Two axes in platelet-derived growth factor signaling: tyrosine phosphorylation and reactive oxygen species

The tyrosine phosphorylation cascade is a hallmark of platelet-derived growth factor (PDGF)- induced signal transduction. The amplitude and propagation of the tyrosine phosphorylation signal relies on the balance between tyrosine kinase and tyrosine phosphatase. The tyrosine kinase is latent in the absence of stimulation, whereas the tyrosine phosphatase is highly and constitutively active. Therefore, the kinase activation should be accompanied by temporal and spatial inactivation of tyrosine phosphatase to achieve the robust amplification of tyrosine phosphorylation. For the past decade, reactive oxygen species have been receiving a great deal of attention with regard to their ability to shut down tyrosine phosphatase activities in a reversible manner. In this article, the crosstalk between tyrosine phosphorylation and reactive oxygen species in PDGF signaling is discussed. Received 2 October 2006; received after revision 13 November 2006; accepted 27 November 2006     

Involvement of reactive oxygen species in the microsomal S-oxidation of thiobenzamide

Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase. This indicates that excited oxygen species (e.g. X O-2,H2O2, X OH) are involved in the catalytic cycle of this enzymatic reaction. CO, which inhibits the cytochrome P-450-dependent oxygen radical formation, had no effect on the oxidation reaction, suggesting that the source of the reactive oxygen species is not the microsomal mixed-function oxidase.     

Involvement of reactive oxygen species in the microsomal S-oxidation of thiobenzamide

Summary Superoxide dismutase, catalase and methional proved capable of inhibiting the microsomal oxidation of thiobenzamide, which is most probably catalyzed by the flavin-containing monooxygenase. This indicates that excited oxygen species (e. g.·O ₂ ^– , H₂O₂, ·OH) are involved in the catalytic cycle of this enzymatic reaction. CO, which inhibits the cytochrome P-450-dependent oxygen radical formation, had no effect on the oxidation reaction, suggesting that the source of the reactive oxygen species is not the microsomal mixed-function oxidase.     

Influence of reactive oxygen species production by monoamine oxidase activity on aluminum-induced mitochondrial permeability transition

Treatment of Ca2+-loaded mitochondria with both aluminum and tyramine results in a swelling of higher amplitude than with aluminum alone, while tyramine alone is ineffective. The phenomenon is accompanied by H2O2 production and thiol and pyridine nucleotide oxidation. Cyclosporin A, N-ethylmaleimide or dithioerythritol completely prevent these effects, while catalase exhibits a lower inhibition, pointing to the induction of the permeability transition (MPT) by an oxidative stress. Reactive oxygen species are generated by the interaction of aluminum with the inner membrane and the oxidation of tyramine by monoamine oxidase on the outer membrane. This different localization determines the oxidation of critical thiol groups located on both internal and external sides of pore-forming structures, resulting in MPT induction. The reduced effect by aluminum or the inefficacy by tyramine, when implied alone, can be attributable to the oxidation of thiol groups located only on the internal or external side, respectively. Ultrastructural observations show that aluminum plus tyramine induce the typical configuration of mitochondria that have undergone the MPT. Instead, with aluminum alone, the sensitive subpopulation, although swollen, preserves the outer membrane and shows an apparently orthodox configuration.     

Metal complex formation by nicotianamine,a possible phytosiderophore

Summary The acid dissociation constants of nicotianamine (1) (pK₁=6.97, pK₂=9.13, pK₃=9.75; 0.1 M KClO₄, 25°C) and the stability constants for its 11 complexes with bivalent metal ions (log K_Cu=18.6, log K_Ni=16.1, log K_Co=14.8, log K_Zn=14.7, log K_Fe=12.1, log K_Mn=8.8, log K_Mg4.5; 0.1 M KClO₄, 25°C) were determined using potentiometric titrations in aqueous solution. Fe(III)-nicotianamine complexes were not detected under the same experimental conditions.Part 13 in the series On the normalizing factor for the tomato mutantchloronerva, for part 12 see Ripperger et al.⁴.     

