechnology have delivered the potential and promise of utilizing and/or targeting sphingolipid metabolites as therapies for diverse diseases.     

Physical exercise stimulates marked concomitant release of β-endorphin and adrenocorticotropic hormone (ACTH) in peripheral blood in man

Summary ACTH and -endorphin have been evaluated by means of a specific and sensitive radioimmunoassay in athletes reaching a status of physical stress. A concomitant marked increase of these 2 peptides has been recorded. The implications of this finding lead to the conclusion that stress stimulates the synthesis of the common precursor (31 K) in the pituitary.     

Measurement of fluorescence decay of substances absorbed by an isolated living cell: an experimental device and early results]

A microfluorometric system allowing the mesurements of fluorescence decay (i.e. fluorescence lifetime) has been built. It will complete the microspectrofluorometric studies of absorbed compounds-polycyclic aromatic hydrocarbons, metabolites of benzo (a) pyrene-by single living cells and allows a better understanding of the intake and metabolisation of these compounds. The preliminary results with benzo (a) pyrene, dibenzocarbazole, pyrene are shown.     

Mapping and quantification of biomolecules in tumor biopsies using bioluminescence

Quantitative bioluminescence and single-photon imaging have been applied for mapping concentration distributions of metabolites, such as adenosine triphosphate (ATP), glucose and lactate, in biopsies of cervical cancers in patients. Biopsies were taken before a conventional radiation treatment, and a number of clinically relevant data, such as local tumor control, patient survival, metastatic spread and so forth, were documented. There was no correlation between staging or grading and any of the metabolic parameters measured. Local correlations between ATP, glucose and lactate on a pixel-to-pixel basis were generally positive, with respective Spearman's correlation coefficients less in patients without clinically documented metastasis compared with those with metastatic spread. Lactate concentrations were significantly higher and scattered over a wider range in tumors with metastatic spread in comparison to malignancies in patients without metastasis. Thus, high local lactate levels of 20 mole/g appear to be associated with a high risk of metastasis, at least in human cervical tumors.     

Activité tuberculostatique de nouvelles N,N′-diarylthiourées

Summary A number of new diversely substituted thiocarbanilides and N-aryl-N-naphthylthioureas have been found which display pronounced tuberculostatic activityin vitro. One of these compounds, 4-ethyl-4-isoamyloxythiocarbanilide, proved to be particularly effective.     

The role of dietary carbohydrates in organismal aging

Carbohydrates are essential nutrients that are used as a primary source of energy. Carbohydrate utilization should be properly controlled, as abnormal regulation of carbohydrate metabolism is associated with diseases, such as diabetes, cardiovascular diseases, and stroke. These metabolic syndromes have become a serious problem in developed countries, and there is an increased need for research examining the influence of carbohydrates on animal physiology. Diets enriched in glucose, a major carbohydrate, are also associated with accelerated aging in several model organisms, including yeast and Caenorhabditis elegans (C. elegans). Genetic factors that mediate the effects of high glucose diets on aging have been identified during the last decade, mostly through the use of C. elegans. In this review, we describe studies that determine the effects of carbohydrate-enriched diets on aging by focusing on the mechanisms through which evolutionarily conserved pathways mediate the lifespan-altering effects of glucose in C. elegans. These include the insulin/insulin-like growth factor-1, sterol-regulatory element-binding protein, and AMP-activated protein kinase signaling pathways. We also discuss the effects of various carbohydrates and carbohydrate-derived metabolites on aging in model organisms and cultured mammalian cells. Finally, we discuss how dietary carbohydrates influence health and aging in humans.