Newly discovered endocrine functions of white adipose tissue: possible relevance in obesity-related diseases

During recent years our view of adipose tissue has been revolutionized. White adipose tissue (WAT) is no longer seen as mere energy store or provider of thermal and mechanical insulation. Neglect of WAT has been overcome by surprising discoveries in recent years, changing the view of this tissue towards a highly endocrine organ that is involved in a wide variety of physiological and pathophysiological processes. In this brief article we will focus on new developments in adipocyte and WAT biology. The appreciation of WAT as an endocrine organ will provide the basis for new and promising perspectives in the management of obesity and obesity-related diseases including diabetes, mellitus type II and arterial hypertension.     

Polyubiquitin chains: functions, structures, and mechanisms

Ubiquitin is a highly conserved 76-amino acid polypeptide that is found throughout the eukaryotic kingdom. The covalent conjugation of ubiquitin (often in the form of a polymer) to substrates governs a variety of biological processes ranging from proteolysis to DNA damage tolerance. The functional flexibility of this post-translational modification has its roots in the existence of a large number of ubiquitinating enzymes that catalyze the formation of distinct ubiquitin polymers, which in turn encode different signals. This review summarizes recent advances in the field with an emphasis on the non-canonical functions of polyubiquitination. We also discuss the potential mechanism of chain linkage specification as well as how structural disparity in ubiquitin polymers may be distinguished by ubiquitin receptors to translate the versatile ubiquitin signals into various cellular functions.     

Methemoglobin formation and reduction in relation to hemoglobin oxygen affinity

Summary It is suggested that although the high oxygen affinity hemoglobin (Hb LR) (143(H21)HisGln) with stabilization of R quaternary conformation is not more susceptible to the oxidizing effect of nitrites in vitro, in an in vivo situation where hemoglobin is partly deoxygenated, it might be more susceptible to methemoglobin formation due to higher oxidation and lower reduction rate.Supported by NIH grant No. 5 RO1 AM 20181-02 and VA grant No. 5455-002.Acknowledgments. The technical assistance of Ms Carol A. Perry is highly appreciated.     

Kank proteins: structure, functions and diseases

The Kank family of proteins, Kank1–Kank4, are characterized by their unique structure, coiled-coil motifs in the N-terminal region, and ankyrin-repeats in the C-terminal region, with an additional motif, the KN motif, at the N-terminus. Kank1 was obtained by positional cloning of a tumor suppressor gene in renal cell carcinoma, while the other members were found by homology search. The family is involved in the regulation of actin polymerization and cell motility through signaling pathways containing PI3K/Akt and/or unidentified modulators/effectors. Their relationship to diseases such as cancer, and to neuronal and developmental disorders, will be an important subject of future study.     

Extrapineal melatonin: sources,regulation, and potential functions

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.     

Effect of NCO-700, an inhibitor of thiol protease,on reactive oxygen production by chemotactic peptide-stimulated rabbit peripheral granulocytes

Summary The specific thiol protease inhibitor, NCO-700, which is related to L-trans-epoxysuccinylpeptides, inhibited oxidant production by chemoattractant-stimulated rabbit polymorphonuclear leukocytes. NCO-700 could also scavenge active oxygen generated from sodium hypochlorite-hydrogen peroxide and hypoxanthine-xanthine oxidase systems.     

Crustacean neuropeptides: Structures,functions and comparative aspects

In this article, an attempt is made to review the presently known, completely identified crustacean neuropeptides with regard to structure, function and distribution. Probably the most important progress has been made in the elucidation of a novel family of large peptides from the X-organ-sinus gland system which includes crustacean hyperglycemic hormone (CHH), putative molt-inhibiting hormone (MIH) and vitellogenesis (=gonad)-inhibiting hormone (VIH). These peptides have so far only been found in crustaceans. Renewed interest in the neurohemal pericardial organs has led to the identification of a number of cardioactive/myotropic neuropeptides, some of them. unique to crustaceans. Important contributions have been made by immunocytochemical mapping of peptidergic neurons in the nervous system, which has provided evidence for a multiple role of several neuropeptides as neurohormones on the one hand and as local transmitters or modulators on the other. This has been corroborated by physiological studies. The long-known chromatophore-regulating hormones, red pigment concentrating hormone (RPCH) and pigment-dispending hormone (PDH), have been placed in a broader perspective by the demonstration of an additional role as local neuromodulators. The scope of crustacean neuropeptide research has thus been broadened considerably during the last years.     

Effect of NCO-700, an inhibitor of thiol protease, on reactive oxygen production by chemotactic peptide-stimulated rabbit peripheral granulocytes

The specific thiol protease inhibitor, NCO-700, which is related to L-trans-epoxysuccinylpeptides, inhibited oxidant production by chemoattractant-stimulated rabbit polymorphonuclear leukocytes. NCO-700 could also scavenge active oxygen generated from sodium hypochlorite-hydrogen peroxide and hypoxanthine-xanthine oxidase systems.     

Crustacean neuropeptides: structures, functions and comparative aspects.

In this article, an attempt is made to review the presently known, completely identified crustacean neuropeptides with regard to structure, function and distribution. Probably the most important progress has been made in the elucidation of a novel family of large peptides from the X-organ-sinus gland system which includes crustacean hyperglycemic hormone (CHH), putative molt-inhibiting hormone (MIH) and vitellogenesis (= gonad)-inhibiting hormone (VIH). These peptides have so far only been found in crustaceans. Renewed interest in the neurohemal pericardial organs has led to the identification of a number of cardioactive/myotropic neuropeptides, some of them unique to crustaceans. Important contributions have been made by immunocytochemical mapping of peptidergic neurons in the nervous system, which has provided evidence for a multiple role of several neuropeptides as neurohormones on the one hand and as local transmitters or modulators on the other. This has been corroborated by physiological studies. The long-known chromatophore-regulating hormones, red pigment concentrating hormone (RPCH) and pigment-dispending hormone (PDH), have been placed in a broader perspective by the demonstration of an additional role as local neuromodulators. The scope of crustacean neuropeptide research has thus been broadened considerably during the last years.     

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27. As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases will be presented.     

Anti-type 2 transglutaminase antibodies as modulators of type 2 transglutaminase functions: a possible pathological role in celiac disease

Auto-antibodies to the ubiquitous enzyme type-2 transglutaminase (TG2) are a specific hallmark of celiac disease (CD), a widely diffused, multi-factorial disease, affecting genetically predisposed subjects. In CD an inflammatory response, at the intestinal level, is triggered by diet consumption of gluten-containing cereals. Intestinal mucosa displays various degrees of atrophy and hyperplasia, with consequent global intestinal dysfunction and other relevant extra-intestinal symptoms. Through deamidation of specific glutamines of gluten-derived gliadin peptides, TG2 strongly enhances gliadin immunogenicity. In addition, TG2 cross-linking activity may generate complexes between TG2 itself and gliadin peptides, and these complexes seem to cause the auto-immune response by means of an apten-carrier-like mechanism of antigen presentation. Anti-TG2 antibodies can be early detected in the intestinal mucosa of celiac patients and are also abundantly present into the serum, thus potentially reaching other organs and tissues by blood circulation. Recently, the possible pathogenetic role of auto-antibodies to TG2 in CD has been investigated. Here, we report an overview about the genesis of these antibodies, their specificity, their modulating ability toward TG2 enzymatic or non-enzymatic activities and their biological effects exerted by interacting with extracellular TG2 or with cell-surface TG2. We also discuss the auto-immune response occurring in CD against other TG members (i.e. type 3 and type 6) and analyze the occurrence of anti-TG2 antibodies in other auto-immune CD-related diseases. Data now available let us to suppose that, even if antibodies to TG2 do not represent the triggering molecules in CD, they could be important players in disease progression and manifestations.